HLA class II restriction of autoreactive T cell responses in pemphigus vulgaris: review of the literature and potential applications for the development of a specific immunotherapy.

Pemphigus vulgaris (PV) is a life-threatening autoimmune bullous disease of the skin and mucous membranes which requires immunosuppressive therapy, most commonly a combination of glucocorticoids and additional immunosuppressive agents. Since the side effects of long-term immunosuppressive therapy contribute to the poor prognosis of this disorder, there is considerable interest in a more specific treatment of this severe skin disease. PV may serve as a model disease for the development of a specific immunotherapy, because its pathogenesis as well as involved immunogenetic factors are well-characterized. This review focuses on the characterization of autoreactive T cell responses to desmoglein 3 (Dsg3), the autoantigen of PV, that presumably regulate the production of autoantibodies by providing help to the autoreactive B cells. Current knowledge on T cell epitopes of Dsg3 and the HLA class II alleles that restrict Dsg3-specific autoreactive T cell responses, as well as potential applications for a specific immunotherapy of PV, are described.

[1]  G. Nepom,et al.  Critical contribution of beta chain residue 57 in peptide binding ability of both HLA-DR and -DQ molecules. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[2]  D. Wiley,et al.  Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1 , 1993, Nature.

[3]  A. Ahmed,et al.  Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[4]  L. Kappos,et al.  Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple-sclerosis patients and healthy donors. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[5]  E. Sercarz,et al.  Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen , 1992, Nature.

[6]  R. Winchester.  The molecular basis of susceptibility to rheumatoid arthritis. , 1994, Advances in immunology.

[7]  W. Aberer,et al.  Detection of disease-specific restriction fragment length polymorphisms in pemphigus vulgaris linked to the DQw1 and DQw3 alleles of the HLA-D region. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Karr,et al.  Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in pemphigus vulgaris. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  P. Gregersen,et al.  The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. , 1987, Arthritis and rheumatism.

[10]  Alessandro Sette,et al.  Structural characteristics of an antigen required for its interaction with Ia and recognition by T cells , 1987, Nature.

[11]  J. Todd,et al.  HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus , 1987, Nature.

[12]  T. Olsson,et al.  The T‐Cell Repertoire in Myasthenia Gravis Involves Multiple Cholinergic Receptor Epitopes , 1992, Scandinavian journal of immunology.

[13]  A. Ahmed,et al.  Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[14]  L. Moiola,et al.  Human acetylcholine receptor presentation in myasthenia gravis. DR restriction of autoimmune T epitopes and binding of synthetic receptor sequences to DR molecules. , 1994, Journal of immunology.

[15]  J. Banchereau,et al.  IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. , 1988, Journal of immunology.

[16]  E. Shevach,et al.  Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. , 1994 .

[17]  A. Ahmed,et al.  Correlation of subclasses of IgG with disease activity in pemphigus vulgaris. , 1994, Dermatology.

[18]  H. Heimberg,et al.  Complementation of HLA-DQA and -DQB genes confers susceptibility and protection to insulin-dependent diabetes mellitus. , 1992, Human immunology.

[19]  A Ando,et al.  HLA class II antigens are associated with Japanese pemphigus patients. , 1991, Human immunology.

[20]  J. Watson,et al.  Lymphocyte responses to DR4/1-restricted peptides in rheumatoid arthritis. The immunodominant T cell epitope on the 19-kd Mycobacterium tuberculosis protein. , 1992, Arthritis and rheumatism.

[21]  N. Nagarwalla,et al.  Correlation of peptide specificity and IgG subclass with pathogenic and nonpathogenic autoantibodies in pemphigus vulgaris: a model for autoimmunity. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[22]  H. Erlich,et al.  Sequence analysis of the HLA-DRß and HLA-DQß loci from three Pemphigus vulgaris patients , 1988 .

[23]  M. Amagai,et al.  Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic. , 1992, The Journal of clinical investigation.

[24]  S. Rodda,et al.  Immunodominant epitopes of glutamic acid decarboxylase 65 and 67 in insulin-dependent diabetes mellitus , 1994, The Lancet.

[25]  L. Steinman,et al.  CD4+ T-cell subsets in autoimmunity. , 1997, Current opinion in immunology.

[26]  N. Rose.  Current concepts of autoimmune disease. , 1988, Transplantation proceedings.

[27]  Don C. Wiley,et al.  Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide , 1994, Nature.

[28]  R. Good,et al.  A common major histocompatibility complex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphigoid. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[29]  J. Todd,et al.  A molecular basis for MHC class II--associated autoimmunity. , 1988, Science.

[30]  P Stastny,et al.  Development and characterization of desmoglein-3 specific T cells from patients with pemphigus vulgaris. , 1997, The Journal of clinical investigation.

