Immunodeficiency

Faculty active in this area of research are listed below. For a brief description of their research interests, click on their name in the list. Clicking on the name at the beginning of the brief description links to their detailed personal website.


T. Prescott Atkinson, MD, PhD, Department of Pediatrics
Randy Q. Cron, MD, PhD, Department of Pediatrics
Harry Schroeder, MD, PhD, Dept of Medicine/Clin Immun & Rheumatology



T. Prescott Atkinson, MD, PhD Research in my laboratory is focused on the role of infection in chronic diseases, especially arthritis and asthma. Ongoing projects in coordination with the UAB Diagnostic Mycoplasma Laboratory are designed to identify mycoplasmas and ureaplasmas in human samples with particular emphasis on the role of those organisms in chronic asthma and extreme prematurity respectively.  Previous studies in my laboratory established that Mycoplasma pneumoniae is able to activate mast cells to produce IL-4 through sialic acid-dependent binding to the high affinity receptor for IgE, a finding with potential implications in the pathogenesis of asthma and potentially a general mechanism in the activation of cells of the immune system by that organism. Work is currently proceeding to determine the current prevalence of macrolide resistance strains of M. pneumoniae in the Birmingham area. I am also actively engaged in the development of rational strategies to determine the molecular basis for unidentified immunodeficiencies in patients in my weekly clinical immunology clinics at Children’s of Alabama. Such patients may represent natural “knockouts” or dominant negative mutations in signaling molecules and provide valuable insights into critical steps in receptor signaling in the human immune system.


Randy Q. Cron, MD, PhD  CD154 (CD40 ligand) dysregulation in lupus.  Systemic lupus erythematosus, the prototypic autoimmune disorder, affects 1 in 2,000 women in the United States. Although the etiology and pathogenesis are unclear, the over-expression of the TNF family member, CD154, on CD4 T lymphocytes clearly contributes to CD154HSSdisease pathology, both in mouse models and in humans with disease. Ourultimate goal is to identify cis- and trans-acting elements that contribute to the dysregulated expression of CD154 in SLE and other autoimmune disorders. We initially characterized the human CD154 transcriptional promoter and demonstrated its cyclosporin A (CsA) sensitivity. We are currently probing the hCD154 gene locus by DNase I hypersensitive site mapping to identify novel regulatory elements.  We have identified and partially characterized a 5’ TFregulateCD154transcriptional enhancer, a 3’ transcriptional enhancer, and a 3’ untranslated mRNA stability element. In addition, we have identified an uncharacterized 5’ hypersensitive site farther upstream of the transcription start site. We are currently exploring the activities of these various CD154 regulatory elements as transgenes in a mouse model of SLE. In conjunction, we have identified various transcription factors and RNA binding proteins, which had not been previously described to regulate CD154 expression. We are currently exploring these factors for their contributions to CD154 dysregulation in SLE.

Host transcription factors exploited by HIV-1. HIV-1, the cause of AIDS, has infected over 40 million individuals world-wide. Although vast improvements in therapy have been developed over the last decade, HIV-1 cannot be totally eliminated from the host due to its ability to enter a resting or latent state in NFATbindHIVCD4 T cells. Because HIV-1 relies on host transcription factors to replicate, we are exploring the role of the calcium activated nuclear factor of activated T cells (NFAT) transcription factors in regulating HIV-1 transcription. We and others have shown that the CsA-sensitive NFAT proteins bind to the proximal HIV-1 promoter/long terminal repeat (LTR) in vitro and up-regulate HIV-1 transcription. We have further demonstrated that NFAT proteins bind to the integrated HIV-1 LTR in primary human CD4 T cells in vivo by chromatin immunoprecipitation, and this binding is disrupted by the regulatory T cell transcription factor, FOXP3. In addition, we are attempting to exploit NFAT activation as a means of activating HIV-1 LTR activity in latently infected cells. Recently, we identified a novel binding site for the c-maf transcription factor located adjacent to the proximal NFAT sites in the HIV-1 LTR. Our studies reveal synergistic transcriptional activation and increased infection of HIV-1 by c-maf, NFAT2, and NFB p65 in primary human IL-4-producing CD4 T cells. Thus, c-maf will likely be a novel therapeutic target in the treatment of HIV-1.


Harry Schroeder, MD, PhD
   Ultimately, it is the identity and specificity of the lymphocyte antigen receptor that determines the nature of the immune response to antigen. The mechanisms that underlie the diversification of the B- and T-cell antigen receptor repertoires appear to generate receptor diversity at random. However, repeated examples of near to absolute identity of receptor sequences between individuals suggest the existence of genetically programmed constraints that may be designed to bias the immune system to produce preferred, and perhaps optimal, repertoires. The implication is that violation of these programs could lead to immune dysfunction, and thus to disease. To test this hypothesis, we are developing mouse models wherein we force expression of altered, polyclonal repertoires that violate normal constraints on antigen receptor sequence or structure. In the first of these mice, where we have forced expression of arginine, histidine and asparagine in the HCDR3 interval of immunoglobulin H chains, we observed somatic selection against antigen binding sites that contained an excess number of these charged amino acids, yet the system ultimately failed to recapture the tyrosine and glycine residues normally encoded by wild-type germline sequence. B-cell development was impeded, immunity to influenza virus was impaired, and expression of IgG anti-DNA antibodies was enhanced. These results support the view that optimal distinction between self and non-self is a product of evolutionary selection.