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Wei, Kevin

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Wei

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Kevin

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Wei, Kevin

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2017 - 20182

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Author's Publications: search.filters.isAuthorOfPublication.c839666c-4874-464a-baf4-0b2c1a3c7749

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    Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis
    (Nature Publishing Group UK, 2018) Mizoguchi, Fumitaka; Slowikowski, Kamil; Wei, Kevin; Marshall, Jennifer L.; Rao, Deepak; Chang, Sook Kyung; Nguyen, Hung; Noss, Erika H.; Turner, Jason D.; Earp, Brandon; Blazar, Philip; Wright, John; Simmons, Barry; Donlin, Laura T.; Kalliolias, George D.; Goodman, Susan M.; Bykerk, Vivian P.; Ivashkiv, Lionel B.; Lederer, James; Hacohen, Nir; Nigrovic, Peter; Filer, Andrew; Buckley, Christopher D.; Raychaudhuri, Soumya; Brenner, Michael
    Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.
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    Pathologically Expanded Peripheral T Helper Cell Subset Drives B Cells in Rheumatoid Arthritis
    (Springer Science and Business Media LLC, 2017-02-02) Rao, Deepak; Gurish, Michael F.; Marshall, Jennifer L.; Slowikowski, Kamil; Fonseka, Chamith Y.; Liu, Yanyan; Donlin, Laura T.; Henderson, Lauren; Wei, Kevin; Mizoguchi, Fumitaka; Teslovich, Nikola; Weinblatt, Michael; Massarotti, Elena; Coblyn, Jonathan; Helfgott, Simon; Lee, Yvonne C.; Todd, Derrick; Bykerk, Vivian P.; Goodman, Susan M.; Pernis, Alessandra B.; Ivashkiv, Lionel B.; Karlson, Elizabeth; Nigrovic, Peter; Filer, Andrew; Buckley, Christopher D.; Lederer, James; Raychaudhuri, Soumya; Brenner, Michael
    CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation1. Here, we used mass cytometry to evaluate activated T cells in joint tissue from patients with rheumatoid arthritis (RA), a chronic immune-mediated arthritis that affects up to 1% of the population2. This approach revealed a strikingly expanded population of PD-1hi CXCR5- CD4+ T cells in RA synovium. These cells are not exhausted. Rather, multidimensional cytometry, transcriptomics, and functional assays define a population of PD-1hi CXCR5- ‘peripheral helper’ T (Tph) cells that express factors enabling B cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hi CXCR5+ T follicular helper (Tfh) cells, Tph cells induce plasma cell differentiation in vitro via IL-21 and SLAMF5-interactions3,4. However, global transcriptomics robustly separate Tph cells from Tfh cells, with altered expression of Bcl6 and Blimp-1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in Tph cells. Tph cells appear uniquely poised to promote B cell responses and antibody production within pathologically inflamed non-lymphoid tissues.