ITGB2 - integrin subunit beta 2 |Elisa - Clia - Antibody - Protein

Background

ITGB2, or integrin subunit beta 2, is a protein that plays a central role in leukocyte adhesion and signaling, facilitating the immune system's response to infections and inflammation. ITGB2, also known as CD18, is part of the integrin family, which consists of transmembrane receptors involved in cell-cell and cell-extracellular matrix (ECM) interactions. Integrins are heterodimeric proteins formed by the association of alpha (α) and beta (β) subunits. In particular, ITGB2 pairs with various alpha integrin subunits to form key receptors known as beta-2 integrins.

Beta-2 integrins are primarily expressed on leukocytes (white blood cells) and are essential for mediating cell adhesion, migration, phagocytosis, and immune surveillance. The four major integrins that involve ITGB2 are LFA-1 (αLβ2, CD11a/CD18), Mac-1 (αMβ2, CD11b/CD18), gp150/95 (αXβ2, CD11c/CD18), and αDβ2 (CD11d/CD18). These integrins are vital for the immune system's ability to respond to infections and regulate inflammation.

Mutations in the ITGB2 gene are associated with severe clinical conditions such as leukocyte adhesion deficiency type I (LAD-I), a rare disorder characterized by impaired leukocyte adhesion, leading to recurrent infections and delayed wound healing. The ITGB2 protein is, therefore, of critical importance for proper immune function and cellular communication.

Protein Structure

The ITGB2 protein is a large transmembrane glycoprotein with a molecular weight of approximately 95 kDa. Like all integrin β subunits, ITGB2 is composed of several structural domains that work together to mediate ligand binding, cell signaling, and leukocyte adhesion. The primary structural components of ITGB2 include:

Extracellular Domain:

• The extracellular domain of ITGB2 is responsible for interacting with ligands, including intercellular adhesion molecules (ICAMs), complement proteins (such as iC3b), and other extracellular matrix components. This domain extends from the plasma membrane and forms part of the ligand-binding interface.
• The β2 integrin subunit, when combined with specific alpha subunits, can bind different ligands. For instance, when paired with CD11a (αL), it forms LFA-1, which binds ICAM-1, ICAM-2, and ICAM-3; when paired with CD11b (αM), it forms Mac-1, which can bind iC3b, ICAM-1, fibrinogen, and other ligands.

I-domain:

• A notable feature of β2 integrins is the I-domain (inserted domain), which is responsible for direct ligand recognition. The I-domain contains a metal-ion dependent adhesion site (MIDAS) that coordinates divalent cations (such as Mg²⁺ or Mn²⁺) to mediate binding to specific ligands.
• The conformational changes in this I-domain between active and inactive states regulate the affinity of ITGB2 for its ligands, contributing to the overall regulation of integrin activation and cell adhesion.

Transmembrane Domain:

• The transmembrane domain of ITGB2 spans the plasma membrane and interacts with the transmembrane domain of the corresponding alpha subunit. This domain plays a role in maintaining the integrity of the integrin complex and transmitting signals across the membrane during outside-in and inside-out signaling.
• The transmembrane domain also plays a role in conformational changes that occur during integrin activation, switching from a bent (inactive) conformation to an extended (active) conformation.

Cytoplasmic Tail:

• The cytoplasmic tail of ITGB2 is critical for interacting with intracellular proteins and signaling molecules, such as talin and kindlin, which are involved in the activation of integrins. Upon binding to these adaptor proteins, integrins undergo conformational changes that enable high-affinity ligand binding.
• ITGB2's cytoplasmic domain is also important for coordinating interactions with actin cytoskeleton and mediating cell migration and signaling events related to immune cell function.

Classification and Subtypes

ITGB2 is part of the integrin superfamily, a large group of heterodimeric cell surface receptors composed of alpha and beta subunits. Within this family, ITGB2 pairs with specific alpha integrins to form the beta-2 integrin subgroup, which plays essential roles in immune cell adhesion, migration, and phagocytosis.

The primary beta-2 integrins formed by ITGB2 include:

LFA-1 (CD11a/CD18, αLβ2):

• LFA-1 is crucial for T-cell and B-cell activation and mediates adhesion to ICAMs, facilitating leukocyte migration and adhesion during immune responses.

