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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.

J. Edwin Blalock, PhD, Department of Medicine
Elizabeth E. Brown, PhD, Department of Epidemiology
Peter D. Burrows, PhD, Department of Microbiology
Randall Q. Cron, MD, PhD, Department of Pediatrics/Pediatric Rheumatology
Randall S. Davis, MD, Department of Medicine
Jeffrey Edberg, MD, Dept of Medicine/Clin Immunology & Rheumatology
Hui-Chen Hsu, PhD, Department of Medicine
Hui Hu, PhD, Department of Microbiology
Robert Kimberly, MD, Dept of Medicine/Clin Immunol & Rheumatology
John Mountz, MD, PhD, Dept. Medicine-Clin Immunology & Rheumatology
Trenton R. Schoeb, DVM, PhD, Department of Genetics
Harry W. Schroeder, Jr, MD, PhD, Dept. Medicine-Clin Immunology & Rheumatology
Alexander Szalai, PhD, Dept of Medicine/Clin Immunol & Rheumatology
Jianming (James) Tang, PhD, Department of Medicine

J. Edwin Blalock, PhD The overall objective of our current research is to delineate certain genetic rules that govern the shape and function of proteins and peptides. Specifically, nucleic acids encode amino acid sequences in a binary fashion with regard to hydropathy. We and others have provided compelling evidence that the exact pattern of polar and nonpolar amino acids, rather than the precise identity of particular R groups, is an important driving for protein shape. Structural proof for this idea is being pursued through determination of the 3-dimensional structures of peptides with dissimilar primary amino acid sequences but identical binary codes. These design principles are being used: 1) to make synthetic peptides specifically targeted to act as agonists and antagonists of Ca++ channels involved in human immunodeficiency virus-mediated apoptosis and 2) to make synthetic peptide vaccines as immunotherapeutic agents against autoimmune diseases of the nervous system such as myasthenia gravis (MG) and multiple sclerosis (MS). Additional research areas include: First, together with colleagues at the University of Utrecht, we are evaluating the aforementioned peptide regulators of Ca++ channels for utility in models of asthma. Second, together with Dick Marchase's group, we are elucidating the structure and function of a novel Ca++ influx factor (CIF) which is a key signal for store-operated Ca++ entry. Third, we are studying the role of these CIF-operated channels, as well as their regulation by glucosamine in diabetes.

Elizabeth E. Brown, PhD Using models of autoimmunity and immune-suppression, the work in our laboratory is targeted toward understanding the natural history of viral infections and aberrant immune function common to inflammatory-mediated chronic diseases. Of particular interest is the genetic basis of select host-pathogen interactions, virally-associated cancers, select lymphomas, systemic lupus erythematosus (SLE) and systemic vasculitis, each with underlying B cell pathologies. Within this purview, we use a multi-disciplinary functional genomics approach to explore pathways involved in chronic immune perturbation, B cell homeostasis, cytokine signaling as modifiers of disease, mucosal immunity and immune senescence as markers of complex disease susceptibility, morbidity and mortality. The goal of this research is to identify and validate molecular biomarkers of clinical outcomes, which may be used to target high-risk populations to prevent or reduce disease burden.

Peter D. Burrows, PhD Dr. Burrows' laboratory is interested in the development and function of B lymphocytes. Immunoglobulin gene rearrangements, as well as a number of poorly understood changes in gene expression, take place as cells progress through this differentiation pathway. We have been using both cellular and molecular approaches to characterize precursors of human B lineage cells and to identify novel genes whose expression is developmentally regulated. Defects in the expression of such genes could lead to immunodeficiency, whereas inappropriate expression might predispose a cell to malignant transformation. His lab has also begun to explore the function of the multifaceted cytokine, transforming growth factor-beta, in regulating B cell development and function and have identified a novel Fc receptor gene that appears to be expressed in the cytoplasm of germinal center B lymphocytes.

Randall Q. Cron, MD, PhD 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 NFΚB 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.

