CD35, also known as complement receptor 1 (CR1), plays a crucial role in the complement system. The complement system is part of the immune system and, through a series of cascades, recognizes and eliminates pathogens, promotes inflammatory responses, and regulates immune function. CD35 is a type I membrane glycoprotein expressed on the surface of red blood cells and immune cells. It is a central regulator of the classical, lectin, and alternative pathways of the complement system. It is a receptor for the C3b/ C4b complement peptides, binding to both the C4b and C3b fragments of complement. It acts on phagocytes, promoting their uptake of complement-activated particles. As a cell membrane immune adhesion receptor, it plays a key role in the capture and clearance of complement-opsonized pathogens by red blood cells and monocytes/macrophages. It mediates the binding of these cells to complement-activated particles and immune complexes, thereby clearing complement from the circulation.

(Data source: Rachel L. Washburn, at al. Int. J. Mol. Sci. 2023)

CD35 composition distribution:

CD35 exists in two forms: a membrane-bound form that functions on the cell surface and participates in the regulation of the complement system, helping to clear immune complexes and C3b/C4b-coated particles in plasma, and modulating inflammatory responses. Another form is the non-membrane-bound soluble form of CR1 (sCR1), found in plasma. This form is produced by proteolytic cleavage of sCR1 released from leukocytes (particularly polymorphonuclear leukocytes) into the circulation. It has immune functions in body fluids, can bind to complement fragments, and may participate in the regulation of local immune responses and inflammatory processes. Soluble CD35 levels may vary in certain disease states, and therefore it can serve as a biomarker for certain pathological conditions.

Distribution of CD35:Mainly present in red blood cells, CD4+T cell subsets, mature B cells, follicular dendritic cells, monocytes, and eosinophils.

CD35 structure:

CD35 is a transmembrane protein. The extracellular region of CD35 is composed of 30 short complement regulatory (SCR) domains, also known as short consensus repeats, Sushi, or complement control protein domains. Each SCR domain contains 61 amino acid residues with two conserved disulfide bonds and a buried conserved tryptophan residue. Within the CR1 sequence, the first 28 SCRs are organized into four long homology repeats (LHRs), each with seven consecutive SCRs. The functional domains of the CR1 protein are also specifically distributed within the different LHRs. The LHR-A region of CD35 primarily binds to C4b, while the LHR-B and LHR-C regions bind to C3b/C4b and PfEMP1 and possess cofactor activity for cofactor I-mediated C3b and C4b cleavage. The LHR-D region contains binding sites for mannose-binding lectin (MBL) and C1q. SCR-25 has binding sites for both the Swain-Langley (Sl) and McCoy (McC) Knops blood group antigens in LHR-D. Soluble CD35 (sCR1) contains 30 short consensus repeat (SCR) domains that are identical to the extracellular region of CR1, but its structure differs from that of cell-surface CR1 because it lacks the transmembrane and cytoplasmic tails.

(Data source: Zhong-XiangNiu, atal. Immunopharmacology and Immunotoxicology. 2009)

CD35 signaling pathway and regulation:

Involved in regulatory T cell activation and proliferation: CD35 binding enhances IL-10 production and reduces IFNγ production, contributing to the transformation of CD4+ T cells into regulatory T cell (Treg) phenotypes. Furthermore, co-binding of CD35 and CD46 synergistically enhances CD4+ T cell proliferation. Furthermore, binding of CD35 and CD46 enhances granzyme B expression in activated CD4+ T cells. Overall, CD35 plays a crucial role in regulating CD4+ T cell function and phenotypic transformation.

Involved in regulating complement system activation: CD35, through its various domains (such as LHR-A, LHR-B, and LHR-C), regulates the degradation-accelerating activity (DAA) of the C3 and C5 convertases of the classical and alternative pathways. Studies have shown that different domains of CR1 contribute differently to the DAA of the classical pathway C3 and C5 convertases. For example, for the classical pathway C3 convertase, the LHR-A domain plays a major role in DAA, while the LHR-B and LHR-C domains contribute less. For the classical pathway C5 convertase, the LHR-A, LHR-B, and LHR-C domains are all required and work synergistically to provide full complement activity. Furthermore, CR1 exerts cofactor activity (CFA) by binding to C3b and C4b, promoting the cleavage of C3b and C4b by complement factor I. Studies have shown that CR1 has a stronger cleavage activity against C3b than against C4b, which correlates with its binding affinity for C3b and C4b. In summary, CR1 regulates the activities of C3 and C5 convertases of the classical and alternative pathways through the action of its different domains, thereby participating in the regulatory mechanism of the signaling pathway.

(Data source: Matthew P. Hardy, at al. Biomolecules. 2023)

Synergistic effect with other complement receptors: CD35 may synergize with other complement receptors (such as CR2, CR3, CR4, etc.) to jointly participate in immune regulation.

Clinical value of CD35:

Diagnosis: CD35 expression levels can be used as a diagnostic marker for certain hematologic diseases, particularly in differentiating chronic lymphocytic leukemia (CLL) from other B-chronic lymphoproliferative disorders (B-CLPDs). Studies have shown that low CD35 expression is significantly associated with the diagnosis of CLL, particularly in the differential diagnosis of other B-CLPDs such as MCL.

Disease Monitoring: Changes in CD35 expression may reflect disease progression or response to treatment. In some cases, changes in CD35 levels may be used to monitor a patient's response to treatment, particularly in immunotherapy or therapies involving the complement system.

Immunomodulation: CD35 plays a key role in regulating complement system activation and inhibiting inflammatory responses. By binding to complement fragments C3b/C4b, it participates in regulating complement system activation, particularly in clearing immune complexes and regulating inflammatory responses.

Therapeutic targets: Due to the role of CD35 in various diseases, it may become a potential target for treatment. For example, regulating the activity of the complement system by targeting CD35 may provide a new approach for the treatment of certain inflammatory diseases and autoimmune diseases.

In summary, CD35, as an important complement receptor, plays a key role in the occurrence and development of many diseases. In-depth research on it will help us understand the disease mechanism and provide new strategies for clinical treatment.