Complement receptor immunoglobulin: a control point in infection and immunity, inflammation and cancer

Abstract

The B7 family-related protein, V-set and Ig domain (VSIG4) / Z39Ig / complement receptor immunoglobulin (CRIg), is a new player in the regulation of immunity to infection and inflammation. The unique features of this receptor as compared with classical complement receptors, CR3 and CR4, have heralded the emergence of new concepts in the regulation of innate and adaptive immunity. Its selective expression in tissue macrophages and dendritic cells has been considered of importance in host defence and in maintaining tolerance against self-antigens. Although a major receptor for phagocytosis of complement opsonised bacteria, its array of emerging functions which incorporates the immune suppressive and anti-inflammatory action of the receptor have now been realised. Accumulating evidence from mouse experimental models indicates a potential role for CRIg in protection against bacterial infection and inflammatory diseases, such as rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus, and also in promotion of tumour growth. CRIg expression can be considered as a control point in these diseases, through which inflammatory mediators, including cytokines, act. The ability of CRIg to suppress cytotoxic T cell proliferation and function may underlie its promotion of cancer growth. Thus, the unique properties of this receptor open up new avenues for understanding of the pathways that regulate inflammation during infection, autoimmunity and cancer with the potential for new drug targets to be identified. While some complement receptors may be differently expressed in mice and humans, as well as displaying different properties, mouse CRIg has a structure and function similar to the human receptor, suggesting that extrapolation to human diseases is appropriate. Furthermore, there is emerging evidence in human conditions that CRIg may be a valuable biomarker in infection and immunity, inflammatory conditions and cancer prognosis.

Cytokines regulate complement receptor immunoglobulin expression and phagocytosis of Candida albicans in human macrophages: A control point in anti-microbial immunity

“…CR1 on erythrocytes plays a major role in the clearance of soluble immune complexes, by transporting them to the liver and spleen, where they are cleared by macrophages. The binding of C3b-coated targets to phagocyte CR1 is not sufficient to trigger phagocytosis, but C3b–CR1 interaction enhances the FcγR-mediated phagocytosis of targets bearing both IgG and C3b 25–27 . When we examined the expression of CR1, it was evident that the cytokines did not alter the expression of this receptor (Fig.…”

“…The importance of CRIg in Kupffer cell-mediated phagocytosis of bacteria has been demonstrated 4, 6, 7 and it is likely that CRIg expression in these cells is also regulated by cytokines during infection and inflammation 56 . While the complexity of the CRIg system and its varied roles in infection and immunity is becoming appreciated 25 , we have now provided further evidence of its importance in host defence and understanding the mechanisms regulating macrophages in immunity to infection.…”

The complex functioning of the complement system in xenotransplantation

“…However, complement may also inhibit the adaptive immune response. CRIg is a strong regulator of T‐cell proliferation and Th1 cytokines . CRIg + DCs (ie, DCs with CRIg binding) may facilitate immunosuppression and promote tolerance .…”

“…CRIg is a strong regulator of T‐cell proliferation and Th1 cytokines . CRIg + DCs (ie, DCs with CRIg binding) may facilitate immunosuppression and promote tolerance . TLR2/4‐CR3 has been shown to suppress IL‐12 expression and inhibit the Th1 response .…”

“…73 CRIg + DCs (ie, DCs with CRIg binding) may facilitate immunosuppression and promote tolerance. 73 TLR2/4-CR3 has been shown to suppress IL-12 expression and inhibit the Th1 response. 28 CD46 acts as a stimulatory factor to generate IL-10-producing T regulatory cells and other immune cells.…”