LILRA2 - leukocyte immunoglobulin like receptor A2 |Elisa - Clia - Antibody - Protein

Background

LILRA2, also known as Leukocyte Immunoglobulin-Like Receptor A2 (LILRA2) or CD85h, is a member of the immunoglobulin superfamily and part of the leukocyte immunoglobulin-like receptor (LILR) family. This receptor is encoded by the LILR gene cluster on chromosome 19q13.4, which is home to various immunoglobulin-like receptors involved in immune regulation. LILRA2 plays an activating role in immune response modulation and is predominantly expressed on monocytes, macrophages, and some other leukocyte subsets, such as granulocytes. It is essential in host defense, participating in immune responses to infections and modulating inflammation through cellular signaling pathways. The receptor interacts with a variety of ligands, likely including MHC class I molecules, which allows it to influence both innate and adaptive immunity.

The immune-modulating role of LILRA2 makes it an essential subject of study in the context of immune responses and inflammation. Unlike other LILR members that may provide inhibitory signaling, LILRA2 is classified as an activating receptor, generally enhancing immune responses through its interaction with signaling adaptors that contain immunoreceptor tyrosine-based activation motifs (ITAMs). This activating function of LILRA2 contrasts with some members of the LILRB subfamily, which contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and thus help suppress immune responses. Research has shown that aberrant expression or dysregulation of LILRA2 can contribute to inflammatory diseases, autoimmunity, and potentially cancer, making it a focal point for therapeutic interventions.

Protein Structure

LILRA2 exhibits the following structural organization typical of the LILR family but with unique features that enable its activating functions:

Extracellular Region:

• The extracellular region of LILRA2 contains two immunoglobulin-like (Ig-like) domains. Each Ig-like domain is approximately 90-110 amino acids long and adopts a beta-sheet structure stabilized by disulfide bonds. These domains are crucial for ligand recognition and binding.
• The first Ig-like domain in LILRA2 contains the primary binding sites that interact with MHC class I molecules and possibly other ligands, positioning it to mediate immune cell activation. The second Ig-like domain likely contributes to structural stability and enhances binding specificity.

Transmembrane Domain:

• LILRA2 is a single-pass transmembrane receptor with a hydrophobic transmembrane domain that anchors it to the cell membrane. The transmembrane segment allows LILRA2 to form stable interactions with signaling molecules that carry ITAMs.
• This domain is essential for associating LILRA2 with adaptor proteins that facilitate downstream signaling events, ultimately leading to immune activation.

Cytoplasmic Tail:

• Unlike inhibitory receptors, LILRA2 has a short cytoplasmic tail without intrinsic signaling motifs such as ITIMs. Instead, it relies on interaction with adaptor proteins containing ITAMs for signal transduction.
• Specifically, LILRA2 associates with the FcRγ adaptor protein, which contains ITAMs that facilitate activation signaling when the receptor binds its ligands. This connection to ITAM-bearing adaptors is what categorizes LILRA2 as an activating receptor within the LILR family, enabling it to amplify immune responses effectively.

Classification and Subtypes

LILRA2 belongs to the LILR family, a group of receptors divided into activating (LILRA) and inhibitory (LILRB) receptors. LILRA receptors, such as LILRA1, LILRA3, and LILRA4, are generally activating and associated with immune amplification, while LILRB members, like LILRB1 and LILRB2, provide inhibitory signals to balance immune activity. LILRA2, as an activating receptor, interacts with ITAM-containing adaptors and thus contrasts with LILRB members that contain ITIMs in their cytoplasmic tails.

No specific subtypes of LILRA2 exist; rather, it is a singular gene product within the LILRA family. Its expression, however, can vary significantly across different cell types and states of immune activation.

