Genetics of Autontibody Diversification

Summary

Principal Investigator: Umesh S Deshmukh
Abstract: The main objective of this KO1 proposal is for the PI to obtain sufficient training and expertise in the areas of molecular biology and genetics to address important questions in autoimmune disorders. The PI is well trained in immunochemistry and cellular immunology and has developed experimental mouse model systems to study immune responses to autoantigens in systemic lupus erythematosus (SLE). His publication record is outstanding and provides evidence that he has the potential and the quality to develop into a first-rate investigator. He has assembled a team of independent investigators to help him to achieve the stated short-term objective. This period of further training will ensure him to develop into a competitive independent investigator in biomedical research. Dr. Shu Man Fu, Professor and Chief of the Division of Rheumatology and Immunology will serve as the primary mentor. He has an outstanding record in mentoring and significant funding to enable the PI to complete the proposed program. Dr. Michael Brown, Assistant professor in the Division and the co-mentor of the award has successfully mapped the NKC region in the mouse. He has the expertise in many of the approaches used in the proposal. In addition, a group of consultants in the areas of molecular biology and genetics will help the PI. Dr. Gary Litman of the University of South Florida and Dr. Chris Amemiya of the Virginia Mason Medical Center at Seattle will provide intense short period of training in molecular biology and cloning. A well thought-out series of courses at the University and elsewhere will be attended by the PI to ensure the needed basic training in molecular genetics and bioinformatics. The University of Virginia School of Medicine has an interactive environment with outstanding faculty and research facilities. The Division of Rheumatology and Immunology has recruited several independent investigators in both basic and clinical research. The Division is well supported by the Medical School and the Department of Internal Medicine. Thus the environment is outstanding for the further development of the PI and there is strong commitment to him from the Division and the Chair for career development. The proposal addresses the hypothesis that certain genes important in immunoregulation are important for autoantibody diversification to SLE-related autoantigens. Two specific aims are proposed: (1) To define non- MHC genetic loci influencing epitope spreading, and (2). To demonstrate that under an appropriate genetic background, MHC Class II genes dictate epitope spreading. The proposal addresses a significant issue in autoimmunity and will serve well as a training vehicle to obtain the stated goals by the PI.
Funding Period: 2004-07-20 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Role of anti-DNA antibodies in the pathogenesis of lupus nephritis
    Umesh S Deshmukh
    Specialized Center of Research on Systemic Lupus Erythematosus, Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA
    Autoimmun Rev 5:414-8. 2006
  2. pmc Pathogenesis of systemic lupus erythematosus revisited 2011: end organ resistance to damage, autoantibody initiation and diversification, and HLA-DR
    Shu Man Fu
    Division of Clinical Rheumatology, University of Virginia, Charlottesville, VA 22908 0412, USA
    J Autoimmun 37:104-12. 2011
  3. pmc Differential responses to Smith D autoantigen by mice with HLA-DR and HLA-DQ transgenes: dominant responses by HLA-DR3 transgenic mice with diversification of autoantibodies to small nuclear ribonucleoprotein, double-stranded DNA, and nuclear antigens
    Chao Jiang
    Division of Rheumatology and Immunology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
    J Immunol 184:1085-91. 2010
  4. pmc Genetic complementation results in augmented autoantibody responses to lupus-associated antigens
    Davis L Sim
    Department of Microbiology, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA
    J Immunol 183:3505-11. 2009
  5. pmc X-linked Foxp3 (Scurfy) mutation dominantly inhibits submandibular gland development and inflammation respectively through adaptive and innate immune mechanisms
    Rahul Sharma
    Center for Inflammation, Immunity, and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA 22908 0412, USA
    J Immunol 183:3212-8. 2009
  6. pmc Activation of innate immune responses through Toll-like receptor 3 causes a rapid loss of salivary gland function
    Umesh S Deshmukh
    Division of Rheumatology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908, USA
    J Oral Pathol Med 38:42-7. 2009
  7. pmc Anti-alpha8 integrin immunoliposomes in glomeruli of lupus-susceptible mice: a novel system for delivery of therapeutic agents to the renal glomerulus in systemic lupus erythematosus
    Yogesh Scindia
    University of Virginia, Charlottesville, VA 22908, USA
    Arthritis Rheum 58:3884-91. 2008
  8. pmc Inflammatory stimuli accelerate Sjögren's syndrome-like disease in (NZB x NZW)F1 mice
    Umesh S Deshmukh
    University of Virginia, Charlottesville, VA 22908, USA
    Arthritis Rheum 58:1318-23. 2008
  9. pmc Pervasive and stochastic changes in the TCR repertoire of regulatory T-cell-deficient mice
    Lingjie Zheng
    Department of Microbiology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908, USA
    Int Immunol 20:517-23. 2008
  10. ncbi A SmD peptide induces better antibody responses to other proteins within the small nuclear ribonucleoprotein complex than to SmD protein via intermolecular epitope spreading
    Umesh S Deshmukh
    Specialized Center of Research on Systemic Lupus Erythematosus, Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA
    J Immunol 178:2565-71. 2007

