Genevier, Helen Charlotte; (1997) The mu-surrogate light chain complex on human B cell precursors: Expression and signal transduction. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

An immunoglobulin-like molecule called the μ-surrogate light chain complex (μΨLC complex) is transiently expressed by B cell precursors in the bone marrow. It is expressed on pre-BII cells before the cell becomes a B cell. This thesis describes the investigation of the expression and function of the μΨLC complex in normal human B cell development, leukaemias and cell lines of B cell precursor origin and X-linked agammaglobulinemia (XLA). When cell lines and leukaemias of B cell precursor origin were investigated for expression of the ΨLC genes, VpreB and λ14.1, the leukaemic samples and most cell lines expressed both genes. Antibody ligation of the pre-B cell receptor on the surface of pre-BII cell lines induced Ca2+ mobilisation and an increase in protein tyrosine kinase activity. The immunodeficiency XLA is caused by mutation of the Btk gene and results in a lack of circulating B cells and immunoglobulin, XLA bone marrow samples were shown to contan B cells expressing IgM and pre-B cells that express the μΨLC complex, albeit at a reduced frequency to that found in normal bone marrow. In two experiments using XLA bone marrow, antibody ligation of μ heavy chain on these cells did not induce a Ca2+ flux, whereas normal bone marrow cells, pre-BII and B cell lines did. In a single experiment, antibody ligation of μ heavy chain on XLA bone marrow cells appeared however to induce tyrosine kinase activity. These results are suggestive of a role for Btk in Ca2+ mobilisation in response to ligation of the B cell receptor and the pre-B cell receptor, whereas at least part of the tyrosine kinase response may be independent of Btk. Attempts to develop culture conditions that support maturation of purified B cell precursors, to generate antibodies specific for VpreB and λ14.1 and to develop methods to detect the activation of tyrosine kinases in single cells are also described.

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