Costimulatory molecules in Wegener's granulomatosis (WG): lack of expression of CD28 and preferential up-regulation of its ligands B7-1 (CD80) and B7-2 (CD86) on T cells.
T cells are most likely to play an important role in the pathogenesis of WG, and recently a predominant Th1 pattern of immune response has been demonstrated in granulomatous inflammation. Since the expression of costimulatory molecules has a significant impact on the cytokine profile and proliferation response of T cells, the goal of this study was to characterize the expression of costimulatory molecules (CD28, CTLA-4 (CD152), B7-1 (CD80), B7-2 (CD86)) on T cells, monocytes and B cells in WG, and to correlate the findings with clinical parameters such as disease activity, extent and therapy. WG patients (n = 24) and healthy controls (HC; n = 17) were examined for the expression of costimulatory molecules by fluorescence-activated cell sorter analysis, both in whole peripheral blood and after in vitro activation of T cells and antigen-presenting cells. Results were correlated with clinical data. The expression of CD28 on CD4+ and CD8+ cells was significantly lower in WG than in HC (CD28+ 81.4% in WG versus 97.9% of CD4+ cells (P < 0.0001); CD28+ 44.6% in WG versus 68.5% of CD8+ cells (P < 0.00001)), both in peripheral blood and after in vitro activation. A lower percentage of monocytes was B7-2+ in WG than in HC in peripheral blood, whereas no significant differences in the expression of B7-1 and B7-2 were observed after in vitro stimulation of monocytes and B cells. After in vitro activation a significantly higher percentage of B7-1+ and B7-2+ T cells was seen in WG. There was no significant difference in the CTLA-4 expression pattern between WG and HC. The percentage of CD28+ lymphocytes correlated negatively with the Disease Extent Index cumulated over the course of disease (r = -0.46, P = 0.03), indicating a more severe manifestation in patients with lower CD28 expression. Correlations with other clinical parameters such as activity or therapy were not seen. WG patients show a lack of CD28 expression on T cells and an unusual up-regulation of its ligands B7-1 and B7-2 on T cells after in vitro activation as well as a lower expression of B7-2 on freshly isolated monocytes compared with HC. These features might promote the Th1 cytokine pattern and thereby contribute to persistently high levels of immune activation in WG.
Department of Rheumatology, Medical University Lübeck, Germany.
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F
Moosig
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Csernok
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Wang
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WL
Gross
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000096:biosynthesis*; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002478:Cells, Cultured; D005260:Female; D014890:Granulomatosis with Polyangiitis / Q000276:immunology*; D006801:Humans; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; C497964:CD86 protein, human; D008024:Ligands; D008562:Membrane Glycoproteins