IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes

Abstract

IntroductionAlthough intravenous immunoglobulin (IVIg) is widely used to treat idiopathic thrombocytopenic purpura, Kawasaki disease, systemic lupus erythrematosus and Guillain-Barré syndrome, 1 the mechanisms by which immune functions are influenced by such preparations remain to be delineated. 2 Because B lymphocytes play a central role in the immunopathologic processes that cause these diseases, several studies have suggested that B cells are the target cells for the beneficial effect of IVIg. For this hypothesis to apply, IVIg would modulate a broad range of B lymphocyte functions including activation, proliferation, 3 and survival. 4 In other words, IVIg would interfere with the expression of genes and, potentially, the functions of proteins involved in cell growth and death.The interaction between IVIg and B lymphocytes could thus modulate intracellular signaling resulting from the engagement of the B-cell antigen (Ag) receptor (BCR). The earliest signaling events of the ensuing cascade involves activation of the Src-family protein-tyrosine kinase (PTK) Lyn. 5 Activated Lyn phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) on the cytoplasmic domain of the membrane ␣ and ␤ proteins (CD79␣ and CD79␤). Once phosphorylated, CD79␣ and CD79␤ recruit another PTK protein, Syk. Syk associates with phospho-ITAMs via its tandem Src-homology 2 (SH2) domains, is phosphorylated, and in turn, phosphorylates the adaptor protein B-cell linker protein (BLNK). The adaptor thus acquires the capacity to bind to and activate Bruton's tyrosine kinase (Btk). This sequence of signaling events leads to the activation of phospholipase C␥2 (PLC␥2), hydrolysis of phosphatidylinisitol-4,5-bisphosphate and the production of inositol-1,4,5-trisphosphate.As a result, released intracellular calcium synergizes with other signals to induce gene transcription. 6 This promotion implies the recruitment of several transcription factors (TFs) that influence B-cell proliferation, differentiation, cytokine production, and apoptosis. 7,8 The outcome of BCR engagement is variable, depending on the status of the B cell and commitment of coreceptors. The latter dictate the ultimate response and associate positive regulators (such as CD19 and CD21) and negative regulators (such as CD22 and CD32) and these ultimately determine the outcome of B-cell responses. Under normal conditions, both groups of proteins are expressed at varying levels on the surface of all B lymphocytes and their engagement contributes to setting the threshold of B-cell activation. This is often achieved by increasing or decreasing tyrosine phosphorylation, thereby enhancing or reducing signal transduction. 9 CD22 conveys the SH2 domain-containing phosphatase 1 (SHP-1) over to the BCR through the immunoreceptor tyrosinebased inhibition motifs (ITIMs) located in its cytoplasmic domain. 10 This membrane protein belongs to the sialic acid (SA)-binding Ig-like lectin (Siglec) superfamily, with 7 Ig-like extracellular domains and an amino-terminal Ig domain. CD22 is u...

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc− mouse model

“…However, we demonstrated a transient delay in B-cell reconstitution for the first 49 days post-injection in the IVIG-treated mice. It was recently shown by Se´ı¨te´et al 78 that IVIG reduced B-cell viability and promoted apoptosis of B-cells by binding to CD22. Our model should allow us to test this hypothesis and investigate the other potential mechanism(s) by which early B-cell reconstitution is affected by IVIG.…”

Dynamics of Memory B-Cell Populations in Blood, Lymph Nodes, and Bone Marrow during Antiretroviral Therapy and Envelope Boosting in Simian Immunodeficiency Virus SIVmac251-Infected Rhesus Macaques

“…However, whether CD22 could contribute to the loss of activated memory B cells in HIV and SIV infections is not known. Previous studies using intravenous immunoglobulin, which is able to bind CD22 by means of its sialic acid component, have shown that the cross-linking of CD22 together with the activation of the B-cell receptor by bound antigen or antibody can induce B-cell apoptosis (52). Whether altered glycosylation patterns arising in HIV or SIV infection might result in such an operative mechanism and contribute to the elimination of activated memory B cells requires further investigation.…”

Acute Intravenous Infusion of Immunoglobulins Protects Against Myocardial Ischemia-Reperfusion Injury Through Inhibition of Caspase-3

“…These effects result from several mechanisms, such as suppression of NLRP1 and NLRP3 inflammasome activity, anti-Fas effects, inhibition of the caspase-3, caspase-8 and caspase-9 cascades, modulation of BCR signaling and inhibition of complement-mediated apoptosis [26, 44-47]. Furthermore, other immunomodulatory effects of IVIG may have played a role in this cardioprotective effect, so further studies are needed to better understand these mechanisms.…”