Dysregulation of humoral immunity, iron homeostasis, and lipid metabolism is associated with multiple sclerosis progression.

BACKGROUND: Though most patients with multiple sclerosis (MS) presented earlier on as a relapsing-remitting (RR) disease, disability progression eventually occurred. Uncovering the mechanisms underlying progression may facilitate the unmet need for developing therapies to prevent progression. Benign MS (BMS), a rare form of MS, is the opposite from secondary progressive MS (SPMS) in that it lacks disease progression defined as Expanded Disability Status Scale (EDSS) ≤3 after at least 15 years of disease onset. BMS is characterized by rare and mild relapses with complete remission of clinical symptoms (lower activity of the disease) and lack of progression. Our study aims to identify transcriptomic and immunological differences between BMS and SPMS to unravel the pathogenesis of disease progression. METHODS: We took multi-modal approaches with microarrays, flow cytometry, and lipidomics by three-way comparisons of patients with BMS vs. RRMS (low disease activity vs. moderate or severe activity), RRMS vs. SPMS (continued activity vs. complete transformation into progressive phase) as well as BMS vs. SPMS, matched for age and disease-duration (low disease activity and no progression vs. progression with or without activity). RESULTS: We found that patients with RRMS and SPMS have a significantly higher percentage of B cells than those with BMS. BMS shows a different transcriptomic profile than SPMS. Many of the differentially expressed genes (DEGs) are involved in B cell-mediated immune responses. Additionally, long-chain fatty acids (LCFA), which can act as inflammatory mediators, are also altered in SPMS. Overall, our data suggest a role for the dysregulation of B cell differentiation and function, humoral immunity, and iron and lipid homeostasis in the pathogenesis of MS disease progression. CONCLUSION: BMS has a unique transcriptomic and immunological profile compared to RRMS and SPMS. These differences will allow for personalized precision medicine and may ultimately lead to the discovery of new therapeutic targets for disease progression.

Teriflunomide modulates both innate and adaptive immune capacities in multiple sclerosis.

BACKGROUND: Teriflunomide (TER) (Aubagio™) is an FDA-approved disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of TER is thought to be related to the inhibition of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway required by rapidly dividing lymphocytes. Several large pivotal studies have established the efficacy and safety of TER in patients with RRMS. Despite this, little is known about how the adaptive and innate immune cell subsets are affected by the treatment in patients with MS. METHODS: We recruited 20 patients with RRMS who were newly started on TER and performed multicolor flow cytometry and functional assays on peripheral blood samples. A paired t-test was used for the statistical analysis and comparison. RESULTS: Our data showed that TER promoted a tolerogenic environment by shifting the balance between activated pathogenic and naïve or immunosuppressive immune cell subsets. In our cohort, TER increased the expression of the immunosuppressive marker CD39 on regulatory T cells (Tregs) while it decreased the expression of the activation marker CXCR3 on CD4+ T helper cells. TER treatment also reduced switched memory (sm) B cells while it increased naïve B cells and downregulated the expression of co-stimulatory molecules CD80 and CD86. Additionally, TER reduced the percentage and absolute numbers of natural killer T (NKT) cells, as well as the percentage of natural killer (NK) cells and showed a trend toward reducing the CD56dim NK pathogenic subset. CONCLUSION: TER promotes the tolerogenic immune response and suppresses the pathogenic immune response in patients with RRMS.

Elevated sCD40L in Secondary Progressive Multiple Sclerosis in Comparison to Non-progressive Benign and Relapsing Remitting Multiple Sclerosis.

BACKGROUND: The long-term prognosis of relapsing-remitting multiple sclerosis (RRMS) is usually unfavorable as most patients transition to secondary progressive multiple sclerosis (SPMS) with accumulative disability. A rare form of non-progressive multiple sclerosis (MS) also exists, known as benign MS (BMS or NPMS), which lacks disease progression defined as Expanded Disability Status Scale (EDSS) ≤3 after 15 years of disease onset without treatment. PURPOSE: Our study aims to identify soluble plasma factors predicting disease progression in multiple sclerosis (MS). RESEARCH DESIGN AND STUDY SAMPLE: We utilized Luminex multiplex to analyze plasma levels of 33 soluble factors, comparing 32 SPMS patients to age-, sex-, and disease duration-matched non-progressive BMS patients, as well as to RRMS patients and healthy controls. RESULTS: Plasma levels of EGF, sCD40L, MCP1/CCL2, fractalkine/CX3CL1, IL-13, Eotaxin, TNFß/LTα, and IL-12p40 were significantly different between the various types of MS. Plasma sCD40L was significantly elevated in SPMS compared to BMS and RRMS. The combination of MCP1/CCL2 and sCD40L discriminated between RRMS and SPMS. MCP1/CCL2 was found to be the most effective classifier between BMS and RRMS, while BMS was most effectively distinguished from SPMS by the combination of sCD40L and IFNγ levels. CONCLUSIONS: These differences may facilitate personalized precision medicine and aid in the discovery of new therapeutic targets for disease progression through the improvement of patient stratification.