The Human Immunodeficiency Diseases and Immune Reconstitution Laboratory investigates B, T cell and dendritic cell immunity in primary immunodeficiency diseases. Primary immune deficiency diseases, now estimated at over 150, provide a valuable resource for investigators in human immunology. The first identified immune defects in humans were described in infants with unusual and/or severe phenotypes; many of these were found due to mutations of genes on the X-chromosome. However, primary immune diseases are now known to affect humans of all ages, both females and males, and to have characteristic complications, but not necessarily lethal consequences.
While there have been amazing advances in the understanding of these diseases, the defects that lead to the most common immune defects of B cells are still largely uncharted territory. For the reasons, this laboratory concentrates on diseases in which antibody production is impaired. A recent theme in one of these diseases, common variable immunodeficiency (CVID) is that the development of B cell memory is impaired. CVID B cells lack the capacity for normal somatic hyper-mutation, secrete immune globulins poorly, and fail to differentiate into plasma cells. The result is reduced serum levels of IgG, IgA and/or IgM and lack of protective antibody, leading to recurrent life threatening infections. A unifying theme in CVID is that the number of peripheral blood isotype-switched memory B cells, is correlated with restricted VH gene families and reduced somatic hyper-mutation of variable heavy chain genes, and loss of antibody production in vitro and in vivo. While the genetic causes of B cell dysfunction in CVID are unknown for most subjects, several genes and pathways contributing to the block in B cell development are known. This laboratory is investigating some of these pathways to better understand this loss of B cell function. One pathway under study relies on signaling via Toll like receptors (TRL) as triggering these receptors leads to immune globulin production and the development of B cell memory. TLR7, 7/8 and 9 function are abnormal in CVID; these defects lead to poor B cell proliferation, loss of cytokine production, lack of cell adhesion and defective B cell memory responses. Plasmacytoid dendritic cells are also unable to respond normally to these and other TLR ligands suggesting that these are not B-cell restricted defects.
In other experiments, we are also particularly interested in the role of specific mutations in the Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) gene, in either producing or influencing the CVID phenotype. These observations suggest that the normal functions of TACI and its ligands, B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) are to initiate and control B cell growth and differentiation. Both TLR receptor and TACI receptor activation lead to the production of antibodies to carbohydrate-rich T independent antigens, which is particularly interesting as TACI activation was recently shown to reply upon one of the central TLR adaptor molecules, MYD88.
As the field of antibody defects is still largely uncharted, other gene candidates are being sought. For this, studies using DNA and RNA gene arrays in the investigation of human B cell defects are ongoing.
Our research is supported by research grants from the NIH, Division of Allergy Immunology and Transplantation, Child Health and Human Development and the USIDNet Consortium.
Charlotte Cunningham-Rundles, MD, PhD
1425 Madison Avenue,1st Floor
New York, NY 10029