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ADVANCES IN

Immunology EDITED BY

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VOLUME 53

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Lymphokine and Cytokine Production by Fc&RI+ Cells WILLIAM E. PAUL,* ROBERT A. SEDER,* AND MARSHALL PLAUT,*,t 'Laboratory of Immunology ond tAsthma and Allergy Branch, Notional Institute of Allergy and Infectious Diseases, Nationol lnstitutes of Health, Bethesda, Marylond 20892

1. Introduction

Lymphokines and cytokines mediate a wide range of biologic functions. They are responsible for much ofthe regulatory activity o f T cells and have potent pro- and antiinflammatory properties. Although cytokines, such as interleukin-1 (IL-l), interleukin-6 (IL-6), tumor necrosis factor (TNF-a), and the family of molecules that include interleukin-8 (IL-8), are produced b y cells of many distinct types, the lymphokines [e.g., interleukin-2 (1L-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-y (IFN-y), and lyniphotoxin (LT, or TNF-P)] have a niuch more restricted range of cellular origins. With the exception of GM-CSF and IFN-y, these molecules were, until recently, regarded as exclusive products of activated T cells. It was therefore of considerable interest when it was recognized that a subset of the lymphokines could tie produced b y mast cell lines (1-6). In this review, we discuss the growing information on production of IL-4 and of a set of related lymphokines (IL-3, IL-5, and GMCSF) by mast cells and other FceRI' cells as well as production of TNF-a, IL-6, IL-1, and IL-8 and its congeners by these cells. We review the pathophysiologic conditions in which lyinphokine production b y FcsRI+ cells is increased and the signaling mechanisms employed by FceHI+ cells that lead to lyinphokine production.

II. Biology of Mast Cells and Basophils Mast cells and basophils are cell types that have two major phenotypic properties in common (7,8).They both store histamine and both express high-affinity FcsR, called FcsRI. IgE binds avidly to this higliaffinity receptor, with a dissociation rate of the order of days. Both cell types also contain basophilic cytoplasmic granules, consisting ofnegatively charged, sulfated proteoglycans, either heparin or chondroitin sulfate. Histamine is positively charged and binds electrostatically to the granules. Recently, a third cell type, Langerhans cells, also has 1

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WILLIAM E. PAUL ET A L .

been shown to express F ~ E R I(9,1O). The role of the FcsRI of Langerhans cells is unknown. Mast cell and basophil secretion of histamine and other mediators, namely, prostaglandin Dz and leukotriene C4, provides the effector arm of immediate hypersensitivity reactions. Recent experimental models suggest that mast cells and basophils have a wider role in inflammatory reactions than previously appreciated. Several inflammatory reactions are mast cell dependent, presumably due to the release of mast cell-derived mediators, including TNF-a ( 11-14). Basophils accumulate in inflammatory reactions in guinea pigs, humans, and rodents, and probably release their mediators in these reactions (15-22). The capacity of these cells to secrete cytokines, discussed in detail in the subsequent sections of this review, provides an explanation for their potentially important role in inflammation. Mast cells and basophils have been used as models of signal transduction by receptors of the immunoglobulin supergene family (7). These cells bind specific IgE antibodies via FcERI; multivalent antigen crosslinks the IgE, resulting in receptor crosslinking and the initiation of a rapid series of biochemical events leading to secretion of granule products, including histamine. Although mast cells and basophils have several common characteristics and they both develop from precursors in hematopoietic tissue, the two cell types differ in characteristics such as size, nuclear morphology, histamine content, proteoglycan type, protease gene expression, and arachidonic acid metabolic pathways of membrane phospholipids. Human basophils are circulating cells that have polymorphonuclear nuclei. They express at least one cell surface glycoprotein, BSP-1, that mast cells do not (23,24).Basophils express very low levels of the membrane tyrosine kinase c-kit (25,26)and contain 1pg histamine/cell (24).By contrast, human mast cells are larger, express high levels of c-kit, and contain 2-3 pg histamine/cell. Rodent basophils have not been well characterized; they have been difficult to identify because they contain very few granules and have a much lower histamine content (approximately 0.002 pg/cell) than do human basophils

(27-29). The phenotypic distinctions between mast cells and basophils raise

the possibility that these two cell types differ in their capacity to produce cytokines. Moreover, within each cell type there are various stages of maturation that may reflect distinct function. A most important distinction is between two types of mast cells. Rodent mast cells are divided into “immature” mucosal types and “more mature” connective types (8,30,31).Mucosal mast cells are found in the intestinal

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and other mucosae. They express specific proteases, granules with chondroitin sulfate as the principal proteoglycan, and relatively low levels of histamine. By contrast, connective tissue mast cells are found in the skin and pleural and peritoneal cavities. They express proteases distinct from those of inucosal mast cells, possess granules with heparin as the principal proteoglycan, and have a relatively high histamine content. Mucosal mast cells are T cell dependent [e.g., they are absent in congenitally athymic (nulnu) mice] (32), presumably because they require T cell-derived IL-3 for growth and survival. They are markedly increased in number during certain intestinal parasistic infections (33). Connective tissue mast cells do not require T cells for growth. It was formerly thought that connective tissue mast cells were inert, but recent results demonstrate that steel factor (the c-kit ligand) is a potent stimulus to their growth (34,35).Furthermore, combinations of IL-3 and IL-4 also are reported to stimulate growth of connective tissue mast cells (36,37). In addition to mucosal and connective tissue mast cells, culture of bone marrow, spleen, or fetal liver in IL-3 for 3-5 weeks results in the appearance of populations of mast cells (often designated bone marrow-derived mast cells) that resemble mucosal mast cells (38-42). When cultured on fibroblast monolayers or when grown in the presence of steel factor, the cultured mast cells undergo further differentiation, to cells with some phenotypic resemblance to connective tissue mast cells (8,43,44),including a higher histamine content and some expression of heparin proteoglycans. Despite the apparent differences between mucosal and bone marrow-derived mast cells versus connective tissue mast cells, some cells of one type can differentiate or dedifferentiate to the other type. Thus, bone marrow-derived mast cells transferred to the peritoneum of mast cell-deficient W/W" mice will develop a connective tissue phenotype (45),whereas peritoneal mast cells transferred to the stomach of mast cell-deficient mice will develop a niucosal phenotype (46). Human mast cells are also heterogeneous. Thus, human mucosal mast cells are T cell dependent (e.g., they are deficient in patients with T cell deficiencies such as AIDS) (47) and express 'a pattern of proteases (tryptase but not chymase) distinct from that of connective tissue mast cells (which contain tryptase, chymase, and carboxypeptidase A) (48-51). However, the pattern of proteoglycans does not match the rodent pattern. Furthermore, although human liasophils grow in the presence of IL-3, mature human mast cells have been reported not to express IL-3 receptors (52).

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WILLIAM E. PAUL E T AL.

111. Lymphokine Production by Transformed Murine Mast Cells

In a search for cell types other than T cells that might produce IL-4, RNA from a wide range of hematopoietic lineage cell lines was examined. Among these, only transformed mast cells expressed IL-4 mRNA constitutively (Fig. 1) ( 1 ) . A group of mast cell lines that had been transformed by infection with the Abelson murine leukemia virus (Ah-MuLV) was examined. Some of these lines had been derived by infection of factor-dependent mast cell lines and others were obtained from mice that had been directly infected with the virus ( 5 3 3 4 ) .Both types of transformation gave rise to cell lines that expressed IL-4 mRNA and secreted IL-4. Indeed, in the initial report describing this observation ( I ) , 6 of 11AB-MuLV-transformed cell lines were found to produce IL-4 constitutively and 8 of 11 were found to produce IL-4, IL-3, or GM-CSF. Production of IL-5 by this initial group of lines was not tested. In more recent studies of lymphokine expression by an additional set of Ah-MuLV-transformed mast cell lines, constitutive lymphokine

FIG.1. IL-4 mRNA in a transformed mast cell line. Total RNA was prepared from the

T cell line EL-4, which had been stimulated with phorbol myristate acetate, and from ABFTL-3 cells. Northern analysis with an 1L-4 cDNA probe was carried out on EL-4 RNA (lane 1) and ABFTL-3 RNA (lane 2). (Adapted from Ref. 1 , with permission.)

LYMPI-IOKINE I'RODUCTION BY FceHl* CE1,I.S

5

production continued to be ohserved, although the frequency of lines producing IL-3 was greater than observed in the initial series and IL-4production was less often observed (A. Keegan, unpublished observations, 1991). The factors that determine whether IL-4 or IL-3 is produced by a given transformed cell and whether a given cell will change its pattern of lymphokine production have not been determined. We have observed, however, that different sublines of such transforined lines can vary in their pattern of lyinphokine production. Thus, an ABFTL-3 line that initially produced IL-4 and not IL-3 continues to maintain this pattern when carried over a 3-year period in one laboratory, whereas another subline of ABFTL-3 no longer produces IL-4 but now secretes IL-3 (M. Brown, personal comniunication, 1991; A. Keegan, unpublished observations, 1991). Although transformed mast cell lines such as ABFTL-3 produce lymphokine constitutively, the production of IL-3 by these cells is enhanced b y the addition ofa calcium ionophore such as ionomycin or by cross linkage of the high-affinity F ~ E K that they express (55).This indicates that exogenous stimuli can enhance lymphokine production, an observation made inore forcefully in the study of nontransformed mast cell lines and of FceKI+ cells freshly harvested from normal and infected mice. Because both IL-3 and IL-4 are mast cell growth factors (56,57),the possibility was considered that constitutive secretion of these lymphokines by transformed mast cells might contribute to the transformed state of these cells. This possibility was directly examined by culturing five different transformed mast cell lines, four of which produced IL-4 but not IL-3, in the presence ofa neutralizing anti-IL-4 antibody (1).In no case did the antibody inhibit the growth of the cells. Furthermore, IL-4 did not enhance the growth of any of these cells. Indeed, in the one case that was examined, it was shown that IL-4 did not improve the cloning efficiency of a transformed IL-4-producing mast cell line. These results thus imply that IL-4 production does not cause the transformed state of Ab-MuLV-transformed mast cells. Indeed, it is possible that constitutive production of IL-4, IL-3, and GM-CSF by Ab-MuLV-transformed mast cells may result from the action of the v-ubl-encoded tyrosine kinase. As is discussed later, receptor cross linkage leading to lymphokine production in mast cells, just a s in T cells and NK cells, leads to activation of the src family of tyrosine kinases and to tyrosine phosphorylation of a series of protein substrates (58-61). Inhibition of tyrosine kinase activity by genestein and herbimycin blocks lymphokine production in each cell type (55,61-63), suggesting that these phosphorylation events are impor-

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WILLIAM E. PAUL ET AL.

tant in inducing lymphokine production. The possibility exists that the tyrosine kinase encoded by v-abl and the receptor-activated tyrosine kinase(s) in mast cells induce lymphokine production by their action on similar substrates. However, it should be pointed out that three of four spontaneously transformed mast cells tested, including the widely used mastocytoma P815, expressed IL-4 mRNA constitutively (1).This suggests that the common phosphorylation substrate concept may not be correct. However, because little is known about the pattern of protein tyrosine phosphorylation in these transformed cell lines, no firm conclusion can be reached on this point. IV. lymphokine Production by Factor-Dependent Murine Mast Cell lines

In contrast to transformed mast cells that often produce IL-4 constitutively, lines of nontransformed mast cells, generated by culture of fetal liver or bone marrow cells in IL-3 for relatively short (3-6 weeks) or for extended periods of time, fail to secrete detectable amounts of lymphokine and have little or no mRNA for IL-3, IL-4, IL-5, or GMCSF. Stimulation of these factor-dependent mast cells by crosslinkage of their high-affinity FceR causes them to express mRNA for several lymphokines (Fig. 2) and to secrete these factors. Two reports describing such production appeared within a short time of one another in 1989. That of Plaut et al. ( 2 ) principally dealt with long-term, IL-3dependent mast cell lines. It was demonstrated that treatment of cells with the calcium ionophore ionomycin caused production of IL-4, IL-3, and IL-5 as well as IL-1 and IL-6. Subsequent studies of these lines also showed that they produced GM-CSF. However, no IL-2 or IFN-.)Iproduction was noted. Although phorbol esters did not by themselves induce lymphokine production, in their presence concentrations of ionomycin that were substimulatory (i.e., lots of extracts of normal human epidermis, both polyclonal and monoclonal antibodies against desinoglein and P F IgG bind to comigrating polypeptides (which are -160 kDa and have a pZ of -5.5) electrophoresed in one (SDSPAGE) and two (isoelectric focusing followed by SDS-PAGE) dimensions (75,76).Third, P F sera bind desmoglein in bovine desniosoma1 extracts (64,75).Fourth, IgG affinity purified from P F sera on the 160-kDa P F antigen froin human epidermal extracts binds to desmoglein extracted from bovine muzzle desmosomes (75).Finally, P F antigen, obtained by sonication of trypsin-resistant human epidermis, can absorb out the antidesmoglein antibodies from P F sera (77). However, as stated above, only about one-third of P F sera can be shown to bind the 160-kDa desinoglein by immunoblotting. What about the other two-thirds of sera? With the technique of inimunoprecipitation of nonionic detergent extracts of epidermis, which, as opposed to imniunoblotting, does not denature proteins, it was shown that all P F sera bind to a complex of polypeptides that includes the 160-kDa desmoglein as well as an 85-, 260-, and minor 110-kDa mol-

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JOHN R. STANLEY

ecule, all in a stoichiometric ratio (78).Antibodies to desmoglein precipitate this same complex. Diagonal gel electrophoresis (unreduced in the horizontal direction, reduced in the vertical second direction) indicates that the desmoglein is linked by disulfide and noncovalent bonds to the 85-kDa peptide in this complex (79). Much, if not all, of this disulfide bonding might take place after extraction of these molecules from the epidermis when they are exposed to a more oxidizing environment. In fact, extraction in the presence of iodoacetamide, which alkylates free sulfhydryl groups and thereby prevents disulfide bond formation, demonstrates much less disulfide linkage and more noncovalent association of these molecules as determined by diagonal gel electrophoresis (unpublished observation, 1988). Sequential immunoprecipitation experiments, in which this complex was denatured, reduced, and alkylated, then reprecipitated, confirm immunoblotting results that demonstrate that the P F antigen epitopes are on desmoglein, not on the 85-kDa polypeptide of this complex (80).The noncovalent interaction of desmoglein and this 85-kDa polypeptide must be a strong and specific one, because the complex is stable in nonionic detergent and because the molecules always show the same relative stoichiometry. Immunofluorescence studies have suggested that PF antibody binding to human epidermis might be dependent on the presence of calcium (81). Consistent with this hypothesis, most PF sera could precipitate the P F complex only in the presence of calcium (78). In fact, the P F sera that were negative by immunoblotting were the same sera that required calcium to precipitate this complex, and those that were immunoblot positive (i.e., those that could bind denatured antigen) were able to precipitate this complex even when the calcium was chelated. These results suggested that most P F sera bind to a calcium-sensitive conformational epitope on desmoglein. Further studies of immunoprecitation of a fragment of' PF antigen released from keratinocytes by trypsin have demonstrated that, in fact, all P F sera have antibodies that bind a calcium-sensitive epitope and that this epitope is extracellular (82). If P F antigen is desmoglein and it is linked in the epidermis to an 85-kDa molecule in a stoichiometric fashion, then is the 85-kDa molecule also desmosome associated? In fact, the sequential imniunoprecipitation studies discussed above demonstrated that the 85-kDa molecule, once dissociated from the P F antigen complex, could be immunoprecipitated by antibodies to plakoglobin, a plaque protein found not only in desmosomes (Fig. 3) but also in another type of intercellular junction called adherens junctions (80,83). These stud-

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ies also demonstrated that the 260-kDa polypeptide prol)ably consists of both the desinoglein and plakoglobin linked by covalent bonds that are not reducible (80). Again, it is not known if these covalent bonds form after extraction from the epidermis. If P F antigen is desmoglein, it should be localized in desniosomes. Early irnmunoelectron microscopic studies, in which investigators used the imniunoperoxidase technique, localized IgG along the entire membrane of keratinocytes in uiuo both in P F patients and in neonatal mice that had been injected with P F antibodies (84-86). However, more recent iinmunoperoxidase studies of IgG localization in patients’ skin indicates that the major binding is to the extracellular aspects of desniosomes (87).In addition, indirect immunoelectron microscopic studies with immunogold labeling indicate that P F IgG binds to the extracellular portion of desmosomes in ciiltured keratinocytes and in noriiial human skin (87,88). The finding that P F antigen is desmoglein resulted in a paradox, because P F antigen, as detected by immunofluorescence, was known to be limited in distribution to stratified squamous epithelia, as discussed above. Yet, desmoglein was found in the desniosomes of all tissues. The answer to this paradox started to become apparent when it was noted that the desinoglein in different tissues was not identical. For example, it displayed slightly different mobilities on SDSPAGE (89). In addition, as with P F antibodies, some monoclonal antibodies also only recognized epitopes of desmoglein expressed in stratified squamous epithelia (21,89,90).The final solution to this paradox has been provided by cDNA cloning of desmoglein, which reveals that there is a gene family encoding these molecules, enabling expression of different gene products in different tissues (see below). In summary, then, P F autoantibodies recognize stratified squamous epithelial-specific, and calcium-sensitive conformational, epitopes on desmoglein, a desmosomal transmembrane glycoprotein. Recent cDNA cloning of desmoglein, as described below, provides a framework in which to understand these findings. P F antibodies also have been used to show that desmoglein in keratinocytes is found in a stoichiometric complex with plakoglobin, a desmosome plaque protein.

C. PEMPHIGUS VULGARISANTIGEN Is A 130-kDa GLYCOPROTEIN COMPLEXED WITH PLAKOCLOBIN The initial studies done to characterize PV.antigen at a molecular level were imniunoprecipitation studies of nonionic detergent extracts of mouse and human cultured keratinocytes that, by immuno-

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fluorescence, were known to express PV antigen (36,37,91). These studies indicated that PV sera precipitated a glycosylated 130-kDa glycoprotein complexed, in a stoichiometric ratio, with an 85-kDa polypeptide (also reported as 80 kDa) (62,92). Under nonreducing conditions these two chains were disulfide crosslinked as a 210-kDa molecule. This PV antigen complex was synthesized by keratinocytes but not fibroblasts (62,92). P F sera did not precipitate any polypeptides from these keratinocyte extracts, probably because keratinocytes in culture synthesize little P F antigen and/or it is not extractable with nonionic detergent. Further studies of immunoprecipitation of human epidermal extracts showed that PV sera precipitated the same 130- and 85-kDa complex (79). In these complexes the 210-kDa molecule was also apparent even on reduced gels, suggesting that it consisted of covalently linked nonreducible chains. No P F sera precipitated this PV antigen complex; however, interestingly, two-thirds of PV sera, in addition to precipitating the PV antigen complex, also precipitated the P F antigen complex, as defined above. As with P F antigen, immunofluorescence of PV sera on normal human skin and monkey esophagus showed less binding (i.e., decreased titer) when calcium was chelated (81,93).Immunoprecipitation analysis of epidermal extracts also showed that decreased amounts of PV antigen complex were precipitated in the absence of calcium, although this effect was not as dramatic as with P F sera (79). Two-dimensional (SDS-PAGE and isolelectric focusing) and diagonal (nonreduced and reduced) gel electrophoresis demonstrated interesting parallels between the PV and P F antigen complexes (79). First, both complexes contained a glycosylated chain linked by noncovalent, disulfide, and nonreducible covalent bonds to an 85-kDa polypeptide. (Some or all of these covalent bonds might form simply from the oxidizing environment outside the cell, as discussed above, or during iodination of the extracted proteins.) Second, the 85-kDa polypeptides from both the P F and the PV antigen complexes showed identical migration in two-dimensional gels. Furthermore, as in the P F antigen complex, the 85-kDa molecule in the PV antigen complex was also identified by sequential immunoprecipitation as plakoglobin (80). Finally, the 130-kDa glycopeptide in the PV antigen complex had the same isoelectric point as the 160-kDa P F antigen (desmoglein). These studies, as well as the calcium sensitivity of their immunoreactivity, suggested a biochemical similarity between the 130-kDa PV antigen glycoprotein and desmoglein, a fact later confirmed by cDNA sequencing (see below).

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The actual antigenic site for PV antibodies was shown by sequential immunoprecipitation to be on the 130-kDa glycopeptide (80).In addition, immunoblotting studies of SDS extracts of normal human epidermis showed binding to a 130-kDa polypeptide (64,65). Is the 130-kDa PV antigen found in desmosomes? The data on this are conflicting. Immunoblot studies of bovine desmosomes do demonstrate that an approximately 130-kDa (reported as 135-140 kDa) antigen is detected (64,65,94,95).However, this does not address the issue of whether PV antigen is concentrated in desmosomes or simply distributed all along the keratinocyte cell membrane. Immunofluorescence studies of cultured mouse keratinocytes suggest that PV sera might bind desmosomes, although light microscopic studies such as these are not definitive (95) (see also Fig. 2C for immunofluorescence of the PV antigen in cultured human keratinocytes). Electron microscopic studies are also conflicting. As seen by direct immunoelectron microscopy of PV patients’ skin (using the immunoperoxidase technique), PV IgG is distributed diffusely along the keratinocyte cell membrane (96). Indirect immunoferritin electron microscopy on trypsinized guinea pig keratinocytes, immiinoperoxidase electron microscopy of the skin of neonatal mice injected with PV IgG, and iminunogold ultrastructural studies of a rabbit antibody raised against the presumed PV antigen from bovine tongue desmosomes all showed localization diffusely along the cell membrane (97-99). On the other hand, direct immunoelectron microscopy of PV patients’ epidermis with immunoferritin localization and indirect immunogold ultrastructural localization of PV antigen on cultured keratinocytes have shown a predominantly desmosonial location of PV antigen (88J 00). In summary, then, these immunochemical studies demonstrate that PV antigen is a 130-kDa glycoprotein complexed in the keratinocyte with plakoglobin. The PV antigen is biochemically similar to the P F antigen (desmoglein) and also seeins to have some calciumdependent epitopes. As with P F antigen, recent cDNA cloning of PV antigen puts these observations in perspective (see below). IV. cDNA Cloning of Autoantigens

Recently, cDNAs reflecting coding sequences for the 230- and 180kDa BP antigens, desmoglein (PF antigen), and pemphigus vulgaris antigen have been cloned. The deduced amino acid sequences for these antigens provide explanations for many of the observed immunochemical findings described above. In addition, the cloning of the

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230-kDa BP antigen has defined a new gene family of adhesion plaque proteins, and the cloning of the pemphigus antigens has definitively assigned them to a gene subfamily of adhesion molecules.

