B10 Cell Frequencies and Suppressive Capacity in Myasthenia Gravis Are Associated with Disease Severity.

Abstract

Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated disease. The mechanisms for loss of self-tolerance in this disease are not well understood, and recently described regulatory B cell (Breg) subsets have not been thoroughly investigated. B10 cells are a subset of Bregs identified by the production of the immunosuppressive cytokine, interleukin-10 (IL-10). B10 cells are known to strongly inhibit B- and T-cell inflammatory responses in animal models and are implicated in human autoimmunity. In this study, we examined quantitative and qualitative aspects of B10 cells in acetylcholine receptor autoantibody positive MG (AChR-MG) patients and healthy controls. We observed reduced B10 cell frequencies in AChR-MG patients, which inversely correlated with disease severity. Disease severity also affected the function of B10 cells, as B10 cells in the moderate/severe group of MG patients were less effective in suppressing CD4 T-cell proliferation. These results suggest that B10 cell frequencies may be a useful biomarker of disease severity, and therapeutics designed to restore B10 cell frequencies could hold promise as a treatment for this disease through restoration of self-tolerance.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.3389/fneur.2017.00034

Publication Info

Yi, John S, Melissa A Russo, Janice M Massey, Vern Juel, Lisa D Hobson-Webb, Karissa Gable, Shruti M Raja, Kristina Balderson, et al. (2017). B10 Cell Frequencies and Suppressive Capacity in Myasthenia Gravis Are Associated with Disease Severity. Front Neurol, 8. p. 34. 10.3389/fneur.2017.00034 Retrieved from https://hdl.handle.net/10161/15573.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Yi

John S Yi

Adjunct Assistant Professor in the Department of Surgery

I am an immunologist, with a focus to characterize the immune system in response to infectious and non-infectious diseases including cancer, HIV, autoimmune disease, and transplantation. My goals are to identify novel biomarkers/immune signatures that clinicians can utilize to diagnosis, predict disease outcomes, and determine patients' response to treatment. 

Massey

Janice Munn Massey

Professor of Neurology

Clinical Research in Neuromuscular diseases including myasthenia gravis, Lambert-Eaton myasthenic syndrome, botulinum toxins, electromyography, dystonic disorders including cervical dystonia (spasmodic torticollis), limb focal dystonia, and blepharospasm.

Juel

Vern Charles Juel

Professor of Neurology
Hobson-Webb

Lisa Deneen Hobson-Webb

Professor of Neurology

Trained in neuromuscular medicine, my clinical career has focused on the care of patients with genetically mediated neuromuscular disorders, rare peripheral neuropathies, and immune-mediated nerve and muscle disorders and performing high quality electrodiagnostic testing (nerve conduction studies/electromyography). As a researcher, the core aim of my work is applying high resolution ultrasound in the care of patients with neuromuscular diseases.  My early work focused on peripheral nerve and is now moving toward muscle imaging.  My current research includes muscle ultrasound in late onset Pompe disease and peripheral nerve imaging in acute inflammatory demyelinating radiculoneuropathy.  Since 2016, I have collaborated with Dr. Kathryn Nightingale’s biomedical engineering laboratory on applying shear wave imaging to diseases of the nerve and muscle.   I am interested in clinical trials for neuromuscular disorders and novel technologies for diagnosing and monitoring neuromuscular disease.

 


Gable

Karissa Lorraine Gable

Associate Professor of Neurology
Raja

Shruti Mukund Raja

Assistant Professor of Neurology
Weinhold

Kent James Weinhold

Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery

The Weinhold Laboratory is currently focused on utilizing a comprehensive repertoire of highly standardized and formerly validated assay platforms to profile the human immune system in order to identify immunologic signatures that predict disease outcomes. These ongoing studies span a broad range of highly relevant clinical arenas, including: 1) cancer (non-small cell lung cancer, head and neck cancer, glioblastoma neoforme, ovarian cancer, and prostate cancer), 2) autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosis, multiple sclerosis, and myasthenia gravis), 3) pulmonary disease (idiopathic pulmonary fibrosis), 4) solid organ transplantation (lung, kidney, liver, and heart), and 5) inflammatory disorders.

Two of the areas that have been especially active over the past few years include the comprehensive immunologic profiling of cancer patients receiving so-called ‘immune checkpoint blockade’ therapies and the search for immune signatures in lung transplant recipients that track with resistance to CMV infection. The laboratory conducted immune monitoring studies associated with a Phase I trial of Ipilimumab (anti-CTLA-4) in a neoadjuvant setting for the treatment of non-small cell lung cancer (NSCLC). For this trial we extensively utilized several high parameter flow cytometry (PFC) platforms to follow activation, maturation, exhaustion, and proliferation patterns within CD4+ and CD8+ subsets of T-cells. We are also utilizing an intracellular cytokine staining (ICS) platform in efforts to detect anti-tumor associated antigen (TAA) responses by CD4+ and CD8+ T cells from peripheral blood mononuclear cells as well as lymphocytes infiltrating the patients’ tumor. These assays are designed to measure antigen-driven intracellular production of IFN-γ, TNF-α, and IL-2, as well as the degranulation marker CD107a. This strategy enables us to not only document individual cytokine responses, but to also assess (through Boolean gating) changes in relative polyfunctionality of the responses. We have also performed similar immune monitoring of a Phase II trial evaluating nivolumab (anti-PD-1) alone vs. combined nivolumamb + ipilimumab vs. avastin (bevacizamab) alone in patients with glioblastomas. In both studies, we are seeking to identify pharmacodynamics markers and immune correlates predictive of clinical responses. In completed studies of a cohort of lung transplant recipients, we identified specific polyfunctional signatures in CD4+ and CD8+ subsets against CMV pp65 and IE-1 antigens that tracked with resistance to CMV infection (manuscript in preparation). These findings now serve as the basis for a Phase I clinical trial to compare conventional 6-month chemoprophylaxis in lung transplant recipients versus a regimen dictated by the presence or absence of the predictive signatures. This trial is the principal component of a recently awarded Clinical Trials in Organ Transplantation or CTOT award made from the NIH to Duke (Scott Palmer, PI). Ongoing studies will test the hypothesis that these signatures that have been validated in lung transplant recipients will also predict resistance to CMV infection in the context of other solid organ transplants such as kidney, liver, and heart.Future studies will also attempt to identify predictive signatures for resistance to BK polyomavirus, the cause of graft threatening nephritis in kidney transplant recipients and cystitis in bone marrow transplant recipients.  

 

Recent publications


Zidar, D.A., Mudd, J.C., Juchnowski, S., Lopes, J.P., Sparks, S., Park, S.S., Ishikawa, M., Osborne, R., Washam, J.B., Chan, C., Funderburg, N.T., Owoyele, A., Alaiti, M.A., Mayuga, M., Orringer, C., Costa, M.A., Simon, D.I., Tatsuoka, C., Califf, R.M., Newby, L.K., Lederman, M.M., and Weinhold, K.J.  Altered maturation status and possible immune exhaustion of CD8 T lymphocytes in the peripheral blood of patients presenting with acute coronary syndromes. Arterioscler., Thromb., and Vasc. Biol. 36(2): 389-397, Feb. 2016 PMID: 26663396

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Guptill

Jeffrey Guptill

Adjunct Associate Professor in the Department of Neurology

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