LILRA3 - leukocyte immunoglobulin like receptor A3 |Elisa - Clia - Antibody - Protein

Background

LILRA3 (Leukocyte Immunoglobulin-Like Receptor A3), also referred to as ILT6 or CD85e, is an intriguing member of the leukocyte immunoglobulin-like receptor (LILR) family, which is predominantly expressed on immune cells. LILRA3 is unique among LILR family members because it lacks a transmembrane domain, functioning as a soluble molecule. Found within the Leukocyte Receptor Complex (LRC) on chromosome 19q13.4, LILRA3 plays a significant role in modulating immune responses, particularly in inflammatory pathways. As a soluble receptor, LILRA3 is capable of binding various ligands, which include MHC class I molecules, and thus can modulate signaling pathways related to immune tolerance and immune response activation. Its specific function in the immune system remains somewhat enigmatic, as both pro-inflammatory and inhibitory effects have been suggested. However, it is recognized as a key player in regulating inflammation and immune homeostasis, with particular relevance in autoimmune diseases, infections, and certain cancers.

Protein Structure

LILRA3 is structurally distinct from other LILR family members, primarily due to its lack of a transmembrane domain, making it a soluble receptor. It comprises an extracellular region with multiple immunoglobulin-like (Ig-like) domains but does not embed in the cell membrane, unlike other LILR receptors.

Extracellular Domain (Ig-like Domains):

• The protein sequence of LILRA3 includes four immunoglobulin-like (Ig-like) domains within its extracellular region, a feature it shares with other LILR family members. These Ig-like domains contribute to its structural stability and binding capabilities, allowing interaction with specific ligands such as MHC class I molecules.
• Each Ig-like domain consists of about 80-100 amino acids arranged into beta sheets stabilized by disulfide bonds. This Ig-like structure is highly conserved across LILR members and provides the necessary framework for ligand binding.
• The conserved domains enable LILRA3 to interact with MHC I molecules and potentially with other ligands relevant to immune signaling. Unlike transmembrane LILRs, the soluble nature of LILRA3 means it acts within the extracellular environment, binding circulating ligands or receptors on other cells.

Absence of Transmembrane and Cytoplasmic Domains:

• Unlike most LILR receptors, LILRA3 lacks both a transmembrane domain and cytoplasmic tail, meaning it does not anchor to the cell surface or directly participate in intracellular signaling. This structural distinction confers LILRA3 with its unique mode of action, as it functions solely in the extracellular matrix without direct signal transduction.
• In other LILRs, the cytoplasmic tail contains either ITIMs (Immunoreceptor Tyrosine-based Inhibitory Motifs) or ITAMs (Immunoreceptor Tyrosine-based Activation Motifs), which play critical roles in modulating cellular signaling. However, since LILRA3 lacks these motifs, its function is restricted to ligand binding and possibly modulating the availability of ligands for other cell surface receptors.

The unique structure of LILRA3, particularly its soluble nature, differentiates it from other LILR family members, making it more comparable to a regulatory protein that can modulate immune interactions without directly signaling in cells.

Classification and Subtypes

The LILR family can be classified into two primary groups: activating receptors and inhibitory receptors. Within this family:

Activating Receptors (e.g., LILRA1, LILRA2):

• These receptors contain ITAMs in their cytoplasmic tails or associate with adapter molecules that contain ITAMs, which activate downstream signaling upon ligand binding.

Inhibitory Receptors (e.g., LILRB1, LILRB2):

• Inhibitory receptors possess ITIMs in their cytoplasmic tails, which recruit phosphatases to inhibit cellular activation upon engagement with ligands.

Soluble Receptors (e.g., LILRA3):

• LILRA3 stands out as a soluble receptor lacking ITIM or ITAM motifs. It does not fit into the activating or inhibitory receptor categories due to its absence of transmembrane and cytoplasmic domains.

Although LILRA3 is often grouped with other LILRs, its specific characteristics place it in a subcategory of soluble receptors within the LILR family. Its role appears more regulatory, as it likely acts as a decoy receptor, binding ligands that may otherwise engage activating or inhibitory LILRs on cell surfaces.

