ICAM4 - intercellular adhesion molecule 4 |Elisa - Clia - Antibody - Protein

Background

ICAM4 (Intercellular Adhesion Molecule 4) is a transmembrane glycoprotein that belongs to the immunoglobulin (Ig) superfamily and is primarily expressed on erythrocytes (red blood cells). ICAM4 functions as an adhesion molecule, playing a significant role in cell-to-cell interactions, particularly between red blood cells and other cell types. It is also known as the Landsteiner-Wiener blood group antigen and is encoded by the ICAM4 gene, which is located on chromosome 19. The primary physiological role of ICAM4 is in mediating interactions with other cells, notably endothelial cells, leukocytes, and macrophages, contributing to the cellular processes in circulation and immune response.

ICAM4 is part of the ICAM family of molecules, which includes ICAM1, ICAM2, ICAM3, and ICAM5. ICAM molecules are generally involved in leukocyte-endothelial cell adhesion and signaling pathways that regulate inflammation and immune responses. ICAM4, although sharing structural similarities with these other molecules, is unique in its specificity to erythrocytes and its function in erythrocyte interactions, notably through binding with integrins such as α4β1 and αV integrins found on various immune cells.

Protein Structure

ICAM4 is a glycoprotein with a complex structure that facilitates its role as an adhesion molecule. It contains approximately 272 amino acids and includes distinct domains that contribute to its adhesive function:

Extracellular Domain:

• The extracellular domain of ICAM4 contains two immunoglobulin (Ig)-like domains that are characteristic of the immunoglobulin superfamily. These Ig-like domains are important for binding to integrins, as they facilitate interactions between erythrocytes and other cell types.
• Each Ig-like domain has loops stabilized by disulfide bonds, contributing to a stable extracellular structure. The domain structure is highly conserved and critical for recognition and binding by integrins on other cells.
• Glycosylation of ICAM4 occurs within the extracellular domain, and this glycosylation modulates its binding affinity with integrins. Post-translational glycosylation patterns can influence the efficiency of ICAM4 in mediating cell-cell adhesion.

Transmembrane Region:

• ICAM4 has a single-pass transmembrane helix composed of hydrophobic amino acids that anchor the protein within the erythrocyte membrane. This transmembrane domain provides structural integrity and stability to ICAM4, ensuring it remains embedded within the red blood cell membrane.
• The transmembrane domain also potentially participates in signal transduction and cellular interactions involving erythrocytes.

Cytoplasmic Tail:

• ICAM4 has a short cytoplasmic tail, which contains sequences that might interact with the intracellular machinery. Although the cytoplasmic domain of ICAM4 is relatively limited compared to other adhesion molecules, it likely contributes to intracellular signaling and cytoskeletal organization.
• The tail could also be involved in the regulation of ICAM4 expression and stability on the cell surface, as well as cellular responses in erythrocytes.

Classification and Subtypes

ICAM4 is one of the five members of the ICAM family:

1. ICAM1-3 are mainly expressed on endothelial and immune cells and play important roles in immune cell trafficking and inflammation.
2. ICAM5 is primarily found in the nervous system.
3. ICAM4 is unique to erythrocytes and mediates adhesion and immune functions specifically related to red blood cells.

ICAM4 itself does not have widely recognized subtypes, as it is a specialized adhesion molecule with restricted tissue expression. Variants in the ICAM4 gene may affect its structure and function, potentially altering red blood cell adhesion properties and impacting blood-related disorders, but specific subtypes are not typically defined as with other ICAM family members.

Function and Biological Significance

The principal function of ICAM4 is to mediate erythrocyte adhesion through interactions with integrins and other receptors. This is significant in several physiological and pathological contexts:

Erythrocyte-Adhesion:

• ICAM4 binds to integrins such as αV integrin on other cells, facilitating erythrocyte adhesion to endothelial cells and macrophages. This binding is important in conditions where red blood cells need to interact closely with other cell types, such as during immune surveillance or in certain disease states where erythrocytes adhere abnormally.

