Fc receptor-like 5, or FcRL5, is a protein in the human body that plays a role in the immune system. It influences how immune cells respond, contributing to the body’s defense mechanisms. Understanding FcRL5’s functions provides insights into immune system regulation.
What FcRL5 Is and Where It’s Found
FcRL5, also known as FcRH5, IRTA2, or CD307, is a protein that belongs to the Fc receptor-like family. This family shares structural similarities with classical Fc receptors, known for binding antibodies. FcRL5 is a type I transmembrane protein, meaning it spans the cell membrane.
The extracellular portion of human FcRL5 typically consists of nine immunoglobulin-like domains, while its intracellular part contains sequences known as immunoreceptor tyrosine-based activation motifs (ITAMs) and immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These motifs are important for transmitting signals inside the cell. FcRL5 is primarily found on specific immune cells, particularly mature B lymphocytes (B cells) and plasma cells, specialized B cells that produce antibodies. It is expressed in lymphoid tissues and blood, with higher levels in bone marrow and secondary lymphoid organs.
FcRL5’s Role in Immune Balance
FcRL5 plays a dual role in regulating B cell activity, capable of both activating and inhibiting immune responses. Its cytoplasmic region contains both ITAM-like and ITIM sequences, which can be phosphorylated to recruit signaling molecules. When FcRL5 is co-ligated with the B cell antigen receptor (BCR), it can inhibit B cell signaling by recruiting SH2-containing protein tyrosine phosphatase 1 (SHP-1) to its ITIMs, leading to reduced calcium mobilization and tyrosine phosphorylation within the cell. This inhibitory action prevents overactive immune responses.
Conversely, FcRL5 can also promote B cell activation and differentiation. Co-stimulation of FcRL5 with the B cell antigen receptor can enhance proliferation and differentiation of naive B cells. This activating function is linked to the recruitment of the Lyn Src-family kinase to its ITAM-like sequence. The balance between these activating and inhibitory signals, mediated by molecules like SHP-1 and Lyn, determines the outcome of B cell activation and contributes to maintaining immune homeostasis. FcRL5’s ability to bind intact IgG antibodies further suggests a role in regulating B cells as a sensor for immunoglobulin status.
When FcRL5 Goes Wrong: Role in Disease
When FcRL5 function or expression becomes unregulated, it can contribute to B cell malignancies. FcRL5 is frequently overexpressed on malignant B cells in conditions such as Multiple Myeloma and Chronic Lymphocytic Leukemia (CLL). In Multiple Myeloma, FcRL5 is found at elevated levels on plasma cells in the bone marrow of patients, making it a distinguishing marker for these cancerous cells. This overexpression is noted in myeloma cells with a gain on chromosome 1q21, a common genetic abnormality.
FcRL5 also influences the survival and growth of myeloma cells through B-cell proliferation and isotype switching. The elevation of soluble FcRL5 in the serum of many B cell leukemia patients further indicates its involvement in disease pathology. While its role is most prominent in B cell cancers, FcRL5’s dysregulation has also been linked to autoimmune conditions. Upregulation of FcRL5 can disrupt B cell anergy, a state that normally prevents autoreactive B cells from attacking the body’s own tissues, contributing to systemic autoimmunity.
FcRL5 as a Therapeutic Target
Given its specific expression on malignant B cells and plasma cells, FcRL5 is investigated as a target for therapies, especially for diseases like Multiple Myeloma. One strategy involves using monoclonal antibodies that can either block FcRL5’s activity or deliver therapeutic agents directly to cells expressing it. Antibody-drug conjugates (ADCs) are a type of therapy where a cytotoxic drug is linked to an antibody that specifically binds to FcRL5.
Upon binding to FcRL5 on the cell surface, these ADCs are internalized, delivering the drug directly to the cancerous cells while minimizing harm to healthy tissues. Examples of ADCs include those combining an anti-FcRL5 antibody with drugs like monomethylauristatin E (MMAE) or maytansinoid DM4. These have shown effectiveness in preclinical models. Chimeric antigen receptor (CAR) T-cell therapies are also being developed to target FcRL5, showing anti-myeloma activity in preclinical studies and are now being explored in clinical settings. The restricted expression pattern of FcRL5 on normal cells makes it an attractive target for therapies that aim to precisely eliminate diseased cells.