A Critical Role for Complement in Maintenance of Self-Tolerance

Abstract

The role of complement in the maintenance of self-tolerance has been examined in two models: an immunoglobulin transgenic model of peripheral tolerance and a lupus-like murine model of CD95 (Fas) deficiency. We find that self-reactive B lymphocytes deficient in complement receptors CD21/CD35 or transferred into mice deficient in the complement protein C4 are not anergized by soluble self-antigen. In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease. These findings suggest a novel role for the complement system in B cell tolerance and provide insight into the genetic association of complement deficiency with susceptibility to systemic lupus erythematosus.

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

“…It is well documented that C4 deficiency confers susceptibility to SLE [2,3,10]. Here, we demonstrate that total splenic IFN-a mRNA levels are elevated in untreated young C4-deficient mice compared to WT.…”

“…Susceptibility genes for SLE include those involved in the deficiency of early complement factors of the classical pathway (C1, C4, C2) [2], which has been confirmed in animal models for complement deficiency [3,4]. Current explanations for the loss of tolerance in states of complement deficiency include impaired elimination of apoptotic bodies [4,5] or dying cells [6] as a source of autoantigens [7,8], and inadequate regulation of follicular B cells via the complement receptor CD21/35 [3], although the absence of CD21, or its most important ligand (C3d), does not seem to be associated with SLE [9,10]. As such, neither model alone can adequately account for the association of complement deficiency and SLE [11].…”

Restoration of C1q levels by bone marrow transplantation attenuates autoimmune disease associated with C1q deficiency in mice

“…One hypothesis invokes a role for complement in the development of self tolerance to the autoantigens of SLE and proposes that B cells with specificity for lupus autoantigens are not effectively silenced or eliminated in the absence of complement [28,29]. The other hypothesis, known as "waste disposal hypothesis", supports the role of complement in the processing and clearance from the body of dying cells and/or immune complexes [30].…”

Defective B cell ontogeny and immune response in human complement receptor 2 (CR2, CD21) transgenic mice is partially recovered in the absence of C3

“…Thus, the ability of fB/C2 deficient sera to cause down regulation of hCR2 expression (Figure 6) demonstrates that the natural generation of inactive C3 could provide ligand to interact with CR2 as well as suggesting that the generation of C3d is not necessarily required for this outcome. Therefore, it is possible that continual activation or natural turn over and the subsequent interaction of C3 breakdown fragments with CR2 could exist as a mechanism to provide the required low level survival signals (Kraus et al, 2004) and/or tolerising signals essential to normal mature B cell function (Carroll, 2000;Prodeus et al, 1998). An extension of this hypothesis to the hCR2 tg mice would suggest that C3, activated in the presence of the pre-BCR, could be interacting with hCR2 in the BM and presumably results in signaling into the B cell.…”

“…Interestingly, the absence of CR1/2 or C4 has been shown to result in increased autoantibody production in lupus prone mice . This led to the conclusion that a central role for complement and CR1/2 was to signal the elimination of self-reactive B cells and thereby maintain B cell tolerance in the periphery (Carroll, 2000;Prodeus et al, 1998). Our data are consistent with this suggestion, in that many of the defects noted in the hCR2 tg mice could be the result of increased selective pressure or more stringent tolerance induction as a result of increased signaling through CD19/CR2 in conjunction with C3d binding in the bone marrow environment and/ or the periphery.…”