title: Active Wegener's granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10.
abstract: Wegener's granulomatosis (WG) is a granulomatous vasculitis that affects the upper respiratory tract, lung, and kidney. Since T cells make up a significant proportion of cells infiltrating granulomatous lesions in WG, we investigated the proliferative response and cytokine profile of T cells from these patients. PBMCs were isolated from 12 patients with active WG, 7 patients with inactive disease, and 12 healthy normal donors. PBMCs from clinically active WG patients exhibited increased proliferation following stimulation with either PMA/ionomycin or anti-CD2 and anti-CD28, when compared with normal donors. In addition, these PBMCs exhibited increased secretion of IFN-gamma, but not of IL-4, IL-5, or IL-10. Furthermore, TNF-alpha production from PBMCs and CD4+ T cells isolated from patients with WG was elevated, when compared with healthy donors. In further studies, we investigated the ability of WG patients' monocytes to produce IL-12 and showed that both inactive and active patients produced increased amounts of IL-12. Finally, the in vitro IFN-gamma production by WG PBMC is inhibited in a dose-dependent manner by exogenous IL-10. These data suggest that T cells from WG patients overproduce IFN-gamma and TNF-alpha, probably due to dysregulated IL-12 secretion, and that IL-10 may therefore have therapeutic implications for this disease.
authors.affiliation: Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA. bludviksson@atlas.niaid.nih.gov
authors.forename: B R
authors.initials: BR
authors.lastname: Lúdvíksson
authors.forename: M C
authors.initials: MC
authors.lastname: Sneller
authors.forename: K S
authors.initials: KS
authors.lastname: Chua
authors.forename: C
authors.initials: C
authors.lastname: Talar-Williams
authors.forename: C A
authors.initials: CA
authors.lastname: Langford
authors.forename: R O
authors.initials: RO
authors.lastname: Ehrhardt
authors.forename: A S
authors.initials: AS
authors.lastname: Fauci
authors.forename: W
authors.initials: W
authors.lastname: Strober
mesh_terms: D000328:Adult; D015704:CD4 Antigens / Q000032:analysis*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D005260:Female; D014890:Granulomatosis with Polyangiitis / Q000276:immunology*; D006684:HLA-DR Antigens / Q000032:analysis*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D016753:Interleukin-10 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; D006684:HLA-DR Antigens; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma