Polymorphisms of HLA class II genes and autoimmune responses to Ro/SS-A-La/SS-B among Japanese subjects

Abs to Ro/SSA Ags in the sera of patients with systemic lupus erythematosus and Sjögren’s syndrome are influenced by the HLA class II genes. To investigate the role of individual HLA class II genes in immune responses to human Ro60 (hRo60), mice lacking murine class II molecules and carrying either HLA genes DR2(DRB1*1502), DR3(DRB1*0301), DQ6(DQA1*0103/DQB1*0601), or DQ8(DQA1*0301/DQB1*0302), were immunized with rhRo60. The results show that hRo60 induces strong T and B cell responses in DR2, DR3, and DQ8 mice in comparison to weaker responses in DQ6 mice. In all mice, the majority of the dominant T cell epitopes were located in the amino portion (aa 61–185) and the carboxy portion (aa 381–525) of the hRo60 molecules. In contrast, the early dominant B cell epitopes were located in the middle and carboxy portion of the hRo60 molecule (aa 281–315 and 401–538). In DR2, DR3, and DQ8 mice, the B cell epitopes subsequently spread to the amino and carboxy portion of the hRo60 molecule but were limited to the middle and carboxy portion in DQ6 mice. The DR2 and DR3 mice produced the highest titers of immunoprecipitating Abs against hRo60 and native mouse Ro60. In addition, only DR2 mice exclusively produced immunoprecipitating Abs to native mouse Ro52 and Abs to mouse La by slot blot analysis, whereas in other strains of mice Abs to mouse La were cross-reactive with the immunogen. The results of the present study demonstrate the importance of HLA class II in controlling the immune responses to the Ro-ribonucleoprotein.

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“…SLE and SS (32)(33)(34)(35)(36)(37). Our identified dominant B cell epitopes corresponding to aa 281-315 lie within this region.…”

Section: Discussionmentioning

confidence: 82%

“…Previous studies have variably identified B cell epitopes of hRo60 from sera of patients with SLE and SS (32)(33)(34)(35)(36)(37)(38)(39). The discrepancies probably reflect the different populations studied and the types of assays and Ags selected.…”

Section: Discussionmentioning

confidence: 99%

HLA Class II Influences the Immune Response and Antibody Diversification to Ro60/Sjögren’s Syndrome-A: Heightened Antibody Responses and Epitope Spreading in Mice Expressing HLA-DR molecules

Paisansinsup

Deshmukh

Chowdhary

et al. 2002

The Journal of Immunology

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“…In the Japanese population in particular, a significant genetic linkage between HLA DQB1 *0302 and anti-RNP has been shown to exist. 8 Miyagawa et al 9 reported that the haplotype DRB1 *08032 / DQA1 *0103 / DQB1 *0601 exhibited associations with anti-SS-B (with anti-SS-A together), and in their study, all the Japanese patients who were positive for anti-SS-A possessed at least one DQB1 *06 or *03 subtypes that shared the same amino acid residues at positions 71-77 of the DQB1 chain. Pt-1 and Pt-3 were positive for anti-dsDNA and lupus nephritis (nephrotic syndrome).…”

Section: Discussionmentioning

confidence: 92%

Human leukocyte antigen haplotype and autoantibodies of a family with systemic lupus erythematosus

et al. 2004

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A search for HLA haplotypes of a family of five indicated that four members had the same haplotype. Systemic lupus erythematosus (SLE) had already developed in three of these four people. SLE has now developed in the remaining person, and the result is that all the members of the family having the same haplotype will develop SLE. Regarding these four SLE patients, the types of autoantibodies and the symptoms were different in each person, so the idea that this haplotype is strongly related to the onset of SLE but minimally related to the symptoms was suggested.

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“…North and West European Whites and North Americans show a higher prevalence of B8, DRw52 and DR3 genes, whereas Scandinavians and Greeks show linkages predominantly to the DR2 and DR5 genes [Bolstad and Jonsson, 2002]. However, it has been found that HLA class II alleles are associated with specific subsets of autoantibodies rather than with the disease itself [Gottenberg et al 2003;Miyagawa et al 1998]. Worthy of mention is the association of gene polymorphisms outside the HLA locus in SS with specific elements of its pathogenesis.…”

Section: Pathologymentioning

confidence: 99%

Current aspects of pathogenesis in Sjögren’s syndrome

Voulgarelis

Tzioufas

2010

Therapeutic Advances in Musculoskeletal

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Sjögren's syndrome is a chronic autoimmune process that primarily affects the exocrine glands and leads to their functional impairment. The exocrine gland involvement is characterized by a focal, mononuclear cell infiltrate which is accumulated around ducts and, in some patients, extends and replaces the secretory functional units. The mechanisms of this autoimmune 'exocrinopathy' are not fully understood. The immune attack that follows activation or apoptosis of glandular epithelial cells exposing autoantigens in genetically predisposed individuals may drive the immune-mediated tissue injury. Abnormalities related to the upregulation of type I interferon-regulated genes (interferon signature), abnormal expression of B-cell-activating factor (BAFF) and activation of the IL-23/TH17 pathway are among the immune mediators implicated in the pathogenesis of autoimmune lesions within the salivary glands. Such abnormalities demonstrate the complex interplay between innate and adaptive immunity that contributes to autoimmune 'exocrinopathy'.

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Polymorphisms of HLA class II genes and autoimmune responses to Ro/SS-A-La/SS-B among Japanese subjects

Cited by 47 publications

References 26 publications

HLA Class II Influences the Immune Response and Antibody Diversification to Ro60/Sjögren’s Syndrome-A: Heightened Antibody Responses and Epitope Spreading in Mice Expressing HLA-DR molecules

HLA Class II Influences the Immune Response and Antibody Diversification to Ro60/Sjögren’s Syndrome-A: Heightened Antibody Responses and Epitope Spreading in Mice Expressing HLA-DR molecules

Human leukocyte antigen haplotype and autoantibodies of a family with systemic lupus erythematosus

Current aspects of pathogenesis in Sjögren’s syndrome

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