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.
|Scott Barnum, PhD, Department of Microbiology
|Elizabeth Brown, PhD, MPH, Department of Epidemiology
|Randy Q. Cron, MD, PhD, Department of Pediatrics
|Hui-Chen Hsu, PhD, Department of Medicine
|Janusz H. Kabarowski, Ph.D., Department of Microbiology
|Robert Kimberly, MD, Dept. Medicine-Clin. Immunology & Rheumatology
|Xiaoli Li, PhD, Dept. Medicine - Clinical Immunology & Rheoumatology
|Robin G. Lorenz, MD, PhD, Department of Pathology
|Frances E. Lund, PhD, Department of Microbiology
|John Mountz, MD, PhD, Dept. Medicine-Clin Immunology & Rheumatology
|Jan Novak, PhD, Department of Microbiology
|Chander Raman, PhD, Department of Medicine
|Hubert Tse, PhD, Department of Microbiology
|Jianming (James) Tang, DVM, PhD, Dept. Medicine
|Tong Zhou, MD, Department of Medicine
Scott Barnum, PhD My research interests have been on the production and regulation of several components in the complement system. These interests focused on the central nervous system (CNS) based on growing evidence for a role for complement in CNS diseases. This led us to examine for the production and cytokine-mediated regulation of additional activation components, as well as, complement regulatory proteins. It is now clear that, at least in vitro, most if not all complement proteins can be synthesized by astrocytes, microglia, and to our surprise, neurons. Since these initial observations, we have moved into in vivo models systems. Using a variety of disease models, including bacterial meningitis, brain trauma, experimental allergic encephalomyelitis (EAE) and a murine stroke model, we have demonstrated that a number of complement proteins and receptors are widely produced in the intact CNS under pathological conditions. We have recently expanded our interest in complement in the CNS to include C-reactive protein (CRP) and beta2-integrins and several of their ligands. We are examining the role of these molecules in EAE using several complement and adhesion molecule knock-out mice. In addition, we are using mice transgenic for CRP and several transgenic mouse lines that express either the complement regulatory protein (sCrry) or the complement anaphylatoxins, C3a or C5a, only in the CNS under the control of an astrocyte-specific promoter. Our data suggest that targeting these molecules has therapeutic value.
In other studies, we are examining the role of gamma/delta T cells in autoimmune disease in the CNS with a particular interest in trafficking and activation mechanisms. We have recently shown that these cells are critical to the development of EAE, but surprisingly little is known about the function of these cells in the pathogenesis of demyelinating disease.
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.
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 disease 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’ transcriptional 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 CD4 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.
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 model 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.
Janusz H. Kabarowski, Ph.D. Dr. Kabarowski’s research program is focused on the study of lipids and lipoprotein metabolism in chronic inflammatory disease (notably atherosclerosis and autoimmune disease). Early work characterized the role of the G2A lipid receptor in atherosclerosis and lipoprotein metabolism, showing that pro-atherogenic effects of this receptor may be mediated through its modulatory influence on hepatic High-Density Lipoprotein (HDL) biogenesis. More recently, Dr. Kabarowski’s group described autoimmune-mediated effects on HDL metabolism in normolipidemic mouse models of Systemic Lupus Erythematosus (SLE) and currently a major effort of his laboratory is directed toward developing therapeutic approaches by which anti-inflammatory and immunosuppressive properties of HDL may be harnessed to improve major Lupus phenotypes and combat premature atherosclerosis, a major cause of morbidity and mortality in this and other rheumatic autoimmune diseases. Emphasis is placed on determining the mechanisms by which protective anti-inflammatory properties of HDL are subverted by chronic inflammation, understanding how this influences immunoregulatory processes involved in SLE and atherosclerosis, and establishing the therapeutic efficacy of HDL-targeted approaches such as HDL mimetic peptides in SLE and other autoimmune diseases.
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.
