CD22 Is Both a Positive and Negative Regulator of B Lymphocyte Antigen Receptor Signal Transduction: Altered Signaling in CD22-Deficient Mice

Abstract

B cell activation following antigen receptor cross-linking can be augmented in vitro by ligation of cell surface CD22, which associates with the SHP1 protein tyrosine phosphatase. The targeted deletion of CD22 in mice demonstrated that CD22 differentially regulates antigen receptor signaling in resting and antigen-stimulated B lymphocytes. B cells from CD22-deficient mice exhibited the cell surface phenotype and augmented intracellular calcium responses characteristic of chronically stimulated B cells, as occurs in SHP1-defective mice. Thus, CD22 negatively regulates antigen receptor signaling in the absence of antigen. However, activation of CD22-deficient B lymphocytes by prolonged IgM cross-linking resulted in modest B cell proliferation, demonstrating that CD22 positively regulates antigen receptor signaling in the presence of antigen.

Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies

“…For CD22-positive B-cell lymphoma, immobilized but not soluble epratuzumab can inhibit cellular proliferation, regardless of crosslinking (Nitschke et al, 1997). CD22 has been observed to negatively regulate signaling (PawlakByczkowska et al, 1989;O'Keefe et al, 1996;Otipoby et al, 1996;Sato et al, 1996), although other studies with human B-lymphoma cells suggest an involvement of CD22 with the BCR that can inhibit proliferation (Nitschke et al, 1997). These and other factors appear to be involved in the activity of epratuzumab in the biologically complex groups of lymphoma and autoimmune diseases.…”

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

“…B cells from mice deficient in Lyn (10)(11)(12), CD22 (13)(14)(15)(16), SHP-1 (17,18) exhibit a hyperreactive phenotype and produce autoantibodies. Indeed, Lyn-deficient mice demonstrate activation of autoreactive B cells and subsequent SLE-like symptoms, such as the production of anti-double-stranded DNA (anti-dsDNA) antibodies, splenomegaly, and glomerulonephritis (11,12).…”

Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

“…The CD22-deficient mouse model is of great interest to investigators of B cell tolerance and autoimmunity because it represents the immunologic and pathologic consequences of a single genetic defect, leading to B cell hyperactivity, loss of self tolerance and the production of autoantibodies [12][13][14][15][16]. Moreover, it may represent a mostly peripheral B cell defect which is likely to have a particular influence on mature B cells in secondary lymphoid organs.…”

“…Negative regulatory roles for CD22 in BCR signaling are proposed to be critical for normal B cell activation, since immunoreceptor tyrosine-based inhibitory motifs with- in CD22 recruit SHP-1, a potent intracellular phosphatase with inhibitory functions in BCR signaling [10,11]. CD22-deficient mice [12][13][14][15] were reported to have decreased numbers of circulating B cells and slightly increased numbers of peritoneal B-1 cells, as well as higher levels of serum IgM [12,14]. Significantly, mature B cells from CD22-deficient mice had decreased expression of cell surface IgM and augmented intracellular calcium responses, characteristic of chronically stimulated B cells [8].…”

“…In the periphery, CD22 is found to be broadly expressed on all mature B cell subsets, including class-switched B cells [8, 9,40]. Additionally, in CD22-deficient mice, expression levels of cell surface IgM are significantly reduced on mature B cells, probably as a consequence of augmented transmembrane signaling through the BCR complex; however, IgM levels on BM immature B cells are unchanged or slightly increased in these mutant mice [41].In this respect, CD22 -/--induced autoimmunity may resemble several other mouse models of SLE, in which the autoimmune driving force is thought to be confined to the periphery, such as chronic graft-versus-host (cGVH) mice [42,43], or B cell-activating factor belonging to the TNF family (BAFF)-Tg mice [44]. In these mouse models, central B cell tolerance may be intact, similarly to non-autoimmune animals, in which non-edited, high-affinity anti-DNA-expressing immature B cells are centrally deleted in the BM very efficiently [32].…”