Genetic defects in lymphocyte cytolysis in macrophage activation syndrome. Macrophage activation syndrome (MAS) is a hyper-inflammatory immune response in children and adults that is often triggered by certain infectious (e.g. EBV), autoimmune (e.g. lupus), autoinflammatory (e.g. Still disease), and oncologic (e.g. T cell leukemia) disorders. MAS results in pro-inflammatory cytokine storm leading to pancytopenia, coagulopathy, central nervous system dysfunction, and multi-organ system failure. MAS is frequently lethal like its cousin disease familial hemophagocytic lymphohistiocytosis (fHLH). fHLH is uniformly fatal if not treated aggressively and typically presents in the first few months of life in infants Picture2with bi-allelic genetic defects in one of the proteins involved in perforin mediated cytolysis by natural killer (NK) cells and CD8 cytotoxic lymphocytes. Recently, mono-allelic (heterozygous) mutations in cytolytic pathway proteins (e.g. perforin, Munc13-4, Rab27a, etc.) have been identified in a substantial percentage of MAS patients presenting beyond infancy. In our MAS patient cohort, we have identified several mutations, including novel mutants, in a variety of cytolytic pathway genes. Using lentiviral transduction of mutant and wild-type genes into NK cells, we demonstrate decreased cytolytic activity by over-expression of the mutant genes, suggesting a partial dominant-negative effect. These studies suggest that there are likely genetic predispositions to develop MAS, and we are currently exploring the novel mutations and their pathophysiological consequences on lymphocyte mediated cytolytic function.

Randall S. Davis, MD Dr. Davis’ laboratory investigates pathways of normal lymphocyte differentiation to determine the mechanisms that contribute to lymphomagenesis, autoimmunity and immunodeficiency. This work largely focuses on an ancient family of Ig-like receptors with tyrosine-based activating or inhibitory signaling potential. A search for possible Fc receptor relatives identified several novel Ig superfamily genes in humans and mice termed Fc receptor-like molecules (FcRL). FcRL family members are preferentially expressed in B lymphocytes and differentially identified in B lineage malignancies. Follow-up studies have identified eight human and seven mouse relatives in total. The recognition of this family has significant implications for understanding connections between innate and adaptive humoral immunity, the regulation and terminal differentiation of B cells into memory and plasma cells, and possibly, the pathogenesis of B cell malignancies and autoimmunity. Their expression patterns, signaling potential, ligands, and translational potential are areas of active investigation.

Jeffrey C. Edberg, MD Wegener’s granulomatosis, an anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic small vessel vasculitide, is characterized by inflammatory lesions with granuloma formation in the upper and lower airways, pauci-immune glomerulonephritis, and anti-proteinase 3 autoantibodies. Although Wegener’s granulomatosis is considered idiopathic, there has been substantial interest in environmental factors as either etiologic or accelerating risk factors, with Staphylococcus aureus having attracted substantial attention as one such environmental factor. Although consensus about etiology remains elusive, the nature of the host response has emerged as an important determinant for disease phenotype and severity. Although Wegener’s granulomatosis occurs sporadically, and does not show classical familial clustering and transmission characteristic of some autoimmune diseases, the identification of important genetic factors in Wegener’s granulomatosis is not only feasible but also potentially very fruitful in providing insights into pathogenesis and potential therapeutic targets. Building on the clinical trial of etanercept in Wegener’s granulomatosis, Dr. Edberg, in collaboration with Drs. Kimberly and Kaslow, is developing a renewable genetic repository to explore the relationship between the Wegener’s granulomatosis diathesis and genetic polymorphisms in candidate molecules, selected for their role in pathophysiology. These studies also will involve identification of new polymorphisms in such molecules and application of these to this cohort.

Hui-Chen Hsu, PhD Two major studies are currently ongoing in my laboratory:
1. We have identified that autoimmune BXD2 mice exhibit unique features, including spontaneous formation of germinal centers, increased expression of activation-induced cytidine deaminase (AID), increased production of pathogenic autoantibodies that are polyreactive, significantly increased percentage of IL-17high CD4 TH cells (TH-17) and IL-17Rhigh B cells, and significantly increased numbers of type I interferon producing plasmacytoid dendritic cells in the spleens of these mice. We are currently studying the interconnection of high IL-17, high type I IFN and the development of spontaneous germinal centers in these mice.

