Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2.

Abstract

Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1-and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B-and T-cell (14)(15)(16)(17)(18). Experiments using the T-cell-dependent antigens from sheep red blood cells (SRBC) and keyhole limpet hemocyanin have suggested that the primary immune response deficit in mice treated with anti-mouse CR1 and CR2 mAb can be overcome by using high doses of the immunogen (14).Here we have further explored the role of these receptors in the development of humoral immunity by generating CR1-and CR2-deficient mice using gene targeting. Our data show that CR1 and CR2 play important roles in the B-cell response and are necessary for appropriate B-cell activation and Ab production at both low and high doses of antigen. In addition, we demonstrate that germinal center formation is retained in the absence of these proteins. These mice should provide an excellent model to study in detail the specific roles of CR1 and CR2 in the immune response.

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

“…(Gustavsson et al, 1995;Hebell et al, 1991;Heyman et al, 1990;Thyphronitis et al, 1991). The independent generation by gene targeting of 3 lines of CR1/2 deficient mice confirmed these earlier findings as well as illustrating the necessity for CR2 expression on both B cells and the highly specialized follicular dendritic cell (FDC) population Croix et al, 1996;Del Nagro et al, 2005;Fang et al, 1998;Haas et al, 2002;Molina et al, 1996). CR2 has been shown to facilitate the activation of B cells to TD antigens through a variety of mechanisms.…”

Reconstructing immune phylogeny: new perspectives

“…To understand the relationships between innate and adaptive immunity, which are intertwined functionally in modern vertebrates [11][12][13][14][15][16] , it is first instructive to consider some key events in the evolution of adaptive (RAG-mediated) immunity. Two central observations that were made two decades ago showed that markedly disparate mechanisms -differing from each other and from the human and mouse pattern of a single rearranging receptor-gene locus that undergoes marked somatic diversification -give rise to B-cell receptor (BCR) diversity in jawed vertebrates.…”

“…The dependence of mammalian immunity on T-and B-cell function and, in turn, the dependence of these cell types on RAG-mediated somatic recombination and subsequent diversification of antigen-receptor genes has understandably resulted in a focus on lymphocytes as the central components of mammalian immunity. However, increasing attention has recently been paid to the interactions of T and B cells with innate immune effectors, and this has produced important insights regarding functional bridges between innate and adaptive immune cells during infection [11][12][13][14][15][16]139,140 . An increasingly rich picture of the diversity of innate immune surveillance and recognition in vertebrates is developing.…”

Complement, natural antibodies, autoantibodies and tissue injury

“…In mice, CR2 is encoded along with the larger complement receptor type 1 (CR1) by the Cr2 gene, which produces both proteins through alternative splicing of a common mRNA (10,11). 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).…”