Complement Receptor Type 1 (CD35) Mediates Inhibitory Signals in Human B Lymphocytes

Abstract

The complement system—particularly component C3—has been demonstrated to be a key link between innate and adaptive immunity. The trimolecular complex of complement receptor type 2 (CR2), CD19, and CD81 is known to promote B cell activation when coligated with the B cell Ag receptor. In the present study, we aimed to elucidate the role of human complement receptor type 1 (CR1), the other C3-receptor on B cells. As ligand, aggregated C3 and aggregated C3(H2O), i.e., multimeric “C3b-like C3”, are used, which bind to CR1, but not to CR2. In experiments studying the functional consequences of CR1-clustering, the multimeric ligand is shown to inhibit the proliferation of tonsil B cells activated with a suboptimal dose of anti-IgM F(ab′)2. Importantly, this inhibitory activity also occurs in the presence of the costimulatory cytokines IL-2 and IL-15. The anti-IgM-induced transient increase in the concentration of intracellular free Ca2+ and phosphorylation of several cytoplasmic proteins are strongly reduced in the presence of the CR1 ligand. Data presented indicate that CR1 has a negative regulatory role in the B cell Ag receptor mediated activation of human B lymphocytes.

Elimination of autoreactive B cells in humanized SCID mouse model of SLE

“…The human CR1 (CD35) negatively regulates the proliferation and differentiation of activated B cells after binding to its natural ligand: the complement activation fragment C3b [6,7,25]. King-Konert et al reported a fast reduction of the titer of anti-dsDNA autoantibodies in SLE patients treated with the chimeric molecule ETI-104, a construct of dsDNA, coupled covalently to a murine human CR1-specific mAb [26].…”

“…We constructed several chimeric antibodies by coupling the dsDNA-mimicking peptides or peptides, parts of histone 1 molecule to a rat anti-mouse FcgRIIb-binding mAb. When administrated in lupus-prone MRL/lpr mice they reduced the levels of anti-histone1 and anti-dsDNA IgG antibodies and proteinuria, and prolonged the overall survival [23,24].The human CR1 (CD35) negatively regulates the proliferation and differentiation of activated B cells after binding to its natural ligand: the complement activation fragment C3b [6,7,25]. King-Konert et al reported a fast reduction of the titer of anti-dsDNA autoantibodies in SLE patients treated with the chimeric molecule ETI-104, a construct of dsDNA, coupled covalently to a murine human CR1-specific mAb [26].…”

“…BCR-mediated activation may be counteracted by a number of inhibitory receptors: CD32 (FcgRIIb), CD22, CD5, CD72, CD66a, ILT2, PIR-B, CD279 (PD-1), LAIR-1, as well as the complement receptor type 1 (CR1, CD35). While a reduced expression of these receptors can result in uncontrolled B-cell activation [4,5] and autoimmunity, their cross-linking inhibits B-cell activation and proliferation and may serve for targeted suppressive signal delivery [6,7].Non-specific immunosuppressive drugs are by now the most frequent therapy for autoimmune diseases, including SLE. Their effects are purely symptomatic while most of them are associated with severe side effects [8][9][10][11].…”

“…BCR-mediated activation may be counteracted by a number of inhibitory receptors: CD32 (FcgRIIb), CD22, CD5, CD72, CD66a, ILT2, PIR-B, CD279 (PD-1), LAIR-1, as well as the complement receptor type 1 (CR1, CD35). While a reduced expression of these receptors can result in uncontrolled B-cell activation [4,5] and autoimmunity, their cross-linking inhibits B-cell activation and proliferation and may serve for targeted suppressive signal delivery [6,7].…”

Expression of complement receptors 1 (CR1/CD35) and 2 (CR2/CD21), and co-signaling molecule CD19 in cattle

“…iC3b can be cleaved again by Factor I to yield C3dg. Human CR1 has also been identiBied as a receptor for MBL, leading to phagocytosis, (Ghiran et al, 2000) and plays an inhibitory role in human adaptive immunity by reducing B lymphocyte proliferation following cross--linking of surface IgM by anti--IgM antibodies (Józsi et al, 2002). In humans, CR1 expressed on erythrocytes has an important function in clearance of immune complexes from blood.…”