Regulation of B Cell Functions by the Sialic Acid-Binding Receptors Siglec-G and CD22

Chair of Genetics, University of Erlangen Erlangen, Germany.
Frontiers in Immunology 11/2011; 2:96. DOI: 10.3389/fimmu.2011.00096
Source: PubMed


B cell antigen receptor (BCR) engagement can lead to many different physiologic outcomes. To achieve an appropriate response, the BCR signal is interpreted in the context of other stimuli and several additional receptors on the B cell surface participate in the modulation of the signal. Two members of the Siglec (sialic acid-binding immunoglobulin-like lectin) family, CD22 and Siglec-G have been shown to inhibit the BCR signal. Recent findings indicate that the ability of these two receptors to bind sialic acids might be important to induce tolerance to self-antigens. Sialylated glycans are usually absent on microbes but abundant in higher vertebrates and might therefore provide an important tolerogenic signal. Since the expression of the specific ligands for Siglec-G and CD22 is tightly regulated and since Siglecs are not only able to bind their ligands in trans but also on the same cell surface this might provide additional mechanisms to control the BCR signal. Although both Siglec-G and CD22 are expressed on B cells and are able to inhibit BCR mediated signaling, they also show unique biological functions. While CD22 is the dominant regulator of calcium signaling on conventional B2 cells and also seems to play a role on marginal zone B cells, Siglec-G exerts its function mainly on B1 cells and influences their lifespan and antibody production. Both Siglec-G and CD22 have also recently been linked to toll-like receptor signaling and may provide a link in the regulation of the adaptive and innate immune response of B cells.

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    • "Reduced calcium signalling in response to BCR cross-linking is seen when B cells are either deficient in the enzyme responsible for generating sialylated ligands (ST6GalI) (Hennet et al, 1998; Collins et al, 2002, 2006; Grewal et al, 2006) or express CD22 with a mutated lectin domain (Mü ller et al, 2013). These findings suggest that the binding of sialic acid can modulate the capacity of CD22 to inhibit BCR signalling (Poe et al, 2004; Jellusova & Nitschke, 2012); however, the molecular mechanisms that link CD22 sialic acid-binding activity to its inhibitory role are not yet known. "
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    ABSTRACT: Receptor organization and dynamics at the cell membrane are important factors of signal transduction regulation. Using super-resolution microscopy and single-particle tracking, we show how the negative coreceptor CD22 works with the cortical cytoskeleton in restraining BCR signalling. In naïve B cells, we found endogenous CD22 to be highly mobile and organized into nanodomains. The landscape of CD22 and its lateral diffusion were perturbed either in the absence of CD45 or when the CD22 lectin domain was mutated. To understand how a relatively low number of CD22 molecules can keep BCR signalling in check, we generated Brownian dynamic simulations and supported them with ex vivo experiments. This combined approach suggests that the inhibitory function of CD22 is influenced by its nanoscale organization and is ensured by its fast diffusion enabling a "global BCR surveillance" at the plasma membrane.
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    • "However, it is not known whether macaque CD22 has similar inhibitory functions, carbohydrate binding properties, and involvement in TLR-signaling as has been reported for human and mouse B-cells [139]. In addition human B-cells express Siglec-5, 6, 9 and 10 [139] which as members of the CD33-related group have been shown to evolve more rapidly than CD22 [137], and may also differ in the rhesus macaque. The extent to which potential siglec differences impact B cell regulation in the macaque should be explored to fully elucidate B cell maturation and development and take full advantage of the NHP model. "
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    ABSTRACT: The RV144 clinical trial in Thailand associated vaccine-induced antibodies with protective efficacy, leading to a focus in HIV vaccine research on protective antibody induction. This has necessitated greater understanding of B cell biology in humans as well as non-human primates (NHP), the principle animal model for pre-clinical HIV/SIV vaccine research. This review covers development and maturation of NHP B cells within the framework of current knowledge of human and murine B cells. Identification of many NHP B cell subpopulations is now possible, although consensus is lacking in some cases, and better distinction of some populations is still needed. Elucidation of mechanisms that control germinal center maintenance, selection of B cells into the memory cell pool, and differentiation of B cells into long-term plasma cells remains critical for improving vaccine design. B cell dysfunction occurs during both HIV and SIV infection. Whether the processes leading to this impairment are identical in humans and NHP is not known. Uncovering the mechanisms involved could lead to improved treatment regimens. The SIV/NHP model effectively mimics HIV infection of people, but key differences between NHP and humans in antibody characteristics such as glycosylation and structure may lead to unexpected outcomes in pre-clinical studies. Important new areas for investigation include the role of B cell cytokines in the immune system and the impact of the microbiome on B cell development and maturation. Enhanced knowledge of B cells in NHP as well as humans should enable improved vaccine design, leading to induction of potent, long-lasting protective antibodies.
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    • "TLRs are expressed on cells of the innate immune system, but are also present on B cells. Both Siglec-G-deficient and CD22-deficient B cell showed increased proliferative responses when stimulated with TLR4, TLR7 or TLR9 ligands (Kawasaki et al. 2011; Jellusova and Nitschke 2012). The exact mechanism of the negative regulation of TLR responses is not known; however, CD22 could inhibit TLR-4-dependent NF-kB activation and could reduce TLR-induced expression of SOCS1 and SOCS3 (Kawasaki et al. 2011). "
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    ABSTRACT: CD22 and Siglec-G are two B-cell expressed members of the Siglec (sialic acid-binding immunoglobulin (Ig)-like lectin) family and are potent inhibitors of B-cell signaling. Genetic approaches have provided evidence that this inhibition of B-cell antigen receptor (BCR) signaling by Siglecs is dependent on ligand binding to sialic acids in specific linkages. The cis-ligand-binding activity of CD22 leads to homo-oligomer formation, which are to a large extent found in membrane domains that are distinct from those containing the BCR. In contrast, Siglec-G is recruited via sialic acid binding to the BCR. This interaction of Siglec-G with mIgM leads to an inhibitory function that seems to be specific for B-1 cells. Both CD22 and Siglec-G control B-cell tolerance and loss of these proteins, its ligands or its inhibitory pathways can increase the susceptibility for autoimmune diseases. CD22 is a target protein both in B-cell leukemias and lymphomas, as well as in B-cell mediated autoimmune diseases. Both antibodies and synthetic chemically modified sialic acids are currently tested to target Siglecs on B cells.
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