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 Löfgren'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 Löfgren's and controls). Further, the analysis of the ability of the HLA-DR allele combinations expressed by the Löfgren's and the chronic sarcoidosis affected subjects to recognize M. avium epitopes demonstrates that a significantly larger number of Löfgren's are capable of top affinity recognition, compared to chronic sarcoidosis (45% vs 17%, p<0.0037). Finally, both Löfgren'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 Löfgren's syndrome represents the hyper-reactive end of the spectrum while pulmonary tuberculosis and atypical mycobacterial infections might represent the opposite end.
Saltini
C
C
Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Pallante
M
M
Puxeddu
E
E
Contini
S
S
Voorter
C E
CE
Drent
M
M
Amicosante
M
M
D000483:Alleles; D001666:Binding Sites, Antibody / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D009162:Mycobacterium avium / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D012507:Sarcoidosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains