CD22 - CD22 molecule |Elisa - Clia - Antibody - Protein

Background

CD22, also known as Siglec-2, is a member of the sialic acid-binding immunoglobulin-like lectins (Siglec) family and is predominantly expressed on B cells. It plays a crucial role in modulating B-cell receptor (BCR) signaling and maintaining B-cell tolerance, making it an essential molecule in the regulation of the immune system. CD22 is primarily found on mature B cells, acting both as an inhibitory coreceptor to dampen BCR signaling and as an adhesion molecule involved in cell-cell interactions.

CD22 is essential for maintaining the delicate balance between immune activation and tolerance, preventing excessive immune responses that could lead to autoimmune diseases. It is an inhibitory receptor that modulates B-cell activity by recruiting SHP-1, a phosphatase that negatively regulates B-cell signaling pathways. In this capacity, CD22 fine-tunes the immune response to antigens, ensuring that B cells are appropriately activated and preventing autoimmunity.

Given its critical function in regulating B-cell activity, CD22 is an important molecule in both normal immunological processes and the pathogenesis of autoimmune diseases and B-cell malignancies. CD22 has become a therapeutic target, particularly in the treatment of B-cell lymphomas and leukemias, where abnormal B-cell activity is a central feature of the disease.

Protein Structure

CD22 is a 135-140 kDa type I transmembrane glycoprotein, and it consists of several distinct structural regions that are crucial for its function. The protein is encoded by the CD22 gene, located on chromosome 19 in humans. The key features of the CD22 protein structure include:

Extracellular Domain:

• The extracellular portion of CD22 contains seven Ig-like domains, which are characteristic of the immunoglobulin superfamily. These domains are involved in binding to sialic acid-containing glycoproteins. The first Ig-like domain is primarily responsible for this sialic acid binding, which mediates both the adhesion functions of CD22 and its role in modulating immune responses.
• This binding is restricted to alpha-2,6-linked sialic acid moieties, which are commonly found on glycoproteins on the surface of B cells. This interaction allows CD22 to engage in homotypic (B cell to B cell) and heterotypic (B cell to other immune cells) adhesion, which is important for the spatial regulation of B-cell activation within lymphoid tissues.

Transmembrane Domain:

• The transmembrane region of CD22 anchors the molecule into the B-cell membrane and plays a role in organizing CD22 into lipid rafts, which are specialized microdomains within the membrane that serve as platforms for receptor signaling. The localization of CD22 in these rafts helps modulate its inhibitory functions by controlling its proximity to the B-cell receptor (BCR) complex.

Cytoplasmic Tail:

• The cytoplasmic domain of CD22 is long and contains multiple immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These ITIMs are phosphorylated upon BCR activation, which allows CD22 to recruit SHP-1 (Src homology 2 domain-containing phosphatase-1). SHP-1 is a phosphatase that dephosphorylates key signaling molecules within the BCR signaling pathway, thus inhibiting BCR-induced signaling and dampening the immune response.
• The cytoplasmic tail also has phosphorylation sites that interact with Grb2 and other intracellular signaling molecules, allowing CD22 to integrate into multiple signaling networks.

Glycosylation:

• CD22 is heavily glycosylated, which influences its ability to interact with other molecules. The glycosylation of CD22, particularly at sites within its Ig-like domains, impacts its affinity for sialic acid-containing ligands and may regulate its inhibitory function.

Classification and Subtypes

CD22 belongs to the Siglec (Sialic acid-binding immunoglobulin-like lectin) family, specifically as Siglec-2. Siglecs are a group of cell surface proteins that bind sialic acid residues on glycoproteins and glycolipids. The Siglec family plays essential roles in immune regulation, particularly in modulating the activities of immune cells like B cells, dendritic cells, and macrophages.

Within the Siglec family, CD22 is categorized based on its ability to bind to alpha-2,6-linked sialic acid. Other Siglecs bind to different linkages or types of sialic acids, contributing to their distinct roles in immune cell signaling. Unlike some Siglecs, CD22 is expressed almost exclusively on B cells, with the highest expression seen on mature B cells in the bone marrow and peripheral blood.

Function and Biological Significance

The primary function of CD22 is to serve as an inhibitory coreceptor for the BCR, modulating B-cell activation and maintaining immune tolerance. This regulation is critical to prevent over-activation of B cells, which could lead to autoimmune responses or excessive inflammation. The key functions of CD22 include:

Negative Regulation of BCR Signaling:

• Upon BCR activation, CD22 is phosphorylated at its ITIMs. This phosphorylation event allows CD22 to recruit SHP-1, which dephosphorylates and thereby attenuates the activation of key signaling molecules such as Syk and BLNK in the BCR signaling pathway. This negative feedback mechanism helps prevent overstimulation of B cells and fine-tunes the immune response to antigens.

Adhesion and Homing:

• CD22 can bind to sialic acid-containing glycoproteins on other cells, which facilitates cell-cell adhesion. This interaction is particularly important in the lymphoid tissues, where B cells must interact with T cells and antigen-presenting cells. CD22-mediated adhesion plays a role in positioning B cells within the germinal centers of lymph nodes, where they undergo selection and differentiation.

Maintenance of B-Cell Tolerance:

• By attenuating BCR signaling, CD22 helps maintain self-tolerance in B cells. B cells that react too strongly to self-antigens may be either eliminated or rendered anergic (unresponsive), a process facilitated by CD22’s inhibitory actions. Dysregulation of this function can contribute to the development of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Role in Germinal Center Reactions:

• CD22 is highly expressed in germinal center B cells, where it plays a role in the selection of high-affinity B cells and the development of memory B cells and plasma cells. By regulating the strength of BCR signals, CD22 ensures that only B cells with the highest affinity for antigens are selected for further differentiation.

Clinical Issues

B-Cell Malignancies:

• CD22 is expressed in many B-cell malignancies, including chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia (ALL). Because CD22 is almost exclusively expressed on B cells, it has become a target for therapeutic interventions in these malignancies.
• Immunotoxins and antibody-drug conjugates (ADCs) targeting CD22 have been developed to selectively eliminate malignant B cells. One example is inotuzumab ozogamicin, a CD22-targeting ADC that delivers a cytotoxic agent specifically to CD22-expressing leukemia cells.

Autoimmune Diseases:

• Abnormalities in CD22 function or expression are associated with autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In these conditions, the failure of CD22 to adequately inhibit BCR signaling can result in the inappropriate activation of autoreactive B cells, leading to the production of autoantibodies and chronic inflammation.
• Therapeutic strategies targeting CD22 are being investigated to restore immune tolerance and reduce the overactivity of B cells in autoimmune diseases.

CD22 Deficiency:

• CD22-deficient mice exhibit increased susceptibility to autoimmune diseases and show evidence of hyperactive B-cell signaling, highlighting the critical role of CD22 in maintaining immune homeostasis. In humans, mutations or deficiencies in CD22 could potentially lead to similar immune dysregulation.

Summary

CD22 (Siglec-2) is a critical regulator of B-cell signaling and plays a pivotal role in modulating the immune response. Structurally, it consists of seven Ig-like domains in its extracellular region, a transmembrane domain, and a cytoplasmic tail containing ITIM motifs that mediate its inhibitory function. By binding to sialic acid-containing ligands on other cells and recruiting the SHP-1 phosphatase, CD22 attenuates BCR signaling, preventing excessive B-cell activation and maintaining immune tolerance.

CD22’s role extends beyond simply regulating B-cell activity; it also contributes to cell adhesion, particularly in lymphoid tissues, and helps guide B cells during germinal center reactions. Its function in immune tolerance and preventing autoimmunity is significant, and dysregulation of CD22 is implicated in diseases such as SLE and RA.

Clinically, CD22 is a promising therapeutic target in the treatment of B-cell malignancies such as ALL and NHL, where its expression on malignant B cells allows for targeted therapies. Its relevance in autoimmune diseases also makes it a target for therapies aimed at restoring immune homeostasis in conditions characterized by B-cell hyperactivity.