Abstract
Abstract: :
VKH is an autoimmune disease targeted against melanocytes in susceptible individuals. We have been studying the significance of the susceptibility allele HLA-DRB1*0405 and melanocyte proteins. Purpose: To analyze the PBMC proliferative response against human melanoma lysate and to further analyze the response to peptides from melanocyte proteins, and peptide-induced-IFN-γ, IL-4 and IL-5 secretion in VKH patients and controls presenting DRB1*0405 or not. Methods: PBMC of 34 patients and 17 controls were tested against human melanoma lysate and 29 synthetic peptides from tyrosinase, tyrosinase-related protein (Trp)-1, Trp-2 and Pmel-17 in proliferation and cytokine assays (ELISA). Peptides were selected based on their predicted binding chance to DRB1*0405 and to the non-disease-related DR15 using the software TEPITOPE. Individuals were analyzed according to their HLA-DR typing: DRB1*0405 (12 patients and 9 controls) and other HLA (22 patients and 8 controls). Results: Patients (44%) recognized melanoma lysate while controls did not (p<.01). DRB1*0405 patients recognized peptides at lower concentrations than non-DRB1*0405 patients (p<.05); furthermore, they recognized 61% of peptides and HLA-matched controls 32% (p=.05). Some peptides, mainly derived from Trp-1, were preferentially recognized by DRB1*0405 patients. An inverse correlation was observed between peptide predicted binding score and peptide-induced IFN-γ secretion concerning DRB1*0405-binder peptides and DRB1*0405 patient responses. Peptide-induced IFN-γ secretion was present in patients and controls, while only controls secreted IL-4 (p<.01). IL-5 secretion was not observed in any group. There was no correlation between peptide recognition and disease severity and activity. Conclusion: Our data suggest that the pathogenic T cells involved in VKH are T1-type. T cells from HLA-DRB1*0405 patients recognize cryptic HLA-DRB1*0405-restricted melanocyte epitopes with high avidity. This peculiar fashion of response points to the importance of the HLA-DRB1*0405 and the role of melanocyte proteins in the pathogenesis of the disease.
Keywords: 612 uveitis-clinical/animal model • 327 autoimmune disease • 463 melanocytes