A. THE230-kDa PEMPHIGOID ANTIGEN Is HOMOLOGOUS TO DESMOPLAKIN I, A DESMOSOME PLAQUE PROTEIN; THE 180-kDa PEMPHIGOID ANTIGEN Is UNIQUE Initial cloning of cDNA with coding sequences for BP antigen was performed with sera from BP patients by immunoperoxidase staining of a h g t l l human keratinocyte cDNA expression library (101). Antibodies from BP serum affinity purified on the expressed protein of this clone stained the epidermal basement membrane by indirect immunofluorescence and immunoprecipitated the 230-kDa BP antigen. These results demonstrated that a partial cDNA clone for the 230kDa BP antigen was obtained. The full-length mRNA encoding the 230-kDa BP antigen was shown by Northern analysis to be 9 kb. Another group used a human monoclonal antibody directed against the 230-kDa BP antigen to screen a hgtll mouse keratinocyte cDNA expression library (102).This allowed isolation of a partial cDNA for the mouse 230-kDa BP antigen. Comparison of the human and mouse amino acid sequences showed 77% identity in corresponding regions, which demonstrates evolutionary conservation of this antigen and suggests that an important physiologic function has been maintained. The partial human cDNA clone was then used for extension cloning to isolate overlapping cDNAs encoding the 230-kDa BP antigen (103-105). What did this cDNA cloning tell us about the antigen? Consistent with the immunofluorescence protein localization studies discussed above, Northern analysis revealed that the 9-kb mRNA for the 230kDa BP antigen was found in keratinocytes but not in fibroblasts or nonstratified squamous epithelial cells (103). Rabbit antibodies raised against a fusion protein within the carboxy-terminal region of the antigen stained the epidermal basement membrane zone by immunofluorescence and were localized by immunoelectron microscopy to the plaque of the hemidesmosome, confirming the studies, discussed above, that were performed with patients’ antibodies (106,107). Antibodies have also been raised against synthetic peptides, 17-19 amino acids long, representing hydrophilic regions in the carboxy-terminal region of this antigen, and these antibodies bind the epidermal basement membrane as seen by immunofluorescence (106) and localize to the hemidesmosome plaque (unpublished observation, 1990). Southern analysis of genomic DNA indicates that

307

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the 230-kDa BP antigen is encoded by a single-copy human gene (103,108); related genes are detectable in mammals but not in the chicken, frog, or fish (108). The antigen has been localized to the short arm of human chromosome 6 (6pll-6p12) (109,110). Most interestingly from a cell biology perspective, cDNA cloning of the 230-kDa BP antigen revealed its sequence and structural hoinology with desmoplakin 1/11, a desmosome plaque protein (111,112) (Figs. 3 and 4). Analysis of the amino acid sequence of human desmoplakin 1/11, as determined from cloned cDNA representing most of the molecule but lacking the far amino-terminal domain, predicted a central coiled-coil a-helical rod domain formed by two molecules lined up in parallel without stagger (113). This prediction is consistent with rotary shadowing images of' desmoplakin 1/11 (114).The rod domain of desmoplakin also shows a regular periodicity of the acidic and basic residues, occurring about every 10.4 amino acids. The basic and acidic residue periodicities are 180" out of phase, suggesting a mechanism by which desnioplakin could selfaggregate by ionic interactions. In addition, at the carboxy terminus there are three domains (called A, B, and C), of 176 amino acids each, that show marked amino acid homology with each other and consist of 38-residue internal repeats with homology to each other. An interesting feature of these dornains is that they display acidic and basic

BPA

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#'

54

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-HOMOLOGY(%)

,

-'63

,

I

,

,

',56'.64,

DPI FIG.4. Structural and amino acid homologies (percentage identical and chemically similar) of BP antigen (BPA) and desmoplakin I (DPI).

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JOHN H. STANLEY

amino acids in a regular periodicity, about every 9.5 residues, the same as that of the 1B rod domain of keratins, suggesting a means of ionic interactions between keratins and desmoplakins. At the time of the original cloning of desmoplakin 1/11, only part of the carboxy terminus of BP antigen had been cloned. It was noted that in this part of the BP antigen there was a 174-residue domain that had 40% identity to the B domain ofdesmoplakin (113). In addition, in comparison to the B domain of desmoplakin, this B domain of BP antigen contained a similar internal 38-residue repeat and had approximately the same periodicity of acidic and basic residues (32,113). Extension cloning of BP antigen revealed further, and striking, homologies with desmoplakin 1/11 in both sequence and structure (Fig. 4)(104,105). BP was discovered not only to have a desmoplakin I/II-like B domain, but also a desmoplakin-like C domain (104,105). In addition, the 230-kDa BP antigen and desmoplakin 1/11 displayed regions of homology in the amino acids linking the B and C domains and in those amino terminal to the B domains (104). In addition, BP antigen, like desmoplakin 1/11, was predicted to have a central coiled-coil rod domain (104,105), and, remarkably, with the same acidic and basic periodicity (104). Finally, when the amino-terminal domains of desmoplakin 1/11 (115) and BP antigen (105) were cloned, these too had remarkable sequence homology (116). Interestingly, the chromosomal localization of desmoplakin 1/11, like that of the 230-kDa BP antigen, was determined to be on the short arm of human chromosome 6 (117). It is therefore possible that a gene duplication on this chromosome gave rise to both genes. These studies, then, suggested that BP antigen, a hemidesmosomal plaque protein, and desmoplakin 1/11, a desmosomal plaque protein, belonged to a gene family of adhesion plaque proteins, perhaps fulfilling similar functions, including the binding of keratin filaments to the adhesion structure. Lending support to this hypothesis, a recent study in which COS cells and fibroblasts were transfected with cDNA encoding the carboxy-terminal domains of desmoplakin 1/11 does demonstrate binding of this region to the intermediate filaments (118). Another member of this gene family is a recently described intermediate filament-binding large protein called plectin (119). Cloning and amino acid sequence analysis of this 466-kDa polypeptide indicated structural and amino acid homology with the 230-kDa BP antigen and with desmoplakin 1/11 (120). As in these latter two molecules, plectin was predicted to have a coiled-coil rod central domain (which was confirmed by rotary shadowing) and, remarkably, had the same acidic and basic perioidicity, 180" out of phase, of approxi-

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mately 10.4 residues throughout much of this domain (116,120).The carboxy terminus of plectin contains six highly homologous domains, containing internal repeats of either 19 or 38 residues, that are similar to the B and C domains of BP antigen and desmoplakin 1/11 ( 116,120). Finally, the amino terminus of plectin shares sequence homology with BP antigen and desmoplakin 1/11(116). In summary, then, cloning of the 230-kDa BP antigen indicated rather striking structural and sequence homology to desmoplakin 1/11, another adhesion junction plaque protein that may have a function similar to that of binding keratin filaments, and to that of plectin, which may also function by binding intermediate filaments. These molecules form a new gene family, and presumably are important in cell-cell adhesion and/or maintaining the structural integrity of the cells through interactions with their intermediate filaments. Cloning of the cDNA encoding most of the 180-kDa BP antigen has recently been reported (58,121,122).A BP serum with antibodies against both the 230- and 180-kDa BP antigens was used for immunoscreening of a h g t l l library representing keratinocyte mRNA sequences (58).Antibodies from BP serum, affinity purified on one of the selected clones, bound the 180-kDa BP antigen as detected b y immunoblotting. In addition, a rabbit antiserum made against the fusion protein of this clone bound the 180-kDa BP antigen and the epidermal hemidesniosome. The mRNA encoding the 180-kDa BP antigen was determined, by Northern blotting with this partial cDNA clone, to be about 6 kb, clearly distinct from the 9-kb message for the 230-kDa BP antigen. This clone was also used to localize the 180kDa BP gene to the long arm of chromosome 10, which provides further and definitive evidence that the 180- and 230-kDa BP antigens are distinct gene products (123). Additional, overlapping cDNA clones with coding sequences for the 180-kDa BP antigen were obtained by screening cDNA libraries with hybridization so that almost the full-length coding sequence was obtained (122).Analysis of the deduced amino acid sequence for the 180-kDa BP antigen indicated a unique and interesting structure (121,122).A hydrophobic region o f 2 3 amino acids is predicted to be a transmembrane domain that would span the membrane once. On the carboxy-terminal side of this hydrophobic region, presumably extracellnlar, is a polypeptide of about 100 kDa made up of 15 collagenous domains of varying sizes. These collagenous domains are interrupted by noncollagenous sequences. On the amino-terminal side of the putative transmembrane region is a very basic peptide containing four internal 24- to 26-residue honiologous repeating

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units. Studies using collagenous digestion confirm the collagenous nature of part of this molecule. Therefore, it is speculated that the 180-kDa BP antigen, as a transmembrane molecule, might interact with the extracellular matrix through its collagenous domains and stabilize basal keratinocyte attachment to the basement membrane.

B. PEMPHIGUS FOLIACEUS ANTIGENIs IN

THE

CADHERIN GENESUPERFAMILY As discussed above, P F antigen was identified as desmoglein by immunochemical techniques. Subsequently, cDNAs with desmoglein coding sequences were isolated from libraries constructed with mRNA from bovine and human stratified squamous epithelia and human keratinocytes (124-127). Analysis of these cDNA clones indicated that desmoglein belonged to the cadherin gene superfamily of cell adhesion molecules (Fig. 5 ) . Cadherins are calcium-dependent cell adhesion molecules that mediate homophilic adhesion (i.e., a molecule on one cell binds to the same molecule on another cell) (128,129). The originally described cadherins (or “typical” cadherins) were E-cadherin (also called uvomorulin; L-CAM in the chicken), N-cadherin, and Pcadherin. These cadherins have the property that they are protected by calcium from proteolytic (trypsin) degradation. Cloning of these typical cadherins indicated that they had certain sequence and structural similarities (Fig. 5 ) . Each has a transmembrane domain that spans the cell membrane once, with the amino terminus outside the cell. These transmembrane molecules are synthesized in the cell as inactive precursor proteins that have to be cleaved at a domain of highly basic amino acids to yield an active adhesion molecule (130). The extracellular region of cadherins can be divided into five domains of about equal size (approximately 100 amino acids). The first four of these domains have sequence homology with each other (131,132). An amino acid sequence in the first (furthest aminoterminal) extracellular domain, histidine-alanine-valine (HAV), is conserved in sequence and location in all the originally described cadherins, and this site is thought to be important in adhesion (133). These cadherins have six putative calcium-binding motifs in their extracellular domains, with sequences such as aspartic acid-any amino acid-aspartic acid (DXD), aspartic acid-any amino acidasparagine-aspartic acid-asparagine (DXNDN), or similar motifs (129,134,135).It was shown by site-directed mutagenesis that substituting one amino acid in one of these domains prevented calcium

CAM TARGETS IN BULLOUS DISEASES

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binding and abolished the adhesive function of E-cadherin (135). It was speculated that calcium influences the adhesive function of cadherins through its effect on the conformation of the molecule. Finally, these typical cadherins also have very well-conserved cytoplasmic domains. The cytoplasmic domains of these typical cadherins bind to cytoplasmic proteins called a-, p-, and y-catenins, molecules that are presumably important in linking the cadherins to the actin cytoskeleton (129,136). Of these three molecules, p-catenin seems to be the most tightly linked to the cadherins (137,138). Recent cDNA cloning of p-catenin indicates that it is a homolog of plakoglobin (139). Like the typical cadherins, desmoglein was found to be a transmembrane protein whose cleavage at a basic domain would result in a mature protein (Fig. 5). Desmoglein has an extracellular domain structure similar to typical cadherins, and has a conservatively substituted arginine-alanine-leucine (HAL) in the same location as the HAV sequence in typical cadherins. Desmoglein has putative calcium-binding motifs in the extracellular domains in locations equivalent to those in typical cadherins. The cytoplasmic portion of desmoglein has a domain that is homologous to that of typical cadherins, but a marked difference is that the cytoplasmic domain of desmoglein is much longer, with another approximately 300 amino