[31]  R. Karr,et al.  Heterogeneous MHC II restriction pattern of autoreactive desmoglein 3 specific T cell responses in pemphigus vulgaris patients and normals. , 1998, The Journal of investigative dermatology.

[32]  R. Karr,et al.  Peptide binding specificity of HLA-DR4 molecules: correlation with rheumatoid arthritis association , 1995, The Journal of experimental medicine.

[33]  J. Mordes,et al.  Immunology of insulin-dependent diabetes mellitus. , 1985, Annual review of immunology.

[34]  J. Rothbard,et al.  Interactions between Immunogenic Peptides and MHC Proteins , 1991 .

[35]  Masayuki Amagai,et al.  Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion , 1991, Cell.

[36]  F. Perler,et al.  Identification of recombinant filarial proteins capable of inducing polyclonal and antigen-specific IgE and IgG4 antibodies. , 1995, Journal of immunology.

[37]  J. M. Boss,et al.  Genetic Complexity and Expression of Human Class II Histocompatibility Antigens , 1985, Immunological reviews.

[38]  Eric O Long,et al.  A myelin basic protein peptide is recognized by cytotoxic T cells in the context of four HLA-DR types associated with multiple sclerosis , 1991, The Journal of experimental medicine.

[39]  J. Bodmer,et al.  Nomenclature for Factors of the HLA System, 1994 , 1994, Human immunology.

[40]  H. Inoko,et al.  HLA-DQA1, -DQB1 and -DRB1 genotyping in Japanese pemphigus vulgaris patients by the PCR-RFLP method. , 1994, Tissue antigens.

[41]  V. Kuchroo,et al.  An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. , 1995, Immunity.

[42]  S. Miller,et al.  Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis , 1995, The Journal of experimental medicine.

[43]  S. Miller,et al.  Evolution of the T‐Cell Repertoire during the Course of Experimental Immune‐Mediated Demyelinating Diseases , 1995, Immunological reviews.

[44]  F. Sinigaglia,et al.  HLA class II peptide binding specificity and autoimmunity. , 1997, Advances in immunology.

[45]  M. Erlander,et al.  Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus. , 1992, The Journal of clinical investigation.

[46]  T. X. Lee,et al.  The pathophysiological significance of nondesmoglein targets of pemphigus autoimmunity. Development of antibodies against keratinocyte cholinergic receptors in patients with pemphigus vulgaris and pemphigus foliaceus. , 1998, Archives of dermatology.

[47]  R. Eming,et al.  Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls. , 1998, The Journal of clinical investigation.

[48]  J. Todd,et al.  A newly characterized HLA DQ beta allele associated with pemphigus vulgaris. , 1988, Science.

[49]  J. Strominger,et al.  Selective binding of self peptides to disease-associated major histocompatibility complex (MHC) molecules: a mechanism for MHC-linked susceptibility to human autoimmune diseases , 1995, The Journal of experimental medicine.

[50]  G. Nepom,et al.  HLA-DQ polymorphisms are highly selective for peptide binding interactions. , 1995, Journal of immunology.

[51]  S. Huilgol,et al.  Management of the immunobullous disorders. II. Pemphigus , 1995 .

[52]  T. Nishikawa,et al.  A case of pemphigus vulgaris showing reactivity with pemphigus antigens (Dsg1 and Dsg3) and desmocollins. , 1995, The Journal of investigative dermatology.

[53]  J. Rothbard,et al.  In vitro proliferative responses and antibody titers specific to human acetylcholine receptor synthetic peptides in patients with myasthenia gravis and relation to HLA class II genes. , 1988, The Journal of clinical investigation.

[54]  B. Mach,et al.  An HLA-DRB α-helix motif shared by DR11 and DR8 alleles is implicated in the pluriallelic restriction of peptide-specific T-cell lines , 1994 .

[55]  J. Stanley.  Pemphigus and pemphigoid as paradigms of organ-specific, autoantibody-mediated diseases. , 1989, The Journal of clinical investigation.

[56]  E. Shevach,et al.  Immune Deviation‐the Third Dimension of Nondeletional T Cell Tolerance , 1996, Immunological reviews.

[57]  M. Amagai,et al.  Recognition of desmoglein 3 by autoreactive T cells in pemphigus vulgaris patients and normals. , 1998, The Journal of investigative dermatology.

[58]  C. Akdis,et al.  Role of interleukin 10 in specific immunotherapy. , 1998, The Journal of clinical investigation.

[59]  Partho Ghosh,et al.  The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3 , 1995, Nature.

[60]  L. Diaz,et al.  Pemphigus foliaceus and pemphigus vulgaris autoantibodies react with the extracellular domain of desmoglein-1. , 1995, The Journal of investigative dermatology.