LAIR1 - leukocyte associated immunoglobulin like receptor 1 |Elisa - Clia - Antibody - Protein

Background

Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) is a critical immune regulatory receptor found primarily on leukocytes. It belongs to the immunoglobulin superfamily and functions predominantly as an inhibitory receptor that helps modulate immune responses to prevent overactivation and maintain immune homeostasis. LAIR1 is expressed on a wide array of immune cells, including T cells, B cells, NK cells, monocytes, and dendritic cells, where it plays a fundamental role in dampening immune cell activation to limit inflammation and protect against autoimmune reactions. The receptor primarily interacts with collagen and collagen-like ligands, commonly found in extracellular matrix proteins, which allows it to exert inhibitory signals in tissues rich in collagen.

LAIR1’s role as an inhibitory receptor has garnered significant attention for its involvement in regulating immune cell activation, migration, and cytokine production. This regulatory function is crucial in autoimmune diseases, where loss of LAIR1 function can lead to unchecked immune responses. Additionally, its expression on a wide range of immune cells allows it to coordinate responses across both the innate and adaptive immune systems, and it has also been implicated in cancer immunology, particularly regarding how tumors may exploit LAIR1 signaling to evade immune detection.

Protein Structure

LAIR1 is a single-pass type I transmembrane protein comprising distinct extracellular, transmembrane, and intracellular domains:

Extracellular Domain:

• The extracellular domain of LAIR1 includes a single immunoglobulin (Ig)-like domain. This domain enables the receptor to interact with collagen and collagen-like domains of various ligands, predominantly those present in the extracellular matrix (ECM). The Ig-like domain is approximately 90 amino acids in length and adopts a beta-sandwich structure composed of two beta sheets arranged face-to-face, which is a common feature in Ig domains and aids in ligand binding.
• Collagen binds to LAIR1 with high affinity, facilitating the receptor's function in collagen-rich tissues, where it modulates immune cell behavior based on tissue environment. This collagen binding also plays a role in the immune system’s ability to recognize tissue context, as LAIR1-mediated signals indicate a non-inflammatory environment.

Transmembrane Domain:

• The transmembrane domain of LAIR1 is composed of hydrophobic amino acids, which anchor the receptor in the plasma membrane. This domain is essential for maintaining the structural integrity of the receptor and positioning the extracellular Ig domain for optimal ligand interaction.

Intracellular Domain:

• LAIR1’s intracellular region contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These motifs are critical for the receptor's inhibitory function. Upon ligand binding, the ITIMs undergo phosphorylation, which allows them to recruit phosphatases, such as SHP-1 and SHP-2 (Src homology region 2 domain-containing phosphatase 1 and 2). These phosphatases dephosphorylate signaling molecules associated with activation pathways, effectively dampening cellular responses.
• The ITIMs are central to LAIR1's role as an inhibitory receptor, allowing it to counterbalance activating signals and regulate downstream responses in immune cells, thus preventing excessive immune activation that could damage host tissues.

Classification and Subtypes

LAIR1 belongs to the leukocyte-associated immunoglobulin-like receptor family and is part of the broader immunoglobulin superfamily (IgSF). It is closely related to LAIR2, a soluble homolog that is structurally similar but lacks a transmembrane domain. LAIR2 can bind to the same collagen ligands as LAIR1, effectively acting as a decoy by competing with LAIR1 for ligand binding. This competitive interaction can modify the regulatory functions of LAIR1 by limiting its access to collagen and other ligands.

Function and Biological Significance

LAIR1’s primary function is to act as an inhibitory receptor on immune cells, modulating cellular responses to maintain immune homeostasis:

Immune Regulation:

• LAIR1 is an essential regulator of immune cell activation. It provides inhibitory signals that counterbalance activating receptors, preventing excessive immune activation and cytokine production. On T and B lymphocytes, LAIR1 engagement suppresses their proliferation and activation, while on NK cells, it reduces cytotoxicity, thereby limiting damage to surrounding tissue.