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acids at the carboxy terminus. This extra cytoplasmic region contains a repeating amino acid sequence of asparagine-valine-any amino acid-valine-threonine-glutamic acid (NVXVTE). Another marked difference in cytoplasmic domains is that there are cysteines in desmoglein but not in typical cadherins. More recent cloning studies have indicated that desmoglein is actually a product of two distinct genes (termed DSG1 and DSGB), both localized to chromosome 18 (140-142). Preliminary data ( i n situ hybridization and Northern analysis) indicate that the first type of desmoglein (dsgl), discussed above, is probably expressed by stratified squamous epithelial cells, whereas the second type (dsg2) is expressed by basal-type cells or simple epithelial cells (141,142). These data on the cloning of desmoglein explain many of the observations made about P F antigen. The fact that P F antigen was identified as desmoglein, yet could only be detected in stratified squamous epithelia, could be explained if P F antigen corresponds to dsgl. The finding of a calcium-sensitive epitope on the extracellular domain of P F antigen is consistent with the calcium-binding properties of cadherins and the finding of putative calcium-binding domains in desmoglein. The immunoreactivity of P F antigen, as determined by immunoflourescence, has been shown to be protected from proteolytic destruction by calcium (81),consistent with a property of cadherins. The ability of P F antigen to bind plakoglobin by disulfide bonds is explained by the presence of cysteines in its cytoplasmic domain. Perhaps most importantly, the finding that PF, a disease in which epidermal cells come apart, is a disease in which autoantibodies are directed against a member of the cadherin family of adhesion molecules implies a functional importance of cadherins in maintaining the integrity of the epidermis and in the pathophysiology of disease. C. PEMPHICUS VULCARIS ANTIGENIs A CADHERIN CLOSELY TO PEMPHICUS FOLIACEUS ANTKCEN RELATED PV antibodies, affinity purified on the 130-kDa PV antigen, were used to clone, from a human keratinocyte expression library, cDNA with coding sequences for PV antigen (143).The clone was verified as coding for PV antigen because (1) antibodies from PV serum, affinity purified on the fusion protein of this clone, bound the cell surface of monkey esophageal epithelium as detected by indirect immunofluorescence, in a pattern indistinguishable from that produced by PV sera, and bound the 130-kDa antigen as detected by immunoblotting; (2) PV sera, but not control sera, bound a fusion protein made

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with this cDNA; and ( 3 ) rabbit antibodies raised against this fusion protein also showed PV-like immunofluorescence and bound the 130-kDa PV antigen as detected by inimunoblotting. Northern blot analysis indicated that PV antigen was encoded b y an approximately 6-kb mRNA that was restricted in distribution to stratified squanious epithelia. Southern analysis indicated that PV antigen was encoded by a single human gene (143). Analysis of the deduced amino acid sequence of PV antigen indicated that it, too, belonged to the cadherin superfamily, but was more closely related to the desrnoglein subfamily than to typical cadherins (Figs. 5 and 6) (143). Like typical cadherins and desmoglein, it has a transmembrane domain predicted to span the membrane once and has a basic domain predicted to be the cleavage site to produce the mature protein. The extracellular domain structure is typical of cadherins. PV antigen has the conserved RAL sequence of desmoglein, as well as six putative calcium-binding motifs and two potential Nglycosylation sites corresponding to those in desnioglein. The three most amino-terminal domains of PV antigen show greater homology to desnioglein than to typical cadherins, whereas the fourth domain shows about equal homology to both. The greatest homology between PV antigen and desmoglein (dsgl) was between the most e x ternal (amino-terminal) domains-about 70% identity and 80% similarity compared to 30% identity and SO% similarity with typical cadherins. The homology also extends into the cytoplasmic domains in which, again, desnioglein shows tnore similarity to PV antigen than do typical cadherins. PV antigen has a longer cytoplasmic tail (360 amino acids) than do typical cadherins (160 atnino acids), although the tail is not as long as that of the desmogleins (480 amino acids). Five cysteines are in similar locations in the cytoplasmic regions of PV antigen and desmoglein. Finally, PV antigen has two repeats corresponding to the NVXVTE repeats of desmoglein. Interestingly, the gene for PV antigen is on chromosome 18, like that of the other desmogleins (144). Thus, PV antigen can be classified as being in the desnioglein subfamily of cadherins. As discussed above with respect to P F antigen, the cloning of PV antigen provides explanations for many of its characteristics. For example, the calcium sensitivity of some of the epitopes on PV antigen as well as the observation, as determined by immunofluorescence, that calcium protects its immunoreactivity from destruction by trypsin (81) are consistent with the properties of cadherins. As with PF antigen, the disulfide binding with plakoglobin could use cysteines in the cytoplasmic domain, which is presumably in close contact with

3 14

JOHN R. STANLEY

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plakoglobin. But most importantly, PV is another autoantibodymediated disease of cell adhesion, which suggests an important function for cadherin-like molecules in maintaining the integrity of the epidermis. This critical function of PV antigen and the pathophysiologic action of antibodies directed against this antigen have recently been demonstrated (145). PV sera reactivity with fusion proteins representing different domains of PV antigen demonstrated that dominant epitopes were present in the most amino-terminal extracellular domains, regions in typical cadherins known to be critical for homophilic adhesion (146). Antibodies from PV sera affinity purified on this region induced loss of cell-to-cell adhesion in the epidermis when injected into neonatal mice. Antibodies from PV sera affinity purified against more carboxy-terminal extracellular domains did not induce this pathology. These studies, therefore, demonstrated that critical adhesion functions could be perturbed by antibodies against PV antigen and, by implication, suggest the critical function of cadherins in maintaining epithelial integrity.

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V. Conclusions and Future Directions

When the blistering diseases pemphigus and pemphigoid were orginally classified according to their clinical presentation and histology, it became clear that the pathology was due to a loss of either epidermal cell-to-cell or cell-to-llasement membrane adhesion. Later, iniinunofluorescence was used to show that these were autoimmune diseases with antibodies directed against the sites of pathology. More recently, these autoantibodies have been used to characterize immunochemically and to clone molecularly their corresponding autoantigens. Most interestingly, in light of the pathology of these diseases, the targets of these autoantibodies have all been discovered to be in gene fbmilies of known adhesion molecules or to be associated with adhesion junctions or both. In two of these diseases, BP and PV, previously unidentified niolecules have been defined. Molecular cloning of the 230-kDa BP antigen, the first known molecular coinporient of hemidesmosonies, not only defined a new molecule but also established a new gene family of adhesion junction plaque proteins and, perhaps, intermediate filament-binding proteins, including desnioplakin 1/11 and plectin. Molecular cloning of the 180-kDa BP antigen defined a unique type of transmembrane molecule. Finally, the PV antigen was shown to be a new member of the desmoglein subfamily of cadherins. Analyses of the deduced amino acid sequences of these cloned autoantigens resulted in predictions of certain structures and functions. Future research will be directed at trying to confirm these predictions experimentally. For the 230-kDa BP antigen the following questions might be among those that will be explored: Does rotary shadowing show the predicted rod structure? Does the predicted coiled-coil rod domain lead to aggregation into a plaque? Does the carboxy terminus bind keratin filaments? Regarding the 180-kDa BP antigen, do the collagenous domains bind the extracellular matrix and, if so, which molecules are bound? What is the function of the various regions of the cytoplasmic domain? Regarding the P F and PV antigens, are these molecules protected by calcium against trypsin degradation, as are typical cadherins? Is the PV antigen localized to desmosomes and/or adherens junctions? How do the cytoplasmic domains of these antigens fiinction? Can these molecules be shown experimentally to mediate hoinophilic adhesion and, if so, which domains are important in this function? In addition, important questions relating to the pathophysiology of disease remain. Specifically, do the autoantibodies in these patients directly mediate loss of cell adhesion? Which epitopes are critical in

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antibody-mediated pathology? For BP, how can the 230-kDa BP antigen, which is inside the cell, be a target for autoantibodies? Is the 180-kDa transmembrane antigen the critical target and, if so, why do only about 50% of patients have antibodies against it? Finally, another area that may be fruitful for investigation is whether these autoantigens are genetic targets in certain hereditary diseases (such as junctional epidermolysis bullosa, Hailey-Hailey disease, and Darier’s disease) that show loss of epidermal basal cellto-substrate or cell-to-cell adhesion. I would predict that the symbiotic relationship, discussed throughout this review, between the study of these autoimmune diseases and the cell biologic study of adhesion structures and molecules will continue to shed light on both of these areas in the future.

ACKNOWLEDGMENTS Dr. Masayuki Amagai helped design the schematic diagrams and reviewed this paper. Dr. Sarolta Karpati performed the immunofluorescence with pemphigus sera on keratinocytes.

REFERENCES 1 . Lever, W. F. (1953).Pemphigus. Medicine 32, 1-123. 2. Lever, W. F. (1965). “Pemphigus and Pemphigoid.” Charles C. Thomas, Springfield, Illinois. 3. Stanley, J. R. (1992). Bullous pemphigoid, cicatricial pemphigoid, and chronic bullous disease of childhood. I n “Dermatology in General Medicine” (T. B. Fitzpatrick, A. Z. Eisen, K. Wolff, 1. M. Freedberg, and K. F. Austen, eds.), 4th Ed. McGraw-Hill, New York. (In press.) 4 . Stanley, J. R. (1992). Pemphigus. I n “Dermatology in General Medicine” (T. B. Fitzpatrick, A. Z. Eisen, K. Wolff, I. M. Freedberg, and K. F. Austen, eds.), 4th Ed. McCraw-Hill, New York. (In press.) 5 . Jordon, R. E., Beutner, E. H., Witebsky, E., Blumental, G., Hale, W. L., and Lever, W. F. (1967). Basement zone antibodies in bullous peniphigoid. JAMA 200,751-756. 6 . Beutner, E. H., and Jordon, R. E. (1964). Demonstration of skin antibodies in sera of pemphigus vulgaris patients by indirect inimunofluorescent staining. Proc. Soc. E x p . B i d . Med. 117,505-510. 7. Beutner, E. H., Lever, W. F., Witebsky, E., Jordon, R., and Chertock, B. (1965). Autoantihodies in pemphigus vulgaris. JAMA 192, 682-688. 8. Beutner, E. H., Jordon, R . E., and Chorzelski, T. P. (1968).Th e inimunopathology of pemphigus and bullous pemphigoid. J . lnoest. Dennatol. 51, 63-80. 9. Beutner, E. H., Chorzelski, T. P., and Jablonska, S. (1987).Clinical significance of immunafluorescerice tests of sera and skin in bullous diseases: A cooperative study. In “Immunopathology of the Skin” (E. H. Reutner, T. P. Chorzelski, and V. Kumar, eds.), 3rd Ed., pp. 177-205. John Wiley & Sons, New York. 20. Lever, W. F. (1979).Pemphigus and pemphigoid.]. Ant. Acad. Dermutol. 1,2-31. 1 1 . Kobayasi, T. (1967). T h e dermo-epidermal junction in bullous pemphigoid. Derrnatologico 134,157-165.

