CD200 - CD200 molecule |Elisa - Clia - Antibody - Protein

Background

CD200, also known as OX-2, is a membrane glycoprotein primarily involved in immune modulation. It is a member of the immunoglobulin superfamily and is widely expressed on various cell types, including neurons, epithelial cells, endothelial cells, thymocytes, and certain immune cells like B cells, T cells, and dendritic cells. CD200 plays a critical role in maintaining immune homeostasis by binding to its receptor, CD200R, predominantly on myeloid cells and some T cells. This interaction triggers an inhibitory signaling pathway that dampens immune responses, helping to prevent overactivation of the immune system and the development of autoimmunity. CD200 is implicated in a range of physiological and pathological processes, including immune tolerance, regulation of inflammation, tumor immunity, and protection of tissues from immune-mediated damage.

Protein Structure

The structure of CD200 is characteristic of a type I transmembrane glycoprotein, and it shares structural similarities with other members of the immunoglobulin superfamily:

Extracellular Domain:

• The extracellular region of CD200 is composed of two immunoglobulin-like domains: a variable (V) domain at the N-terminus and a constant (C) domain. This structure allows CD200 to interact with the extracellular portion of its receptor, CD200R. These domains are stabilized by intramolecular disulfide bonds, which help maintain their structural integrity.
• The immunoglobulin-like structure of CD200 is essential for binding specificity with CD200R, which is critical in the downstream immune inhibitory signaling pathways.

Transmembrane Domain:

• CD200 has a single hydrophobic transmembrane region that anchors it to the cell membrane. This region does not participate in signal transduction but provides stability to the molecule’s position on the cell surface.

Cytoplasmic Tail:

• The cytoplasmic domain of CD200 is short and lacks any signaling motifs or enzymatic activity, indicating that CD200 does not signal directly into the cell on which it is expressed. Instead, it requires binding to CD200R on adjacent cells to exert its biological function. This design reflects CD200’s primary role as a ligand rather than a signaling receptor.

Classification and Subtypes

CD200 is part of the immunoglobulin superfamily and functions within a class of molecules involved in immunoregulation rather than in the direct recognition of pathogens. It does not have functionally distinct subtypes; however, CD200 has orthologs across multiple species, including mice, where its immune-regulatory role is conserved. Its receptor, CD200R, also belongs to the immunoglobulin superfamily and has several isoforms in humans and animals, each contributing variably to the immune-suppressive effects of CD200.

Function and Biological Significance

CD200 is crucial in maintaining immune balance by downregulating immune responses, particularly those mediated by macrophages, dendritic cells, and neutrophils. The CD200-CD200R interaction plays an essential role in modulating inflammation, autoimmunity, and anti-tumor immunity, making it a key target for studying immune tolerance and immune evasion mechanisms.

Immune Inhibition:

• CD200 binds to CD200R on myeloid lineage cells, activating an inhibitory signaling cascade that reduces the production of pro-inflammatory cytokines. This binding plays a crucial role in suppressing the immune response, preventing overactivation, and minimizing tissue damage.
• This inhibitory interaction is important in situations where immune suppression is necessary, such as during pregnancy, in the eye and brain, and in the maintenance of immune tolerance.

Modulation of Inflammation:

• The CD200-CD200R pathway helps regulate inflammation by controlling the activity of macrophages and dendritic cells, which are responsible for initiating and sustaining inflammatory responses. This regulation helps prevent chronic inflammation and is critical in conditions where inflammation must be tightly controlled, such as in neuroinflammatory diseases and autoimmune disorders.
• In the central nervous system (CNS), CD200 is abundantly expressed on neurons, contributing to the “immune privilege” of the CNS by keeping local microglia, the brain’s resident macrophages, in an anti-inflammatory state.

Tumor Immune Evasion:

• In the tumor microenvironment, CD200 is often upregulated on certain cancer cells, such as leukemia and melanoma cells, allowing tumors to evade immune detection. By engaging CD200R on tumor-associated macrophages and other immune cells, tumors can suppress the local immune response, aiding in immune escape and tumor progression.
• This feature of CD200 has prompted interest in CD200 as a target for immunotherapy. Blocking the CD200-CD200R interaction could potentially enhance anti-tumor immune responses by lifting the immune suppression around tumor cells.

Protection Against Autoimmunity:

• CD200 has a protective effect against autoimmune diseases by dampening overly aggressive immune responses that could damage healthy tissues. It achieves this by limiting the activity of autoreactive T cells and macrophages. In experimental autoimmune models, mice lacking CD200 experience exacerbated disease symptoms, illustrating CD200’s role in maintaining self-tolerance.

Clinical Issues

The dysregulation of CD200 expression or signaling has been linked to various clinical conditions, including autoimmune diseases, cancer, and neurodegenerative disorders.

Autoimmune Disorders:

• Abnormal CD200 expression has been associated with autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis (RA). In these conditions, insufficient CD200 expression or defective CD200-CD200R signaling may contribute to unchecked immune activation, leading to tissue damage and chronic inflammation. Therapeutic strategies to enhance CD200 signaling may help restore immune tolerance in these diseases.

Cancer:

• CD200 expression is often elevated in hematological malignancies like chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), as well as in solid tumors such as melanoma. This overexpression aids tumor cells in evading immune surveillance by suppressing local immune responses through CD200R engagement on immune cells.
• Anti-CD200 therapies are being investigated as potential cancer treatments. By blocking the CD200-CD200R interaction, it may be possible to enhance the immune system’s ability to recognize and destroy tumor cells. However, clinical development of these therapies requires careful balance to avoid autoimmunity due to excessive immune activation.

Neurodegenerative Diseases:

• CD200’s expression on neurons and its regulatory role in microglial activation position it as a critical factor in neuroinflammatory and neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. The loss or dysfunction of CD200-CD200R signaling in the brain may lead to chronic microglial activation, contributing to neuroinflammation and subsequent neuronal damage. Therapeutic modulation of CD200 signaling may help control neuroinflammation and protect neurons in these diseases.

Transplantation:

• In organ transplantation, CD200 signaling may aid in establishing immune tolerance to transplanted tissues, reducing the likelihood of graft rejection. Strategies to enhance CD200-CD200R interactions could potentially be utilized to prolong graft survival and reduce the need for immunosuppressive drugs in transplant recipients.

Summary

CD200 is an immune-regulatory glycoprotein of the immunoglobulin superfamily that plays a pivotal role in modulating immune responses, primarily by engaging CD200R on myeloid and other immune cells to inhibit inflammation. Structurally, CD200 consists of an extracellular domain with two immunoglobulin-like folds, a transmembrane region, and a short cytoplasmic tail. The interaction of CD200 with CD200R initiates an inhibitory signal cascade, leading to the suppression of pro-inflammatory cytokine production and reduced immune cell activation. This function is critical for maintaining immune homeostasis and protecting tissues from immune-mediated damage.

CD200’s role in immune suppression makes it essential for tissue protection, preventing autoimmune responses, regulating inflammation, and allowing immune evasion by certain tumor cells. Clinically, CD200 is significant in the context of autoimmune diseases, cancer, neurodegenerative disorders, and transplantation. Targeting the CD200-CD200R pathway offers promising therapeutic avenues for enhancing immune responses against tumors or dampening immune reactions in autoimmunity and neuroinflammation. Further research into CD200's precise regulatory mechanisms may pave the way for novel treatments in immunotherapy and immune-modulation strategies.