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.
Moosig
F
F
Department of Rheumatology, Medical University Lübeck, Germany.
Csernok
E
E
Wang
G
G
Gross
W L
WL
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