Joseph Holoshitz, M.D.
Professor of Internal Medicine
Associate Chief for Research
Division of Rheumatology
jholo@umich.edu


Research Interests

The research theme of Dr. Holoshitz' laboratory is the role of signal transduction events in health and disease. Using cellular, molecular, signal transduction and protein chemistry strategies, the laboratory is focusing on three research projects:

1. We have recently discovered that the rheumatoid arthritis (RA) shared epitope (SE) is capable of altering important signaling events. The cell surface receptor of the SE has been identified. We are presently characterizing the intracellular events that the SE triggers and deciphering the structure/function requirements of ligand-receptor interaction, using empiric and combinatorial peptide design approaches as well as mutational analysis of the binding domain(s) on the receptor. In a related project, the effect of the SE on endothelial and dendritic cells activation and differentiation is being studied. Beyond their potential utility for understanding immune mechanisms in RA, these studies could provide new insights into MHC-disease association.

2. The second project involves non-peptidic phosphoantigens, which activate a subset of T cells, called gamma-delta T cells. We have made progress in understanding the signaling pathway triggered by these compounds. We are currently investigating the effect of phosphoantigens on the cytolytic activity of gamma-delta T cells and the mechanisms involved in attenuation of that activity with SE ligands.

3. The focus of the third project is aberrations in program cell death (apoptosis) signaling in RA. We have identified a pathway that aberrantly attenuates apoptotic signals in lymphocytes and synovial fibroblasts from patients with RA. We are currently focusing on a family of G protein coupled receptors, which transduce the aberrant signal. In addition, proteome and microarray gene expression analyses are being employed to identify gene and protein expression patterns of RA lymphocytes in response to activation of these G protein-coupled receptors.

Representative Publications

Wu Y., Zheng J., Linden J. and Holoshitz J. Genoprotective Pathways: I. Extracellular Signaling Through G s Protein-Coupled Adenosine Receptors Prevents Oxidative DNA Damage. Mutat. Res . 546: 93-102, 2004.

Ling S, Wu Y, Zheng J, Linden J, and Holoshitz J. Genoprotective Pathways: II. Attenuation of Oxidative DNA Damage by Isopentenyl Diphosphate. Muat. Res . 554: 33-43, 2004.

Pi X, Tan S-Y, Hayes M, Xiao L, Shayman JA, Ling S and Holoshitz J. Sphingosine kinase 1 – mediated inhibition of Fas death signaling in rheumatoid arthritis B lymphoblastoid cells. Arthritis Rheum. 54:754-64 2006.

Haas, C, Creighton CJ, Pi X, Maine I, Koch EA, Haines GK III, Ling S, Chinnaiyan AM and Holoshitz J. Identification of genes modulated in rheumatoid arthritis using cDNA microarray analysis of disease-discordant monozygotic twin cells. Arthritis Rheum. 54: 2047-2060, 2006.

Ling S, Lai A, Borschukova O, Pumpens P and Holoshitz J. Activation of nitric oxide signaling by the rheumatoid arthritis shared epitope. Arthritis Rheum. 54, 3423-3432, 2006.

Tan SY, Xiao L, Pi X and Holoshitz J. Aberrant Gi protein-coupled receptor-mediated cell survival signaling in rheumatoid arthritis B cell lines. Frontiers in Bioscience, 12, 1651-1660, 2007.

Ling S, Li Z, Borschukova O, Xiao L, Pumpens P, and Holoshitz J. The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway. Arthritis Res. Therapy. 9, R5, 2007.

Holoshitz J and Ling S. Nitric oxide signaling triggered by the rheumatoid arthritis shared epitope: a new paradigm for MHC-disease association? Ann New York Acad Sci, 1 110:73-83, 2007.

Ling S, Pi X and Holoshitz J. The rheumatoid arthritis shared epitope triggers innate immune signaling via cell surface calreticulin. J Immunol. 179:6359-6367, 2007.

Holoshitz J. The rheumatoid arthritis HLA-DRB1 shared epitope. Current Opinion in Rheumatology, 22:293-298, 2010.

De Almeida DE, Ling S, Pi X, Hartmann-Scruggs AM, Pumpens P and Holoshitz J. Immune dysregulation by the rheumatoid arthritis shared epitope. J Immunol. 185: 1927-34, 2010.

Holoshitz J, De Almeida DE and Ling S. A role of calreticulin in the pathogenesis of rheumatoid arthritis. Ann New York Acad Sci.1209:91-8, 2010.

Ling S, Cheng A, Pumpens P, Michalak M and Holoshitz J. Identification of the Rheumatoid Arthritis Shared Epitope Binding Site on Calreticulin. PlosONE. 5:11703, 2010.

De Almeida DE, Holoshitz J. MHC molecules in health and disease: At the cusp of a paradigm shift. Self Nonself. 2:43-8, 2011.

De Almedia DE, Ling S, Holoshitz, J. New insights into the functional role of the rheumatoid arthritis shared epitope. FEBS Lett. 2011 Mar 22. [Epub ahead of print].