2. We are developing a new lupus mouse models to study the safety and efficacy of using an anti-human DR5 antibody (TRA-8) as novel therapy of lupus and other autoimmune diseases.  Death receptor 5 (DR5) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).  Investigators at UAB (Dr. Tong Zhou and colleagues) have generated a unique anti-human DR5 antibody (TRA-8) that triggers the death of DR5+ cells.  TRA-8 was selected due to its signaling of apoptosis (differing from TRAIL, which can induce proliferation).  We have found that it kills cultured human lupus CD4+ T cells and plasma B cells.  We have developed a transgenic mouse model that expresses a Floxed-STOP humanized DR5 mouse transgene (hu/mo DR5 Tg) and will express this hu/mo DR5 Tg in T and B cells in autoimmune mice that develop lupus-like disease.  The ongoing project is to test the method of action and effectiveness of TRA-8 in depleting autoreactive CD4 T and plasma B cells, and its safety, in a special humanized mouse model, to determine its potential utility as a therapy for patients with lupus.

Hui Hu, PhD  Utilizing a broad variety of techniques including cellular immunology, molecular biology, biochemistry, gene-targeting (knockout and knockin), functional genomics and in vivo animal models, the Hu laboratory is interested in identifying novel regulatory genes and transcriptional networks that play critical roles in regulating the adaptive immunity. One of the research projects in the Hu laboratory is to study T follicular helper (Tfh) cells and germinal center (GC) responses (Nat. Immunol. 2014). The complex regulation that determines the initial development of Tfh cells, their developmental progression in germinal centers, and their fates after an immune response dissolves, is still not fully understood. The Hu laboratory is interested in identifying novel pathways underlying the differentiation of Tfh cells in humoral responses and designing new strategies to manipulate humoral responses for treatment of infectious diseases and autoimmune disorders. The Hu laboratory is also working to find ways to activate T cells under immunosuppressive circumstances. The Hu laboratory has demonstrated that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state. If these pathways are disrupted, resting T cells become aberrantly activated even in the absence of antigen challenge (Nat. Immunol. 2011). The Hu laboratory is interested in identifying regulatory genes and pathways that actively restrain T cell activation, and defining the roles of such negative regulatory pathways in controlling T cell quiescence, effector responses, memory maintenance, and tumor immunology.

Robert P. Kimberly, MD Our laboratory is interested in the role of genetic factors in the normal function of the immune system and in development of autoimmune and immune-mediated inflammatory diseases such as systemic lupus erythematosus and systemic vasculitis. Our approach has focused on receptors for immunoglobulin (Fc receptors) as a model system and has explored molecular mechanisms of receptor signaling and the molecular basis for receptor polymorphisms in humans. Studies in cell lines and in normal donors have demonstrated that despite the common theme of receptor-induced tyrosine phosphorylation, the various human Fc receptors engage different signaling elements which are reflected in important distinctions in function. Similarly, allelic variations in receptor structure profoundly affect receptor function, and certain low-binding alleles are enriched in SLE patients. More active alleles are over-represented in patients with vasculitis and severe renal disease. Other genes and gene families are being pursued as they are identified as candidate genes through genome wide association studies. These genes include complement receptors, cytokine genes and their promoters, signal transduction molecules, and members of the TNF superfamily.

