Disease Relevant HLA Class II Alleles Isolated by Genotypic, Haplotypic, and Sequence Analysis in North American Caucasians With Pemphigus Vulgaris

Lee, Erica; Lendas, Katherine A.; Chow, S. K.; Pirani, Yasmin; Gordon, Derek; Dionisio, Robert; Nguyen, Daniela; Spizuoco, Amy; Fotino, M; Zhang, Yun; Sinha, Animesh A.

doi:10.1016/j.humimm.2005.09.003

Cited by 79 publications

(88 citation statements)

References 53 publications

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“…Our results do not support these negative associations. In a recent study which was carried out in the USA among both Jewish and non-Jewish patients, Lee et al 11 reported that the frequencies of three alleles at the DRB1 locus, DRB1*0402, 1401 and 1404, were significantly overrepresented in non-Jewish US patients with PV. They found that 50% of these nonJewish patients carried the DRB1*0402 allele, 36% carried 1401, and 11% carried 1404.…”

Section: Discussionmentioning

confidence: 99%

Association of human leukocyte antigen class II alleles with pemphigus vulgaris in a Turkish population

Tunca¹,

Muşabak

Sağkan

et al. 2010

The Journal of Dermatology

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Pemphigus vulgaris (PV) is a severe autoimmune blistering skin disorder that is strongly associated with major histocompatibility complex class II alleles. Human leukocyte antigen (HLA) subtypes vary with racial ⁄ ethnic backgrounds. The purpose of this study was to determine the association of HLA class II alleles and haplotypes with PV in Turkish patients. Twenty-five patients with PV and 113 healthy transplant donors were genotyped for HLA class II alleles. HLA DNA typing was performed by the polymerase chain reaction ⁄ sequence specific primer method. The frequency of HLA DRB1*04 allele was 68.00% in patients compared to 30.97% in controls (P = 0.0012) and the frequency of HLA DRB1*14 allele was 32.00% in the patient group compared to 8.85% in the control group (P = 0.0054). Also, the frequency of HLA DRB1*04 ⁄ DQB1*03 and HLA DRB1*14 ⁄ DQB1*05 haplotypes in PV patients was significantly higher than controls (32.0% vs 6.2%, v 2 = 28.142, P < 0.001; and 16% vs 2.7%, v 2 = 15.143, P = 0.001, respectively). A preventive allele or haplotype for the manifestation of PV has not been identified in this study. Our findings suggest that HLA DRB1*04 and DRB1*14 alleles, and HLA DRB1*04 ⁄ DQB1*03 and HLA DRB1*14 ⁄ DQB1*05 haplotypes are genetic markers for general susceptibility to PV in the Turkish population.

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Section: Discussionmentioning

confidence: 99%

Association of human leukocyte antigen class II alleles with pemphigus vulgaris in a Turkish population

Tunca¹,

Muşabak

Sağkan

et al. 2010

The Journal of Dermatology

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“…The hypothesis that autoreactive CD4 + T cells are critical initiators and perpetuators of the autoimmune pathology of PV is based on epidemiological observations which show a strong association of PV with two distinct HLA class II alleles, DRB1*04:02 and HLA-DQB1*05:03 (4,5,27,28). HLA-DRB1*04:02 possesses a negative charge at positions DRb70 (aspartate) and DRb71 (glutamate) contributing to the shape and the charge of the p4 pocket which is critical for the binding of Dsg3 peptides for presentation to autoaggressive T cells in PV (6,10).…”

Section: Discussionmentioning

confidence: 99%

“…Overall, PV can be considered as a Th2-driven autoimmune disorder because most of the autoantibodies belong to the IgG 4 and IgE subclasses (7,(33)(34)(35)(36)(37). Moreover, patients with PV have significantly lower frequencies of peripheral IL-10-secreting Dsg3-reactive type 1 regulatory T (Tr1) cells than healthy carriers of HLA-DRB1*04:02 that suppress proliferative responses of T effector cells in vitro (38).…”

Section: Discussionmentioning

confidence: 99%

“…Pemphigus can be considered as a paradigm of an autoantibody-mediated organ-specific autoimmune disease because the targeted autoantigens are known and its immune pathogenesis is relatively well characterized (2,3). Although rare, PV is more common in distinct ethnic groups such as Jews, Iranians, Irakis, and Indians where the disease-associated HLA class II alleles HLA-DRB1*04:02 and HLA-DQB1*05:03 are more common (4,5).…”

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confidence: 99%

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Pathogenic IgG Antibodies against Desmoglein 3 in Pemphigus Vulgaris Are Regulated by HLA-DRB1*04:02–Restricted T Cells