Collagen Recognition and Immune Homeostasis:

• The ability of LAIR1 to bind collagen allows it to recognize signals from the tissue environment, providing an immune-regulatory mechanism that links cellular behavior to the extracellular matrix. In collagen-rich environments, such as connective tissues, LAIR1 engagement by collagen can attenuate immune responses, promoting a state of immune tolerance that is critical in areas prone to injury and inflammation.

Tumor Immunology:

• Many tumors express collagen or collagen-like molecules in their microenvironments, which can engage LAIR1 on immune cells and inhibit immune responses against the tumor. This mechanism is thought to be one way tumors evade immune detection, as LAIR1 signaling suppresses T cell and NK cell activity, which would otherwise target tumor cells. Understanding this interaction has implications for cancer immunotherapy, as blocking LAIR1 signaling could enhance immune responses against tumors.

Autoimmune Diseases:

• In autoimmune diseases, where the immune system erroneously attacks self-tissues, LAIR1’s inhibitory function is often impaired. Deficient LAIR1 activity or expression has been associated with diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Without sufficient LAIR1 signaling, immune cells may become overactive, producing inflammatory responses that target healthy tissues.

Role in Infection and Inflammation:

• LAIR1 is also involved in regulating inflammatory responses during infections. By inhibiting excessive activation of immune cells, LAIR1 can prevent the development of a hyper-inflammatory state, such as a cytokine storm. This regulation is particularly significant in preventing tissue damage during viral infections and chronic inflammation.

Clinical Issues

Given its significant role in immune regulation, LAIR1 is associated with several clinical conditions:

Cancer:

• In the tumor microenvironment, collagen production can lead to excessive LAIR1 signaling, resulting in immune cell inhibition and enabling tumors to evade the immune response. Blocking LAIR1 or modifying its signaling pathway could potentially boost anti-tumor immunity. Immunotherapies that inhibit LAIR1 function are being investigated to enhance immune cell activation against cancer cells.

Autoimmune Diseases:

• Dysregulated LAIR1 signaling contributes to the pathogenesis of autoimmune diseases. In conditions like systemic lupus erythematosus, low levels or dysfunctional LAIR1 can result in heightened immune activation. Therapies that mimic LAIR1 activity or increase its expression may help in treating autoimmune diseases by suppressing unwanted immune responses.

Chronic Inflammatory Diseases:

• LAIR1 also plays a role in chronic inflammatory conditions by controlling the balance between pro-inflammatory and anti-inflammatory responses. Targeting LAIR1 may be beneficial in diseases characterized by chronic inflammation, such as atherosclerosis or inflammatory bowel disease.

Infectious Diseases:

• By limiting the immune response in collagen-rich tissues, LAIR1 may impact responses to certain pathogens. In bacterial and viral infections, manipulating LAIR1 signaling could potentially control excessive inflammation, though it could also limit effective pathogen clearance. The therapeutic implications of LAIR1 modulation in infectious diseases are still under exploration.

Summary

LAIR1 (leukocyte-associated immunoglobulin-like receptor 1) is a vital inhibitory receptor within the immune system that modulates the activation of various immune cells. It plays a crucial role in maintaining immune homeostasis by binding to collagen in the extracellular matrix and delivering inhibitory signals through its ITIM motifs. This inhibition is crucial for regulating immune responses, as it balances activating signals to prevent excessive inflammation and autoimmunity.

Structurally, LAIR1 is characterized by an extracellular Ig-like domain that binds collagen, a hydrophobic transmembrane domain, and an intracellular domain containing two ITIMs that recruit phosphatases, such as SHP-1 and SHP-2, to inhibit downstream activation pathways. LAIR1's interactions with collagen in the tissue environment help immune cells recognize non-inflammatory or non-danger signals, which is essential for limiting immune activity in collagen-rich tissues.

LAIR1’s dysregulation is linked to various clinical issues, including cancer, autoimmune diseases, and chronic inflammatory diseases. Its expression in the tumor microenvironment, for instance, can suppress immune responses, aiding tumor evasion. Similarly, impaired LAIR1 signaling is implicated in autoimmune conditions like systemic lupus erythematosus, where insufficient inhibitory signaling results in hyperactive immune responses. Due to these diverse roles, LAIR1 is a promising therapeutic target in immunotherapy, autoimmunity, and inflammatory diseases.