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12. Lever, W. F., and HashimotoJ. (1969). The etiology and treatment of peniphigus and peniphigoid.]. Itiotzst. Ucnntrtol. 53, 373-389. 13. Wintroub, B. U., Mihm, M. C., Goetzi, E. J., Soter, N. A., and Austen, K. F. (1978). Morphologic and functional evidence for release of mast-cell products i n bullous pemphigoid. N . E r g / . ] . Med. 298,417-421. 14. Dvorak, A. M., Mihm, Jr., M. C., Osage, J. E., Kwan, T. H., Austen, K. F., and ~ an ultrastructural study of thc i n Wiiitrouh, B. U. (1982). B ~ i l l o i ipempliigoid, flammatory response: Eosinophil, hasophil and mast cell granule changes i n multiple biopsies from one patient.]. Incest. Uermutol. 78, 91-101. 1 5 . Owaribe, K . , Kartenbeck, J., Stumpp, S., Magin, T. M., Krieg, T., Diaz, L. A,, and Franke, W. W. (1990).The liemidesniosonial plaque. I. Characterization o f a major constituent protein as a differentiation marker for certain forms of epithelia. D~fferetitiutioii45, 207-220. 16. Hashimoto, K. and Lever, W. F. (1967). An electron microscopic stndy on peniphigus vulgaris of the mouth and the skin with special reference to the intercellular cenient.]. Ztioest. Dermutol. 48, 540-552. 17. Barnett, M. L. (1978). Effect of peniphigus antibodies on desinosoirial structure in o i t r o . ] . Inoest. Dennutol. 70, 141-142. 18. Grando, S. A,, Terman, A. K., Stupina, A. S.,Glukhenky, B. T., and Romarrenko, A. €3. (1991). Ultrastructural study of clinically uninvolved skin of patients with peinphigus vulgaris. Clin. E x p . Dennuto/. 16, 359-363. 19. Wilgram, G. F., Caulfield, J. B., and Madgic, E. H. (1964). An electron microscopic study of acantholysis and dyskeratosis in pemphigus foliaceus. ]. Itioest. Dennutol. 43, 287-299. 20. Krasny, S. A,, Beutner, E. H., and Chorzelski, T. P. (1987). Specificity and sensitivity of indirect and direct inimunofluorescent findings in the diagnosis of pemphigus. I n “Imiiiunopatliology of the Skin” (E. H. Beutner, T. P. Chorzelski, and V. Kumar, eds.), 3rd Ed., pp. 207-247. Wiley, New York. 21. Rubinstein, N., and Stanley, J. R. (1987). Peniphigus foliaceus antibodies and a monoclonal antibody to desmoglein I denionstrate stratified squanious epithelialspecific epitopes of desniosonies. Am.]. Deri,icito)icitho/.9, 510-514. 22. Schauniburg Lever, G., Rule, A , , Schmidt Ullrich, R., and Lever, W. F. (1975). Ultrastructural localizatiori of in oioo-bonnd immunoglobulins in bullous pempliigoid-A preliminary report.]. Ztioest. Uennutol. 64,47-49. 23. Holubar, K., Wolff, K., Konrad, K., and Reutner, E. H. (1975). Ultrastructural localization of immunoglobulins in bullous peniphigoid skin. Eniploymcnt of a new peroxidase-antiperoxidase multistep method. J. I n t e s t . Dennuto/. 64, 220227. 24. Schmidt Ullrich, B., Rule, A,, Schauniburg Lever, G., and Leblanc, C. (197-5). Ultrastructural localization of i n oioo-bound complement in bullous pemphigoid. 1.Ztroest. Dennntol. 65, 217-219. 25. Mutasim, D. F . , Takahashi, Y., Labib, R. S., Anhalt, G. J., Patel, H. P., and Diaz, L. A. (1985).A pool of bullous peinphigoid antigen(s) is intracellular arid associated with the basal cell cytoskeleton-lieiiiidesiiiosoiiie complex. 1. Incest. Dermatol. 84, 47-53. 26. Regnier, M., Vaigot, P., Michel, S., and Prunieras, M. (1985). Localization of bullous peniphigoid antigen (BPA) in isolated hunian keratinocytes. 1. Inoest. Dennutol. 85, 187-190. 27. Westgate, G . E . , Weaver, A. C., and Couchnian, J. R. (1985).Bullous peniphigoid antigen localization suggests an intracellular association with hemidesniosomes. /. Invest. Denncitol. 84, 218-224.

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28. Mutasini, D. F., Morrison, L. H . , Takahashi, Y., Labih. R. S., Skouge, J., Diaz, L. A,, and Anhalt, G . J. (1989). Definition of hullous pemphigoid antibody binding to intracellular and extracellular antigen associated with hemidesmosomes. 1.Invest. Dermutol. 92,225-230. 29. Ikeda, S., Yaguchi, H . , and Ogawa, H. (1990). Expression of extracellular and intracellular bullous pemphigoid antigens at the dermal-epibolic junction in organ culture of human skin. J. Inuest. Dermcitol. 94,336-340. 30. Yamasaki, Y., and Nishikawa, T. (1983). Ultrastructural localization of i n uitro binding sites of circulating anti-basement membrane zone antibodies in bullous pemphigoid. Actu Derm. Venereol. (Stockholm)63,501-506. 31. Jones, J. C. R., Yokoo, K. M., and Goldman, R. D. (1986).Is the liemidesmosoiiie a half desmosonie? An inimunological comparison of mammalian desniosomes and hemidesmosomes. Cell Motil. Cytoskel. 6,560-569. 32. Schwarz, M. A., Owaribe, K., Kartenbeck, J., and Franke, W. W. (1990). Desmosomes and hemidesmosomes: Constitutive molecular components. Annu. Reo. Cell B i d . 6,461-491. 33. Odland, G. F. (1958). The fine structure of the interrelationship of cells in the human epidermis. J . Biophysic. Biochem. Cytol. 4, 529-538. 34. Kelly, D. E. (1966). Fine structure of desmosomes, hemidesmosomes, and an adepidermal globular layer in developing newt epidermis. J . Cell Biol. 28,51-72. 35. Shiniizu, H., McDonald, J. N., Kennedy, A. R., and Eady, R. A. J. (1989).Denionstration of intra- and extracellular localization of bullous pemphigoid antigen using cryofixation and freeze substitution for postembedding immunoelectron microscopy. Arch. Dermutol. Res. 281,443-448. 36. Diaz, L. A., and Marcelo, C. L. (1978). Peniphigoid and pemphigus antigens in cultured epidermal cells. Br. J . Dermatol. 98,631-637. 37. Stanley, J. R., Hawley Nelson, P., Poirier, M., Katz, S. I., and Yuspa, S. H. (1980). Detection of pemphigoid antigen, pemphigus antigen, and keratin filaments by indirect immunofluorescence in cultured human epidermal cells. J . Invest. Dermutol. 75, 183-186. 38. Stanley, J . R., Hawley Nelson, P., Yuspa, S. H., Shevach, E. M., and Katz, S. I. (1981). Characterization of bullous peinphigoid antigen: A unique basement membrane protein of stratified squanious epithelia. Cell (Cambridge,M U S S . )24, 897-903. 39. Stanley, J. R., Hawley Nelson, P., Yaar, M., Martin, G. R., and Katz, S. I . (1982). Laminin and bullous pemphigoid antigen are distinct 1)asement membrane proteins synthesized by epidermal cells. J . Inuest. Dermutol. 78,456-459. 40. Okada, N., Kitano, Y., Miyagawa, S., Sakamoto, K., and Steinberg, M. L. (1986). Expression of pemphigoid antigen by SV40-transformed human keratinocytes. J. Invest. Dermatol. 86,399-401. 41. Mueller, S., Klaus-Kovtun, V., aiid Stanley, J. R. (1989).A 230-kD basic protein is the major bullous peniphigoid antigen. J. Invest. Dermutol. 92,33-38. 42. Stanley, J. R., and Yuspa, S. H. (1983). Specific epidermal protein markers are modulated during calcium-induced terminal differentiation. J. Cell B i d . 96, 1809-1814. 43. Stanley, J. R., Woodley, D. T., and Katz, S. I. (1984). Identification and partial characterization of pemphigoid antigen extracted from normal human skin. J. lnuest. Dermatol. 82, 108-111. 44. Labib, R. S., Anhalt, G. J., Patel, H. P., Mutasim, D . F., and Diaz, L. A. (1986). Molecular heterogeneity of the bullous pemphigoid antigens as detected by imniunoblotting. J. lmmunol. 136, 1231-1235.

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45. Bernard, P., Didierjean, L., Denis, F., Saurat, J. H., atid Ronnetblanc, J. M. (1989). Heterogeneous bullous pemphigoid antibodies: Detection and characterization by imtiiunohlotting when absent by indirect inimunofltiorescence. J. Irioest. Dertnutol. 92, 171-174. 46. Owaribe, K., Nishizawa, Y., and Franke, W. W. (1991). Isolation and characterization of heniidesmosomes from Imvine corneal epithelial cells. E x p . Cell Res. 192,622-630. 47. Mever, L. J., Taylor, T. B., Kadunce, D. P., and Zone, J. J. (1990). Two groups of bullous pemphigoid antigens are identified by affinity-purified antibodies. J. Znw s t . Derniutol. 94, 611-616. 48. Meyer, L. J., Taylor, T. B., Kadunce, D. P., Thuong-Nguyen, V., and Zone, J. J. (1991). Bullous peniphigoid antigens: Extraction and degradation of antigens duriiig epidermal preparation. J. Incest. Dennutol. 96, 991-993. 49. Klatte, D. H., Kurpakus, M. A,, Grelliug, K. A,, and Jones, J. C. R. (1989). Initnunochemical characterization of three components of the heniidesmosome and their expression in cultured epithelial cells. /. Cell B i d . 109,3377-3390, 50. Riddelle, K. S., Green, K. J., and Jones, J. C . R. (1991). Formation of hemidesmosome it1 citro by il transformed rat bladder cell line. J. Cell R i o l . 112, 159-168. 51. Thacher, S . M., and Hefti, P. L. (1991). Characterization of230-kD bullous pemphigoid antigen associated with the detergent-insoluble fraction of cultured keratinocytes. J. Incest. Dertnutol. 96, 139-143. 52. Robledo, M. A., Kim, S. C., Korman, N. J., Stanley, J. R., Labib, H. S., Futamura, S., and Anhalt, G . J. (1990). Studies of the relationship of the 230-kD and 180-kD bullous peniphigoid antigens. J. Invest. Derniutol. 94,793-797. 53. Shimizu, H., Hashimoto, T., Nishikawa, T., and Eady, R. A. J. (1991). Human monoclonal anti-basement membrane zone antibodies derived from virally transformed lymphocytes of a patient with bullous pemphigoid recognize epitopes associated with hemidesniosonies. Br. J. Dermatol. 124, 217-220. 5 4 . Zhu, X. J., and Bystryn, J. C. (1983). Heterogeneity of pemphigoid antigens. J. Itioest. Dermutol. 80, 16-20. 5!5. Morrison, L. H., Labib, H. S., Zone, J. J., Diaz, L. A., and Anhalt, G . J. (1988). Herpes gestationis autoantibodies recognize a 180-kD human epidermal antigen. J. Clit~.Irluest. 81, 2023-2026. 56. Cook, A. L., Hauahoe, T. H., Mallett, R. B., and Pye, R. J. (1990).Recognition of two distinct major antigens by I d l o u s pemphigoid sera. Br. J. Dertnutol. 122, 435-444. 57. Ehihara, T., Hashimoto, T., Nishikawa, T., Kudoh, J., Gamou, S., Shimizu, N., and Owaribe, K. (1992). Detection of the 170KD bullous pemphigoid antigen by imiiiunoprecipitation technique. /. Ititjest. Dermutol. 98, 586 (abstr.). Fj8. Diaz, L., Ratrie, H., Saunders, W. S., Futamura, S., Squiquera, H. L., Anhalt, G. J., and Giudice, G. J. (1990). Isolation of a hunian epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. J. Cliri. Iticest. 86, 1088-1094. 59. Venning, V. A,, Whitehead, P. H., Leigh, I. hl., Allen, J . , and Wojnarowska, F. (1991).The cliuical expression of bullous pemphigoid is not determined by the specificity of the target antigen. Br. J. Derntutol. 125,561-565. 60. Domloge-Hultsch, N., Utecht, L., James, W., and Yancey, K. B. (1990). AutoantiIioclies from patients with localized and generalized bullous peniphigoid immunoprecipitate the sanie 230-kd keratinocyte antigen. Arch. Dertiintol. 126, 1,3371341. 61. Soh, H., Hosokawa, H., Miyauchi, H., Izumi, H., and Asada, Y. (1991). Localized

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This article was accepted for publication on 23 September 1992.