Xiaoli Li, PhD Research focused on signaling and functional regulation mediated by Fcgamma Receptors. Dr. Li's major goals are (1) to define the unique cytoplasmic domain binding partners of the Fc gamma-chain associated CD16A and to define their contributions to receptor signaling and function; (2) to identify contributions of the unique Fcgamma Receptor gamma-chain cytoplasmic domains to specific signaling capacities and immunological functions.
Robin G. Lorenz, MD, PhD The focus of research in our laboratory is the study of the cellular components of the mucosal immune system and their interactions with the gastrointestinal epithelium, the GI microbiome, and the systemic immune response. Our first area of interest is the cellular immune response to Helicobacter in a mouse model of gastric infection and inflammation. The bacteria Helicobacter pylori is a major pathogen which is linked to acute and chronic gastritis and adenocarcinoma. It is also linked to protection from esophageal cancers and allergic asthma. We are currently investigating the interactions between gastric Helicobacter infection and asthma susceptibility in a mouse model of lung inflammation.
The second area of focus in our laboratory is the role of the intestinal epithelium and innate immune responses in the development of inflammatory bowel disease (IBD). The chronic intestinal inflammation that characterizes IBD is the result of a poorly controlled mucosal immune response to normal intestinal microbiota. The mechanisms that initiate this aberrant response are not well elucidated; however, one possibility is that a change in the intestinal epithelial barrier results in increased systemic exposure to microbial products. The P-glycoprotein (mdr1a-/-) deficient mouse is a unique model of spontaneous colitis that demonstrates an increase in colonic epithelial permeability, as well as a change in the sensitivity of toll-like receptors (TLRs) to bacterial products. Our laboratory focuses on investigating the relationships between the membrane pump- P-glycoprotein, microbial sensors-such as TLRs, and IBD. These studies utilize both in vivo models of IBD, as well as in vitro primary and continuous epithelial cell culture systems. The understanding of the basic mechanisms by which the host maintains intestinal homeostasis and barrier integrity will lay the foundation for future studies on the regulation of the inflammatory response and the design of therapies for human IBD.
The third focus of our laboratory is the influence of mucosal immune factors on the risk of type 1 diabetes development. The incidence of autoimmune Type I Diabetes (T1D) in both human patients and animal models is altered by genetic and environmental factors. These factors include an increased incidence after exposure to high fat diets and hygienic environments. These environmental effects are reproduced in the NOD mouse model of disease, where animals raised in a sterile environment have an increased incidence of disease. In addition to diabetic effects, these environmental exposures have in common the fact that they alter two components of the gastrointestinal (GI) ecosystem, the resident microbiota and the intestinal immune response. Our research focuses on the interrelationship between the GI microbiota, the intestinal immune response, and the risk of T1D development in the NOD mouse model.
Frances E. Lund, PhD The overarching research objective of the Lund laboratory is to identify the key players that suppress or exacerbate mucosal inflammatory responses with the long-term goal of developing therapeutics to treat immunopathology associated with chronic infectious, allergic and autoimmune disease. One of the lab’s major projects is to characterize the roles that cytokine-producing “effector” B cells play in modulating inflammation and T cell-mediated immune responses to pathogens, autoantigens and allergens. In a second project, the lab evaluates how inflammatory signals regulate the balance between the development of the antibody-producing long-lived plasma cells and the memory B cell compartment within lymphoid tissues. The lab also studies how these cells are maintained long-term at inflammatory sites. Finally, the lab examines how oxidative stress induced by reactive oxygen species impacts inflammation, immune responses and cellular metabolism. In particular, the lab is experimentally modulating the NAD metabolome of immune cell in order to alter the responsiveness of these cells to oxidative stress.
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.
Jan Novak, PhD
Research interests involve a wide area of biologically active compounds of natural origin (multidisciplinary approaches to identification, isolation, and analyses of novel compounds, studies on their structure, biosynthesis, and genetics, mode of action and mechanism of resistance), biochemistry and genetics of post-translationally modified peptides and proteins, enzymes and pathways of primary and secondary metabolism and cellular regulations, intercellular communication and signaling, and glycosylated compounds. Of particular interest more recently are studies on glycosylation of immunoglobulins in health and disease in humans (IgA nephropathy, chronic inflammatory diseases, Kawasaki syndrome) and regulation of immunoglobulin glycosylation.
