Mice Deficient in Complement Receptors 1 and 2 Lack a Tissue Injury-Inducing Subset of the Natural Antibody Repertoire

Abstract

Intestinal ischemia-reperfusion (IR) injury is initiated when natural Abs recognize neoantigens that are revealed on ischemic cells. Cr2−/− mice, deficient in complement receptors (CR)1 and CR2, demonstrate defects in T-dependent B-2 B cell responses to foreign Ags and have also been suggested to manifest abnormalities of the B-1 subset of B lymphocytes. To determine whether these CRs might play a role in the generation of the natural Abs that initiate intestinal IR injury, we performed experiments in Cr2−/− and control Cr2+/+ mice. We found that Cr2−/− mice did not demonstrate severe intestinal injury that was readily observed in control Cr2+/+ mice following IR, despite having identical serum levels of IgM and IgG. Pretreatment of Cr2−/− mice before the ischemic phase with IgM and IgG purified from the serum of wild-type C57BL/6 mice reconstituted all key features of IR injury, demonstrating that the defect involves the failure to develop this subset of natural Abs. Pretreatment with IgM and IgG individually demonstrates that each contributes to unique features of IR injury. In sum, CR2/CR1 play an unanticipated but critical role in the development of a subset of the natural Ab repertoire that has particular importance in the pathogenesis of IR injury.

Complement, natural antibodies, autoantibodies and tissue injury

“…Of interest, transferred IgM and IgG each contributed to different aspects of tissue injury but together allowed the development of a complete injury phenotype (6). These findings demonstrated a previously unrecognized role for complement receptors in the development within the natural antibody repertoire of a tissue injury-inducing subset of antibodies.…”

“…The exact mechanism of complement activation during intestinal IR remains unclear as there is evidence that more than one complement pathway (classical, alternative or lectin) may become activated and enhance tissue injury (1,5,6). However, two observations have strongly implicated the classical pathway in this process.…”

“…CR2-/-mice demonstrate a substantial defect in the generation of IgG switched isotype responses (12, 13) as well as impaired B cell memory following immunization with T-dependent antigens (13,14). To determine if CR2 plays a role in mesenteric IR, Cr2-/-mice were subjected to intestinal IR injury and were shown to be protected from the induction of tissue injury (6). Because the levels of complement molecules and complement activation are normal in Cr2-/-mice, other factors were considered to be responsible for this protection.…”

The Central Role of the Alternative Complement Pathway in Human Disease

“…The major function of complement traditionally has been thought to be recognition and elimination of pathogens through direct killing (3) and/or stimulation of phagocytosis (4,5). However, over the last decade the complement system has also been shown to play central immunoregulatory roles such as enhancing humoral immunity (6), modifying T cell immunity (7), shaping the development of the natural Ab repertoire (8), and regulating tolerance to nuclear self Ags such as DNA and chromatin (9,10). In addition to its immunoregulatory functions, many studies have also elaborated on the pathogenic role of complement during ischemic, inflammatory, and autoimmune diseases (reviewed in Ref.…”

Evidence That Complement Protein C1q Interacts with C-Reactive Protein through Its Globular Head Region

“…The mechanism of activation in the latter condition involves natural Abs (3,4) as well as the acute phase protein C-reactive protein (CRP) 4 (5-7). These molecules bind to newly exposed epitopes or ligands present on ischemic and/or apoptotic cells (8 -10).…”