Index A

B

AB-Mu1 V-transformed mast cell lines, lymphokine production by (murine), 4-6 Adhesion molecules affecting migration of naive and memory cells, 248-249 as targets of autoantibodies in pemphigus and pemphigoid, 309, 312,314 Affinity chromatography, leukemia inhibitory factor, 32 Affinity maturation, of memory B cells, 233-234 Allergic asthma, IL-4 storage by lung mast cells, 15 Amino acid sequences desmoglein, 314 human LIF, 40 oncostatin M, 40 PV antigen, 314 Antigenic stimulation memory generation by, 221223 sensitivity of naive and memory T cells to, 228 T cell differentiation after, 229230 Apoptosis, Fas antigen/APO-1 role, 241-242 Autoantibodies targeted adhesion molecules in pemphigus and pemphigoid, 309, 312, 314 Autoantigens, cDNA cloning BP antigen, 306-310 P F antigen, 310-312 PV antigen, 312-314 Autoimmune disease CD5' B cells in, 182-183 genetic defects in B lineage cells, 144-147 Autoimmunity, immunological memory and, 251-252

Basophils characterization, 2-3 and IL-4 production in response to FcR crosslinkage, 13 phenotypic properties, 1-2 precursors, 2 properties, 1-2 role in inflammatory reactions, 2 secretions, 2 B cells CD5+, in autoimmune disease, 182-183 CD5+/CD5- dichotomy, 178-183 circulating, functions, 201-203 classes of, 178-179 differential expression of lineagerelated markers, 125-127 differentiation in CBA/N immunodeficient mice, 142-143 surrogate L chain functions in, 136-143 genetic defects leading to autoimmune disease, 144-147 intermitotic life span of, 237-241 in lymph follicles, 185-187 memory adhesion molecules affecting migration, 248-249 affinity maturation, 233-234 functional properties, 236 generation, alterative models for, 236-238 germinal centers and, 231-233 life span, 240-241 migration pattern, 247-248 pathways of differentiation, 232-233 phenotype of, 234-235 immunoglobulin isotypes, 235 surface markers, 235-236 naive adhesion molecules afyecting, 248-249 migration pattern, 247-248

327

328

INDEX

in peripheral compartments, 177-186 in peritoneum, 183-185 pools, 135-136 pre-B cells contacts with stromal cells, 133-134 differentiation into B cells in bcl-2 transgenic mice, 143-144 in uitro, 140-141 in uivo, 141-142 long-term proliferating, 131-136 nonproliferating on stromal cells,

134-135

pro-B cells, long-term proliferating,

131-136

steady state production, 135-136 subpopulations, proliferation and differentiation capacities, 127-130 bcl-2 oncogene, immunological memory and, 241 bcl-2 transgenic mice, pre-B cell differentiation into B cells, 143-144 Blastocysts, LIF regulatory role, 34 Bone marrow FceRI+ cells, lymphokine production by (murine), 9-14 forbidden alp T cells, 166 mast cells derived from, 3 T cells, characterization, 171-173 Bone metabolism, leukemia inhibitory factor role, 36-37 Bullous pemphigoid antigen 180-kDa, uniqueness of, 305-310 230-kDa, homology to desmoplakin I,

305-310

cDNA cloning, 305-310 hemidesmosome localization,

297-300

structural and amino acid homologies with desmoplakin I, 307 clinical presentation, 292-295 histology, 292-295 immunopathology, 292-295

C Cachexia, LIF role, 37-38 Cadherin gene superfamily, pemphigus foliaceus antigen in, 310-312

Calcium ionophore and factor-dependent mast cell lymphokine production, 6 and transformed mast cell lymphokine production, 5 CBA/N mice, B cell differentiation in,

142-143 CD4

as accessory molecule, 60 coreceptor effects on selection, 103-104 coreceptor/MHC binding sites, 68-70 coreceptor model, 65-66 cytoplasmic tail " ~ protein tyrosine kinase ~ 5 6 and,

61-64

role in mediating coreceptor signal,

73-74

differential signaling, 91-94 function in TCR-mediated recognition and activation, 59-61 GTP-binding protein association,

64-65

mechanism of function during thymocyte selection, 104-108 MHC class I interactions, 60 and negative selection, 101-102 and negative signaling, 61 and positive selection, 97-98 signaling role in thymocytes, 82 T cells, development models, 108-113 TCR-coreceptor molecule association,

66-68

and TCR-mediated recognition and activation, 59-61 and thymocyte development and selection, 94-97

CD8

as accessory molecule, 60 CD8a role in T cell recognition and activation, 84-85 coreceptor effects on selection, 103-104 coreceptor/MHC binding sites, 68-70 coreceptor model, 65-66 cytoplasmic tail, protein tyrosine kinase ~ 5 6 and, " ~ 61-64 differential signaling, 91-94 function in TCR-mediated recognition and activation, 59-61 GTP-binding protein association, 64-65 mechanism of function during thymocyte selection, 104-108

329

INDEX

MHC class I interactions, 60 and negative selection, 102-103 and negative signaling, 61 and positive selection, 98-100 T cells, development models, 108-1 13 TCR-coreceptor molecule association, 66-68 and thymocyte development and selection, 94-97 CD14, role in cellular recognition of LPS, 281-286 CD45, phenotypic identification of memory T cells with, 225-227 CD45RAt T cells, functional and phenotypic properties, 225-227 CD45R- T cells, life span, 240 Cholinergic nerve differentiation factor, see Leukemia inhibitory factor Chronic myelogenous leukemia, circulating IL-4 levels, 14-15 Ciliary neurotrophic factor receptor and high-affinity LIF receptor, 43-44,46 pleiotropic nature of, 46-47 Cloning leukemia inhibitory factor, 31-32 LIF receptor, 38-40 CNTF, see Ciliary neurotrophic fictor Complementary DNA cloning of autoantigens BP antigen, 306-310 P F antigen, 310-312 PV antigen, 312-314 human LIF receptor, 38-40 Coreceptor model, of CD4 and CD8 and adhesiveness during TCR triggering, 83-84 coreceptor/MHC binding sites, 68-70 cytoplasmic tail role in signal mediation, 73-74 description, 65-68 effects on positive vs. negative selection, 103-104 function, gene transfer for, 70-78 ~56'~ role ' in TCR-mediated signaling, 74 TCR-coreceptor simultaneous binding,

66-68 Crosslinking FceRI and factor-dependent mast cell lymphokine production, 6

and IL-3 regulation of lymphokine production, 21-22 and IL-4 production by splenic and bone marrow FceRI+ cells, 10 and signaling of IL-4 production, 19-22 and transformed mast cell lymphokine production, 5 photochemical, for lipid A receptor identification, 277-279 Cytokines LPS-induced release, CD14 role, 284 pleiotropy of, 47 redundancy of, 47 Cytoplasmic domains, L I F receptor, 39-40

D Desmoglein amino acid sequence homologies and conserved sites with PV antigen, 314 characterization, 300-303 comparison with PV antigen and cadherins, 311 Desmoplakin I homology with 230-kDa pemphigoid antigen, 305-310 structural and amino acid homologies with BP antigen, 307 Desmosomes pemphigus foliaceus antigen localization, 300-303 ultrastructure diagram, 297 Development B cells differential expression of lineagerelated markers, 125-127 subpopulation proliferation and differentiation, 127-130 CD4 vs. CD8 T cells, 108-113 LIF role in, 33-37 Differentiation B cells in CBAiN immunogenic mice, 142-143 subpopulations, 127-130 surrogate L chain functions in, 136-143

330

INDEX

pre-B cells into B cells in bcl-2 transgenic mice, 143-144 in oitro, 140-141 in U ~ U O ,141-142 T cells, CD4 and CD8 roles, 94-113 negative selection, 101-103 positive selection, 97-98 thymocyte development and selection, 94-97 Differentiation-inhibiting factor/ differentiation-retarding factor, see Leukemia inhibitory factor

E Effector T cells functional and phenotypic properties, 225-227 functional differences with memory and naive cells, 227-228 maturation into, 229-230 migration basic pattern, 242-244 tissue topic subsets, 244-247 primary and secondary, 227-228 Embryonic stem cells, LIF effects (murine), 33-34 Erythrocyte membranes, LPS-binding proteins, 279 Escherichia coli, lipopolysaccharide structure, 269-270 Extracellular domains, LIF receptor, 39

Fas antigen/APO-1, immunological memory and, 241 FceRI+ cells bone marrow, lymphokine production by (murine), 9-14 human, lymphokine production by, 14-15 IL-4 production, and T cell lymphokineproducing phenotype, 18 lymphokine production, molecular regulation, 22 murine, infected or immunized, IL-4 production, 15-17

peritoneal, lymphokine production by (murine), 9-14 role in disease process, 17 signaling processing in response to FcR crosslinkage, 20-21 splenic, lymphokine production by (murine), 9-14 FceRI crosslinkage and basophil IL-4 production, 13 and factor-dependent mast cell lymphokine production (murine), 6 and IL-4 production by splenic and bone marrow FceRI+ cells, 10 and signaling of IL-4 production, 19-22 and transformed mast cell lymphokine production, 5 FceRI receptor, polypeptide components a,P, and y, 21 5D3 monoclonal antibody, LPS mimesis, 276-277 Follicular dendritic cells, stored antigen on, 222, 231 Forbidden T cells, in peripheral immune system, 164-166

G Genetic defects, in B lineage cells leading to autoimmune disease, 144-147 Gene transfer, for CD4/CD8 coreceptor function, 70--78 Germinal centers and memory B cells, 231-233 pathways of cell differentiation, 232-233 somatic hypermutation in, 233-234 GM-CSF, see Granulocyte-macrophage colony-stimulating factor gp130, and high-affinity OSMlLIF receptor, 43 Granulocyte-macrophage colonystimulating factor factor-dependent mast cell production of, 8-9 transformed mast cell production of, 4-6 GTP-binding protein, association with CD4-p56lCkand CD8Irk,64-65 Gut, lymphokine production by isolated T cells, 167

INDEX

H Heat-stable antigen, for B and T cells, 235-236 Hematopoiesis, leukemia inhibitory factor role, 35-36 Hemidesmosonies pemphigoid antigen localization, 297-300 ultrastructure diagram, 297 Hepatocyte-stimulating factor 111, see Leukemia inhibitory factor Human interleukin for DA cells, see Leukemia inhibitory factor Hypermutation, in germinal centers, 233-234

I IgE, plate-bound, IL-4 production in response to, 20-21 IL-1, see Interleukin-1 IL-2, see Interlenkin-2 IL-3, see Interleukin-3 IL-4, see Interleukin-4 IL-5, see Interleukin-5 IL-6, see Interleukin-6 IL-8, see Interleukin-8 Immune system B cell, and memory affinity maturation, 233-234 bcl-2 oncogene role, 241 Fas antigen/APO-1 role, 241-242 germinal centers role, 231-233 intermitotic life span and, 237-241 memory cells functional properties, 236 generation of, 236-238 phenotype of, 234-236 peripheral, compartmentalization anatomic localization of colonizing lymphocytes, 159 B cells CD5+/CD5- dichotomy, 178-183 in lymph follicles, 185-186 in peritoneum, 183-185 generation of compartments, 187-194 significance of, 199-203 site-dependent tolerance, 201-203 specialized functions of, 199-201

33 1

T cells intestinal intraepithelial, 163-167 y / 6 invariant intraepithelial cells, 167-169 in liver, 169-171 in lymph nodes, 161-163 in peritoneum, 173-177 in spleen, 161-163 T cell, and memory bcl-2 oncogene role, 241 differentiation after antigenic stimulation, 229-230 effector cells, 227-230 Fas antigen/APO-1 role, 241-242 intermitotic life span and, 237-241 memory cells, 227-230 naive cells, 227-230 phenotypic identification of memory T cells, 224-227 TCR and signal transduction, 238239 Immunological memory and autoimmunity, 251-252 and B cell immune system, germinal centers role, 231-233 bcl-2 oncogene and, 241 Fas antigen/APO-1 and, 241 generation, theories of, 219-220 life span of, 218-219 lymphocyte migration and, 242 maintenance by constant antigenic stimulation, 22 1-222 by long- and short-lived cells, 223-224 by long-lived clonally expanded cells, 220-22 1 and self-tolerance, 249-251 and T cell immune system differentiation after antigenic stimulation, 229-230 effector T cell function, 227-228 memory T cell functions, 227-228 naive T cell function, 227-228 TCR and signal transduction, 228-229 Inflammation, LIF role, 37-38 Interleukin-3 production by crosslinkage of FceR on peritoneal mast cells, 9

332

INDEX

by factor-dependent mast cell lines,

6-8

by transformed mast cells, 4-6 regulation of lymphokine production by FcsRIt cells, 21-22 Interleukin-4, production by FceR+ cells in infected/immunized mice, 15-17 by FcsRI' bone marrow cells, 10 by FcsRIt cells, and lymphokineproducing phenotypes of CD4t T cells, 17-19 by FcsRI+ spleen cells, 9-10 by human FcaRt cells, 14-15 by N . brasiliensis-infected mice, 15-17 in response to plate-bound IgE, 20-21 signaling mechanisms, 17-22 by transformed mast cells, 4-6 Interleukin-5, production by factordependent mast cell lines, 6-8 Interleukin-6 common signaling pathways, 44-46 and LIF, 44-47 pleiotropic nature of, 44 production by crosslinkage of FceR on peritoneal mast cells, 9 by factor-dependent mast cell lines,

