A CASE OF PRIMARY IMMUNODEFICIENCY DUE TO A DEFECT OF THE MAJOR HISTOCOMPATIBILITY GENE-COMPLEX CLASS-I PROCESSING AND PRESENTATION PATHWAY

Introduction: We report a case of primary immunodeficiency due to a de fect of the TAP transporter, an heterodimeric complex which controls t he expression of HLA class I molecule by delivering peptides from the cytosol into the lumen of the endoplasmic reticulum. Since childhood, the 36 year old female suffered from recurrent sinusitis/bronchitis. S he later developed bronchiectasis and destructive nasal epitheloid gra nulomata in conjunction with a generalized vasculitic syndrome that di d not improve upon immunosuppression and antibiotics. Methods: The cla ss I monomorphic W6/32 was used for cell surface staining and immunopr ecipitation of MHC class I molecules. Peptide transport assay was carr ied out in semi-permeabilized cells with iodinated peptides. Antigen p resentation experiments were performed using chromium 51 labelled pati ent B cell line and EBV specific CTL. TAP1 and TAP2 specific antibodie s were used for Western blotting and immunoprecipitation of the TAP co mplex. Results and conclusions: A severe reduction of MHC class I mole cules at the cell surface of the B-cell lines was observed, whereas MH C class II expression was not altered. Isoelectric focusing of metabol ically labelled MHC class I molecules revealed that class I heavy chai ns remain unsialylated, consistent with a block of TAP dependent pepti de translocation. These conclusions were confirmed by further experime nts showing that peptide translocation was completely abolished. We al so demonstrated that presentation of viral antigens through endogenous class I molecules was severely Impaired. Immunoprecipitation and West ern blotting of TAP1/2 complex showed that TAP2 was not detectable. Fu rther experiments are in progress to identify the site of the mutation . (C) 1997 Elsevier Science B.V.