TY - JOUR
T1 - Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules
AU - Moins-Teisserenc, Hélènet
AU - Gadola, Stephan D.
AU - Cella, Marina
AU - Dunbar, P. Rod
AU - Exley, Andrew
AU - Blake, Neil
AU - Baycal, Can
AU - Lambert, Julien
AU - Bigliardi, Paul
AU - Willemsen, Maria
AU - Jones, Margaret
AU - Buechner, Stanislaw
AU - Colonna, Marco
AU - Gross, Wolfgang L.
AU - Cerundolo, Vincenzo
N1 - Funding Information:
We thank K Welsh (Oxford Transplant Centre) for tissue typing the patients, A Kelly (Cambridge) for analysis of the stability of HLA class-I molecules in the B cells from patient 1, S Fuggle, L Cerundolo (Nuffield Department of Surgery, Oxford), D Mason G Roncador (Division of Cellular Sciences, Oxford), and A-C-Feller (Institute of Pathology, University of Lubeck, Germany) for their help in analysing the biopsy samples; G Mertons (Bloedtransfusiecentrum Antwerpe HLA lab, Edegem) for tissue typing patient 4; W H Schmitt for assistance in the clinical chracterisation of patient 1; and G Bird (Clinical Immunology, Churchill Hospital, Oxford) for advice and helpful discussion. This work was funded by the Medical Research Council of UK and by the Cancer Research Campaign. H T Moins-Teisserenc was supported by Fondation de France and S Gadola was supported by grants of the Swiss National Foundation, Novartis Foundation, and Roche Research Foundation.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 1999/11/6
Y1 - 1999/11/6
N2 - Background. Granulomatous syndromes, such as Wegener's granulomatosis, are defined according to complex criteria, but the underlying cause is rarely identified. 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 respiratory tract and skin, associated with recurrent bacterial respiratory infections and skin vasculitis, were identified. A diagnosis of Wegener's granulomatosis was considered in all of them, but abandoned because of an incompatible disease course and resistance to immunosuppressive treatments. Peripheral-blood samples were taken and analysed by immunohistochemistry and fluorescent-activated-cell-sorter analysis. Since all five patients were homozygous 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 molecule was seen in all patients. Defective expression of the transporter associated with antigen presentation (TAP) genes was responsible for the HLA class-I down-regulation, and in two patients we identified a mutation in the TAP2 gene responsible for the defective expression of the TAP complex. We showed the presence of autoreactive natural killer (NK) cells and γδT lymphocytes in the peripheral blood cells of two patients. Correction of the genetic defect in vitro restored normal expression of HLA class-I molecules and prevented self-reactivity in the patients' cells. Histology of granulomatous lesions showed the presence of a large proportion of activated NK cells. Interpretation. Our findings define the cause and pathogenesis of a new syndrome that affects patients with a defective surface expression of HLA class-I molecules. The syndrome resembles Wegener's granulomatosis both clinically and histologically. Patients have chronic necrotising granulomatous lesions in the upper respiratory tract and skin, recurrent infections of the respiratory tract, and skin vasculitis. A predominant NK population within the granulomatous lesions suggests that the pathophysiology of the skin lesions 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 better understanding of the cause and pathogenesis of a disease.
AB - Background. Granulomatous syndromes, such as Wegener's granulomatosis, are defined according to complex criteria, but the underlying cause is rarely identified. 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 respiratory tract and skin, associated with recurrent bacterial respiratory infections and skin vasculitis, were identified. A diagnosis of Wegener's granulomatosis was considered in all of them, but abandoned because of an incompatible disease course and resistance to immunosuppressive treatments. Peripheral-blood samples were taken and analysed by immunohistochemistry and fluorescent-activated-cell-sorter analysis. Since all five patients were homozygous 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 molecule was seen in all patients. Defective expression of the transporter associated with antigen presentation (TAP) genes was responsible for the HLA class-I down-regulation, and in two patients we identified a mutation in the TAP2 gene responsible for the defective expression of the TAP complex. We showed the presence of autoreactive natural killer (NK) cells and γδT lymphocytes in the peripheral blood cells of two patients. Correction of the genetic defect in vitro restored normal expression of HLA class-I molecules and prevented self-reactivity in the patients' cells. Histology of granulomatous lesions showed the presence of a large proportion of activated NK cells. Interpretation. Our findings define the cause and pathogenesis of a new syndrome that affects patients with a defective surface expression of HLA class-I molecules. The syndrome resembles Wegener's granulomatosis both clinically and histologically. Patients have chronic necrotising granulomatous lesions in the upper respiratory tract and skin, recurrent infections of the respiratory tract, and skin vasculitis. A predominant NK population within the granulomatous lesions suggests that the pathophysiology of the skin lesions 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 better understanding of the cause and pathogenesis of a disease.
UR - http://www.scopus.com/inward/record.url?scp=0033530372&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(99)04206-3
DO - 10.1016/S0140-6736(99)04206-3
M3 - Journal articles
C2 - 10560675
AN - SCOPUS:0033530372
SN - 0140-6736
VL - 354
SP - 1598
EP - 1603
JO - Lancet
JF - Lancet
IS - 9190
ER -