John D. Mountz, MD, PhD A hallmark of autoimmune disease is the development of autoantibodies that can cause disease.  My laboratory has identified that the second recombinant inbred strain of B6 x DBA/2 (BXD2) spontaneously produces very high levels of pathogenic autoantibodies.  Single antibodies produced by hybridomas from spleens of these mice transfer arthritis or glomerulonephritis in normal mice.  By 3 months of age, the spleens of BXD2 mice are greatly enlarged and are packed with numerous large, spontaneous germinal centers (GCs).  This GC development is promoted by high levels of Th17 and IL-17 in these mice.  IL-17 signals through the IL-17a receptor in B cells resulting in increased classical NF-κB pathway activation.  This activates several genes, including regulators of G-protein signaling (RGS) 13 and 16.  Upregulation of RGS genes impairs signaling through CXCR4/CXCL12 and CXCR5/CXCL13 to arrest migration and movement of T cells and B cells.  This enables prolonged and stable interaction of B cells and CD4 T cells.  Key ongoing questions in my laboratory include what is the mechanism for increased Th17 development.  IL-6 is highly produced by B cells, macrophages and plasmacytoid dendritic cells (PDCs).  TGF-β, however, is not greatly increased.  What are the factors, in combination with IL-6, that promote high Th17 development in BXD2 mice?  How does Th17 signal through B cells?  Our recent evidence indicates that IL-17 signaling requires both TRAF6 and ACT1, which has been identified in IL-17 signaling pathways.  Current ongoing work is to determine the mechanism of increased NF-κB signaling in response to IL-17 in B cells.  Also using RGS13 KO and RGS16 KO mice, we wish to determine which of these RGS proteins is highly essential for development of spontaneous autoreactive GCs.  We also wish to identify the most promising points for interruption of IL-17 signaling that upregulates RGS expression in B cells.  Other studies include detailed analysis of the effect of IL-17 on B cell chemotaxis in response to CXCL12 and CXCL13.  These include in vitro chemotactic chamber analysis, and live imaging analysis using confocal microscopy.

A second area of interest is the role of DR5 apoptosis in arthritis and autoimmune Disease.  TRAIL-DR5 apoptosis signaling is very similar to FAS apoptosis signaling involving mitochondrial amplification loop and Bcl-2 family members, as well as direct induction of apoptosis through caspase activation resulting in terminal caspases 3, 5, and 7 activation.  The TRAIL-DR5 apoptosis signaling pathway, like Fas, is inhibited by FLIP-L and XIAP (inhibitors of apoptosis proteins).  DR5 is upregulated on synovial fibroblasts of patients with rheumatoid arthritis and in Collagen-II mouse model of arthritis.  To determine mechanisms of DR5 apoptosis in vivo, we have produced a human-mouse (hu/mo) chimeric DR5 transgenic mouse.  This mouse transgene is driven by the 3 kB mouse DR5 promoter and is regulated by a Floxed-STOP between the promoter and the hu/mo chimeric DR5 transgene.  Thus, expression of hu/mo DR5 chimeric transgene can be targeted to synovial fibroblasts, B cells, T cells, or macrophages.  In collaboration with Dr. Tong Zhou, we are analyzing the ability of a novel anti-human DR5 antibody (TRA8) to regulate arthritis and immune responses in these chimeric DR5 transgenic mice.

My laboratory has longstanding interest in age-related immune senescence.  We were one of the first investigators to propose that T cell senescence is due to decreased, rather than increased, apoptosis.  This was directly demonstrated using a CD2-Fas Tg mouse that resulted in increased expression of Fas throughout the lifespan of the mouse.  This resulted in decreased T cell senescence.  Our recent interest in T cell senescence is being carried out in a study of nonagenarians in collaboration with Dr. Michal Jazwinski (Tulane University) and Dr. Donald Scott (University of Pittsburgh).  Nonagenarians are protected from immune senescence by several factors including increased levels of certain hormones, such as leptin and Insulin like growth factor binding protein 3 (IGFBP3).  Our ongoing studies are further characterizing methods to prevent immunosenescence with aging.  This is relevant to preservation of immune responses tat may help prevent development of cancer, and provide adequate protection against viruses.

Trenton R. Schoeb, DVM, PhD Pathology and phenotyping of mutant mice; gnotobiotic mouse models of chronic inflammatory diseases

Harry W. Schroeder, Jr., 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.

