Mountz, John D., MD, PhD
Goodwin-Blackburn Chair Professor of Medicine
Co-Director, UAB Center for Aging, Basic Biology of Aging
Director, UAB Rheumatic Diseases Core Center
Director, UAB Comprehensive Flow Cytometery Core (CFCC) at Shelby
Shelby building, room 307
1825 University Blvd
Birmingham, AL 35294
Administrative Associate: Ms. Karen Beeching
Shelby Building, Suite 301
1825 University Blvd.
BS, Wright State University, Dayton, OH, 1969
MS (Physics), Michigan State University, East Lansing, MI, 1971
PhD (Physics), Michigan State University, East Lansing, MI, 1974
Postdoctoral Fellow, National Science Foundation, East Lansing, MI, 1974-1975
MD, Ohio State University, Columbus, OH, 1978
Internship and Residency, Internal Medicine Residency Program, North Carolina Baptist Hospital,1978-1981
Rheumatology Fellow, Bowman Gray School of Medicine
Medical Staff Fellow, NIH, National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases
Development of Spontaneous, Pathogenic, Autoreactive Germinal Centers (GCs) in BXD2 mice. 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 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. CD86-CD28 interactions between B and T cells are essential for development of spontaneous GCs.
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. This activates the classical NF-κB (p65/p50) resulting in rapid nuclear translocation. This results in a greater than 10-fold increase in expression of RGS16 and a 2-fold increase in RGS13. 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 third area of interest is the role of IL-23 in production of spontaneous GCs. Unlike the ability of IL-23 to potentiate Th17 pathogenicity in inflammatory bowel disease, IL-23 interferes with the ability of IL-17 to induce GCs. Ongoing studies will determine if IL-23 interferes with IL-17 upregulation of RGS proteins or if IL-23 regulates chemotaxis through a different mechanism.
The essential of CD28-CD86 interactions in the development of spontaneous GCs has been demonstrated using both an Ad-CTLA4-Ig which blocks CD28-CD86 interactions and by using CD86 KO mice backcrossed to BXD2 mice. Our current questions are to determine if CD86 KO mice exhibit also a defect in Th17 development, and if so, what is the mechanism for decreased Th17 development? Our preliminary data also indicates that hyper-induction of NF-κB signaling in B cells of BXD2 mice does not occur in CD86 KO mice. Ongoing work will explore NF-κB signaling pathways in CD86 KO and IL-17 receptor KO mice, backcrossed to BXD2 mice.
DR5 Apoptosis in Arthritis and Autoimmune Disease. My laboratory has a longstanding interest in apoptosis. We were one of the first investigators to identify that the lpr mutation is due to an insertion of a retro-transposon in the 2nd intron of the CD95/Fas gene. We were also the first laboratory to directly correct autoimmune disease by producing a CD2-Fas transgene that restores normal Fas expression directly in T cells of MRL-lpr/lpr mice. We have also developed the antigen-presenting cell-FasL tolerance method (APC-Ad-FasL). An adenovirus capable of producing high levels of FasL was transfected into macrophages which were then pulsed with antigens. Such antigen-pulsed APC-Ad-FasL macrophages could specifically eliminate autoreactive T cells upon transfer. Our recent interest in apoptosis has focused on the TRAIL-DR5 apoptosis system. 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.
Immunosenescence in Mice and Humans. 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.
- Last Updated on September 11, 2013