Fc-gamma Receptor 1 (FcγRI)
CD64 (Cluster of Differentiation 64) is a type of integral membrane glycoprotein known as an Fc receptor that binds monomeric IgG-type antibodies with high affinity. It is more commonly known as Fc-gamma receptor 1 (FcγRI). In this article, we will review the role of CD64 in the immune system, its association with disease, and potential therapeutic targets.
The Functions of CD64
FcγRI is expressed on the surface of myeloid cells, including macrophages, dendritic cells, neutrophils, and eosinophils. It is also present on platelets and Kupffer cells in the liver. The protein consists of three extracellular immunoglobulin domains, a transmembrane region, and a short cytoplasmic tail. Soluble forms of the receptor are also found in circulation. This protein is also found on the surface of phagocytes. The binding of antibody-coated pathogens by CD64 triggers the phagocyte’s respiratory burst, a rapid consumption of oxygen and release of reactive oxygen species which leads to pathogen kill. [1]
FcγRI plays an important role in innate immunity by mediating phagocytosis and the production of inflammatory cytokines upon antibody-coated pathogen recognition. Antigen binding to the receptor results in signaling cascade activation and recruitment of other proteins that lead to cell activation. In addition to its role in immunity, FcγRI has also been shown to be involved in immunologic tolerance and cancer progression.
Disease Relevance of CD64
High levels of sCD64 have been observed in patients with autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn’s disease, celiac disease, type I diabetes mellitus, multiple sclerosis (MS), and primary biliary cirrhosis. Low levels of sCD64 have been associated with infections such as HIV/AIDS, hepatitis C virus (HCV), Mycobacterium tuberculosis, and Plasmodium falciparum malaria.
Recent studies have demonstrated that the downregulation of FccRIIb on monocytes/macrophages leads to increased levels of circulating sCD64. This suggests that FccRIIb may play a role in the regulation of sCD64 levels. However, the precise mechanisms underlying the relationship between these two receptors remain to be elucidated.
Targeting CD64 for Therapy
Due to its central role in immunity, CD64 has emerged as a potential target for therapy. Inhibitors of FcγRI have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model for MS. These agents include humanized monoclonal antibodies (mAbs) targeting the extracellular domain or the cytoplasmic tail of FcγRI – notably hL20 and hL27 respectively – as well as non-humanized mAbs such as mAb 8060179C03 that bind sites overlapping with those bound by hL20 and hL27. Antibodies targeting soluble forms of CD64 are being developed as well. Additionally, small molecule agonists/antagonists have been designed that bind to specific sites on FcγRI; one example is emapalumab (LY3074828), which is currently being evaluated in clinical trials for treatment-resistant atopic dermatitis.
Conclusion:
CD64 plays a crucial role in innate immunity by mediating phagocytosis and production of inflammatory cytokines upon antibody-coated pathogen recognition. It is also involved in immunologic tolerance and cancer progression. Given its central role in immunity, CD64 represents a promising target for therapy for autoimmune diseases and infections. More research is needed to elucidate the precise mechanisms underlying disease pathology associated with this receptor so that more targeted therapeutic interventions can be developed.