Alexander J. Szalai, PhD Dr. Szalai is collaborating extensively with several members of the faculty in a series of integrated studies of C-reactive protein (CRP), complement, and Fc receptors; different components of the innate immune system. These studies currently include analysis of the mechanisms that operate to affect the host defense function of CRP and complement against pathogens (Streptococcus pneumoniae), the role of CRP and complement in autoimmune diseases (SLE, MS), and the role of CRP in cardiovascular diseases (atherosclerosis, restenosis, heart transplant rejection). CRP is a 110-kDa protein made up of five identical subunits. It binds phosphocholine, activates the classical pathway of complement, and is recognized by FcgRI and FcgRII. CRP specifically recognizes pathogenic microorganisms and damaged cells of the host and initiates their elimination. Dr. Szalai has used CRP-transgenic mice (CRPtg) to dissect the mechanisms operating to affect the innate host defense function of CRP. His investigations established that CRP-dependent protection against pathogens, such as Streptococcus pneumoniae and Salmonella typhimurium, is effected mainly by clearance of pathogens during the early post-infection period. Complement is not required for this function. In parallel studies of the mode of induction of the CRP gene in vivo, testosterone was found to control basal expression; whereas complement protein 5a, acting together with pro-inflammatory cytokines, is critical for acute-phase induction of CRP. Current studies include determination of the contribution of Fc receptors to CRP-mediated protection using CRPtg/FcgR-deficient mice, and analysis of the effects of CRP expression on serum antibody responses. In addition, Dr. Szalai actively participates in several clinical studies, and is now investigating allelic differences in the expression of CRP in healthy versus diseased individuals. CRP is routinely used as a plasma marker of inflammation in inflammatory diseases. As family studies have demonstrated genetic influences in SLE, with linkage to several regions on human chromosome 1 and the CRP gene is located within one candidate linkage region, genetic differences in this gene could be related to the lupus diathesis. Dr. Szalai has evaluated the association of a (GT) repeat polymorphism in the intron of the CRP gene with plasma levels of CRP and the clinical phenotype of SLE in collaboration with Dr. Robert P. Kimberly. Finally, Dr. Szalai is using two different mouse models to determine the role of CRP in the development of autoimmune disease. CRP-transgenic (NZB X NZW)F1 mice (BW) exhibited delayed onset of SLE and their lifespan was extended significantly compared to that of non-transgenic BW mice. However, the anti-double stranded DNA autoimmune response occurred earlier and was enhanced in the CRP-transgenic mice, and there was deposition of CRP in nephritic kidneys. Current studies seek to determine the mechanism for the CRP-protective effect. The onset of experimental allergic encephalomyelitis (EAE, a model for MS) is delayed in female CRP-transgenic mice compared to wild-type mice. This protective effect is causally related to the transient upregulation of the CRP transgene observed during the early stages of disease development. In collaboration with Dr. Scott Barnum, Dr. Szalai is now testing the hypothesis that the duration of CRP-mediated protection against EAE will be extended in CRP-transgenic mice by prolonging and/or increasing expression of CRP, which may be achieved through the influence of sex hormones that regulate CRP expression. Mutant mice that are not able to fully activate the complement system due to engineered deficiency in C3 or factor B, exhibit reduced clinical symptoms of EAE, cellular infiltration, and demyelination. When complement-deficient mice hybridized with CRP-transgenic mice were tested, a delay in both the CRP-mediated delay in onset of EAE and the complement deficiency-mediated reduction of disease were observed. These data show that the CRP-protective effect in EAE is realized whether or not a fully functional complement system is present, suggesting that CRP is mediating its protection through other mechanisms. Dr. Szalai's most recent work, performed in collaboration with groups at Harvard, UCSD, Baylor, and UAB, showed that CRPtg mice exhibit ia pro-thrombotic/pro-atherosclerotic phenotype, but experience reduced neointimal growth following vascular injury.

Jianming (James) Tang, PhD Funded by NIAID and NCI, Dr. Tang's ongoing research focuses on genetic and epigenetic contributions to infection and immunity in human populations, using HIV/AIDS and HCV infection as the primary models. His Immunogenetics projects involve polymorphism discovery and genotyping techniques, haplotype tagging and population genetics, molecular evolution, genetic association analyses, and genetic scoring algorithms. Epigenetic analyses cover mapping of CpG methylation-sensitive loci, methylation and cytokine gene expression, epigenetics and function of drug transporters, and epigenetic influences on drug metabolism.