ABSTRACT
PURPOSE OF REVIEW: To describe novel immunological and molecular findings regarding early B cell development arrest resulting in autosomal recessive agammaglobulinemia. RECENT FINDINGS: Recently two different groups identified mutations in Ig beta, a component of the pre-B cell receptor, responsible for agammaglobulinemia in humans. These are the first two patients ever described with mutations in Ig beta. SUMMARY: These novel findings broaden the spectrum of genetic defects underlying this rare condition. This novel cause of agammaglobulinemia not only sheds light into early B cell development in humans but also sets the basis for potential alternative therapeutic approaches such as gene therapy.
Subject(s)
Agammaglobulinemia/genetics , Agammaglobulinemia/pathology , B-Lymphocyte Subsets/metabolism , B-Lymphocytes/metabolism , CD79 Antigens/deficiency , Agammaglobulinemia/therapy , Animals , B-Lymphocyte Subsets/pathology , B-Lymphocytes/pathology , CD79 Antigens/genetics , CD79 Antigens/immunology , DNA Mutational Analysis , Genes, Recessive/immunology , Genetic Therapy/trends , Humans , Mice , Mice, Knockout , MutationABSTRACT
Signals from the pre-B cell receptor (pre-BCR) mediated by the cytoplasmic tails of Ig-alpha/Ig-beta are essential for developing B cells. To analyze the role of Ig-alpha ITAM and non-ITAM tyrosines in pre-BCR signaling, we reconstituted individual tyrosine mutants of Ig-alpha in src homology 2 domain-containing leukocyte protein of 65 kDa (SLP-65)/Ig-alpha double-deficient pre-B cells. We show that the Ig-alpha mutants led to comparable pre-BCR expression on the cell surface, while the pre-BCR-induced tyrosine phosphorylation was different. We further show that the reconstitution of Ig-alpha and the resulting pre-BCR expression led to enrichment of the pre-BCR-expressing cells in vitro irrespective of the introduced Ig-alpha mutation. We show that, even though the enrichment rate increased by lowering the IL-7 concentration, residual amounts of IL-7 were required for optimal enrichment. Our results indicate that surface IL-7 receptor expression is modulated by the pre-BCR, thereby increasing the IL-7 sensitivity of the respective cells. In contrast to the comparable pre-B cell proliferation, however, the Ig-alpha mutants differed in their capacity to induce calcium flux and activate efficient pre-B cell differentiation. Together, our data suggest that ITAM tyrosines and Y204 are required for efficient pre-B cell differentiation but not proliferation.