Function and Biological Significance

LILRA2 has a significant role in regulating immune activation, primarily through its interaction with FcRγ, and contributes to the following functions:

Immune Cell Activation:

• LILRA2 is expressed on immune cells such as monocytes, macrophages, and some granulocytes, where it enhances cell activation in response to pathogens. Binding of LILRA2 to its ligands (possibly MHC class I molecules) activates the ITAM signaling pathway via its association with FcRγ, which leads to a cascade of phosphorylation events that stimulate inflammatory cytokine release, immune cell recruitment, and activation of downstream immune responses.

Promotion of Inflammatory Cytokine Production:

• When engaged, LILRA2 signaling enhances the production of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β, which are essential in recruiting immune cells to sites of infection or inflammation. These cytokines facilitate both innate and adaptive immunity by promoting leukocyte migration, increasing vascular permeability, and inducing fever as part of the acute immune response.

Host Defense Against Pathogens:

• LILRA2 is crucial for antimicrobial defense and can be upregulated in response to bacterial, viral, and fungal infections. The receptor’s ability to amplify cytokine production and activate immune cells helps to control pathogen spread, particularly in the early stages of infection.
• Some studies suggest that LILRA2 may play a specific role in viral infections, where it aids in the clearance of virally infected cells, though this is still under investigation.

Regulation of Monocyte and Macrophage Activity:

• LILRA2 expression on monocytes and macrophages allows these cells to act as key modulators in immune responses. By activating monocytes, LILRA2 contributes to the differentiation of these cells into macrophages or dendritic cells, thereby amplifying immune surveillance and antigen presentation.

Clinical Issues

Autoimmune Diseases:

• Dysregulated LILRA2 expression or function has been linked to several autoimmune diseases. Overactivation of LILRA2 can lead to excessive inflammation, as observed in conditions like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The elevated cytokine production and immune cell recruitment driven by LILRA2 may exacerbate tissue damage in these autoimmune conditions.

Infectious Diseases:

• LILRA2 is often upregulated in response to infections, and its role in modulating immune activation makes it essential in the context of chronic infections, such as HIV and hepatitis B. However, excessive activation of LILRA2 may lead to immune exhaustion, where chronic stimulation reduces immune cell efficacy over time.

Cancer:

• Some studies have suggested a possible role for LILRA2 in cancer, where it may modulate immune responses in the tumor microenvironment. LILRA2 expression on tumor-associated macrophages could either promote or suppress tumor immunity, depending on the context. The receptor’s influence on cytokine production and immune cell activation could theoretically contribute to anti-tumor immunity, although its exact role remains unclear.

Therapeutic Targeting:

• LILRA2 represents a potential therapeutic target, especially for autoimmune diseases and chronic infections. Modulating LILRA2 activity could help reduce inflammation in autoimmune diseases by limiting cytokine production. In chronic infections, balancing LILRA2 activity might prevent immune exhaustion while preserving sufficient immune activation to control the infection.

Summary

LILRA2 is a key activating receptor in the immune system, part of the leukocyte immunoglobulin-like receptor family, predominantly expressed on monocytes, macrophages, and granulocytes. Structurally, LILRA2 contains two Ig-like domains that bind ligands, a transmembrane region for membrane anchoring, and a cytoplasmic tail that interacts with the ITAM-bearing adaptor FcRγ to activate immune signaling. Its classification within the LILRA family highlights its role in immune amplification, particularly in response to infections and inflammatory stimuli.

Functionally, LILRA2 promotes immune cell activation, inflammatory cytokine production, and antimicrobial defense, enhancing both innate and adaptive immunity. It is critical in the host defense against pathogens, where its activation aids in the clearance of infections. Dysregulation of LILRA2, however, is associated with autoimmune diseases and chronic inflammation, underscoring its significance in immune homeostasis. As a clinical target, LILRA2 modulation holds promise for autoimmune diseases, chronic infections, and potentially cancer therapy. Its role in immune activation, particularly within the context of inflammation, makes LILRA2 a molecule of considerable interest in both basic research and therapeutic development.