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Faculty Detail     Name JOHN D MOUNTZ   Campus Address SHEL 307 Zip 2182 Phone 205-934-8909 E-mail jdmountz@uab.edu Other websites

Faculty Appointment(s) Appointment Type Department Division Rank Primary  Medicine  Med - Immunology/Rheumatology Professor Secondary  Medicine  Gene Therapy Center Professor Secondary  Medicine  Med-Gerontology/Geriatrics/Palliative Care Professor Secondary  Microbiology  Microbiology Assistant Professor Secondary  Pathology   Pathology Chair Office Professor Center  Arthritis & Musculoskeletal Diseases Center  Arthritis & Musculoskeletal Diseases Center Professor Center  Pathology   Cell Adhesion & Matrix Research Center Professor Center  Center for Aging  Center for Aging Professor Center  Center for AIDS Research  Center for AIDS Research Professor Center  Center for Metabolic Bone Disease  Center for Metabolic Bone Disease Professor Center  Comprehensive Cancer Center  Comprehensive Cancer Center Professor Center  Cell, Developmntl, & Integrative Biology  Ctr for Exercise Medicine Professor

Graduate Biomedical Sciences Affiliations Cell, Molecular, & Developmental Biology  Cellular and Molecular Biology Program  Genetics and Genomic Sciences  Hughes Med-Grad Fellowship Program  Immunology  Medical Scientist Training Program  Pathobiology and Molecular Medicine

Biographical Sketch  Dr. Mountz is a Professor of Medicine and Director of the UAB Recombinant Inbred Strain Facility. Dr. Mountz is the Co-Director of the UAB Bone Center, the UAB Center for Aging, Basic Biology Component, and is a Physician at the Birmingham Veterans Administration Medical Center. Dr. Mountz is the recipient of the J. W. & Virginia Goodwin-Warren D. Blackburn, Jr. Research Chair in Rheumatology (2002) and recipient of the Max Cooper Award for Excellence in Research (2003). Dr. Mountz was designated one of 50 Arthritis Foundation ¡§Heroes¡¨for outstanding contributions for research in Rheumatology (2002). Dr. Mountz was Co-Chair of the National Institutes on Aging Task Force on Immunology and Aging and Co-Chair of the ¡§Leukocyte Trafficking in Inflammatory Disease¡¨ symposium at the 2004 annual meeting of the American Association of Immunologists. Dr. Mountz received a Ph.D. in High Energy Physics and graduated Summa Cum Laude before carrying out a post-doctoral fellowship in the area of biophysics studying bilayer lipid membranes. Dr. Mountz then received an MD from Ohio State University and carried out an internship of residency and a one-year fellowship in Internal Medicine in Rheumatology. Dr. Mountz was a research staff fellow at the National Institutes of Health for five years and also an Assistant Professor of Medicine at the Naval Bethesda Medical Center. During this time, Dr. Mountz was the first investigator to identify that Onco genes were elevated in autoimmune mice and humans. Dr. Mountz became an Assistant Professor of Medicine at The University of Alabama at Birmingham in 1987, where he produced the first transgenic mouse expressing Fas in T cells and ameliorated the lymphoproliferative autoimmune disease in /lpr (Fas mutant mice). Dr. Mountz then identified the Fas mutation in MRL-lpr/lpr mice as being an insertion of the Etn retrotransposon. Dr. Mountz also was the first investigator to study clono-deletion and energy induction in PCR transgenic mice on the lpr/lpr background. Dr. Mountz continues an active research program in arthritis, molecular nuclear imaging, immune response to virus and poxvirus and gene therapy, as well as T-cell senescence in aging in both mice and humans.

Research/Clinical Interest Title autoimmunity, immune senescence, gene therapy Description 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-17R; receptor in B cells resulting in increased classical NF-kB 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-beta, 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-kB 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.

Selected Publications  Publication PUBMEDID Hsu H-C, Yang PA, Wu Q, Wang J, Godwin J, Guentert T, Li J, Stockard CR, Le T, Chaplin DD, Grizzle WE, and Mountz, JD. Inhibition of the catalytic function of activation-induced cytidine deaminase (AICDA) promotes apoptosis of germinal center B cells. Arthritis Rheum, 2011 Jan 21. doi: 10.1002/art.30257  21305519   Wang JH, Wu Q, Yang PA, Li H, Li J, Mountz JD and Hsu H-C. Type I IFN-dependent CD86high marginal zone-precursor B cells are potent T-cell costimulators. Arthritis Rheum. 2011 Apr;63(4):1054-64.  21225691   Hsu HC, Mountz JD. Metabolic syndrome, hormones and maintenance of T cells during aging. Curr Opin Immunol 22: 541-548, 2010.   20591642   He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, Xu H. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J Immunol 184: 2281-8, 2010.   20118280   Xie S, Wang J, Wu Q, Li H, Li J, Hsu H-C, Smythies LE, and Mountz JD. IL-17 activates the canonical NF-kB signaling pathway in autoimmune B cells of BXD2 mice to upregulate the expression of regulators of G-protein signaling 16. J Immunol 184:2289-96, 2010.  20118280   Wang JH, Li J, Wu Q, Yang P, Pawar RD, Xie S, Timares L, Raman C, Chaplin DD, Lu L, Mountz JD, Hsu HC. Marginal zone precursor B cells as cellular agents for Type I IFN-promoted antigen transport in autoimmunity. J Immunol, Epub ahead of print, November 30, 2009.   19949066   Chen J, Li J, Lim FC, Wu Q, Douek DC, Scott DK, Ravussin E, Hsu HC, Jazwinski SM, Mountz JD, The Louisiana Healthy Aging Study. Maintenance of naïve CD8 T cells in nonagenarians by leptin, IGFBP3 and T3. Mech Ageing Dev 131(1):29-37, 2010.   19941883   Chen J, Li J, Lim FC, Wu Q, Douek DC, Scott DK, Ravussin E, Hsu HC, Jazwinski SM, Mountz JD; for The Louisiana Healthy Aging Study. Maintenance of naïve CD8 T cells in nonagenarians by leptin, IGFBP3 and T3. Mech Ageing Dev 131(1):29-37, 2010.  19941883   Wang X, Fujita M, Prado, R, Tousson A, Hsu H-C, Ynonne YL, Kelly DR, Yang PA, Wu Q, Chen J, Xu H, Elemets CA, Mountz JD and Edwards CKIII. X. Visualizing CD4 T cell Migration into Inflamed Skin and Its Inhibition by CCR4/CCR10 Blockades using in vivo Imaging Model. Br J Dermatol. 2009 Oct 15  19832835   Xu X, Hsu H-C, Grizzle WE, Chatham WW, Wu Q, Stockard CR, Yang PA, Tunmire D, Holers M and Mountz JD. Increased expression of activation-induced cytidine deaminase (AID) is associated with anti-CCP and rheumatoid factor (RF) in rheumatoid arthritis (RA). Scan J Immunol 70:309-316, 2009.   19703021  First Prev   1 2 of  2  Next Last

Keywords IL-17, IL-23, germinal centers, thymus, DR5, apoptosis, rheumatoid arthritis

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