Charlotte Cunningham-Rundles, MD, PhDCharlotte Cunningham-Rundles (Preferred Name)

In this laboratory, the area of investigation is human immunodeficiency diseases and immuno-reconstitution. This work has been supported by research grants from the Food and Drug Administration and the NIH, Division of Allergy Immunology and Transplantation, Child Health and Human Development and USIDNet. We are investigating B, T cell and dendritic cell immunity in a primary immunodeficiency disease, common variable immunodeficiency (CVID.) A recent theme is the investigation of B cell memory in this and other immune defects; CD27+B cells, and especially isotype switched B memory cells are deficient, which is related to lack of normal vaccine responses. How the development of B cell memory relies upon triggering of Toll like Receptors is under investigation, using methylated oligonucleotides containing CpG motifs. TLR9 function is abnormal in this immune defect a factor that leads 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 or other TLR ligands. We are also particularly interested in the role of specific mutations in the TACI gene, either producing or influencing the CVID phenotype, and the role of related TNF family members in the abnormal immunity in B cell defects. Further studies using gene arrays in the investigation of human B cell defects are ongoing. While the phenotype of this disease is hypogammaglobulinemia, T cell and antigen processing defects result in anergy, defective co-stimulation, accelerated apoptosis and deficient cytokine production. We previously found that some of these T cell defects could be reversed by the administration of IL-2, allowing an opportunity to explore some of the mechanisms by which this cytokine activates and regulates human T cell immunity. Since T cell receptor co-stimulation is abnormal in CVID, a deficiency of intracellular signaling pathways could explain defective proliferation, anergy, cytokine deficiency, and premature apoptosis. We have investigated in what way the CD28 signaling other co stimulatory pathways differ from normal T cells, analyzing early signaling events, membrane reorganization, up-regulation of Bcl-xL, and the effects of receptor triggering on transcription and stabilization of cytokine mRNA. In other studies we have found markedly deficient production of IL-12 by monocycle derived dendritic cells, a deficit that could further lead to anergy. We have also investigated ICOS gene and its ligand, in CVID subjects, since mutation of ICOS in humans can lead to the CVID phenotype.