6-8

Interleukin-7 pre-B cells nonproliferating on stromal cells, 134-135 pro- and pre-B cells reactive to, 131-136 Interleukin-8, production by factordependent mast cell lines, 8 Interleukin-11, relationship to LIF, OSM, CNTF, and IL-6,47 Intermitotic life span, of B and T cells, 237-241 Intestine, intraepithelial lymphocytes, 163-167 Intraepithelial lymphocytes intestinal, differentiation, 163-167 invariant y / 6 T cells (skin, female reproductive tract), 167-169 Ion-exchange chromatography, leukemia inhibitory factor, 32 Ionomycin, effects on factor-dependent mast cell lymphokine production, 6 IL-3 production by mast cells, 5

J J774.1 cell line, specific binding of LPS, 277-278

K Knockout mouse gene LIF role and, 48 targeting technology, 33

1 Langerhans cells, FceRI expression, 1-2 Leukemia inhibitory factor and blastocyst regulation, 34 in cachexia, 37-38 in development, 33-37 effects on mouse embryonic stem cells, 33-34 in hematopoiesis, 35-36 human, amino acid sequence, 40 and IL-6,44-47 immobilized form, 34 in inflammation, 37-38 LIF knockout mouse, 48-49 local action of, 49 matrix-associated form, 34 molecular cloning, 31-32 pleiotropic nature of, 44 polyfunctionality in uitro, 32-33 pseudonyms for, 32-33 purification, 31-32 soluble form, 34 as stem cell factor, 35 Leukemia inhibitory factor receptor alternatively spliced versions (murine), 39 cloned, 38-39 cytoplasmic domain, 39-40 extracellular domain, 39 genes, chromosome locations, 39 high affinity characterization, 38 and CNTF receptor, 43-44,46 oncostatin M binding, 41-43 human, 38-39 low affinity, 38 transfected, 41 types of, 38

INDEX

Life span of immunological memory, 218-219 intermitotic, of B and T cells, 237-241 Ligand blotting, for LPS receptor identification, 279-280 Lipid A antagonists, 272-274 binding proteins, 274-281 chemical structure, 270 from enterobacteria, 269 from nonenterobacteria, 269-270 receptor identification, 274-281 recognition by receptor-mediated mechanisms, 271-272 structure, 269 structure-function relationships, 272-274 Lipid IVa 3’PP-labeled,for lipid A binding site characterization, 278-279 recognition by scavenger receptor, 280 Lipopol ysaccharide bacterial, structure, 268-271 cellular recognition, role of LBPICD4 pathway, 281-286 heterodimeric receptor models, 285-286 lipid A antagonists, 272-274 binding proteins, 274-281 chemical structure, 270 from enterobacteria, 269 from nonenterobacteria, 269-270 receptor identification, 274-281 recognition by receptor-mediated mechanisms, 271-272 structure, 269 structure-function relationships, 272-274 Lipopolysaccharide-binding protein, in LPS-induced macrophage stimulation, 281-286 Liver, T lymphopoiesis in, 169-171 LPS, see Lipopolysaccharide Lung mast cells, IL-4 storage by, 15 Lymph follicles B cell populations, 186-187 zonal organization, 185-186 Lymph node forbidden alp T cells, 166 T lymphocyte populations, 161-163 Lyniphoblasts, germinal center, 186

333

Lymphocytes anatomic compartments colonized by, 159 B, see B cells biology, LIF role, 36 circulating, functions of, 201-203 Compartments site-dependent tolerance, 201-203 specialized functions of, 199-201 compartments, generation by different lineages, 188-189 by local selection, 192-199 by selective migration and extravasation, 189-192 T, see T cells Lymphokines, production by AB-Mu1 V-transformed mast cells (murine), 4-6 factor-dependent mast cell lines (murine), 6-9 human FceRt cells, 14-15 murine FceRIt cells (peritoneal, splenic, bone marrow), 9-14 Lymphopoiesis, T cells in liver, 169-171

MAH cell line, LIFiCNTF receptors, 43-44 Major histocompatibility complex proteins, CD4-CD8 coreceptor/MHC binding sites, 68-70 Markers, lineage-related, differential expression during development (murine B cells), 125-127 Mast cells AR-Mu1 V-transformed, lymphokine production (murine), 4-6 bone marrow-derived, 3 characterization, 2-3 connective type, 2-3 differentiation/dedifferentiation, 3 factor-dependent cell lines, lymphokine production (murine), 6-9 mucosal, 2-3 phenotypic properties, 1-2 precursors, 2 properties, 1-2 role in inflammatory reactions, 2 secretions, 2

334

INDEX

Megakaryopoiesis, LIF effects, 36 Melanoma-derived lipoprotein lipase inhibitor, see Leukemia inhibitory factor Memory, see Immunological memory Memory B cells adhesion molecules affecting migration,

248-249

affinity maturation, 233-234 functional properties, 236 generation, alterative models for,

naive T cells adhesion molecules and, 248-249 basic pattern, 242-244 tissue-specific, 244-247 plasma cells, 247-248 Monoclonal antibodies, 5D3, 276-277 Monocyte/macrophages LIF role in, 35-36 LPS receptors, 274-281

236-238

germinal centers and, 231-233 life span, 240-241 migration adhesion molecules and, 248-249 basic pattern, 247-248 migration pattern, 247-248 pathways of differentiation, 232-233 phenotype of, 234-235 immunoglobulin isotypes, 235 surface markers, 235-236 Memory T cells differentiation after antigenic stimulation, 229-230 functional differences with naive and effector cells, 227-228 maturation into, 229-230 migration basic pattern, 242-244 tissue topic subsets, 244-247 phenotypic identification with CD45,

224-227 TCR and signal transduction, 228-229

Migration effector T cells basic pattern, 242-244 tissue-specific, 244-247 lymphocyte, and immunological memory, 242 memory B cells adhesion molecules and, 248-249 basic pattern, 247-248 memory T cells adhesion molecules and, 248-249 basic pattern, 242-244 tissue tropic subsets, 244-427 naive B cells adhesion molecules and, 248-249 basic pattern, 247-248

Naive B cells, migration adhesion molecules and, 248-249 basic pattern, 247-248 Naive T cells functional differences with memory and effector cells, 227-228 migration adhesion molecules and, 248-249 basic pattern, 242-244 tissue topic subsets, 244-247 TCR and signal transduction, 228-229 Negative signaling CD4 and, 61 CD8 and, 61 Nippostronglyus brasiliensis infections, IL-4 production by FcER+cells in,

15-17

0 Oncostatin M amino acid sequence, 40 binding to high-affinity L I F receptor,

41-43

and CNTF, 44-47 and LIF, 44-47 pleiotropic nature of, 46 OSM, see Oncostatin M Osteoblasts, LIF effects, 36-37

P Pemphigus foliaceus antigen of cadherin gene superfanlily,

310-312

cDNA cloning, 310-312

335

INDEX

desmosonial localization, 300-303 relationship to PV antigen, 312-314 clinical presentation, 295-297 histology, 295-297 irnrnunopathology, 295-297 Pemphigus vulgaris antigen amino acid sequence homologies and conserved sites with desmoglein,

314

characterization, 303-305 identification as P F antigen-related cadherin, 312-314 clinical presentation, 295-297 histology, 295-297 irnmunopathology, 295-297 Peripheral immune system, compartmentalization anatomic localization of colonizing lymphocytes, 159 B cells CDSt/CD5- dichotomy, 178-183 in lymph follicles, 185-186 in peritoneum, 183-185 generation of compartments, 187-194 significance of, 199-203 site-dependent tolerance, 201-203 specialized functions of, 199-201 T cells intestinal intraepithelial, 163-167 y / 6 invariant intraepithelial cells,

167-169

in liver, 169-171 in lymph nodes, 161-163 in peritoneum, 173-177 in spleen, 161-163 Peritoneum B cells, 183-185 forbidden alp T cells, 166 lymphokine production by FceRI+ cells (murine), 9-14 T cells, characterization, 173-177 PF, see Pemphigus foliaceus Photochemical crosslinking, for lipid A receptor identification, 274-279 Plakoglobin, 130-kDA glycoprotein complexed with, 303-305 Plasma cells, migration, 247-248 Pleiotropy, LIF, OSM, CNTF, and IL-6,

44-47

Primordial germ cells, LIF effects, 34-35 Proliferation B cell subpopulations, 127-130 long-term, pro- and pre-B cells, 131-136 PV, see Pemphigus vulgaris

RAW264.7 cell line, lipid A binding sites, 278-279 Redundancy, LIF, OSM, CNTF, and IL6, 44-47 Reproductive tract, female, invariant intraepithelial y / 6 T cells, 167-169 Reverse-phase high-performance liquid chromatography, leukemia inhibitory factor, 32

S SASD, identification of lipid A-binding membrane proteins, 274-275 Schistosoma mansoni infections, lymphokine production in, 16 SCID mice, expression of defective B lineage cells, 146 Self-tolerance, immunological memory and, 249-251 70Z/3 murine pre-B cells, crosslinking of '251-labeled ASD-Re595 LPS, 278 Signaling differential, between CD4 and CD8, 91-94 in IL-4 production, mechanisms, 17-22 in naive and memory T cells, 228-229 TCR-mediated and CD4,85-91 and CD8,85-91 and p56'", 85-91 Site-specific tolerance, of peripheral lymphocytes, 201-203 Skin, invariant intraepithelial y / 6 T cells, 167-169 Somatic hypermutation, in germinal centers, 233-234 Spleen B cells, CD5' and CD5-, 180-181 FceRIt cells, lymphokine production by . (murine), 9-14

336

INDEX

forbidden (YIPT cells, 166 T lymphocyte populations, 161-163 Stem cells, embryonic B cells from, 124-130 LIF effects (murine), 33-34 Stromal cells contacts with pre-B cells, 133-134 pre-B cell nonproliferation on, 134-135 pro- and pre-B cells reactive to, 131-136 Sulfosuccinimidyl-2( p-azidosalicyamino)-1,3'dithiopropionate, identification of lipid A-binding membrane proteins, 274-275 Surface markers, for memory B cells, 235 Systemic lupus erythematosus-like autoimmune disease, in B/WF, mice, 144-147

T T cells activation CD8a role, 84-85 tyrosine kinase p56Ickrole, 78-82 bone marrow, characterization, 171-173 CD4 determination of lymphokineproducing phenotypes, 17-19 development models, 108-113 CD8, development models, 108-1 13 CD45RAt, functional and phenotypic properties, 225-227 CD45ROt, functional and phenotypic properties, 225-227 circulating, functions, 199-201 differentiation, CD4 and CD8 roles, 94-113 in negative selection, 101-103 in positive selection, 97-100 effector functional differences with memory and naive cells, 227-228 maturation into, 229-230 migration pattern, 242-244 primary and secondary, 227-228 tissue-specific migration, 244-247 forbidden, in peripheral immune system, 164-166

and growth requirements, 167 intermitotic life span of, 237-241 intestinal intraepithelial lymphocytes, 163-167 invariant intraepithelial y / 6 T cells (skin, female reproductive tract), 167-169 in lymph nodes, 161-163 lymphogenesis in liver, 169-171 from lymphoid compartment, origins, 164 and lymphokine production, 167 memory adhesion molecules affecting migration, 248-249 differentiation after antigenic stimulation, 229-230 functional differences with naive and effector cells, 227-228 maturation into, 229-230 migration pattern, 242-244 phenotypic identification with CD45, 224-227 TCR and signal transduction, 228-229 tissue-specific migration, 244-247 naive adhesion molecules affecting migration, 248-249 functional differences with memory and effector cells, 227-228 migration pattern, 242-244 TCR and signal transduction, 228229 in peripheral compartments, classification, 159-161 site-dependent tolerance, 201-203 in spleen, 161-163 TCR-mediated signaling and CD4,85-91 and CD8,85-91 in naive and memory T cells, 228-229 and ~ 5 6 " 85-91 ~, TCR triggering, coreceptor molecules modulation of adhesiveness during, 83-84 TFN-a, see Tumor necrosis factor-a Thymocytes CD4 signaling role, 82 development and selection, CD4/CD8 roles, 94-97