Eming

Hennerici

Bäcklund

et al. 2014

The Journal of Immunology

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Pemphigus vulgaris (PV) is considered as a model for an autoantibody-mediated organ-specific autoimmune disorder. IgG autoantibodies directed against the desmosomal cadherin desmoglein 3 (Dsg3), the major autoantigen in PV, cause loss of epidermal keratinocyte adhesion, resulting in blisters and erosions of the skin and mucous membranes. The association of human autoimmune diseases with distinct HLA alleles is a well-known phenomenon, such as the association with HLA-DRB1*04:02 in PV. However, direct evidence that HLA-DRB1*04:02–restricted autoreactive CD4+ T cells recognizing immunodominant epitopes of Dsg3 initiate the production of Dsg3-reactive IgG autoantibodies is still missing. In this study, we show in a humanized HLA-DRB1*04:02–transgenic mouse model that HLA-DRB1*04:02–restricted T cell recognition of human Dsg3 epitopes leads to the induction of pathogenic IgG Abs that induce loss of epidermal adhesion, a hallmark in the immune pathogenesis of PV. Activation of Dsg3-reactive CD4+ T cells by distinct human Dsg3 peptides that bind to HLA-DRβ1*04:02 is tightly regulated by the HLA-DRB1*04:02 allele and leads, via CD40-CD40L–dependent T cell–B cell interaction, to the production of IgG Abs that recognize both N- and COOH-terminal epitopes of the human Dsg3 ectodomain. These findings demonstrate key cellular and humoral immune events in the autoimmune cascade of PV in a humanized HLA-transgenic mouse model. We show that CD4+ T cells recognizing immunodominant Dsg3 epitopes in the context of the PV-associated HLA-DRB1*04:02 induce the secretion of Dsg3-specific IgG in vivo. Finally, these results identify Dsg3-reactive CD4+ T cells as potential therapeutic targets in the future.

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“…1,9 The association of HLA class II antigens with susceptibility to PV has been demonstrated in numerous studies. [10][11][12][13][14] In Ashkenazi Jews, PV appears tightly linked to the rare haplotype HLA-DR4 (DRB1*0402): DQB1*0302, while in non-Jewish patients, it is linked to the haplotype DRB1*404X: DQB1*0503. 15 MMP affects mucous membranes of the body and is characterized by the presence of autoantibodies to human β4 integrin, 16,17 while BP which predominantly affects the skin and is associated with bullous pemphigoid antigen 1 (BPAg1) and 2 (BPAg2).…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics-Based Predictions of Peptide Binding to Disease-Associated HLA Proteins Suggest Explanation for Shared Autoimmunity

Glutting

Reche

Fridkis-Hareli³

2011

Immunol Immunogenet Insights

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Abstract:Aim: This study was designed to examine the immunogenetic basis for shared autoimmunity, resulting in autoantigen presentation that leads to the production of two or more disease-specific autoantibodies. Methods: A bioinformatics approach based on peptide binding predictions to disease-associated HLA determinants has been developed and tested here using 11 disease associations between autoimmune systemic and mucocutaneous blistering disorders. Various HLAs associated with antigens within a given "disease model" (set of HLA class II and protein sequences known to be associated with a specific autoimmune disease) were tested and ranked against the antigenic proteins, first with proteins they are known to associate with and then with proteins known to be implicated in a second disease model. In every case binding predictions were compared for different proteins binding to the same HLA. Subsequently, disease-related autoantigens have been tested for their binding affinity against each disease-specific HLA class II protein.Results: For a single HLA haplotype, several binders have been generated from a related autoantigen with the variable binding score. In most cases, the binding score corresponding to the interactions between the autoantigen-derived epitope and the HLA associated with one disease was similar or lower than the interactions between the epitope from proteins associated with the second disease and the same HLA. Notably, there was no compelling promiscuity in peptide binding to each of the HLA molecules, in spite of the promiscuous nature of HLA class II binding. Conclusions:The data suggest that, in susceptible individuals, shared autoimmunity might be initiated by two types of HLA/peptide interaction; first between an autoantigen-derived epitope and its disease-associated HLA molecules, and second, between a different peptide of the same autoantigen and HLA proteins specific for the second disease.

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Disease Relevant HLA Class II Alleles Isolated by Genotypic, Haplotypic, and Sequence Analysis in North American Caucasians With Pemphigus Vulgaris

Cited by 79 publications

References 53 publications

Association of human leukocyte antigen class II alleles with pemphigus vulgaris in a Turkish population

Association of human leukocyte antigen class II alleles with pemphigus vulgaris in a Turkish population

Pathogenic IgG Antibodies against Desmoglein 3 in Pemphigus Vulgaris Are Regulated by HLA-DRB1*04:02–Restricted T Cells

Bioinformatics-Based Predictions of Peptide Binding to Disease-Associated HLA Proteins Suggest Explanation for Shared Autoimmunity

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