LAIR2 - leukocyte associated immunoglobulin like receptor 2 |Elisa - Clia - Antibody - Protein

Background

Leukocyte-associated immunoglobulin-like receptor 2 (LAIR2) is a soluble member of the immunoglobulin superfamily and is structurally similar to LAIR1. Unlike LAIR1, which is a membrane-bound receptor, LAIR2 is found freely in extracellular fluids and serves as a natural decoy receptor. LAIR2 primarily binds to collagen and collagen-like molecules in the extracellular matrix (ECM) and modulates immune responses by blocking the collagen-binding sites of LAIR1. By competing with LAIR1 for ligand binding, LAIR2 plays a significant role in fine-tuning immune responses, particularly in collagen-rich tissues.

LAIR2 is predominantly expressed in various immune tissues, such as the spleen, bone marrow, and lymph nodes, and circulates in the blood. It interacts with collagen and similar ECM proteins, influencing immune regulation in areas where collagen is abundant. LAIR2’s decoy function allows it to block the inhibitory effects of LAIR1, effectively providing a modulatory balance to the immune system and ensuring appropriate immune responses. This role is particularly important in the contexts of inflammation, infection, cancer, and autoimmune diseases.

Protein Structure

The structure of LAIR2 is simpler compared to LAIR1, reflecting its function as a soluble decoy receptor rather than a signaling receptor on cell surfaces. Key structural features include:

Immunoglobulin (Ig)-like Extracellular Domain:

• LAIR2 contains a single extracellular Ig-like domain of around 90 amino acids, resembling the Ig-like domain in LAIR1. This domain enables LAIR2 to bind collagen, the primary ligand for both LAIR1 and LAIR2.
• This Ig domain adopts a typical beta-sandwich structure composed of two beta sheets arranged face-to-face, which is common in immunoglobulin domains. These structural features allow for strong ligand-binding interactions with collagen.

Absence of Transmembrane and Intracellular Domains:

• Unlike LAIR1, which contains both transmembrane and intracellular regions that enable it to anchor to cell membranes and relay inhibitory signals, LAIR2 lacks these domains. This absence makes LAIR2 a soluble protein, allowing it to function freely in extracellular spaces.
• The lack of intracellular signaling motifs like ITIMs means that LAIR2 does not directly participate in signaling pathways. Instead, its main function is to bind to LAIR1 ligands and modulate LAIR1 signaling indirectly.

The overall structure of LAIR2 is highly specialized for binding collagen and other related ligands, but it does not participate in signaling directly. Its structural simplicity compared to LAIR1 reflects its specialized role as a decoy receptor.

Classification and Subtypes

LAIR2 is part of the leukocyte-associated immunoglobulin-like receptor (LAIR) family, which includes both LAIR1 and LAIR2. This family is within the broader immunoglobulin superfamily (IgSF), which includes a range of immune-related receptors. LAIR2 does not have further subtypes but shares significant structural homology with LAIR1, particularly in its Ig-like domain. This similarity is essential for its decoy function, allowing it to compete effectively with LAIR1 for collagen binding.

Function and Biological Significance

Decoy Function in Immune Regulation:

• LAIR2 primarily acts as a soluble decoy receptor, binding to collagen and collagen-like molecules. By doing so, it competes with LAIR1 and prevents the inhibitory signaling that would otherwise occur through LAIR1 binding to its ligands. This competition is a key mechanism through which LAIR2 modulates immune responses in collagen-rich environments.
• By blocking LAIR1’s access to collagen, LAIR2 reduces the inhibitory signals transmitted through LAIR1, allowing immune cells to remain more active. This function is crucial in scenarios where increased immune activation is necessary, such as during infections or in response to tumor cells.

Immune Modulation and Inflammation:

• LAIR2 is particularly relevant in tissues with high collagen content, where it can effectively modulate immune cell activity by counteracting the inhibitory effects of LAIR1. In inflammatory conditions, LAIR2 can help promote immune responses by blocking LAIR1-mediated inhibition, allowing immune cells to respond robustly to inflammatory stimuli.
• Additionally, during infections, LAIR2 may help ensure that immune responses are appropriately active, especially in tissues that might otherwise signal tolerance or low activation due to the presence of collagen. This modulation is crucial in balancing the immune system’s need for active responses in the face of pathogens.

