Published by: Science Advances – April 27, 2022
Abstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screened for T cell autoreactivity against 63 CNS-expressed proteins. We identified four previously unreported autoantigens in MS: fatty acid–binding protein 7, prokineticin-2, reticulon-3, and synaptosomal-associated protein 91, which were verified to induce interferon-γ responses in MS in two cohorts. Autoreactive profiles were heterogeneous, and reactivity to several autoantigens was MS-selective. Autoreactive T cells were predominantly CD4+ and human leukocyte antigen–DR restricted. Mouse immunization induced antigen-specific responses and CNS leukocyte infiltration. This represents one of the largest systematic efforts to date in the search for MS autoantigens, demonstrates the heterogeneity of autoreactive profiles, and highlights promising targets for future diagnostic tools and immunomodulatory therapies in MS.
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INTRODUCTION
Multiple sclerosis (MS) is an organ-specific inflammatory, likely autoimmune, disease of the central nervous system (CNS) in which cells of the adaptive immune system cross the blood-brain barrier (BBB) and cause localized CNS inflammation, demyelination, and axonal damage (1). While more common in certain brain regions and the spinal cord, the inflammation can occur practically anywhere within the CNS and gives rise to a wide variety of neurological impairments. A definite trigger for the disease has not yet been identified but is believed to depend on an interplay of genetic, environmental, and lifestyle factors, which leads to pathological immune responses (2). The human leukocyte antigen (HLA) class II DRB1 locus with a DR15 haplotype, carrying the DRB1*15: 01 and DRB5*01:01 alleles, is the strongest genetic risk factor for MS, with an approximately threefold increased risk of disease, and implicates a central role for CD4+ T cells in disease development (3).
Much effort has been put into identifying MS-relevant T cell autoantigens. While myelin proteins such as myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) are currently considered T cell targets in MS, data remain inconsistent (4–11). Several other candidates have been reported in recent years, notably RAS guanyl-releasing protein 2 (12), GDP-L-fucose synthase (13), β-synuclein (14), αB-crystalline (15), and the autoantibody target anoctamin 2 (16), but the autoantigen repertoire known so far is likely to be incomplete (17).
With the emergence of antigen-specific immunotherapies, the interest in identifying novel autoantigens has intensified alongside their potential as future treatment targets (18). This treatment strategy is hypothesized to be effective while safer than currently available broadly acting immune-modulatory agents associated with risks for side effects such as infections and possibly cancer (19, 20). In animal models, where the autoantigens are both limited and defined, this strategy has shown promising results (21, 22), whereas in clinical trials in MS treatments targeting myelin antigens, they have been, if safe, of modest efficacy at best (23–27). One explanation for the lack of efficacy is that effective tolerization therapy requires targeting of a greater number of autoantigens and preferably personalized according to each individual’s disease-driving autoantigens (17).
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