The hallmark of IgA nephropathy (IgAN), the most common glomerulonephritis in the world, is deposition of IgA1-containing immune complexes into the glomerular mesangium. Proliferation of mesangial cells (MC) and extracellular matrix (ECM) expansion occurs from early stages, progressing into glomerulosclerosis and development of end stage renal disease. High levels of IgA1-containing circulating immune complexes (CIC) are often observed in IgAN patients indicating a defect in CIC clearance. Galactose (Gal) -deficient O-glycans were detected in the hinge region of IgA1 molecules in CIC in IgAN patients. These Gal-deficient IgA1 molecules are complexed with IgG (IgA1) antibodies with anti-GalNAc specificity. Importantly, Gal-deficient IgA1 is also found in kidney immune deposits in IgAN patients. Dr. Novak's group hypothesizes that the glycosylation aberrance of a fraction of IgA1 molecules results in formation of CIC that ultimately deposit in the mesangium, leading to IgAN. Based on preliminary results, they postulate that the CIC bind to MC through a novel IgA receptor and possibly other receptors, and trigger signaling events resulting in proliferation of MC and ECM expansion. The group has studied interactions of CIC with MC using various approaches, including for example confocal laser scanning microscopy, differential gene and protein expression using DNA arrays and proteomics approaches, respectively. The ultimate goal of these studies is to understand how CIC form, what are major factors inducing aberrant IgA glycosylation, and how CIC trigger pathological response of MC leading to IgAN. We are hopeful that a better understanding of this chronic disease may open new ways for diagnosis or even treatment.
Chander Raman, PhD The overall research focus of the laboratory is the elucidation of mechanisms that regulate generation and maintenance of immune tolerance in T and B lymphocytes. Autoimmunity and predisposition to development of leukemias are the often of the outcomes of alterations in generation and/or maintenance of tolerance. The development of inability of T and B lymphocytes to respond to self antigens while maintaining the ability to respond to self antigens is an active process in which the signals initiated by the engagement of the T cell antigen receptor (TCR) or B cell antigen receptor (BCR) are regulated by a complex of other lymphocyte surface molecules. Signaling cascades initiated by these lymphocyte surface molecules range form those that directly alter the quality and quantity of antigen receptor signals to those that promote cell survival or initiate programmed cell death or apoptosis. Dr. Raman's experimental approaches include in vitro structure function studies to define protein-protein interactions to the use of animal models of disease that naturally occur or are genetically created. Currently, the lab's focus is on the cell surface receptors CD5, DR6 and the family of receptors that bind to lignads Blys and April. Each of these receptors plays a key role in regulating lymphocyte function and homeostasis and alterations in their signaling activities leads to diverse pathologies. The ultimate goal of these studies is to identify key targets for the development of therapeutic strategies for the treatment of leukemias and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.
