Human Leukocyte Antigen Class II Amino Acid Epitopes

Abstract

Chronic beryllium disease (CBD) is a hypersensitivity granulomatosis characterized by beryllium hypersensitivity (BH) and mediated by CD4+ T cells. However, all individuals with BH may not develop CBD. To examine the role of the three different human leukocyte antigen (HLA) Class II isotypes in BH with (CBD) and without clinical disease (BHWCD), we performed DNA-based typing of HLA-DPB1, HLA-DQB1, and HLA-DRB1 loci on 55 subjects with BH (25 with established CBD and 30 with BHWCD), and compared this with the results for 82 beryllium-exposed workers with no evidence of BH. The allele distribution was utilized to identify candidate amino acid epitopes that differed between the study groups. HLA-DPB1-E69 was the most important marker for BH, and did not differentiate BHWCD from CBD. A significant association with CBD was observed with HLA-DQB1-G86 (p(corr) < 0.04), and HLA-DRB1-S11 was significantly increased in CBD as compared with BHWCD (p < 0.03). These observations suggest that HLA-DPB1-E69 is a marker for susceptibility to BH and not just a progression marker for CBD. In addition, HLA amino acid epitopes on HLA-DRB1 and -DQB1, in concert with or independently of HLA-DPB1-E69, may be associated with progression to CBD.

Severe Pulmonary Sarcoidosis Is Strongly Associated With the Haplotype HLA-DQB1*0602–DRB1*150101

“…Because this disease is manifested by accumulation of activated CD4-positive T lymphocytes and macrophages at disease sites, a functional role for HLA class II molecules, presenting antigenic peptides to the T-cell receptor, was postulated [26]. Furthermore, in berylliosis, a disease with clinical presentation and pathology comparable to sarcoidosis, a close association with HLA class II antigens was reported [27][28][29][30][31]. Although for sarcoidosis associations with DRB1 and DQB1 have been reported, a recent study of Rybicki et al [18] that used microsatellite markers in the MHC region, revealed that DQB1 rather than DRB1 is the more important gene in susceptibility to sarcoidosis in African Americans.…”

Chronic Beryllium Disease, HLA-DPB1, and the DP Peptide Binding Groove

“…Although E69 is a strong marker of sensitization and disease, questions remain whether certain alleles confer greater risk of disease than others. Some studies have suggested that a greater prevalence of a non-*02 E69 variant is found in CBD and BeS (8, 10–13), whereas others have not (14, 15). Since the time of these first studies of associations between the HLA-DPB1 gene and CBD, many new alleles have been identified owing to improvements in typing methods.…”

Ethical Considerations in Testing Workers for the -Glu69 Marker of Genetic Susceptibility to Chronic Beryllium Disease

“…46 -48 Further work has established that HLA-DPB1-Glu69 is a supratypic marker with increased susceptibility associated with glutamic acid at position 69 in any of several HLA-DPB1 alleles, eg, *0201 or *1701, 0601, 0901, 1001, etc. 49,50 Attempts to elucidate the roles of specific alleles with respect to sensitization and disease progression have yielded mixed results. 47,49,51 The composition and structure of the beryllium-antigen complex have yet to be determined; however, several mechanisms and models have been proposed.…”

“…49,50 Attempts to elucidate the roles of specific alleles with respect to sensitization and disease progression have yielded mixed results. 47,49,51 The composition and structure of the beryllium-antigen complex have yet to be determined; however, several mechanisms and models have been proposed. 41,52,53 Several studies have attempted to shed light on the interaction between the HLA-DPB1-Glu69 marker and environmental factors in the development of CBD.…”