Background

The gut microbiota is emerging as a critical regulator of immune responses and appears to play an important role in MS. The International Multiple Sclerosis Microbiome study (iMSMS) is a global collaboration aimed at elucidating the role of commensal gut bacteria in MS by acquiring and analyzing samples from 2000 patients and 2000 household healthy controls.

Objectives

The iMSMS focuses on identifying the microbes, genes and pathways that are involved in MS pathogenesis and on investigating how the microbiome changes response to treatment.

Methods

A total of 576 case and household healthy control pairs were recruited from 7 centers located in the US (West and East coasts), Europe and South America. Stool samples were collected and evaluated by both 16S and shallow whole metagenome shotgun sequencing. Univariate and multivariate linear regression analyses were conducted to understand patterns of variation on gut microbiome.

Results

This is the largest MS microbiome study reported to date. Our results showed a statistically significant difference of beta diversity between MS and healthy controls for the first time in MS. Intriguingly, multiple species of Akkermansia, including the known mucin-degrading bacterium Akkermansia muciniphila, were significantly enriched in untreated MS patients after adjusting for confounding factors, but the difference was not detected in treated MS group versus control. Ruminococcus torques and Eisenbergiella tayi were also among the top significantly enriched bacteria in MS. Inversely, a main butyrate producer, Faecalibacterium prausnitzii, was significantly decreased in the untreated MS group. Functional pathways of L-tryptophan biosynthesis and L-threonine biosynthesis were slightly increased in untreated MS patients, while 5-aminoimidazole ribonucleotide biosynthesis I was increased in the treated group.

Conclusions

Our large household-controlled study allowed us to identify modest but statistically robust MS-associated changes in bacterial composition and functions. It provides the foundation for all future studies of the gut microbiota in MS. The strain-level genomic variation and microbiome-derived molecules need to be further explored for understanding microbial adaptation and pathogenicity.

Background

Obesity in childhood and in adolescence increases the risk of MS by inducing a chronic low-grade inflammatory state, characterized by altered secretion of adipokines, of which leptin is the best characterized.

Objectives

The main goal of this study was to investigate the effects of leptin on different T cell populations, in order to gain more insight into the link between leptin and obesity.

Methods

Three hundred and nine RRMS patients and 322 matched controls were invited to participate in a cross-sectional survey, to confirm whether excess weight/obesity in adolescence or early adulthood were associated with increased risk of MS.

Serum leptin levels were determined by ELISA. MBP_83-102, and MOG_63-87 peptide-specific T cells lines were expanded from peripheral blood mononuclear cells. Leptin receptor, p-STAT3, pERK1/2, and p27^kip1 expression were assayed using RT-PCR. Apoptosis induction was determined by Annexin V detection. Cytokines were assessed by ELISPOT and ELISA, and regulatory T cells (Treg cells) detected by flow cytometry.

Results

Logistic regression analysis, with smoking as covariate, showed excess weight at age 15 and obesity at age 20 increased the risk of developing MS (OR=2.16, p=0.01 and OR=3.89, p=0.009). Leptin levels correlated with BMI(r=0.88, p<0.0001) in both groups. Addition of Leptin to cultures increased proliferation of autoreactive T cells, reduced apoptosis induction, and promoted pro-inflammatory cytokines secretion (p values < 0.001). Obese patients produced higher numbers of pro- inflammatory cytokines-secreting cells compared to overweight/normal/underweight subjects (p<0.001).

Inverse correlation was found between leptin levels and circulating CD4⁺CD25⁺ Treg cells (r=-0.97, p<0.0001). Leptin also inhibited Treg cell proliferation, inducing hypo-responsiveness. Effects of leptin on autoreactive T cells were mediated by increased STAT3 and ERK1/2 phosphorylation and down modulation of the cell cycle inhibitor P27^kip1. By contrast, leptin effects on Treg cells were mediated by decreased phosphorylation of ERK1/2 and upregulation of p27^kip1.

Conclusions

Leptin has a dual effect on T cell modulation. On one hand it promotes proliferation of autoreactive T cells, secretion of pro-inflammatory cytokines, and exerts an anti-apoptotic action. On the other, leptin inhibits Treg cell proliferation, inducing hypo-responsiveness, mediated by the opposite effects of STAT3, ERK1/2 phosphorylation, and p27^kip1 expression.

Background

Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have been identified in several clinical phenotypes of demyelinating diseases, including acute disseminated encephalomyelitis, isolated optic neuritis (ON), and seronegative neuromyelitis optica. Manifestations during pregnancy and puerperium have not been described.

Objectives

To describe two cases of non relapsing anti-MOG ON presenting during pregnancy and early puerperium. Both cases negativized six months after delivery.

Methods

Case reports. Both patients signed informed consent. Samples were analyzed for binding to AQP4 and MOG using fixed cell-based assays (Euroimmun). Antibodies to full-length AQP4 and MOG were detected with anti-human IgG1.

Results

Case 1. 35-year-old female presented, 15 days after delivery, retro-orbital pain and severe vision loss of the left eye (LE). General examination was normal. In the LE, visual acuity (VA) was hand motion and fundus revealed a mild optic disc edema. Right eye (RE) exam was normal. Brain MRI was normal, orbit MRI showed enhancement of the left optic nerve and perineural enhancement with extension of the surrounding orbital tissues. CSF was normal and oligoclonal bands negative. AQP4-IgG was negative, and MOG-IgG was positive. She received 1000 mg of intravenous (IV) methylprednisolone for three day with complete recovery in a week. She did not experience any recurrence during 2 years of follow up. No further treatment was established. Anti-MOG-IgG was repeated and resulted negative 6 and 18 months after the event.

Case 2. 34 years-old women at week 30 of gestation presented headache and severe bilateral visual loss (20/100 LE, 20/70 RE). Fundus, general examination and brain MRI were normal. Orbit MRI showed slight hyperintensity of the left optic nerve. Gadolinium was not used because of pregnancy. AQP4-IgG was negative, and anti-MOG-IgG was positive. She received 500 mg of IV methylprednisolone for three days with complete recovery of vision in two months. She delivered a healthy baby at term. Anti-MOG-IgG was repeated at 6 months of puerperium and resulted negative. No further treatment was established.

Conclusions

We report two cases of non-relapsing anti-MOG-ON presenting in late pregnancy and early puerperium that spontaneously negativized during the follow up. Since anti-MOG-ON is associated with humoral immunity, pregnancy and delivery might adversely affect its course, as observed in other antibodies mediated autoimmune diseases.