In the normal immune system, a fine balance between lymphocyte proliferation on the one hand, and apoptosis, on the other, assures right sizing of the peripheral pool of lymphocytes. Perturbation of this balance could result in immunopathology, as illustrated by certain experimental animal models and human diseases involving immunodeficiency or autoimmunity. This research proposal implicates a novel paradigm of MHC - associated immunopathology. The underlying hypothesis of the proposed research is that a class II MHC - associated defect in death signaling may lead to disproportionate expansion of certain lymphocyte subpopulations in genetically susceptible individuals. Those expanded lymphocyte subsets may allow the emergence of autoimmune lymphocyte clones in some individuals, with resultant autoimmune disease. This hypothesis is based on recent preliminary data showing an HLADRB 1-associated impairment of protein kinase A (PKA)-mediated signaling that may be involved in the expansion of an otherwise rare T cell subset, the CD4+, CD45RO+. CD7- subpopulation of alpha beta T cells. This subset has been shown to be necessary for the expansion of another, normally minor, subset of peripheral T cells, Vgamma9/Vdelta2 cells. It is intriguing that these two subsets have been previously shown to co-accumulate in autoimmune states. In order to investigate the mechanisms involved in the expansion of these T cell subsets, experiments are proposed to further define the chemical composition of PKA signal-inducing ligands and identify the peripheral blood subset of cells unresponsive to those ligands. Additionally, the inhibitory role of nitric oxide on PKA signaling and its involvement in the resistance to apoptosis will be examined. The mechanism contributing to the aberrant PKA signaling pathway in resistant cells will be characterized. Finally, the role of heat shock protein (HSP) 60, as a target cell molecule recognized by the cytolytic cells will be investigated. These studies will examine a novel paradigm relevant to a physiologic regulatory mechanism in the immune system, whose perturbation may set the stage for immunopathology.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunological Sciences Study Section (IMS)
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Johnson, David R
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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de Almeida, Denise E; Ling, Song; Holoshitz, Joseph (2011) New insights into the functional role of the rheumatoid arthritis shared epitope. FEBS Lett 585:3619-26
Holoshitz, Joseph; De Almeida, Denise E; Ling, Song (2010) A role for calreticulin in the pathogenesis of rheumatoid arthritis. Ann N Y Acad Sci 1209:91-8
Holoshitz, Joseph (2010) The rheumatoid arthritis HLA-DRB1 shared epitope. Curr Opin Rheumatol 22:293-8
De Almeida, Denise E; Ling, Song; Pi, Xiujun et al. (2010) Immune dysregulation by the rheumatoid arthritis shared epitope. J Immunol 185:1927-34
Ling, Song; Cheng, Andrew; Pumpens, Paul et al. (2010) Identification of the rheumatoid arthritis shared epitope binding site on calreticulin. PLoS One 5:e11703
Ling, Song; Pi, Xiujun; Holoshitz, Joseph (2007) The rheumatoid arthritis shared epitope triggers innate immune signaling via cell surface calreticulin. J Immunol 179:6359-67
Holoshitz, Joseph; Ling, Song (2007) Nitric oxide signaling triggered by the rheumatoid arthritis shared epitope: a new paradigm for MHC disease association? Ann N Y Acad Sci 1110:73-83
Tan, Shi-Yu; Xiao, Liqun; Pi, Xiujun et al. (2007) Aberrant Gi protein coupled receptor-mediated cell survival signaling in rheumatoid arthritis B cell lines. Front Biosci 12:1651-60
Ling, Song; Li, Zhanguo; Borschukova, Olga et al. (2007) The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway. Arthritis Res Ther 9:R5
Haas, Christian S; Creighton, Chad J; Pi, Xiujun et al. (2006) Identification of genes modulated in rheumatoid arthritis using complementary DNA microarray analysis of lymphoblastoid B cell lines from disease-discordant monozygotic twins. Arthritis Rheum 54:2047-60

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