Interferon-ß Intensifies Interleukin-23-Driven Pathogenicity of T Helper Cells in Neuroinflammatory Disease.

Interferon (IFN)-ß is a popular therapy for multiple sclerosis (MS). However, 25-40% of patients are nonresponsive to this therapy, and it worsens neuromyelitis optica (NMO), another neuroinflammatory disease. We previously identified, in both NMO patients and in mice, that IFN-ß treatment had inflammatory effects in T Helper (TH) 17-induced disease through the production of the inflammatory cytokine IL-6. However, other studies have shown that IFN-ß inhibits the differentiation and function of TH17 cells. In this manuscript, we identified that IFN-ß had differential effects on discrete stages of TH17 development. During early TH17 development, IFN-ß inhibits IL-17 production. Conversely, during late TH17 differentiation, IFN-ß synergizes with IL-23 to promote a pathogenic T cell that has both TH1 and TH17 characteristics and expresses elevated levels of the potent inflammatory cytokines IL-6 and GM-CSF and the transcription factor BLIMP. Together, these findings help resolve a paradox surrounding IFN-ß and TH17-induced disease and illuminate the pathways responsible for the pathophysiology of NMO and MS patients who are IFN-ß nonresponders.

CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS.

OBJECTIVE: B cells have emerged as a therapeutic target for MS. Anti-CD20 antibodies, which deplete B cells, are effective therapies for MS. However, atacicept (TACI-Fc), which blocks BAFF and APRIL and reduces B cells, unexpectedly exacerbates MS. We tested the hypothesis that B cell maturation antigen (BCMA), a receptor for BAFF and APRIL, plays a role in the paradoxical effects of anti-CD20 antibody and TACI-Fc using experimental autoimmune encephalomyelitis (EAE). METHODS: EAE was induced in wild-type (BCMA+/+) and BCMA-deficient (BCMA-/-) mice with an immunization of rodent myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. Treatment with anti-CD20 antibody, TACI-Fc, and isotype controls was administered by intraperitoneal injections. CNS infiltration was evaluated by histology; immune cell phenotypes were evaluated by flow cytometry; MOG-specific antibodies were determined by ELISA. Mixed bone marrow chimeras and cell culture assays were used to identify the specific subsets of immune cells affected by BCMA deficiency. RESULTS: First, we found that BCMA-/- mice had more severe EAE compared with BCMA+/+ mice and the increased disease was associated with elevated anti-MOG B-cell responses. Second, we found that anti-CD20 therapy attenuated EAE in BCMA-/- mice but not in BCMA+/+ mice. Third, TACI-Fc attenuated EAE in BCMA+/+ mice but not in BCMA-/- mice. Mixed bone marrow chimeric and cell culture experiments demonstrated that BCMA deficiency elevates inflammatory B-cell responses but inhibits inflammatory responses in macrophages. CONCLUSIONS: BCMA has multifaceted roles during inflammation that affects therapeutic efficacies of anti-CD20 and TACI-Fc in EAE. Our results from BCMA-deficient mice provide insights into the failure of atacicept in MS.

Transcriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica.

Type I interferon (IFN-I) and T helper 17 (TH17) drive pathology in neuromyelitis optica spectrum disorder (NMOSD) and in TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE). This is paradoxical because the prevalent theory is that IFN-I inhibits TH17 function. Here we report that a cascade involving IFN-I, IL-6 and B cells promotes TH17-mediated neuro-autoimmunity. In NMOSD, elevated IFN-I signatures, IL-6 and IL-17 are associated with severe disability. Furthermore, IL-6 and IL-17 levels are lower in patients on anti-CD20 therapy. In mice, IFN-I elevates IL-6 and exacerbates TH17-EAE. Strikingly, IL-6 blockade attenuates disease only in mice treated with IFN-I. By contrast, B-cell-deficiency attenuates TH17-EAE in the presence or absence of IFN-I treatment. Finally, IFN-I stimulates B cells to produce IL-6 to drive pathogenic TH17 differentiation in vitro. Our data thus provide an explanation for the paradox surrounding IFN-I and TH17 in neuro-autoimmunity, and may have utility in predicting therapeutic response in NMOSD.

Role of TFH Cells in Promoting T Helper 17-Induced Neuroinflammation.

Both T cells and B cells are implicated in the pathology of multiple sclerosis (MS), but how these cells cooperate to drive disease remains unclear. Recent studies using experimental autoimmune encephalomyelitis (EAE) demonstrated that the TH17 pathway is correlated with increased numbers of ectopic B-cell follicles in the central nervous system (CNS). As follicular T helper (TFH) cells are regulators of B cell responses, we sought to examine the role of TFH cells in EAE induced by the transfer of myelin-specific TH17 cells (TH17-EAE). In this study, we first confirmed previous reports that B-cells are a major cell type infiltrating the CNS during TH17-EAE. In addition, we found that B cells contribute to the severity of TH17-EAE. Class-switched B-cells in the CNS were positively correlated with disease and, strikingly, the severity TH17-EAE was diminished in B cell deficient mice. We next focused on the role TFH cells play in TH17-EAE. We found substantial numbers of CXCR5+PD1+CD4+ TFH cells in the CNS tissue of TH17-EAE mice and that at the peak of disease, the number of infiltrating TFHs was correlated with the number of infiltrating B-cells. Using congenic CD45.1+ donor mice and CD45.2+ recipient mice, we determined that the TFH cells were recipient-derived, whereas IL-17+ cells were donor-derived. We assessed whether myelin-specific TFH cells are capable of inducing EAE in recipient mice and found that transferring TFH cells failed to induce EAE. Finally, we tested the effects of blocking TFH trafficking in TH17-EAE using an antagonistic antibody against CXCL13, the chemokine ligand for CXCR5 on TFH cells. We found anti-CXCL13 treatment significantly reduced TH17-EAE disease. This treatment blocked CD4+ T cells from entering the CNS, but had no effect on infiltration of B cells. Strikingly, this antibody treatment had no measurable effect on TH17 disease in B cell-deficient mice. These data demonstrate that infiltrating TFH cells are a key cell type that contributes to an inflammatory B cell response in TH17-EAE and provide evidence for targeting TFH cells as a treatment for neuro-autoimmune diseases like MS.