Memory B Cells Activate Brain-Homing Autoreactive CD4+ T Cells in Multiple Sclerosis

摘要

class="head no_bottom_margin" id="sec1title">IntroductionMultiple sclerosis (MS) is considered a prototypic organ-specific autoimmune disease. It mainly affects young adults and approximately 2.5 million people worldwide. Patients often develop impairments of visual, sensory, motor, neurocognitive, and autonomic functions. Its etiology involves a complex genetic trait with >100 quantitative trait loci (, ), most importantly the HLA-DR15 haplotype, for which an association with MS has already been described in 1973 (). Since HLA-class II molecules restrict CD4⁺ T cells, the genetic association provides a strong argument for the central role of adaptive immunity and CD4⁺ T cells in MS. Yet, how HLA-DR15 and other risk alleles induce and sustain MS is incompletely understood including the lack of an autoantigen unequivocally associated with MS pathogenesis. Epstein-Barr virus (EBV) infection, low vitamin D3, smoking, and obesity () have been identified as environmental risk factors, and genes and environment likely act in concert to trigger an autoimmune reaction against CNS tissue (, ).The vast majority of MS risk-conferring genes including HLA-DR15 are immune function related, while CNS-related genes are remarkably absent (, ). Considering data from the animal model of MS, experimental autoimmune encephalitis (EAE) (, , ), there is now compelling evidence that MS is an autoimmune disease with dysregulated adaptive immunity at its core. Findings from EAE and blood cells of MS patients together with the strong genetic HLA-DR15 association hint at the importance of myelin-reactive CD4⁺ T cells (). However, characterization of CNS-infiltrating immune cell populations and experience from B cell-depleting therapies suggest that CD8⁺ T cells, proinflammatory B cells, and autoantibodies are likely also involved (, , , href="#bib50" rid="bib50" class=" bibr popnode">Sospedra and Martin, 2005). A central question is how disease-relevant T and B cells interact.Starting from MS risk genes involved in T cell activation, differentiation, and homeostasis and the prominent role of HLA-DR15, we searched for experimental systems to approach this issue. The observation that myelin-specific T cell clones can be activated by antigen-presenting cells (APCs) in the absence of exogenous nominal antigen and the involvement of CD4, HLA-class II, and self-peptides provided the basis for such a system (href="#bib5" rid="bib5" class=" bibr popnode">Cai and Hafler, 2007, href="#bib22" rid="bib22" class=" bibr popnode">Kondo et al., 2001). Further, in MS reduced thymic output of T cells (href="#bib11" rid="bib11" class=" bibr popnode">Duszczyszyn et al., 2006, href="#bib19" rid="bib19" class=" bibr popnode">Hug et al., 2003), alterations in T regulatory cells (href="#bib6" rid="bib6" class=" bibr popnode">Carbone et al., 2014), increased T cell proliferation and related signatures (href="#bib6" rid="bib6" class=" bibr popnode">Carbone et al., 2014, href="#bib55" rid="bib55" class=" bibr popnode">Tuller et al., 2013), decreased autologous mixed lymhocyte reaction (AMLR) (href="#bib16" rid="bib16" class=" bibr popnode">Hafler et al., 1985), and reduced T cell receptor (TCR) repertoire diversity (href="#bib24" rid="bib24" class=" bibr popnode">Laplaud et al., 2004, href="#bib34" rid="bib34" class=" bibr popnode">Muraro et al., 2005) indicate perturbed T cell homeostasis. In distinction to the defective AMLR, which was shown to be altered not only in MS, but also in other autoimmune diseases like rheumatoid arthritis already three decades ago (href="#bib21" rid="bib21" class=" bibr popnode">Kitas et al., 1988) and which remained unexplained, we recently showed that spontaneous in vitro T cell proliferation is increased in MS patients (href="#bib31" rid="bib31" class=" bibr popnode">Mohme et al., 2013). We refer to this phenomenon as “autoproliferation” (AP). The HLA-DR15 haplotype and DR15-presented self-peptides take part in this process (href="#bib31" rid="bib31" class=" bibr popnode">Mohme et al., 2013), but which cells induce and maintain T cell proliferation and whether AP T cells may be pathogenic are unknown. Here, we characterized in detail the cellular interactions that lead to increased AP and provide evidence for its potential involvement in MS.