Interleukin 6 Influences Germinal Center Development and Antibody Production via a Contribution of C3 Complement Component

Abstract

Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell–dependent antigens. Antigen-specific immunoglobulin (Ig)M levels were unaffected whereas all IgG isotypes showed varying degrees of alteration. Germinal center reactions occurred but remained physically smaller in comparison to those in the wild-type mice. This concurred with the observations that molecules involved in initial signaling events leading to germinal center formation were not altered (e.g., B7.2, CD40 and tumor necrosis factor R1). T cell priming was not impaired nor was a gross imbalance of T helper cell (Th) 1 versus Th2 cytokines observed. However, B7.1 molecules, absent from wild-type counterparts, were detected on germinal center B cells isolated from the deficient mice suggesting a modification of costimulatory signaling. A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6–deficient mice. Indeed, C3 provided an essential stimulatory signal for wild-type germinal center cells as both monoclonal antibodies that interrupted C3-CD21 interactions and sheep anti–mouse C3 antibodies caused a significant decrease in antigen-specific antibody production. In addition, germinal center cells isolated from C3–deficient mice produced a similar defect in isotype production. Low density cells with dendritic morphology were the local source of IL-6 and not the germinal center lymphocytes. Adding IL-6 in vitro to IL-6–deficient germinal center cells stimulated cell cycle progression and increased levels of antibody production. These findings reveal that the germinal center produces and uses molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses.

Restraint of B Cell Activation by Foxj1-Mediated Antagonism of NF-κB and IL-6

“…Therefore, Foxj1 deficiency might be found in only a subset of affected individuals or mice, and may only be relevant to specific disease subtypes. Nonetheless, the present findings correlate well with the previously demonstrated importance of the NF-B pathway in the pathogeneses of several autoimmune syndromes (26); the role of IL-6 in autoreactive germinal centers (7,8); the spontaneous germinal center formation that occurs in humoral autoimmune diseases, likely in response to endogenous autoantigens (22,27); as well as the proposed utility of IL-6 blockade in the treatment of humoral autoimmune diseases like lupus (28). As such, our present findings raise the intriguing possibility that functional Foxj1 deficiency, by whatever genetic mechanism, could perhaps underlie a large proportion of autoimmune syndromes.…”

“…We find that Foxj1 modulates germinal center B cell formation in vivo via its ability to inhibit the NF-B-regulated cytokine IL-6 (7,8). Foxj1 appears to prevent inappropriate B cell responses at least in part by antagonizing NF-B target genes like IL-6, which would otherwise propagate pathogenic autoimmune responses through dysregulated B cell hyperactivation.…”

“…Curiously, in addition to its demonstrated role in autoreactive germinal center formation (7,8), IL-6 has been heavily implicated in plasma cell survival (29). The ability of Foxj1-deficient B cells to generate significantly enhanced anti-hapten titers (Fig.…”

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

“…Such wide ranges of IL-6 activities are believed to constitute an important link between adaptive and innate immunity by mediating the T cell and B cell responses involved in autoimmunity (6). In vitro studies in IL-6-knockout mice have shown a marked reduction in B cell immune responses (7), particularly reductions in the levels of IgG1, IgG2a, and IgG3 upon immunization with a T cell-dependent antigen (8), suggesting that IL-6 is central for the induction and/or maintenance of plasma cells that produce these immunoglobulin subclasses. A recent study showed that antibody production is indirectly promoted by B cell helper capabilities of CD4ϩ T cells through increased IL-21 production upon IL-6 stimulation (9).…”

An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint

“…However, only the two-component system was strongly dependent on the endogenous IL-6 activity in vivo (Figure 8). This was expected as the complement C3 upregulation in response to an immunogen was completely absent in the IL-6 À/À mice 41,42 and was probably regulated at the level of complement C3 promoter activation. 43,44 It is known that the TAT protein can transactivate inflammatory host genes, 45 including the IL-6 gene.…”