Potential Role in Cancer:

• LAIR2’s decoy function is particularly relevant in the context of cancer. Tumor cells often modify their microenvironment to evade immune detection, sometimes by producing collagen-like molecules that engage LAIR1, thus dampening immune responses. By binding these collagen molecules, LAIR2 can counteract this effect, reducing immune suppression and enhancing the immune system’s ability to detect and attack tumor cells.
• Due to its ability to counteract LAIR1, LAIR2 is being investigated as a potential therapeutic agent in cancer immunotherapy, where enhancing immune cell activity against tumors is a primary goal.

Role in Autoimmune Diseases:

• In autoimmune conditions, where immune regulation is impaired, LAIR2’s modulation of LAIR1 signaling becomes essential. By blocking LAIR1, LAIR2 may help mitigate excessive immune suppression and allow for balanced immune activation.
• This regulatory effect has potential therapeutic implications for autoimmune diseases, where enhancing immune tolerance is essential to prevent self-reactive immune responses.

Clinical Issues

Cancer Immunotherapy:

• In cancers where the tumor microenvironment suppresses immune responses through collagen production, LAIR2’s ability to block collagen from engaging LAIR1 offers therapeutic potential. Researchers are investigating the use of LAIR2 or LAIR2-mimicking molecules to enhance immune responses in the tumor microenvironment, potentially boosting the efficacy of immunotherapies.
• Since LAIR2 can enhance immune cell activation by preventing LAIR1-mediated inhibition, it may serve as an adjunctive therapy in cancer treatment strategies that rely on boosting immune responses against tumors.

Autoimmune and Inflammatory Diseases:

• Autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), are characterized by dysregulated immune responses, often exacerbated by insufficient regulatory control. By blocking excessive LAIR1-mediated inhibition, LAIR2 may help restore balance in these diseases, allowing immune cells to remain active without overreacting to self-antigens.
• Some studies have suggested that manipulating LAIR2 levels could help prevent immune cells from becoming overly inhibited in the presence of collagen, which may be beneficial in treating chronic inflammation and autoimmune diseases.

Infectious Diseases:

• In infectious disease settings, LAIR2’s role in blocking immune inhibition can be significant. Pathogens that infect collagen-rich tissues could benefit from LAIR1-mediated inhibition, so increased LAIR2 activity could help counteract these effects and improve immune response to infections.
• Targeting LAIR2 as a potential immune-modulating agent is an emerging area of research in infectious diseases, where the balance of immune activation and inhibition is critical to effective pathogen clearance and minimizing tissue damage.

Summary

LAIR2, or leukocyte-associated immunoglobulin-like receptor 2, is a soluble immunoglobulin-like receptor that functions as a decoy receptor in the immune system. It binds to collagen in the extracellular matrix, preventing LAIR1 from engaging with its ligands and thereby blocking the inhibitory signaling that would otherwise suppress immune responses. This function is essential for regulating immune responses, especially in collagen-rich environments where immune cell inhibition may be contextually inappropriate, such as during infections or tumor responses.

Structurally, LAIR2 is defined by a single Ig-like domain that closely resembles that of LAIR1, enabling it to bind collagen and other similar ligands effectively. Unlike LAIR1, LAIR2 lacks transmembrane and intracellular domains, making it a soluble protein that circulates in the extracellular space without engaging in intracellular signaling.

LAIR2’s decoy function is biologically significant in various contexts, including inflammation, infection, cancer, and autoimmunity. By counteracting the effects of LAIR1, LAIR2 helps to maintain a balance between immune activation and inhibition, ensuring that immune cells can respond appropriately to various challenges. This function has implications for diseases where immune regulation is disrupted, such as cancer, where tumors exploit collagen to suppress immune responses, and autoimmune diseases, where dysregulated immune responses target host tissues.

Clinically, LAIR2 is being explored as a potential therapeutic target in cancer immunotherapy, autoimmune disease management, and infectious diseases. By blocking LAIR1-mediated inhibition, LAIR2 may enhance immune activation where needed, offering therapeutic benefits in conditions that require modulated immune responses. LAIR2’s role as a natural immune modulator underscores its importance in maintaining immune homeostasis and highlights its potential for therapeutic applications across various disease contexts.