337

INDEX

mechanism of selection by CD4 and CD8, 104-108 Tolerance immunological memory and, 249-251 site-specific, of peripheral lymphocytes, 201-203 Transcriptional regulation, of lymphokine production by FceRI+ cells, 22 Tumor necrosis factor-a, production by crosslinkage of FceR on peritoneal mast cells, 9 by factor-dependent mast cell lines, 8-9 by FcERI' cells, 9 by human mast cells, 14-15

Tyrosine kinase p56Ick binding to CD4 and CD8 cytoplasmic tails, 61-64 role in T cell activation, 78-82 structure, 62-64 and TCR-mediated signaling, 85-91 Tyrosine phosphorylation of protein substrates, and lymphokine production, 5-6

Z Zonal organization, lymph follicles, 185-186

CONTENTS OF RECENT VOLUMES

Volume

42

The Clonotype Repertoire of B Cell Subpopulations

NORMAN R. KLINMANA N D PHYLLISJEANLINTON The Molecular Genetics of the Arsonate ldiotypic System of A/J Mice

GARYRATHBUN, INAKISANZ, KATHERYN MEEK,PHILIPTUCKER, AND J . DONALD CAPIU

The Interleukin 2 Receptor KENDALL A. SMITH

Structure of Antibody-Antigen Complexes: Implications for Immune Recognition

P. M. COLEMAN The y6 T Cell Receptor

MICHAELB. BRENNER, JACKL. STROMINGER, AND MICHAEL S. KHANGEL

Specificity of the T Cell Receptor for Antigen

STEPHENM. HEDRICK Transcriptional Controlling Elements in the Immunological and T Cell Receptor Loci

KATHRYNCALAME AND SUZANNE EATON

Characterization of Functional Surface Structures on Human Natural Killer Cells

JEROMERITZ, REINHOLD E. SCHMIDT, Molecular Aspects of Receptors and Binding Factors for IgE JEANMICHON, THIERRY HERCEND, AND HENRYMETZCER STUARTF. SCHLOSSMAN

The Common Mediator of Shock, Cachexia, and Tumor Necrosis B. BEUTLER AND A. CERAMI Myasthenia Gravis

JONLINDSTROM, DIANESHELTON, ANII YOSHITAKA FUJII Alterations of the Immune System in Ulcerative Colitis and Crohn’s Disease

RICHARD P. MACDERMOTT AND WILLIAM F. STENSON

INDEX

Volume 44 Diversity of the Immunoglobulin Gene Superfamily

TIM HUNKAPILLER AND LEROYHOOD Genetically Engineered Antibody Molecules SHERIEL. MORRISON AND VERNONT. 01

INDEX

Volume 43 The Chemistry and Mechanism of Antibody to Protein Antigens ELIZABETH D. GETZOFF,JOHNA. TAINER,RICHARDA. LERNER, AND

H. MARIOGEYSEN

Antinuclear Antibodies: Diagnostic Markers for Autoimmune Diseases and Probes for Cell Biology

ENG.M. TAN

Interleukin-1 and Its Biologically Related Cytokines CHARLES A. DINAHELLO

339

340

CONTENTS OF RE:CENT VOLUMES

Molecular and Cellular Events of T Cell Development

Volume 46

B. J. FOWLKES AND DREW M. PARDOLL Physical Maps of the Mouse and Human lmmunoglobulin-like Loci

Molecular Biology and Function of CD4 and CD8

JANER. PAHNES Lymphocyte Homing

TEDA. YEDNOCKAND STEVEND. ROSEN

INDEX

Volume 45 Cellular Interactions in the Humoral Immune Response ELLENS. VITETTA, RAPAEL

FERNANDEZ-BOTRAN, CHRISTOPHERD. MYERS,AND VIRGINIAM. SANDERS

MHC-Antigen Interactions: What Does the

ERICLAI, RICHARDK. WILSON,AND LEROY E. HOOD

Molecular Genetics of Murine Lupus Models

ARGYRIOSN. THEOFILOPOULOS, RIENHOLDKOPLER,PAULA. SINGER, AND FRANK J. DIXON

Heterogeneity of Cytokine Secretion Patterns and Functions of Helper T Cells

TIMR. MOSMANN AND ROBERTL. COFFMAN

The Leukocyte lntegrins

TAKASHI K. KISHIMOTO,RICHARDS. LARSON, ANGELL. CORBI,MICHAELL. DUSTIN,DONALD E. STAUNTON,AND TIMOTHY A. SPRINGER

T Cell Receptor See? Structure and Function of the Complement PHILIPPEKOURILSKY AND JEAN-MICHEL Receptors, CR1 (CD35) and CR2 (CD21) CLAVERIE JOSEPHM. AHEARNAND DOUGLAS T. FEAROW Synthetic T and B Cell Recognition Sites: Implications for Vaccine Development

DAVIDR. MILICH

Rationale for the Development of on Engineered Sporozoite Malaria Vaccine

VICTORNUSSENZWEIG AND RUTH S. NUSSENZWEIG Virus-Induced Immunosuppression: Infections with Measles Virus and Human Immunodeficiency Virus

MICHAELB. MCCHESNEYAND MICHAELB. A. OLDSTONE The Regulators of Complement Activation (RCA) Gene Cluster

DENNIS HOURCADE,V. MICHAEL HOLERS,AND JOHNP. ATKINSON Origin and Significance of Autoreactive T Cells

MAURICEZAUDERER

INDEX

The Cellular and Subcellular Bases of lmmunosenescence

MARILYNL. THOMAN AND WILLIAM0. WEIGLE

Immune Mechanisms in Autoimmune Thyroiditis

JEANNINECHARREIRE

INDEX

Volume 47 Regulation of lmmunoglobin E Biosynthesis

KIMISHIGEISHIZAKA

Control of the Immune Response at the Level of Antigen-Presenting Cells: A Comparison of the Function of Dendritic Cells and B Lymphocytes

JOSHUAP. METLAY,ELLENPURI?,AND RALPH M. STEINMAN

CONTENTS OF RECENT VOLUMES

34 1

The CD5 B Cell

Volume 49

Biology of Natural Killer Cells

Human Immunoglobulin Heavy-Chain Variable Region Genes: Organization, Polymorphism, and Expression

THOMAS J. KIPPS GIORCIOTRINCHIERI

The lmmunopathogenesis of HIV Infection

ZEDA F. ROSENBERC AND FAUCI

ANTHONY

s.

The Obeses Strain of Chickens: An Animal Model with Spontaneous Autoimmune Thyroiditis

GEORGE WICK,HANSPETER BHEZINSCHEK, KARELHALA,HEHMANN DIETRICH,HUGOWOLF,AND GUIDO KROEMER

VIRGINIA PASCUAL AND J. DONALD CAPRA Surface Antigens of Human Leucocytes

v. HOREJSf

Expression, Structure, and Function of the CD23 Antigen

G . DELESPESSE, U. SUTER,D. MOSSALAYI, B. BETTLER,M. SARFATI, H. HOFFSTETTER, E. KILCHERR, P. DEBRE,AND A. DALLOUL Immunology and Clinical Importance of Antiphospholipid Antibodies

INDEX

H. PATRICKMCNEIL,COLINN . CHESTERMAN, AND STEVEN A. KRILIS

Volume 48 Internal Movements in Immunoglobulin Molecules

ROALDNEZLIN Somatic Diversification of the Chicken Immunoglobulin Light-Chain Gene

WAYNE T. MCCORMACK A N D CRAIGB. THOMPSON T Lymphocyte-Derived Colony-Stimulating Foctors

ANNEKELSO

AND

DONALD METCALF

The Molecular Basis of Human Leukocyte Antigen Class II Disease Associations

DOMINQUE CHARRON

Adoptive T Cell Therapy of Tumors: Mechanisms Operative in the Recognition and Elimination of Tumor Cells

PHILIPD. GREENBERC The Development of Rational Strategies for Selective lmmunotherapy against Autoimmune Demyelinating Disease

LAWRENCE STEINMAN The Biology of Bone Marrow Transplantation for Severe Combined Immune Deficiency

ROBERTSON PARKMAN INDEX

Neuroimmunology

E. J. GOETZL,D. C. ADELMAN,AND S. P. SREEDHARAN

Immune Privilege and Immune Regulation in the Eye JERRY

Y. NIEDERKORN

Molecular Events Mediating T Cell Activation

AMNONALTMAN, K. MARK COGGESHALL, AND TOMAS MUSTELIN

INDEX

Volume 50 Selective Elements for the Vp Region of the TCell Receptor: Mlsand the Bacterial Toxic Mitogens

CHARLES A. JANEWAY, JH. Programmed Cell Death in the Immune System

J . JOHN COHEN

342

CONTENTS OF RECENT VOLUMES

Avian T Cell Ontageny

The Central Role of Follicular Dendritic

Structural and Functional Chimerism Results from Chromosomal Translocation in Lymphoid Tumors

The Murine Autoimmune Diabetes Model: N O D and Related Strains

MAX D. COOPER, CHEN-LOH. CHEN, Cells in Lymphoid Tissues SCHRIEVER AND LEEMARSHALL R. PATBUCY,AND CRAIGB. THOMPSON FOLKE NADLER

T. H. RABBITTSAND T. BOEHM

Interleukin-2, Autotolerance, and Autoimmunity GUIDOKROEMEH,JOSO LUISANDREV, J o s B ANGELGONZALO, J o s O C.

GUTIERHEZ-RAMOS, AND CARLOS MARTfNEZ-A.

Histamine Releasing Factors and CytokineDependent Activation of Basophils and Mast Cells ALLEN P. KAPLAN, SESHAREDDIGARI,

MARIABAEZA,AND PIOTRKUNA

Immunologic Interactions of T Lymphocytes with Vascular Endothelium JORDAN

HITOSHIKIKUTANIAND SUSUMU MAKINO

The Pathology of Bronchial Asthma JONATHAN

P. ARM AND TAKH. LEE

INDEX

Volume

52

Cell Biology of Antigen Processing and Presentation to Major Histocompatibility Complex Class I Molecule-Restricted T Lymphocytes JONATHAN W. YEWDELL AND JACK R.

BENNICK

S. POBER AND RAMZIS. COTHAN Human B Lymphocytes: Phenotype,

Adoptive Transfer of Human Lymphoid Cells to Severely Immunodeficient Mice: Models for Normal Human Immune Function, Autoimmunity, Lymphomagenesis, and AIDS

DONALD E. MOSIER

INDEX

Volume 51 Human Antibody Effector Function

DENNISR. BURTONAND JENNY M

WOOF

The Development of Functionally Responsive T Cells

ELLENV. ROTHENBERG

Role of Perforin in Lymphocyte-Mediated Cytolysis

HIDEOYAGITA, MOTOMINAKATA, AKEMIKAWASAKI,YOICHI SHINKAI, AND KO OKUMURA

Proliferation, and Differentiation JACQUES BANCHEHEAU AND

ROUSSET

FHANCOISE

Cytokine Gene Regulation: Regulatory cisElements and DNA Binding Factors Involved in the Interferon System

NOBUYUKITANAKA AND TADATSUGU TANIGUCHI Cellular and Molecular Mechanisms of B Lymphocyte Tolerance G . J. V. NOSSAL Cell Surface Structures on Human Basophils and Mast Cells: Biochemical and Functional Characterization

PETERVALENTAND PETER BETTELHEIM

Animal Models for Acquired Immunodeficiency Syndrome

THOMAS J. KINDT,VANESSAM. HIRSCH, PHILIPR. JOHNSON, AND SANSANA SAWASDIKOSOL

INDEX