CD93 belongs to the Group XIV C-Type lectin family, a group containing two other members, endosialin (CD248) and thrombomodulin, a well characterized anticoagulant. All of them contain a C-type lectin domain, a series of epidermal growth factor like domains, a highly glycosylated mucin-like domain, a unique transmembrane domain and a short cytoplasmic tail. Due to their strong homology and their close proximity on chromosome 20, CD93 has been suggested to have arisen from the thrombomodulin gene through a duplication event.
CD93 was originally identified in mice as an early B cell marker through the use of AA4.1 monoclonal antibody. Then this molecule was shown to be expressed on an early population of hematopoietic stem cells, which give rise to the entire spectrum of mature cells in the blood. Now CD93 is known to be expressed by a wide variety of cells such as platelets, monocytes, microglia and endothelial cells. In the immune system CD93 is also expressed on neutrophils, activated macrophages, B cell precursors until the T2 stage in the spleen, a subset of dendritic cells and of natural killer cells. Molecular characterization of CD93 revealed that this protein is identical with C1qRp, a human protein identified as a putative C1q receptor. C1q belongs to the complement activation proteins and plays a major role in the activation of the classical pathway of the complement, which leads to the formation of the membrane attack complex. C1q is also involved in other immunological processes such as enhancement of bacterial phagocytosis, clearance of apoptotic cells or neutralisation of virus. Strikingly, it has been shown that anti-C1qRp significantly reduced C1q enhanced phagocytosis. A more recent study confirmed that C1qRp is identical to CD93 protein, but failed to demonstrate a direct interaction between CD93 and C1q under physiological conditions. Recently it has been shown that CD93 is re-expressed during the late B cell differentiation and CD93 can be used in this context as a plasma cell maturation marker.
CD93 was initially thought to be a receptor for C1q, but now is thought to instead be involved in intercellular adhesion and in the clearance of apoptotic cells. The intracellular cytoplasmic tail of this protein contains two highly conserved domains which may be involved in CD93 function. Indeed, the highly charged juxtamembrane domain has been found to interact with moesin, a protein known to play a role in linking transmembrane proteins to the cytoskeleton and in the remodelling of the cytoskeleton. This process appears crucial for both adhesion, migration and phagocytosis, three functions in which CD93 may be involved.
In the context of late B cell differentiation, CD93 has been shown to be important for the maintenance of high antibody titres after immunization and in the survival of long-lived plasma cells in the bone marrow. Indeed, CD93 deficient mice failed to maintain high antibody level upon immunization and present a lower amount of antigen specific plasma cells in the bone marrow.
^Nepomuceno RR, Henschen-Edman AH, Burgess WH, Tenner AJ (February 1997). "cDNA cloning and primary structure analysis of C1qR(P), the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro". Immunity. 6 (2): 119–29. doi:10.1016/S1074-7613(00)80419-7. PMID9047234.
^Webster SD, Park M, Fonseca MI, Tenner AJ (January 2000). "Structural and functional evidence for microglial expression of C1qR(P), the C1q receptor that enhances phagocytosis". J. Leukoc. Biol. 67 (1): 109–16. PMID10648005.
^McGreal EP, Ikewaki N, Akatsu H, Morgan BP, Gasque P (May 2002). "Human C1qRp is identical with CD93 and the mNI-11 antigen but does not bind C1q". J. Immunol. 168 (10): 5222–32. doi:10.4049/jimmunol.168.10.5222. PMID11994479.
Ghebrehiwet B, Peerschke EI, Hong Y, et al. (1992). "Short amino acid sequences derived from C1q receptor (C1q-R) show homology with the alpha chains of fibronectin and vitronectin receptors and collagen type IV". J. Leukoc. Biol. 51 (6): 546–56. PMID1377218.
Peerschke EI, Ghebrehiwet B (1990). "Platelet C1q receptor interactions with collagen- and C1q-coated surfaces". J. Immunol. 145 (9): 2984–8. PMID2212670.
Eggleton P, Lieu TS, Zappi EG, et al. (1994). "Calreticulin is released from activated neutrophils and binds to C1q and mannan-binding protein". Clin. Immunol. Immunopathol. 72 (3): 405–9. doi:10.1006/clin.1994.1160. PMID8062452.
Nepomuceno RR, Tenner AJ (1998). "C1qRP, the C1q receptor that enhances phagocytosis, is detected specifically in human cells of myeloid lineage, endothelial cells, and platelets". J. Immunol. 160 (4): 1929–35. PMID9469455.
Nepomuceno RR, Ruiz S, Park M, Tenner AJ (1999). "C1qRP is a heavily O-glycosylated cell surface protein involved in the regulation of phagocytic activity". J. Immunol. 162 (6): 3583–9. PMID10092817.
Norsworthy PJ, Taylor PR, Walport MJ, Botto M (1999). "Cloning of the mouse homolog of the 126-kDa human C1q/MBL/SP-A receptor, C1qR(p)". Mamm. Genome. 10 (8): 789–93. doi:10.1007/s003359901093. PMID10430665.
Joseph K, Shibayama Y, Ghebrehiwet B, Kaplan AP (2001). "Factor XII-dependent contact activation on endothelial cells and binding proteins gC1qR and cytokeratin 1". Thromb. Haemost. 85 (1): 119–24. PMID11204562.