Function and Biological Significance

LILRA3 has a distinctive functional profile among LILR receptors, as it operates outside the cell membrane, exerting effects on immune cells indirectly. Some of its key functions include:

Decoy Receptor Function:

• Due to its soluble nature, LILRA3 may act as a decoy receptor, binding ligands that would otherwise interact with cell-surface LILR receptors. By capturing these ligands, LILRA3 can modulate immune cell responses indirectly, potentially mitigating overactivation or inhibition of immune responses.

Regulation of Inflammatory Responses:

• LILRA3 is thought to play a regulatory role in inflammation, given its ability to bind pro-inflammatory ligands and limit their engagement with other activating LILRs. This function is especially relevant in chronic inflammatory conditions where immune modulation is necessary to prevent tissue damage.

Modulation of Immune Tolerance:

• By binding to MHC class I molecules and potentially other ligands, LILRA3 may help to promote immune tolerance, reducing the likelihood of autoimmune reactions. In autoimmune diseases, the expression and function of LILRA3 are of particular interest, as dysregulation can contribute to pathological immune responses.

Potential Role in Cancer:

• LILRA3’s ability to modulate immune responses also has implications in cancer, where an immune-suppressive environment often favors tumor growth. LILRA3 could potentially limit pro-tumorigenic inflammation or impact immune recognition of tumor cells by modulating available ligands for activating receptors.

The function of LILRA3 as a soluble molecule in the immune system is complex and remains an active area of research, particularly for its implications in immune tolerance and inflammation regulation.

Clinical Issues

Autoimmune Diseases:

• LILRA3 has been linked to autoimmune diseases, especially multiple sclerosis (MS) and rheumatoid arthritis (RA), where its levels or function may be altered. Genetic variations that result in reduced LILRA3 function or expression have been associated with increased risk of these autoimmune diseases, suggesting that LILRA3 plays a role in suppressing pathogenic immune responses.
• Therapeutic strategies targeting LILRA3 could help modulate immune responses in autoimmune diseases, offering potential treatments aimed at restoring immune balance.

Inflammatory Disorders:

• In chronic inflammatory diseases, LILRA3’s role in dampening inflammation makes it a molecule of interest for therapeutic modulation. Conditions like Crohn’s disease and ulcerative colitis, which involve prolonged inflammation, could potentially benefit from interventions aimed at increasing LILRA3’s anti-inflammatory effects.

Infectious Diseases:

• Given that LILRA3 can bind MHC class I molecules, it may modulate immune responses to persistent infections, such as HIV or hepatitis. Modulating LILRA3 function or levels could have potential therapeutic benefits in chronic infections, where immune system suppression may help manage excessive inflammatory responses without compromising pathogen control.

Cancer:

• LILRA3’s involvement in immune regulation makes it relevant in the context of cancer, where immune evasion is a common strategy. Modulation of LILRA3 in the tumor microenvironment could help enhance anti-tumor immune responses. Some cancer therapies are exploring LILR pathways to boost immune responses against tumors, and LILRA3, as a soluble receptor, might influence this regulatory balance.

Summary

LILRA3 is a unique member of the LILR family due to its soluble nature, which allows it to modulate immune responses without direct cellular signaling. Structurally, it consists of four immunoglobulin-like domains but lacks the transmembrane and cytoplasmic domains typically required for cell surface localization and intracellular signaling. This structure positions LILRA3 as a decoy receptor, potentially binding ligands that would otherwise interact with cell-bound LILRs, thus influencing immune responses indirectly.

The primary functions of LILRA3 include modulation of inflammatory and immune tolerance responses, which is especially important in chronic inflammatory conditions and autoimmune diseases. Clinically, alterations in LILRA3 expression or function are associated with autoimmune diseases like multiple sclerosis and rheumatoid arthritis, where its regulatory role in immune responses could be protective. The relevance of LILRA3 also extends to infectious diseases, cancer, and other conditions where immune modulation plays a central role.

As research advances, LILRA3 may emerge as a significant target for therapies aimed at modulating immune responses in various diseases, especially in the fields of autoimmune disease management and cancer immunotherapy. Its structural distinction as a soluble receptor offers a unique approach to immune modulation, differing from traditional activating or inhibitory receptors.