Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules

Background Granulomatous syndromes, such as Wegener's granulomatosis, are d efined according to complex criteria, but the underlying cause is rarely id entified. We present evidence for a new aetiology for chronic granulomatous lesions associated with a recessive genetic defect, which is linked to the human leucocyte antigen (HLA) locus. Methods Five adults with necrotising granulomatous lesions in the upper res piratory tract and skin, associated with recurrent bacterial respiratory in fections and skin vasculitis, were identified. A diagnosis of Wegener's gra nulomatosis was considered in all of them, but abandoned because of an inco mpatible disease course and resistance to immunosuppressive treatments. Per ipheral-blood samples were taken and analysed by immunohistochemistry and f luorescent-activated-cell-sorter analysis. Since all five patients were hom ozygous for the HLA locus, we looked for genetic defects located within the HLA-locus with PCR and restriction fragment length polymorphism. Findings A severe decrease in cell-surface expression of HLA class-I molecu le was seen in all patients. Defective expression of the transporter associ ated with antigen presentation (TAP) genes was responsible for the HLA clas s-I down-regulation, and in two patients we identified a mutation in the TA P2 gene responsible for the defective expression of the TAP complex. We sho wed the presence of autoreactive natural killer (NK) cells and gamma delta T lymphocytes in the peripheral blood cells of two patients. Correction of the genetic defect in vitro restored normal expression of HLA class-I molec ules and prevented self-reactivity in the patients' cells. Histology of gra nulomatous lesions showed the presence of a large proportion of activated N K cells. Interpretation Our findings define the cause and pathogenesis of a new synd rome that affects patients with a defective surface expression of HLA class -I molecules. The syndrome resembles Wegener's granulomatosis both clinical ly and histologically. Patients have chronic necrotising granulomatous lesi ons in the upper respiratory tract and skin, recurrent infections of the re spiratory tract, and skin vasculitis. A predominant NK population within th e granulomatous lesions suggests that the pathophysiology of the skin lesio ns may relate to the inability of HLA class-I molecules to turn off NK cell responses. Accurate genetic analysis of a defined syndrome can provide a b etter understanding of the cause and pathogenesis of a disease.