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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...

Human Breg cells control T cell maturation, expand follicular regulatory T cells, and inhibit the T cell-mediated antibody secretion. These novel observations demonstrate a role for the Breg cell in germinal center reactions and suggest that deficient activities might impair the T cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses.

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