Type 1 diabetes (T1D) is an autoimmune-mediated disease resulting in the destruction of insulin-secreting pancreatic beta cells. Adaptive immune maturation and the induction of an efficient T cell effector response requires three signals mediated by antigen-presenting cell and naïve T cell interactions: signal 1 (T cell receptor – MHC), signal 2 (co-stimulatory molecules), and signal 3 (reactive oxygen species and pro-inflammatory cytokines). T cell activation in the absence of a pro-inflammatory third signal prevents the maturation of CD8+ T cells to gain cytolytic effector function and CD4+ T cells are unable to clonally expand or provide help for B cells to undergo isotype class switching. The focus of my research involves signal 3 inhibition by targeting the innate immune response and signaling pathways that are responsible for reactive oxygen species (ROS) and pro-inflammatory cytokine synthesis by macrophages and dendritic cells with a metalloporphyrin-based catalytic antioxidant. Prophylactic use of catalytic antioxidants are very efficient in generating antigen-specific hyporesponsiveness in vitro and in vivo by specifically targeting pro-inflammatory third signal generation and preventing the maturation and effector response of antigen-specific CD4+ and CD8+ T cells such as IFN-g synthesis and CTL effector molecules (perforin, granzyme B, and LAMP-1), respectively. A detailed understanding of how redox modulation of innate immune-derived pro-inflammatory signal 3 generation and synergism with adaptive immune maturation will help in the design of more efficient immunotherapeutics for the treatment and prevention of T1D. In an effort to corroborate the importance of ROS-dependent signaling in T1D, we have generated a murine model to further dissect the importance of pro-inflammatory third signal synthesis in autoreactive T cell activation. While T lymphocytes (both CD4+ and CD8+ T cells) in insulitic infiltrates are likely the final effectors, activated macrophages in the preclinical infiltrates release high concentrations of ROS that are efficient in destroying co-cultured islets in vitro, yet the role of ROS as initiators and effectors in T1D is not clear. A dominant negative p47phox (Ncf1m1J) mutation was introduced into the non-obese diabetic (NOD) mouse, a murine model for studying Type 1 diabetes. The Ncf1m1J mutation prevented NADPH oxidase complex assembly, activity, and the inhibition of superoxide synthesis. Homozygous NOD.Ncf1m1J mice do not develop spontaneous diabetes and are also resistant to adoptive transfer of diabetes with the diabetogenic BDC-2.5 T cell clone. The resistance in spontaneous and adoptive transfer of diabetes was due to the absence of a sufficient innate immune-derived pro-inflammatory third signal that prevented the maturation and effector response of antigen-specific T cells. Currently, I seek to understand how this mutation prevents the onset of spontaneous diabetes as well as the importance of superoxide in autoreactive T cell activation in Type 1 diabetes.
Jianming (James) Tang, DVM, PhD Dr. Tang's ongoing research focuses on genetic and epigenetic contributions to infection and immunity in human populations. Immunogenetic studies deal with genes that govern innate and adaptive immune responses to infectious diseases or vaccination. Epigenetic analyses target CpG methylation and microRNA. Disease models range from HIV/AIDS to malignant glioma.
Tong Zhou, MD Dr. Zhou’s research is centered on the characterization of apoptotic pathways with a view to therapeutic manipulation in autoimmune and inflammatory disease. In the first approach, Drs. Zhou has collaborated closely with Dr. Mountz, to demonstrate that strategies centered on Fas ligand might prove useful in the therapeutic regulation of autoimmune disease. To by-pass the toxic effect of soluble Fas ligand, Dr. Zhou, in close collaboration with Dr. Mountz, has used cell-gene therapy consisting of an antigen presenting cell transfected with AdFas ligand to eliminate chronic inflammation and autoimmune disease in a number of murine models of these disease. The utility of this approach is being improved by the incorporation of elements that permit timed induction of discrete levels of Fas ligand to eliminate activated T cells in an antigen-specific manner. This APC-Fas L cell-gene therapy approach has proven useful in the experimental analysis of Fas-mediated apoptosis and antigen-induced cell death in autoimmune disease and may prove useful as a therapeutic strategy in the prevention of post-infectious chronic inflammation or organ-specific disease. In the second approach, Dr. Zhou has developed agonistic and antagonistic monoclonal antibodies that discriminate the DR5 TRAIL receptor and is using these to characterize the distribution of this receptor among T cell populations during activation responses as well as the associated signal transduction events. The ability of these monoclonal antibodies to specifically inhibit autoimmune reactions is being analyzed in various murine models, including models of SLE, collagen II-induced arthritis, and experimental allergic encephalitis. Similar approaches are now being used to characterize the role of B lymphocyte stimulator (BLyS) in SLE in a coordinated effort involving collaboration with Drs. Alarcon, Fessler, and Kimberly.