Mac-1 (CD11b/CD18, αMβ2):

• Mac-1 is involved in neutrophil and macrophage adhesion, phagocytosis, and the immune response to pathogens. It can bind to ligands such as iC3b, fibrinogen, and ICAM-1, playing a role in inflammation and host defense.

gp150/95 (CD11c/CD18, αXβ2):

• This integrin is primarily expressed on dendritic cells, macrophages, and some neutrophils. It is involved in cell adhesion, phagocytosis, and immune complex clearance.

αDβ2 (CD11d/CD18):

• αDβ2 is primarily expressed on macrophages and plays a role in adhesion and migration of immune cells, particularly in chronic inflammation.

Function and Biological Significance

ITGB2, as part of beta-2 integrins, is crucial for the immune system's ability to detect and respond to pathogens, regulate inflammation, and mediate tissue repair. The primary functions of ITGB2-containing integrins include:

Leukocyte Adhesion and Migration:

• ITGB2 integrins enable leukocytes to adhere to endothelial cells and migrate through tissues to reach sites of infection or inflammation. This process, known as extravasation, involves the rolling, firm adhesion, and transmigration of leukocytes across the endothelial barrier.
• LFA-1 (αLβ2) mediates the firm adhesion of leukocytes to endothelial cells by binding to ICAM-1, ICAM-2, and ICAM-3, which are expressed on the surface of endothelial cells.

Phagocytosis and Immune Response:

• ITGB2 integrins like Mac-1 (αMβ2) and gp150/95 (αXβ2) are involved in the phagocytosis of pathogens and cellular debris. These integrins bind to complement-coated targets (e.g., iC3b) and facilitate their internalization by neutrophils and macrophages.
• This phagocytic function is critical for clearing infections and resolving inflammation.

Signaling and Immune Cell Activation:

• Beta-2 integrins transmit signals inside the cell upon ligand binding (outside-in signaling), leading to the activation of immune cells like T cells, B cells, neutrophils, and macrophages.
• ITGB2-containing integrins also participate in inside-out signaling, where intracellular signals (e.g., from chemokines or cytokines) modulate the affinity and avidity of the integrin for its ligands, thus regulating cell adhesion and migration.

Tissue Repair and Immune Surveillance:

• ITGB2 integrins are also involved in tissue repair by promoting the clearance of apoptotic cells and debris at sites of injury. They contribute to immune surveillance by enabling immune cells to migrate efficiently through tissues and detect pathogens.

Clinical Issues

Mutations or dysfunction in ITGB2 can lead to severe immune deficiencies and other pathological conditions. The most notable clinical condition associated with ITGB2 is leukocyte adhesion deficiency type I (LAD-I).

Leukocyte Adhesion Deficiency Type I (LAD-I):

• LAD-I is a rare autosomal recessive immunodeficiency caused by mutations in the ITGB2 gene, leading to defective expression or function of beta-2 integrins. As a result, leukocytes cannot adhere properly to endothelial cells or migrate to sites of infection or inflammation.
• Patients with LAD-I suffer from recurrent bacterial infections, delayed wound healing, and an inability to form pus, as neutrophils cannot migrate to infection sites.
• LAD-I is often diagnosed in infancy and requires early intervention, including stem cell transplantation, to correct the underlying immune deficiency.

Autoimmune and Inflammatory Diseases:

• Dysregulation of ITGB2 function has also been implicated in autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). In these conditions, aberrant leukocyte adhesion and migration contribute to excessive inflammation and tissue damage.

Chronic Infections and Impaired Phagocytosis:

• Impaired function of ITGB2 integrins, particularly Mac-1, can lead to reduced phagocytic capacity, making individuals more susceptible to chronic infections. This is seen in conditions where neutrophil or macrophage function is compromised.

Summary

ITGB2 (CD18) is a key integrin subunit that forms essential heterodimeric receptors with alpha integrins to mediate leukocyte adhesion, migration, phagocytosis, and immune cell activation. These beta-2 integrins are critical for immune surveillance, pathogen clearance, and tissue repair. Dysfunction in ITGB2 leads to serious immunological disorders such as leukocyte adhesion deficiency type I (LAD-I), characterized by impaired leukocyte migration and recurrent infections. Beta-2 integrins, including LFA-1, Mac-1, and others, play an integral role in the immune system, and their proper function is vital for maintaining immune homeostasis and responding to infections and inflammation.