NIH Genetic Aspects of Immunodeficiency

St. Jude Children'S Research Hospital, Memphis TN

Investigators

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Abstract

DESCRIPTION (provided by applicant): The overall goal of this project is the identification and characterization of genes that are responsible for agammaglobulinemia and absent B cells in patients with immunodeficiency. Approximately 85% of patients with early onset of infections, pan-hypogammaglobulinemia and markedly reduced or absent B cells have X-linked agammaglobulinemia (XLA), which is caused by mutations in the cytoplasmic tyrosine kinase Btk. XLA is a leaky defect in B cell development, and most patients do have a small number of B cells in the peripheral circulation. These B cells have a characteristic phenotype with high intensity surface IgM and low intensity CD19. Our laboratory has identified 197 different mutations in Btk in 239 unrelated families. We have shown that the specific mutation in Btk is one of the factors that influences the severity of disease, but the genotype/phenotype correlation is not strong. There are likely to be other genetic factors that influence the severity of XLA. We have shown that mutations in ? heavy chain, ?5, Ig?, Ig? or BLNK account for half of the remaining 15% of patients. Like the patients with mutations in Btk, a patient with an amino acid substitution in Ig? and a patient with a defect in BLNK had a small number of B cells in the blood with decreased intensity of CD19, suggesting that this phenotype represents diminished signaling through the B cell receptor. Among the 70 unrelated families with defects in B cell development of unknown etiology that we have studied, three unrelated patients are of particular interest because they have a small number of B cells that have high intensity CD19 but no surface B cell receptor. EBV lines from these patients show no functional VDJ rearrangements. We hypothesize that these patients have mutations resulting in constitutive activation of the BCR pathway. The study families, which have been referred from all over the world, are a unique resource. A better understanding of the genetic requirements for normal B cell development will help in the design of strategies for vaccine development and treatment of autoimmune disease. The specific aims of this proposal are: 1) To examine the functional consequences of mutations and polymorphic variants identified in components of the B cell receptor signaling pathway. We will determine whether variants in ? heavy chain, ?5, Ig?, Ig?, Btk or BLNK result in decreased protein stability, failure to interact with other components of the BCR or if they inhibit signal transduction. The influence of polymorphic variants in the components of the pre-BCR and BCR on the severity of the B cell defect in patients with XLA will also be examined. 2) The possibility that constitutive activation of the BCR signaling pathway is responsible for the unusual B cell phenotype in patients with a small number of BCR- , CD19 bright B cells will be explored. 3) Unbiased approaches will be used to identify mutant genes in patients with defects in B cell development of unknown etiology. Homozygosity mapping, using SNP microarrays, and expression arrays will be evaluated.