Role in Sickle Cell Disease (SCD):

• In patients with sickle cell disease (SCD), erythrocytes often become abnormally adhesive. ICAM4 has been implicated in this increased adhesion, which can lead to vaso-occlusive crises and pain episodes. Studies suggest that ICAM4 may contribute to the formation of aggregates or clots of sickle cells that block blood vessels, leading to severe pain and tissue ischemia in SCD patients.

Immune Interactions and Phagocytosis:

• ICAM4 has been found to interact with macrophages and other immune cells. This interaction may help regulate the clearance of aging or damaged red blood cells, a critical process for maintaining the health of circulating erythrocytes.
• The ICAM4-integrin interactions with immune cells also contribute to signaling pathways that can lead to erythrophagocytosis (the engulfment and digestion of red blood cells), which is particularly relevant in diseases that cause hemolysis, or red blood cell breakdown.

Regulation of Erythrocyte Aggregation:

• ICAM4 plays a role in erythrocyte aggregation, which can be affected by its interactions with different integrins. The aggregation of red blood cells is influenced by conditions such as pH, oxygen levels, and the presence of inflammatory molecules. Under hypoxic conditions, ICAM4-mediated aggregation might be enhanced, leading to further complications in circulatory health.

Clinical Issues

ICAM4 has implications in several clinical contexts, particularly in blood disorders and immune-related conditions:

Sickle Cell Disease (SCD):

• One of the major clinical implications of ICAM4 is in sickle cell disease. The abnormal adhesion mediated by ICAM4 is a contributing factor to the vaso-occlusive crises experienced by SCD patients. These crises occur when sickled erythrocytes adhere to endothelial cells and obstruct blood flow, leading to severe pain and potential organ damage.

Malaria:

• Malaria, caused by the Plasmodium parasite, leads to changes in erythrocyte properties. ICAM4 may be involved in the adhesion of infected red blood cells to blood vessel walls, contributing to the vascular complications observed in severe malaria cases. The parasite modifies red blood cell surface proteins, potentially increasing the adhesive properties of erythrocytes through interactions with ICAM4.

Autoimmune Hemolytic Anemia:

• In autoimmune hemolytic anemia, ICAM4 may play a role in the removal of erythrocytes by the immune system. Antibodies targeting red blood cells could increase the interaction of ICAM4 with macrophages, leading to accelerated erythrophagocytosis and anemia.

Aging-Related Erythrocyte Clearance:

• ICAM4 interactions with macrophages are part of the mechanism by which aging red blood cells are removed from circulation. Disruptions in ICAM4 function could potentially lead to the improper clearance of red blood cells, contributing to hemolytic disorders or abnormal erythrocyte lifespan.

Summary

ICAM4 is an intercellular adhesion molecule that primarily mediates interactions between erythrocytes and other cell types. Its structure, including two Ig-like extracellular domains, a single-pass transmembrane region, and a cytoplasmic tail, is optimized for adhesion functions. The molecule binds integrins such as αV integrin, facilitating erythrocyte adhesion to endothelial cells, macrophages, and other immune cells. The functional significance of ICAM4 is particularly evident in pathological conditions such as sickle cell disease and malaria, where increased erythrocyte adhesion exacerbates disease severity. ICAM4’s role in immune interactions also suggests its involvement in erythrocyte clearance, as it may mediate the removal of aging or damaged erythrocytes by macrophages.

Clinically, ICAM4 is relevant to disorders where erythrocyte adhesion or lifespan is altered, including sickle cell disease, malaria, autoimmune hemolytic anemia, and aging-related red blood cell clearance. In summary, ICAM4 is a key erythrocyte adhesion molecule with important implications in immune function, cell aggregation, and various blood-related disorders, making it an important target for research in hematology and transfusion medicine.