In the logistic regression models evaluating the association between HLA alleles and chronic sarcoidosis adjusted for rs1049550 and rs2076530, only DRB1*03 was significantly associated with disease resolution.
Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities.
Among sarcoidosis patients, the HLA A*23, A*80, B*08, B*41, DQB1*05 and DRB1*14 antigens tended to be more common than in the controls, whereas the B*44, B*45, B*51, B*58, DRB1*15 and DRB1*16 alleles were more frequently found in control subjects than in the sarcoidosis patients.
In the group of patients with chronic sarcoidosisDRB1*11 (P=0.0219; OR=2.44), DRB1*15 (P=0.0414; OR=2.47) demonstrated statistically significant difference in comparison to controls only, while a lower frequency of DRB1*13 (P=0.0156; OR=0.24) in this group was statistically significant when compared to both patients with acute sarcoidosis and controls.
ESAT-6 and katG presented by antigen-presenting cells expressing DRB1*1101-induced Th-1 responses from sarcoidosis T cells, thus providing a mechanistic insight for the association of HLA DRB1*1101 with sarcoidosis, and sarcoidosis T cell interaction with microbial antigens.
Initially, we studied the association of sarcoidosis with DQB1, and in the present study, we evaluated all amino acid variants of the HLA-DPB1, -DQB1, -DRB1, -DRB3, -DRB4 and -DRB5 genes to identify possible polymorphisms associated with the disease.
The association of the HSP(+2437)-C allele with sarcoidosis and LS appeared to be independent of the presence of DRB1*03, although this HLA specificity was associated with LS manifestation.
DQB1*02, DQA1*0201/*0501 (Ls) and DRB1*15/*13 (Stage II) were more frequently present in SA than in TB, but after correction, only DRB1*15, DQB1*02, DQA1*0501 were significantly different.
Recent studies in sarcoidosis have identified association of a single nucleotide polymorphism (SNP) rs2076530 within BTNL2, a potential T-cell inhibitor, independent of the known DRB1 association.
In addition, we found a highly significant correlation of HLA-DRB1*11 or -DRB1*15 alleles and/or the presence of M. tuberculosis DNA to a chronic disease course, whereas HLA-DRB1*03 or -DRB1*04 alleles combined with the absence of M. tuberculosis DNA were associated with an acute sarcoidosis (p = 0.009).
The overrepresentation of TNF-308*A, LTAlpha+252*G and HLA-DRB1*03 allele carriers was found in a subgroup of sarcoidosis patients presenting with Lofgren's syndrome (LS) by comparison with the subgroup of patients without LS (NLS; phenotype frequency LS vs NLS: 68.8 vs 37.1% for TNF-308*A, 93.8 vs 66.3% for LTA+252*G and 68.8 vs 21.3% for DRB1*03).
However, we also showed the presence of a combined association between DRB1*03 and IFN-gamma 3,3 in sarcoidosis (P = 0.017) and LS patients (P = 0.001).
Further, multivariate logistic regression analysis revealed that the presence of DRB1*11(odds ratio [OR] 9) and DRB1*14 (OR 7), and absence of DRB1*07 (OR 63 and DQB1*0201(OR 3) alleles, were independent predictors of sarcoidosis.
In addition to being susceptibility markers, HLA class II alleles may be markers for different phenotypes of sarcoidosis (DRB1*0401 for eye in blacks and whites, DRB3 for bone marrow in blacks, and DPB1*0101 for hypercalcemia in whites).
HLA-DRB3*0101 as well as DRB1*0301 positive sarcoidosis patients may have the capacity to present specific sarcoidosis associated antigens in such a way that AV2S3+ CD4+ T cells are stimulated preferentially, generating lung restricted AV2S3+ T cell expansions.
These studies support the thesis that one of the major genetic factors controlling the development of sarcoidosis is located within the DRB1 locus in the HLA class II region.
Sarcoidosis is a systemic granulomatous disease and the DRB1 gene of the DR subregion has been implicated for determining the genetic susceptibility to the disease.
Our finding of a high frequency of DRB1*08 (which lacks the DRB3 gene encoding the DR52 antigen) in patients living in both eastern Japan and in Hokkaido, confirms that it is the HLA-DRB1 locus, rather than that of the HLA-DRB3, -DQA1, or -DQB1, which determines the susceptibility to sarcoidosis.
The significantly increased frequency of the DR8 (DRB1*08) haplotype, which lacks the DRB3 gene encoding DR52 antigen, suggested that the DR5 (DRB1*11), DR6 (DRB1*14) and DR8 (DRB1*08) of the DRB1 alleles may determine the susceptibility to sarcoidosis among the Japanese.