Multiple sclerosis (MS) is a complex disease with many different immune cells involved in its pathogenesis, and in particular T cells as the most recognized cell type. Recently, the innate immune system has also been researched for its effect on the disease. Hence, cells of the immune system play vital roles in either ameliorating or exacerbating the disease. The genetic and environmental factors, as well as the etiology and pathogenesis are of utmost importance for the development of MS. An insight into the roles play by T cells, B cells, natural killer cells, and dendritic cells in MS and the animal model experimental autoimmune encephalomyelitis, will be presented. Understanding the mechanisms of action for current therapeutic modalities should help developing new therapeutic tools to treat this disease and other autoimmune diseases.

Natural killer (NK) cells have both cytolytic and immunoregulatory functions. We recently described that these cells release the inflammatory cytokines IL-17 and IFN-γ. However, the precise identity of the NK cell subset(s) that secrete these cytokines is not known. To isolate the cells secreting IL-17 and IFN-γ, we took advantage of the findings that Th17/Th1 cells express chemokine receptors. Therefore, CD56⁺NK cells were stained with antibodies against various chemokine receptors and intracellularly with antibodies toward IL-17 and IFN-γ. Consequently, we identified previously unrecognized subset of NK cells generated from normal human peripheral blood after activation with IL-2 but not PMA plus ionomycin. The cells are characterized by the expression of CD56⁺ and CCR4⁺, produce IL-17 and IFN-γ and are consequently named NK17/NK1 cells. They also express CD161, NKp30, NKp44, NKp46, NKG2D, CD158, CCL22, IL-2Rβ and the common γ chain but not CD127 or IL-23R. Further, they possess T-bet and RORγt transcription factors. Antibodies to IL-1β, IL-6, IL-21, or TGF-β1 do not inhibit IL-2-induced generation of NK17/NK1 cells, suggesting that IL-2 has the capacity to polarize these cells. Notably, NK17/NK1 cells are abundant in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) without activation, and are generated from the peripheral blood of these patients after activation with IL-2. NK17/NK1 cells identified here have not been previously described in healthy or MS patients.

Objective: To prospectively investigate the long-term relationship between body mass index (BMI) in adolescents and young adults, and risk for multiple sclerosis (MS) at population level. Methods: We utilized data from the population-based compulsory Norwegian tuberculosis screening program during 1963-1975, including objectively measured height and weight from approximately 85% of all eligible citizens. This was combined with data from the Norwegian MS registry and biobank up to November 2020. BMI was standardized according to age and sex, and risk for MS was calculated using Cox proportional hazard models. Results: During 30,829,506 years of follow-up we found 1,409 cases of MS among 648,734 participants in eligible age groups (14-34 years). Overall, obesity was associated with increased MS risk (HR 1.53 [95% CI 1.25-1.88]), and the risk was similar in men (HR 1.4 [95% CI 0.95-2.06] and women (HR 1.59 [95% CI 1.25-2.02]). Risk was highest for the youngest age groups (age 14-16: HR 1.73 [95% CI 1.19-2.53], 17-19: HR 1.61 [95% CI 1.08-2.39] and 20-24: HR 1.56 [95% CI 1.04-2.36]) and was no longer present for those older than 30 years. Conclusion: High BMI in individuals aged 14 to 24 years was associated with increased MS-risk later in life, in both males and females.

Background Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease. It is thought to be mediated by CD4 + Th1/Th17 cells. More recently, cells of the innate immune system such as dendritic cells (DCs) and natural killer (NK) cells have been in focus. Glatiramer acetate (GA) is an approved drug for treating MS patients. Methodology/Principal Findings In the current study we examined the activities of NK and DCs in nine relapsing remitting MS patients for up to one year after initiation of GA treatment. We observed that NK cells isolated from most of these patients have increased cytotoxic activity against K562 cells. Further analysis showed that the same NK cells lysed both autologous immature (i) and mature (m) DCs. In most patients this increased activity was correlated with increased NK cell activating cytotoxicity receptors such as NKp30, NKp44, NKp46 and NKG2D, and reduced expression of the inhibitory molecule CD158 on the surface of these NK cells. The expression of HLA-DR was increased on iDCs and mDCs in the majority of the patients, but no consistency was observed for the expression of HLA-I or HLA-E. Also, the co-stimulatory receptors CD80, CD83 or CD86 expression was down-regulated on iDCs and mDCs in most cases. Further, the expression of CCR6 was increased on mDCs at later time points of therapy (between 32–48 weeks). Conclusions/Significance Our results are the first showing the effects of GA treatment on NK cells in MS patients, which may impact future use of this and other drugs to treat this disease.

Cysteine cathepsins are critical components of the adaptive immune system involved in the generation of epitopes for presentation on human leukocyte antigen (HLA) molecules and have been implicated in degradation of autoantigens. Immunoglobulin variable regions with somatic mutations and random complementarity region 3 amino acid composition are inherently immunogenic. T cell reactivity towards immunoglobulin variable regions has been investigated in relation to specific diseases, as well as reactivity to therapeutic monoclonal antibodies. Yet, how the immunoglobulins, or the B cell receptors, are processed in endolysosomal compartments of professional antigen presenting cells has not been described in detail. Here we present in silico and in vitro experimental evidence suggesting that cysteine cathepsins S, L and B may have important roles in generating peptides fitting HLA class II molecules, capable of being presented to T cells, from monoclonal antibodies as well as from central nervous system proteins including a well described autoantigen. By combining neural net models with in vitro proteomics experiments, we further suggest how such degradation can be predicted, how it fits with available cellular models, and that it is immunoglobulin heavy chain variable family dependent. These findings are relevant for biotherapeutic drug design as well as to understand disease development. We also suggest how these tools can be improved, including improved machine learning methodology.