M. avium binding to HLA-DR expressed alleles in silico: A model of phenotypic susceptibility to sarcoidosis

Sarcoidosis is a systemic granulomatosis disease of unknown origin where a number of microbes, in particular M tuberculosis and non-tuberculous mycobacteria, have been hypothesized to play a role in disease pathogenesis, possibly through bacterial antigen-driven hypersensitivity. To test this concept, we used bioinformatic tools allowing the identification of antigenic peptides in whole microbial genomes to analyze the interaction between the expressed HLA-DR gene allelic variants and the HLA-DR immunome of all pathogenic bacteria in a population of 149 sarcoidosis affected subjects and 447 controls, all HLA-typed at high resolution. We show here that patients with the Lofgren's syndrome, express HLA-DR alleles that recognize in silico a significantly higher number of bacterial antigen epitopes compared to the control population (18,496+9,114 vs 17,954+8,742; p<0.00001), and the chronic sarcoidosis affected population (17,954+8,742; p<0.00001 vs Lofgren's and controls). Further, the analysis of the ability of the HLA-DR allele combinations expressed by the Lofgren and the chronic sarcoidosis affected subjects to recognize M avium epitopes demonstrates that a significantly larger number of Lofgren's are capable of top affinity recognition, compared to chronic sarcoidosis (45% vs 17%, p<0.0037). Finally, both Lofgren's and chronic sarcoidosis subjects expressed HLA-DR allele combinations capable of M tuberculosis and M avium epitope recognition at higher affinity than tuberculosis affected subjects (p<0.01 all comparisons). In conclusion, we propose that - at least in a subgroup of affected subjects sarcoidosis might be part of a spectrum of granulomatous responses to several agents where the Lofgren's syndrome represents the hyper-reactive end of the spectrum while pulmonary tuberculosis and atypical mycobacterial infections might represent the opposite end. (Sarcoidosis Vasc Diffuse Lung Dis 2008; 25: 100-116)