Increased expression of CTLA-4 (CD152) by T and B lymphocytes in Wegener'sgranulomatosis

CTLA-4 (CD152) is a surface molecule of activated T cells with sequence hom ology to CD28. Both molecules bind to the same ligands, B7.1 (CD80) and B7. 2 (CD86) but have antagonistic functions. While CD28 is an important costim ulator, CTLA-4 has an essential inhibitory function in maintaining the home ostasis of the immune system. Furthermore, CTLA-4 has a role in inducing a Th1 response and suppressing Th2 cytokines, an effect which is antagonized by CD28. Many autoimmune diseases are characterized by an overwhelming prod uction of Th1 cytokines. Recently, the predominance of the Th1 cytokine pat tern has been directly observed in the granulomatous inflammation of patien ts with Wegener's granulomatosis. The balance between CD28 and CTLA-4 expre ssion by T lymphocytes could be a factor in the pathogenesis of autoimmune diseases. Down regulation of CD28 predominantly on CD8(+) T cells has been described in Wegner's granulomatosis; however, analysis of CTLA-4 is compli cated by its low expression levels. Here we have used potent signal enhance ment to study CTLA-4 on PBMC in patients with Wegener's granulomatosis (n = 25) in comparison with healthy controls (n = 19). Expression levels of CTL A-4 were significantly increased selectively on CD4(+) and possibly also on CD4(-)/CD8(-) T cells in Wegener's granulomatosis. High CTLA-4 expression by T lymphocytes was associated with more severe disease. In contrast, afte r stimulation with the mitogen PHA, CTLA-4 levels were strongly increased o n T cells from controls but in T cells from Wegener's granulomatosis patien ts this response was severely impaired. Interestingly, while CTLA-4 was see n exclusively on T cells in control individuals, about half of the Wegener' s patients showed CTLA-4 expression by a fraction of peripheral B lymphocyt es. CTLA-4 positive B cells in the periphery were associated with less acut e disease.