Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Abstract

CD8 + T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8 + T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8 + T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8 + T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8 + T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramerpositive myelin-specific CD8 + T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8 + T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8 + T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20 + CD8 + T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8 + T cells in MS, indicates these cells may be attractive targets in MS therapy. multiple sclerosis | CD8 + T cells | myelin antigen | anti-CD20 therapy

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

“…CD8 + and CD4 + T RM cells were identified in human brain and in lesions of MS patients [212,213], and recent research primarily focused on the role of CD8 + T RM cells and their contribution to autoimmune pathology in MS and EAE [212][213][214][215][216]. However, autoimmune CD4 + T RM are not as well studied, and many critical questions remain as to their potential contribution to autoimmune disease pathology.…”

Role of B Cells in Multiple Sclerosis and Related Disorders

“…11,12 It is noteworthy that a small proportion of circulating T cells express CD20, and these are also depleted with anti-CD20 therapy; however, because anti-CD19 therapy also seemed effective in MS, the robust effects of anti-CD20 in MS are not likely to be exclusively mediated by removal of CD20-expressing T cells. 13 In addition, B cells have the capacity to produce anti-inflammatory cytokines such as transforming growth factor β1, IL-35, and IL-10. 1 In mice with experimental autoimmune encephalomyelitis (EAE), gut-derived immunoglobulin A (IgA) + B cells are mobilized to the CNS, where they attenuate neuroinflammation through expression of IL-10.…”

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

“…Although it is widely considered that CD4, TH17 T cells are the central mediators of MS (Kunkl et al, 2020), all active DMT inhibit memory B cell activity in a hierarchical fashion that reflects their therapeutic activity (Pardo and Jones 2017, Baker et al 2017. This could be secondary to inhibition of T cell function (Sabatino et al, 2019a(Sabatino et al, , 2019b. Targeting memory B cell subsets, and possibly CD4, Th17 T cells, is not likely to prevent SARS-CoV-2 elimination by CD8 T cells and the innate immune responses.…”