Detail Information

Publications13

  1. ncbi Role of anti-DNA antibodies in the pathogenesis of lupus nephritis
    Umesh S Deshmukh
    Specialized Center of Research on Systemic Lupus Erythematosus, Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA
    Autoimmun Rev 5:414-8. 2006
    ..Thus, reactivity to dsDNA should be considered as one of the characteristic of polyreactive autoantibodies and not a primary requisite for the pathogenesis of lupus nephritis...
  2. pmc Pathogenesis of systemic lupus erythematosus revisited 2011: end organ resistance to damage, autoantibody initiation and diversification, and HLA-DR
    Shu Man Fu
    Division of Clinical Rheumatology, University of Virginia, Charlottesville, VA 22908 0412, USA
    J Autoimmun 37:104-12. 2011
    ..This hypothesis accounts for most of the features unique to SLE and has clinical implications as to how patients should be treated...
  3. pmc Differential responses to Smith D autoantigen by mice with HLA-DR and HLA-DQ transgenes: dominant responses by HLA-DR3 transgenic mice with diversification of autoantibodies to small nuclear ribonucleoprotein, double-stranded DNA, and nuclear antigens
    Chao Jiang
    Division of Rheumatology and Immunology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
    J Immunol 184:1085-91. 2010
    ..In addition, our findings provide insights into the origin of the anti-dsDNA Abs often detected in patients with systemic lupus erythematosus...
  4. pmc Genetic complementation results in augmented autoantibody responses to lupus-associated antigens
    Davis L Sim
    Department of Microbiology, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA
    J Immunol 183:3505-11. 2009
    ..In NZM/NOD F(1) mouse, genetic complementation between NZM and NOD genes leads to expression of phenotypes similar to those seen in certain lupus patients...
  5. pmc X-linked Foxp3 (Scurfy) mutation dominantly inhibits submandibular gland development and inflammation respectively through adaptive and innate immune mechanisms
    Rahul Sharma
    Center for Inflammation, Immunity, and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA 22908 0412, USA
    J Immunol 183:3212-8. 2009
    ..Our study demonstrates that Sf mutation affects SMG development through adaptive immunity against accessory reproductive organs, and the manifestation of SMG inflammation in Sf mice is critically controlled through innate immunity...
  6. pmc Activation of innate immune responses through Toll-like receptor 3 causes a rapid loss of salivary gland function
    Umesh S Deshmukh
    Division of Rheumatology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908, USA
    J Oral Pathol Med 38:42-7. 2009
    ..As viral infections are considered to be a trigger for SS, in this study we investigated whether in vivo engagement of TLR3 affects salivary gland function...
  7. pmc Anti-alpha8 integrin immunoliposomes in glomeruli of lupus-susceptible mice: a novel system for delivery of therapeutic agents to the renal glomerulus in systemic lupus erythematosus
    Yogesh Scindia
    University of Virginia, Charlottesville, VA 22908, USA
    Arthritis Rheum 58:3884-91. 2008
    ..This study was undertaken in a mouse model of lupus GN to identify mesangial markers and to develop a system for targeted drug delivery to the glomerulus...
  8. pmc Inflammatory stimuli accelerate Sjögren's syndrome-like disease in (NZB x NZW)F1 mice
    Umesh S Deshmukh
    University of Virginia, Charlottesville, VA 22908, USA
    Arthritis Rheum 58:1318-23. 2008
    ..This study was undertaken to determine whether induction of systemic inflammation accelerates the development of Sjögren's syndrome (SS) in genetically susceptible mice...
  9. pmc Pervasive and stochastic changes in the TCR repertoire of regulatory T-cell-deficient mice
    Lingjie Zheng
    Department of Microbiology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908, USA
    Int Immunol 20:517-23. 2008
    ..Collectively, the data demonstrate that Treg deficiency allows polyclonal expansion of T cells in a stochastic manner, resulting in widespread changes in the TCR repertoire...
  10. ncbi A SmD peptide induces better antibody responses to other proteins within the small nuclear ribonucleoprotein complex than to SmD protein via intermolecular epitope spreading
    Umesh S Deshmukh
    Specialized Center of Research on Systemic Lupus Erythematosus, Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA
    J Immunol 178:2565-71. 2007
    ..Thus caution must be taken in the identification of Ags responsible for initiating autoimmune responses based solely on serological analysis of patients and animals with systemic autoimmune disorders...
  11. ncbi A regulatory T cell-dependent novel function of CD25 (IL-2Ralpha) controlling memory CD8(+) T cell homeostasis
    Rahul Sharma
    Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA
    J Immunol 178:1251-5. 2007
    ..Our study demonstrates the critical control of CD8(+) T(M) cell homeostasis by a Treg cell-dependent novel function of CD25 and resolves its mechanism of action...
  12. ncbi Role for nephritogenic T cells in lupus glomerulonephritis: progression to renal failure is accompanied by T cell activation and expansion in regional lymph nodes
    Harini Bagavant
    Department of Internal Medicine, Division of Rheumatology and Immunology, Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia, Charlottesville, VA 22908, USA
    J Immunol 177:8258-65. 2006
    ..This T cell activation and infiltration are influenced by gender-dependent end-organ factors and may determine the progression of acute GN to chronic GN and renal failure...
  13. pmc HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD
    Umesh S Deshmukh
    Division of Rheumatology and Immunology, Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA
    J Autoimmun 37:254-62. 2011
    ..In addition, the novel findings reported herein may have significant implications in the pathogenesis of SLE...