The B cell receptor

The B-cell receptor

The B-cell receptor is a multimeric complex formed by the assembly of a surface immunoglobulin homodimer and a non-covalently-bound heterodimer Igα/Igβ (CD79A/CD79B). Low expression of the B-cell receptor is the hallmark of lymphocytes in chronic lymphocytic leukaemia.[23]

The mechanisms accounting for poor expression of the B-cell receptor in chronic lymphocytic leukaemia remain elusive. With the exception of one report of mutation in CD79B,[24] no genetic defects in B-cell-receptor components have been recorded.[25] and [26] By contrast with their poor expression at the membrane level, transcription and intracellular synthesis of components of the B-cell receptor are normal,[26] and [27] but they cannot be assembled and transported from the endoplasmic reticulum to the cell surface because of a folding and glycosylation defect of the μ and CD79A chains, although not of the CD79B chain. Poor expression of the CD22 molecule in B-cell chronic lymphocytic leukaemia cells was also shown to result from a folding defect arising in CD79A.[28]

Most B-cell chronic lymphocytic leukaemia cells express CD5 and IgM/IgD and, thus, have a mantle zone-like phenotype of naive cells that, in normal conditions, express unmutated immunoglobulin genes.[29] However, 50–70% of cases of chronic lymphocytic leukaemia have somatic mutations of IGHV genes,[30] as if they had matured in a lymphoid follicle. Presence or absence of somatic mutations is associated with particular IGHV genes. Specific alleles of the IGHV1-69 gene [31] and the IGHV4-39 gene have an unmutated profile.32 Subsequently, workers have reported [32] that more than 20% of patients with chronic lymphocytic leukaemia carry stereotypic B-cell receptors.[33], [34] and [35] Of note, the IGHV3-21 gene shows strikingly homologous IGHV and IGLV gene rearrangements and is associated with poor prognosis, whether expressed in a mutated or unmutated form.[36] and [37] These results strongly suggest that a common antigen epitope is recognised by these highly homologous molecules. With respect to the epitope recognised, research has shown that unmutated chronic lymphocytic leukaemia cells express highly polyreactive antibodies, whereas most mutated ones do not.[38] and [39] Infections with encapsulated organisms might be a trigger for development of chronic lymphocytic leukaemia, and work has shown that individuals with a history of pneumonia are significantly more likely to develop chronic lymphocytic leukaemia than are people without this history, and that the risk increases with number of attacks.[40] and [41]

When stimulated through the B-cell receptor pathway, the response of chronic lymphocytic leukaemia cells is impaired. Low expression of the B-cell receptor correlates with reduced induction of protein tyrosine kinase activity and defective intracellular calcium mobilisation and tyrosine phosphorylation.[42] Individuals have differing responses to IgM ligation, related to IGHV gene status. Findings of one study showed that chronic lymphocytic leukaemia cells expressing unmutated IGHV genes had a better response in most cases to stimulation via the B-cell receptor than did cells expressing mutated IGHV genes.[43]

Unexpectedly, high amounts of ZAP70—a receptor-associated protein tyrosine kinase usually found in T cells and natural killer cells but not in normal circulating B cells—are detected in most patients with unmutated chronic lymphocytic leukaemia.[44] Chronic lymphocytic leukaemia B cells that express ZAP70 are more likely to respond to IgM crosslinking with increased tyrosine phosphorylation and calcium flux than are those that do not express ZAP70. This effect might happen for any or all of the following reasons. First, after B-cell receptor ligation, ZAP70 undergoes tyrosine phosphorylation and becomes associated with surface immunoglobulin and CD79B.[45] Second, ZAP70 mediates inhibition events that terminate the signalling response.[46] Finally, ZAP70 expression is associated with advantageous survival responses because of enhanced access to proliferation centres.[47] Altogether, expression of ZAP70 in chronic lymphocytic leukaemia allows effective IgM signalling in B cells, which might lead to an aggressive disease course.

The apparently anomalous expression of ZAP70 in chronic lymphocytic leukaemia cells is not accounted for completely. Heat-shock protein 90 (HSP90) is a molecular chaperone that catalyses the conformational maturation of many signalling proteins in cancer, known collectively as clients. With inhibitors of HSP90, Castro and colleagues [48] showed that ZAP70 is a client protein in tumour cells, but not in T cells, from patients with ZAP70-positive chronic lymphocytic leukaemia, suggesting that the presence of ZAP70 is an oncogenic event. On the other hand, ZAP70 is expressed at various stages of B-cell maturation and in other B-cell malignant diseases. It is present in normal pre-B cells and pro-B cells and in acute leukaemias derived from them.[49] By studying normal tonsillar cells, Nolz and coworkers [50] and Cutrona and colleagues [51] detected ZAP70-positive B cells, concentrated particularly in germinal centres. ZAP70 seems to be coexpressed with other activation markers. In chronic lymphocytic leukaemia, higher amounts of ZAP70 are expressed by lymph-node cells than by circulating cells.[52] In turn, high levels of ZAP70 expression lead to increased sensitivity to chemokine migratory signals.[53] Whether expression of ZAP70 in chronic lymphocytic leukaemia cells is a result of frequent visits to proliferation centres or is the cause of enhanced access to them is still not clear.

Another unexpected molecule expressed by a subset of chronic lymphocytic leukaemia B cells is CD38. In the B-cell compartment, CD38 is not a lineage marker, but this molecule is expressed at times during B-cell development when cell-to-cell interactions are crucial.[54] Examples include an early bone-marrow precursor cell, cells in the germinal centre, and plasma cells.[55] In chronic lymphocytic leukaemia, expression of CD38 predominates in patients with unmutated IGHV genes and is associated with poor prognosis.18 Expression of CD38 in chronic lymphocytic leukaemia B cells favours B-cell growth and survival through sequential interactions between CD38 and CD31 and between CD100 and plexin B1 (PLXNB1).[56]

The activation-induced cytidine deaminase (AICDA), a B cell-restricted enzyme needed for somatic mutation and isotype switching, is upregulated in unmutated chronic lymphocytic leukaemia cells.[57], [58] and [59] Although evidence exists that AICDA expression could be confined to a small proportion of the clone,[60] AICDA seems to be functional, since unmutated cases of chronic lymphocytic leukaemia can generate isotype-switched transcripts and proteins and mutations in the pre-switch μ region.[57] Upregulation of AICDA could be associated with loss of target specificity, resulting in mutations in non-immunoglobulin genes such as BCL6, MYC, PAX5, and RHOH, which are linked to aggressive disease.[61] and [62]

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