title: Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules.
abstract: 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.
  
  
  RESULTS
  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 gammadelta T 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Nuffield Department of Medicine, Institute of Molecular Medicine, Oxford, UK.
authors.forename: H T
authors.initials: HT
authors.lastname: Moins-Teisserenc
authors.forename: S D
authors.initials: SD
authors.lastname: Gadola
authors.forename: M
authors.initials: M
authors.lastname: Cella
authors.forename: P R
authors.initials: PR
authors.lastname: Dunbar
authors.forename: A
authors.initials: A
authors.lastname: Exley
authors.forename: N
authors.initials: N
authors.lastname: Blake
authors.forename: C
authors.initials: C
authors.lastname: Baykal
authors.forename: J
authors.initials: J
authors.lastname: Lambert
authors.forename: P
authors.initials: P
authors.lastname: Bigliardi
authors.forename: M
authors.initials: M
authors.lastname: Willemsen
authors.forename: M
authors.initials: M
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Buechner
authors.forename: M
authors.initials: M
authors.lastname: Colonna
authors.forename: W L
authors.initials: WL
authors.lastname: Gross
authors.forename: V
authors.initials: V
authors.lastname: Cerundolo
authors.forename: C
authors.initials: C
authors.lastname: Baycal
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000483:Alleles; D015153:Blotting, Western; D003062:Codon; D003937:Diagnosis, Differential; D015536:Down-Regulation; D005260:Female; D014890:Granulomatosis with Polyangiitis / Q000175:diagnosis; D006105:Granulomatous Disease, Chronic / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018528:ATP-Binding Cassette Transporters; D003062:Codon; D015395:Histocompatibility Antigens Class I