Complement receptor 1 (CR1, CD35) serves as a pivotal mediator of erythrocyte immune function, orchestrating processes that range from immune complex clearance to modulation of host-pathogen interactions. CR1's structural heterogeneity, including the F and S allelic forms, contributes to variable receptor expression and clustering, thereby influencing erythrocyte deformability, immune adherence, and susceptibility to pathogen-mediated rosetting (Vik & Wong, 1993; Rowe et al., 1997). The molecular mechanisms underlying CR1 clustering involve complex interactions with cytoskeletal scaffolding proteins such as FAP-1 and ATP-mediated signaling pathways, which enhance receptor aggregation and facilitate efficient immune complex transport (Ghiran et al., 2008; Melhorn et al., 2013). CR1's role extends beyond erythrocyte-mediated clearance, influencing complement-mediated tissue injury in ischemia-reperfusion scenarios, where soluble CR1 demonstrates protective effects against microvascular and myocardial damage (Lindsay et al., 1992; Shandelya et al., 1993).

This review integrates molecular, cellular, and translational perspectives on CR1 function, emphasizing receptor clustering dynamics, immune adherence, and erythrocyte deformability. Theoretical frameworks and historical studies contextualize CR1’s evolution as a critical immune modulator, while contemporary research elucidates the interplay between receptor polymorphisms, ligand binding, and immune signaling pathways. Mechanistic insights from human and animal models reveal the receptor’s dual role in pathogen defense and modulation of complement-mediated injury (Pringle et al., 2012; Sun et al., 2012). Additionally, CR1-targeted interventions, including soluble recombinant constructs, offer therapeutic potential in ischemia-reperfusion injury and infectious disease contexts, underscoring the clinical relevance of receptor modulation (Smith et al., 1993; Chavez-Cartaya et al., 1995).

This article provides a comprehensive synthesis of the CR1 literature, critically evaluating empirical findings, methodological approaches, and theoretical constructs. Emphasis is placed on the implications of receptor clustering for immunological homeostasis, the influence of genetic polymorphisms on receptor functionality, and the translational significance of manipulating CR1 in disease contexts. By integrating cellular, molecular, and clinical perspectives, this review delineates current knowledge gaps and proposes directions for future research, including high-resolution mapping of receptor-ligand interactions, longitudinal assessment of erythrocyte-mediated immune clearance, and therapeutic modulation of complement activity.

Complement receptor 1, erythrocyte immune adherence, receptor clustering, ischemia-reperfusion injury, polymorphism, immune complex clearance, cytoskeletal interactions

Chevalier, J. and M.D. Kazatchkine (1989). Distribution in clusters of complement receptor type one (CR1) on human erythrocytes. J. Immunology (Baltimore, Md.: 1950), 142(6), 2031–2036. DOI: 10.4049/jimmunol.142.6.2031

Deng, H., Q. Pang, B. Zhao, and M. Vayssier-Taussat (2018). Molecular mechanisms of bartonella and mammalian erythrocyte interactions: a review. Frontiers in Cellular and Infection Microbiology, 8, 431. DOI: 10.3389/fcimb.2018.00431

Ghiran, I., A.M. Glodek, G. Weaver, L.B. Klickstein, and Nicholson-A. Weller (2008). Ligation of erythrocyte CR1 induces its clustering in complex with scaffolding protein FAP-1. Blood, 112(8), 3465–3473. DOI: 10.1182/blood-2008-04-151845

Glodek, A.M., R. Mirchev, D.E. Golan, J.A. Khoory, J.M. Burns, S.S. Shevkoplyas, A. Nicholson-Weller, and I.C. Ghiran (2010). Ligation of complement receptor 1 increases erythrocyte membrane deformability. Blood, 116(26), 6063–6071. DOI: 10.1182/blood-2010-04-273904

Hornbeck, P.V., B. Zhang, B. Murray, J.M. Kornhauser, V. Latham, and E. Skrzypek (2015). PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Research, 43(Database issue), D512–D520. DOI: 10.1093/nar/gku1267

Lindsay, T.F., J. Hill, F. Ortiz, et al. (1992). Blockade of complement activation prevents local and pulmonary albumin leak after lower torso ischemia-reperfusion. Ann Surg, 216(6), 677–683.

Pemberton, M., G. Anderson, V. Vetvicka, et al. (1993). Microvascular effects of complement blockade with soluble recombinant CR1 on ischemia/reperfusion injury of skeletal muscle. J Immunol, 150(11), 5104–5113.

Shandelya, S.M., P. Kuppusamy, A. Herskowitz, et al. (1993). Soluble complement receptor type 1 inhibits the complement pathway and prevents contractile failure in the postischemic heart. Circulation, 88(6), 2812–2826.

Smith, E.F., 3rd, D.E. Griswold, J.W. Egan, et al. (1993). Reduction of myocardial reperfusion injury with human soluble complement receptor type 1 (BRL 55730). Eur J Pharmacol, 236(3), 477–481.

Chavez-Cartaya, R.E., G.P. DeSola, L. Wright, et al. (1995). Regulation of the complement cascade by soluble complement receptor type 1. Protective effect in experimental liver ischemia and reperfusion. Transplant