title: B cell development and activation defects resulting in xid-like immunodeficiency in BLNK/SLP-65-deficient mice.
abstract: Engagement of the B cell receptor (BCR) leads to the activation of tyrosine kinases and other signaling molecules that ultimately determine the type and magnitude of the B lymphocyte's cellular response. The adaptor protein BLNK/SLP-65 plays a pivotal role in BCR signal transduction by coupling Syk activation to downstream elements such as Grb2, phospholipase C-gamma, Vav and Nck. We have generated BLNK(-/-) mice to determine the physiological role of this protein in B cell development and activation. BLNK(-/-) mice exhibit an incomplete block in B cell development with a severe inhibition of pro-B to pre-B cell differentiation. BLNK(-/-) sIgM(+) cells can develop, seed the peripheral lymphoid tissues and accumulate in numbers overtime. However, these mutant B cells failed to mature and are non-responsive to BCR cross-linking in terms of proliferation and up-regulation of activation markers such as CD69 and CD86 (B7-2). In addition, the CD5(+) subset of B cells is absent. The immune response to T cell-independent antigen but not T cell-dependent antigen is also impaired. Overall, the phenotype of BLNK(-/-) mice bears a striking resemblance to that of xid mice which is the murine model of human XLA that has a mutation in Bruton's tyrosine kinase. This raises the interesting possibility that mutation in BLNK/SLP-65 may be responsible for certain human immunodeficiencies.
authors.affiliation: Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Drive, Singapore 117609, Republic of Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.forename: J E
authors.initials: JE
authors.lastname: Tan
authors.forename: E P
authors.initials: EP
authors.lastname: Wong
authors.forename: A
authors.initials: A
authors.lastname: Manickam
authors.forename: S
authors.initials: S
authors.lastname: Ponniah
authors.forename: K P
authors.initials: KP
authors.lastname: Lam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology*; D001853:Bone Marrow / Q000473:pathology; D018956:CD5 Antigens / Q000032:analysis; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D006801:Humans; D007072:Immunoglobulin D / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D010529:Peritoneal Cavity / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000888:Antibodies, Anti-Idiotypic; C113939:B cell linker protein; D018956:CD5 Antigens; D002352:Carrier Proteins; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D010750:Phosphoproteins; C044203:anti-IgM