Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus.

Abstract

SummaryInterleukin-10 (IL-10) is produced at a high level by B lymphocytes and monocytes of patients with systemic lupus erythematosus (SLE). In the present work, we analyzed whether this increased production of IL-10 contributed to the abnormal production of immunoglobulins (Ig) and of autoantibodies in SLE. The role of IL-10 was compared with that of IL-6, another cytokine suspected to play a role in these abnormalities. The spontaneous in vitro production of IgM, IgG, and IgA by peripheral blood mononuclear cells from SLE patients was weakly increased by recombinant IL (rlL)-6, but strongly by rlL-10. This production was not significantly affected by an anti-IL-6 mAb but was decreased by an anti-IL-10 mAb. We then tested the in vivo effect of these antibodies in severe combined immunodeficiency mice injected with PBMC from SLE patients. The anti-IL-6 mAb did not significantly affect the serum concentration of total human IgG and of anti-double-stranded DNA IgG in the mice. In contrast, the anti-IL-10 mAb strongly inhibited the production of autoantibodies, and, to a lesser extent, that of total human IgG. These results indicate that the Ig production by SLE B lymphocytes is largely IL-10 dependent, and that the increased production of IL-10 by SLE B lymphocytes and monocytes may represent a critical mechanism in the emergence of the autoimmune manifestations of the disease.

IL-12 inhibits in vitro immunoglobulin production by human lupus peripheral blood mononuclear cells (PBMC)

“…On the other hand, our data indicate that IFN-g, the cytokine whereby T cells usually mediate the effects of IL-12 in vivo [7,9,17,18], is not implicated in the inhibition exerted by IL-12 on lupus B lymphocytes. Finally, the critical role played by IL-10 in SLE B cell activation [1,3] prompted us to test the possibility that the negative effects of IL-12 on immunoglobulin production were due to down-regulation of endogenous IL-10 production, the more so as IL-10 production by CD4 þ allergen-specific human T cells was shown to be inhibited by IL-12 [22]. Interestingly, IL-10 production was significantly down-regulated in lupus PBMC cultures stimulated with IL-12, an effect that was attributed to IFN-g up-regulation by IL-12.…”

“…Recent advances in our understanding of the biology of cytokines have shed new light on the mechanisms underlying this inappropriate antibody production. Thus, it was demonstrated that IL-10 is overexpressed in lupus patients [1,2] and mediates, at least in part, the excessive immunoglobulin production and the autoantibody response associated with human and murine SLE [3,4]. Such results demonstrate that cytokines are closely involved in the pathogenesis of lupus and suggest that cytokine manipulation might be useful for the control of the disorder.…”

Differential regulation of interleukin-10 production by genetic and environmental factors – a twin study

“…3 Contrary to its inhibitory function in T cells and macrophages, in B cells IL-10 stimulates the production of immunoglobulins and the expression of MHC class II antigens. 4 IL-10 has a central role in the pathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE) 5 and influences susceptibility and the course of various infectious diseases. [6][7][8] The constitutive expression of IL-10 in monocytes and lymphocytes is low.…”

Association tests with systemic lupus erythematosus (SLE) of IL10 markers indicate a direct involvement of a CA repeat in the 5′ regulatory region

“…6,7 Therefore, IL10 production may contribute to the disease by direct effect on B cell survival and on autoantibody production. 8 Moreover, B cells and monocytes of SLE patients produce an increased amount of IL10 compared to non-affected individuals. 9,10 Besides its functional relevance, IL10 is an attractive positional candidate gene since it maps in 1q32, in a region homologous to a murine SLE susceptibility region (reviewed in Ref.…”