Interferon-β is the major treatment for multiple sclerosis (MS). However, this treatment is not always effective. Here we see congruence in outcome between responses to IFN-β in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting MS (RRMS). IFN-β is effective in reducing EAE induced by TH1 cells, but exacerbated disease induced by TH17. Effective treatment in TH1 EAE correlated with increased IL-10 in the spleen. In TH17 disease, the amount of IL-10 was unaltered by treatment, though unexpectedly IFN-β still reduced IL-17 without benefit. Both inhibition of IL-17 and induction of IL-10 depended on IFN-γ. In the absence of IFN-γ signaling, IFN-β therapy was ineffective in EAE. In RRMS, IFN-β non-responders had higher IL-17F in serum compared to responders. Non-responders had worse disease with more steroid usage and more relapses than responders. Hence, IFN-β is pro-inflammatory in TH17 induced EAE. Moreover, high IL-17F in the serum of RRMS patients is associated with non-responsiveness to therapy with IFN-β.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in about 1/100,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and 1/2,500 other individuals, is much more frequent in patients with tuberculosis than in ethnicity-adjusted controls (p = 8.37×10−8, odds ratio = 89.31 [95%CI: 14.7–1,725]). We also show that the frequency of P1104A in Europeans has decreased significantly, from about 9% to 4.2%, over the last 4,000 years, consistent with purging of this variant by endemic tuberculosis. Moreover, we show that catalytically inactive P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Finally, we show that catalytically competent TYK2 is critical for IL-23 but not IL-12 responses, whereas catalytically competent JAK2 is redundant for both. Homozygosity for the P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

The role of interferon (IFN)-γ in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), has remained as an enigmatic paradox for more than 30 years. Several studies attribute this cytokine a prominent proinflammatory and pathogenic function in these pathologies. However, accumulating evidence shows that IFN-γ also plays a protective role inducing regulatory cell activity and modulating the effector T cell response. Several innate and adaptive immune cells also develop opposite functions strongly associated with the production of IFN-γ in EAE. Even the suppressive activity of different types of regulatory cells is dependent on IFN-γ. Interestingly, recent data supports a stage-specific participation of IFN-γ in EAE providing a plausible explanation for previous conflicting results. In this review, we will summarize and discuss such literature, emphasizing the protective role of IFN-γ on immune cells. These findings are fundamental to understand the complex role of IFN-γ in the pathogenesis of these diseases and can provide basis for potential stage-specific therapy for MS targeting IFN-γ-signaling or IFN-γ-producing immune cells.

Multiple sclerosis (MS) is the principal cause of autoimmune neuroinflammation in humans, and its animal model, experimental autoimmune encephalomyelitis (EAE), is widely used to gain insight about their immunopathological mechanisms for and the development of novel therapies for MS. Most studies on the role of interferon (IFN)-γ in the pathogenesis and progression of EAE have focused on peripheral immune cells, while its action on central nervous system (CNS)-resident cells has been less explored. In addition to the well-known proinflammatory and damaging effects of IFN-γ in the CNS, evidence has also endowed this cytokine both a protective and regulatory role in autoimmune neuroinflammation. Recent investigations performed in this research field have exposed the complex role of IFN-γ in the CNS uncovering unexpected mechanisms of action that underlie these opposing activities on different CNS-resident cell types. The mechanisms behind these two-faced effects of IFN-γ depend on dose, disease phase, and cell development stage. Here, we will review and discuss the dual role of IFN-γ on CNS-resident cells in EAE highlighting its protective functions and the mechanisms proposed.

Vitamin D plays key roles as a natural immune modulator and has been implicated in the pathophysiology of autoimmune diseases, including systemic lupus erythematosus (SLE). This review presents a summary and analysis of the recent literature regarding immunoregulatory effects of vitamin D as well as its importance in SLE development, clinical severity, and possible effects of supplementation in disease treatment.

