TH17-Driven Inflammation is Present in All Clinical Forms of Multiple Sclerosis; Disease Quiescence is Associated with Gata3-Expressing Cells

Abstract

Multiple Sclerosis (MS) presents in a variety of clinical forms associated with a diverse grade of neurological impairment, different prognosis and, possibly, multiple pathogenic mechanisms. Thus, whereas relapsing-remitting (RR) MS appears to be largely driven by inflammatory processes, neurodegeneration, partially independent from inflammation, drives primary progressive (PP) and secondary progressive (SP) MS. An extensive analysis of neuroinflammation in the different forms of MS was performed by evaluating immunophenotypic and functional parameters in MBP-stimulated T lymphocytes of 103 MS patients (26 benign (BE) MS, 30 RRMS, 33 SPMS and 14 PPMS) and 40 healthy controls (HC). Results showed that: i) IL-17-producing and RORC/yt-expressing CD4+ T cells (THI7 lymphocytes), as well as IL-6 expressing CDI4+ cell were augmented in all patients; ii) IL-22-expressing cells were increased in all forms of MS with the exception of PPMS; iii) TGF-p-expressing B cells were increased only in RRMS; and iv) GATA3-, NFATc-l, IL-13-, and IL-25-expressing cells (TH2 lymphocytes) were augmented in RRMS and BEMS patients alone. Data herein indicate a pivotal pathogenic role of THl7-driven inflammation in all clinical forms of MS and suggest that control over disease (RRMS and BEMS) is associated not with lack of inflammation per se, but rather with the activation of immune-mediated anti-inflammatory mechanisms. These results could help the design of novel diagnostic and therapeutic approaches.Multiple sclerosis (MS), a demyelinating autoimmune disease ofthe central nervous system, is triggered by molecular mimicry with cross-reacting and yet undefined epitopes and is associated with the activation of CD4+ TH I and TH I7 lymphocytes, CD8+ T lymphocytes, and B lymphocytes, as well as myeloid dendritic cells. The activation of these cells drives the neuroinflammation that plays an important role in damaging the myelin sheath (I, 2).The most common clinical phenotype ofMS is the relapsing-remitting (RR) form, which is characterized by an acute onset of symptoms and signs suggestive of neurological dysfunction, followed by complete or partial recovery. The long-term prognosis of RRMS is usually unfavorable, since patients enter the so-called secondary progressive (SP) phase of

Immunological and Clinical Effect of Diet Modulation of the Gut Microbiome in Multiple Sclerosis Patients: A Pilot Study

“…We have previously shown that, whereas CD4+/Th17+ and CD4+/PD-1+ T lymphocytes are increased in MS compared to HC ( 43 ), CD14+/PD-L1+ monocytes prevail during disease remission ( 44 ); this is the immune profile we observed in MS patients undergoing a HV/LP diet. Taken together, these results could explain the attenuation of disease activity observed in these individuals during follow-up.…”

A novel data mining system points out hidden relationships between immunological markers in multiple sclerosis

“…The latter can provide binary correlation, and show immunological pattern best associated to a clinical phenotype but it is unsuitable to finger out the non-linear interconnections among variables. In order to find the natural associations among immunological markers we applied a fuzzy clustering approach based on evolutionary programming (PST) and Semantic connectivity map (AutoCM) to the data of a wide immunological study, dissecting new pathways of immunological mechanisms [7]. AutoCM is a special kind of Artificial Neural Network able to find consistent trends and associations among variables.…”

“…Moreover these cells seem to be the trigger of the inflammatory response driven by Th17 during MS [20]. However our previous study [7] failed to detect a clear difference in IL-9-secreting cells between any clinical MS phenotype and HC. AutoCM strengthen this finding with a different analysis indicating the contemporary association of Th9 cells to the 3 main immune CD4+ T lymphocytes phenotypes: Th2 (CD4GATA+), Th1 (CD4TBET) and Th17 (CD4IL22).…”

“…The same clinical and immunological dataset was previously studied with traditional statistical analyses [7]. …”

B Lymphocytes in Multiple Sclerosis: Bregs and BTLA/CD272 Expressing-CD19+ Lymphocytes Modulate Disease Severity

“…In experimental allergic encephalomyelitis (EAE), in particular, the most widely investigated animal model of MS, interleukin (IL)-10 producing B cells were shown to have an important immunomodulatory role 7 . The ability of CD19+ B cells to secrete IL-10 is greatly reduced as well in patients with MS 8 9 10 11 12 , suggesting that the MS-associated inflammatory milieu is at least partly attributable to a defect in IL-10 generation by B lymphocytes. In contrast with what is observed with IL-10, the production of pro-inflammatory cytokines by activated B lymphocytes is increased in MS, and lymphotoxin (LT) and tumor necrosis factor alpha (TNFα) were shown to mediate oligodendrocyte toxicity in vitro 13 .…”