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

Moins-Teisserenc, Hélène T., Gadola, Stephan D., Cella, Marina, Dunbar, P. Rod, Exley, Andrew, Blake, Neil, Baykal, Can, Lambert, Julien, Bigliardi, Paul, Willemsen, Maria, Jones, Margaret, Buechner, Stanislaw, Colonna, Marco, Gross, Wolfgang L. and Cerundolo, Vincenzo (1999) Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules The Lancet, 6, (354), pp. 1598-1603. (doi:10.1016/S0140-6736(99)04206-3). (PMID:10560675).

Record type: Article


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 ??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.

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.

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Published date: 6 November 1999
Organisations: Infection Inflammation & Immunity


Local EPrints ID: 175441
ISSN: 0140-6736
PURE UUID: d3339edb-d859-4857-97e4-aae592d4ee02

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Date deposited: 23 Feb 2011 14:30
Last modified: 18 Jul 2017 12:09

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Author: Hélène T. Moins-Teisserenc
Author: Stephan D. Gadola
Author: Marina Cella
Author: P. Rod Dunbar
Author: Andrew Exley
Author: Neil Blake
Author: Can Baykal
Author: Julien Lambert
Author: Paul Bigliardi
Author: Maria Willemsen
Author: Margaret Jones
Author: Stanislaw Buechner
Author: Marco Colonna
Author: Wolfgang L. Gross
Author: Vincenzo Cerundolo

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