GENETICALLY DETERMINED IMMUNODEFICIENCIES--ANALYSES OF DEFECTS AND THERAPIES

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

The overall goal of this research is to define the cellular and, ultimately, the molecular bases for both currently recognized and yet to be defined primary immunodeficiency diseases, so as to provide the most rational and effective therapies for them. Correlative studies of lymphocyte phenotypes and function in patients with genetically-determined immuno-deficiency will provide clues to as yet undiscovered molecular derangements and also permit the discovery of atypical phenotypes resulting from known mutations. Most boys with SCID who have a high percentage of B cells and very low percentages of NK cells and low NK function will prove to have mutations in the gene encoding gamma-c, even though a majority will have a negative family history. Girls with this phenotype (or boys with this phenotype who do not have mutations in the gene encoding gamma-c) will prove to have Jak3 deficiency. SCID infants who express no gamma-c or Jak3 mRNA or protein will have more profound defects in B and NK cell function and will be clinically more severely affected than infants expressing gamma-c or Jak3 mRNA and proteins with amino acid substitutions. SCIDs who do not have gamma-c or Jak3 mutations will be studied for the presence of other known mutations, such as RAG1 or RAG2 deficiencies (ADA is usually excluded at the initial evaluation) or as yet unknown mutations, such as IL-7 or IL7R mutations. Studies of B cell isotype switching and immunoglobulin production with anti-CD40 monoclonal antibody plus IL-4 and other cytokines whose receptors do or do not share the gamma-c will contribute to the understanding of the nature of the B cell defect in severely antibody-deficient SCID's, as well as in other types of primary antibody deficiency diseases (such as non-X-linked Hyper IgM). Serial post-transplantation analyses of phenotypes, functions and genetic origins of lymphocytes in SCID recipients of haploidentical T cell-depleted parental marrow stem cells will reveal new information about T, B, and NK cell ontogeny not available in any other human experimental system.