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 ligand 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.
A link to lay language description of some of the laboratory recent activity:
Research Opportunities for Rotating Students
1. HLA-activated ranscriptome in mouse and human macrophages
2. Characterization of new HLA-binding cell surface receptors
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].
De Almedia DE, Ling S, Holoshitz, J. New insights into the functional role of the rheumatoid arthritis shared epitope. FEBS Letters 585(23):3619-26, 2011
Naveh S, Tal-Gan Y, Ling S, Hoffman A, Holoshitz J, Gilon, C. Developing potent backbone cyclic peptides bearing the shared epitope sequence as rheumatoid arthritis drug-leads. Bioorg & Medicinal Chem Lett 22(1):493-6, 2012.
Holoshitz J, Liu Y, Fu J, Joseph J, Ling S, Colletta A, Sharma P, Begun D, Goldstein S, Taichman R. An HLA-DRB1-Coded Signal Transduction Ligand Facilitates Inflammatory Arthritis. A New Mechanism of Autoimmunity. J. Immunol. 190:48-57, 2013.
Ling S, Cline EN, Haug T, Fox DA, Holoshitz J. Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling. Arthritis Rheum. 65:618-26, 2013.
Fu J, Ling S, Liu Y, Yang J, Naveh S, Hannah M, Gilon C, Zhang Y, Holoshitz J. A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis. J Immunol. 191:2096-103, 2013.
Blanco LP, Plegue M, Fung-Leung W-P, Holoshitz J. Gender-biased regulation of human IL-17-producing cells in vitro by peptides corresponding to distinct HLA-DRB1 allele-coded sequences. Journal of Immune Based Therapies, Vaccines and Antimicrobials 2:29-38, 2013.
Holoshitz J. The quest for better understanding of HLA-disease association: scenes from a road less travelled by. Discovery Medicine. 16:93-102, 2013.
Ling S, Liu Y, Jiaqi Fu J, Colletta A, Gilon C, Holoshitz J. Shared epitope antagonistic ligands - a new therapeutic strategy in mice with erosive arthritis. Arthritis Rheumatol. 67:2061-70, 2015.
Chukkapalli S, Rivera-Kweh M, Gehlot P, Velsko I, Bhattacharyya I, Calise J, Satoh M, Chan E, Holoshitz J, Kesavalu L. Periodontal bacterial colonization in synovial tissues exacerbates collagen-induced arthritis in B10.RIII mice. Arthritis Res Ther. 18:161, 2016.
Van Drongelen V and Holoshitz J. A reciprocal HLA-Disease Association in Rheumatoid Arthritis and Pemphigus Vulgaris. Frontiers in Bioscience, 22, 909-919, 2017.
Van Drongelen, V and Holoshitz, J. HLA-Disease Associations in Rheumatoid Arthritis. Rheumatic Disease Clinics of North America, 43: 363-376, 2017
Gehlot P, Volk SL, Rios HF, Jepsen KJ and Holoshitz J. Spontaneous Destructive Periodontitis and Skeletal Bone Damage in Transgenic Mice Carrying a Human Shared Epitope-Coding HLA-DRB1 allele. Rheumatic and Musculoskeletal Dis. 2 (2), 2016.
Gehlot P, Holoshitz J. Human Leukocyte Antigens and Autoimmunity. In Encyclopedia of Immunology. Ed: Ratcliffe, MJH. Publisher: Elsevier, Vol. 2, pp. 297–303. Oxford: Academic Press, Oxford, UK, 2016.
Fu J. Nogueira SV, van Drongelen V, Coit P, Ling S, Rosloniec EF, Sawalha AH, Holoshitz J. Shared epitope–aryl hydrocarbon receptor crosstalk underlies the mechanism of gene–environment interaction in autoimmune arthritis. Proc. Natl. Acad. Sci. (USA) 15(18):4755-4760, 2018.
Van Drongelen V, Ali WH, Holoshitz. Uncovering a Shared Epitope-Activated Protein Citrullination Pathway. J Immunol. 2020 Jun 26;ji1901108. doi: 10.4049/jimmunol.1901108. Online ahead of print.