Type I IFNs (IFN-α and IFN-β) and type II IFN (IFN-γ) mediate both regulation and inflammation in multiple sclerosis (MS), neuromyelitis optica (NMO) and in experimental autoimmune encephalomyelitis (EAE). However the underlying mechanism for these Janus-like activities of type I and II IFNs in neuroinflammation remains unclear. Although endogenous type I IFN-signaling provides a protective response in neuroinflammation, we find that when IFN-γ signaling is ablated, type I IFNs drive inflammation resulting in exacerbated EAE. IFN-γ has disease stage-specific opposing function in EAE. Treatment of mice with IFN-γ during initiation phase of EAE leads to enhanced severity of disease. In contrast, IFN-γ treatment during effector phase attenuated disease. This immunosuppressive activity of IFN-γ required functional type I IFN-signaling. In IFN-α/β receptor (IFNAR) deficient mice, IFN-γ treatment during effector phase of EAE exacerbated disease. Using an adoptive transfer-EAE model, we found that T-cell intrinsic type I and type II IFN signals are simultaneously required to establish chronic EAE by encephalitogenic Th1 cells. However in Th17 cells loss of either IFN signals leads to the development of a severe chronic disease. The data implies that type I and type II IFN signals have independent but non-redundant role in restraining encephalitogenic Th17 cells in vivo. Overall our data show that type I and type II IFNs function in an integrated manner to regulate the pathogenesis in EAE.

Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system. It is a heterogeneous pathology that can follow different clinical courses, and the mechanisms that underlie the progression of the immune response across MS subtypes remain incompletely understood. Here, we aimed to determine differences in the immunological status among different MS clinical subtypes. Blood samples from untreated patients diagnosed with clinically isolated syndrome (CIS) (n = 21), different clinical forms of MS (n = 62) [relapsing–remitting (RRMS), secondary progressive, and primary progressive], and healthy controls (HCs) (n = 17) were tested for plasma levels of interferon (IFN)-γ, IL-10, TGF-β, IL-17A, and IL-17F by immunoanalysis. Th1 and Th17 lymphocyte frequencies were determined by flow cytometry. Our results showed that IFN-γ levels and the IFN-γ/IL-10 ratio were higher in CIS patients than in RRMS patients and HC. Th1 cell frequencies were higher in CIS and RRMS than in progressive MS, and RRMS had a higher Th17 frequency than CIS. The Th1/Th17 cell ratio was skewed toward Th1 in CIS compared to MS phenotypes and HC. Receiver operating characteristic statistical analysis determined that IFN-γ, the IFN-γ/IL-10 ratio, Th1 cell frequency, and the Th1/Th17 cell ratio discriminated among CIS and MS subtypes. A subanalysis among patients expressing high IL-17F levels showed that IL-17F and the IFN-γ/IL-17F ratio discriminated between disease subtypes. Overall, our data showed that CIS and MS phenotypes displayed distinct Th1- and Th17-related cytokines and cell profiles and that these immune parameters discriminated between clinical forms. Upon validation, these parameters might be useful as biomarkers to predict disease progression.

Inhibitors of glycogen synthase kinase 3 (GSK3) are being explored as therapy for chronic inflammatory diseases. We previously demonstrated that the GSK inhibitor lithium is beneficial in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. In this study we report that lithium suppresses EAE induced by encephalitogenic interferon-γ (IFN-γ)-producing T helper (Th1) cells but not by interleukin (IL)-17-producing T helper (Th17) cells. The therapeutic activity of lithium required functional IFN-γ-signaling, but not the receptor for type I IFN (IFNAR). Inhibitor/s of GSK3 attenuated IFN-γ dependent activation of the transcription factor STAT1 in naïve T cells as well as in encephalitogenic T cells and Th1 cells. The inhibition of STAT1 activation was associated with reduced IFN-γ production and decreased expansion of encephalitogenic Th1 cells. Furthermore, lithium treatment induced Il27 expression within the spinal cords of mice with EAE. In contrast, such treatment of Ifngr−/− mice did not induce Il27 and was associated with lack of therapeutic response. Our study reveals a novel mechanism for the efficacy of GSK3 targeting in EAE, through the IFN-γ-STAT1 axis that is independent IFNAR-STAT1 axis. Overall our findings set the framework for the use of GSK3 inhibitors as therapeutic agents in autoimmune neuroinflammation.