Introduction to a Special Issue on Cytokines in Neuroinflammation and Immunity

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating and degenerative disease of the central nervous system (CNS). It is pathologically characterized by infiltration of activated inflammatory cells across the blood–brain barrier into the brain and spinal cord tissue resulting in demyelination and loss of cells, including oligodendrocytes, neurons, and axons. The inciting antigen has not been characterized and is likely to be heterogeneous. Genetic and environmental risk factors have been identified and their interaction is believed to underlie the immune dysregulation that leads to MS. MS is clinically heterogeneous, but the most common phenotype is relapsing remitting (RRMS), which ultimately transitions into secondary progressive (SPMS) with accumulation of disability. Fewer patients begin with a progressive form of the disease from the outset without relapses or remissions, referred to as the primary progress form (PPMS). No consistent immune differences among the different forms of the disease have been identified. While currently available immunomodulatory drugs are relatively effective in RRMS; unfortunately, they do not impact the course of PPMS.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS induced either by active immunization of the animal with myelin proteins and complete Freund's adjuvant, or by passive transfer of encephlitogenic T-cells. Although not a prefect model of MS, EAE is commonly used to study MS immunopathogenesis and to screen for potential therapies.

In this special issue of Journal of Interferon & Cytokine Research (JICR), leading experts in neuroimmunology address current hot topics in MS, including pathogenesis and disease triggers, relevant signaling pathways, biomarkers, and potential novel therapeutic targets. Ben Segal highlights MS as a dynamic disease with stage-specific immune alterations. He reviews potential biomarkers for different phases of the disease and how these biomarkers could be utilized as outcome measures in clinical trials.

V. Wee Yong and colleagues discuss the interactions between microglia and T cells in MS. They present evidence for reciprocal stimulation between the two cell types that could result in injurious or neurotrophic outcomes. They propose that this interaction could be targeted therapeutically.

Kiel and Kasper review gut commensalism and its relationship to CNS demyelination. They discuss the role of the gut microbiome in disease severity as well as in disease-free state and the contribution of T-helper, T-regulatory, and B cells to immune homeostasis within the gut.

Two contributions to this issue highlight the importance of specific signaling pathways in MS. Benveniste and colleagues discuss the involvement of the JAK/STAT signaling pathway in MS and its animal model EAE and how this pathway mediates the biological effects of the cytokines believed to contribute to MS pathogenesis. Racke and colleagues propose that the transcription factor T-bet is critical for T-cell encephalogenecity and could be targeted therapeutically in MS.

Interferon-beta (IFN-B) was the first drug to be approved for the treatment of MS more than two decades ago. Nallar and Kalvakolanu reviewed the known mechanisms of IFN action and the recently emerged ones in their article. Some of these signaling pathways are involved in neurotoxicity and others in neuroprotection. A number of experimental animal models that may have potential relevance to the CNS and IFN signaling have been identified in that review. However, a direct relevance of the proposed players needs to be established in the context of MS with more detailed studies. Thus, there is a great need to fill the gap between IFN action and its pro- and anti-CNS effects.

Tony Reder discusses how IFN-B works in MS and comments on some unexpected mechanistic effects for IFN-B in the context of risk factors and other therapeutic interventions in MS. Graber and Dhib-Jalbut review potential biomarkers to monitor clinical efficacy of IFN-B therapy in MS. Finally, Makar and colleagues discuss the role of neurotrophic factors—specifically, brain-derived neurotrophic factor—in EAE and how this molecule could be utilized therapeutically using genetically modified stem cell delivery into the CNS.

We hope that this special issue of JICR will advance the reader's appreciation of the cytokines and signaling pathways involved in MS and how knowledge of these intricate pathways can potentially lead to better therapies and animal models of the disease. We realize that this issue is not an exhaustive treatment of the subject and will organize other detailed reviews in the near future. We thank all authors of this special issue for providing articles in a timely manner despite their busy schedule.