Brain Antigens Stimulate Proliferation of T Lymphocytes With a Pathogenic Phenotype in Multiple Sclerosis Patients.

A method to stimulate T lymphocytes with a broad range of brain antigens would facilitate identification of the autoantigens for multiple sclerosis and enable definition of the pathogenic mechanisms important for multiple sclerosis. In a previous work, we found that the obvious approach of culturing leukocytes with homogenized brain tissue does not work because the brain homogenate suppresses antigen-specific lymphocyte proliferation. We now report a method that substantially reduces the suppressive activity. We used this non-suppressive brain homogenate to stimulate leukocytes from multiple sclerosis patients and controls. We also stimulated with common viruses for comparison. We measured proliferation, selected the responding CD3+ cells with flow cytometry, and sequenced their transcriptomes for mRNA and T-cell receptor sequences. The mRNA expression suggested that the brain-responding cells from MS patients are potentially pathogenic. The T-cell receptor repertoire of the brain-responding cells was clonal with minimal overlap with virus antigens.

The Association of Gut Microbiota and Treg Dysfunction in Autoimmune Diseases.

Autoimmune conditions affect 23 million Americans or 7% of the US population. There are more than 100 autoimmune disorders, affecting every major organ system in humans. This chapter aims to further explain Treg dysfunction autoimmune disorders, including monogenic primary immune deficiency such as immune dysregulation polyendocrinopathy, enteropathy, X-linked inheritance (IPEX) syndrome, and polygenic autoimmune diseases with Treg dysfunction such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and food allergy. These conditions are associated with an abnormal small intestinal and colonic microbiome. Some disorders clearly improve with therapies aimed at microbial modification, including probiotics and fecal microbiota transplantation (FMT). Approaches to prevent and treat these disorders will need to focus on the acquisition and maintenance of a healthy colonic microbiota, in addition to more focused approaches at immune suppression during acute disease exacerbations.

Lactobacillus reuteri Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Mice by Modulating Gut Microbiota.

The gut microbiome plays an important role in immune function and has been implicated in multiple sclerosis (MS). However, how and if the modulation of microbiota can prevent or treat MS remain largely unknown. In this study, we showed that probiotic Lactobacillus reuteri DSM 17938 (L. reuteri) ameliorated the development of murine experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, a model which is primarily mediated by TH17 and TH1 cells. We discovered that L. reuteri treatment reduced TH1/TH17 cells and their associated cytokines IFN-γ/IL-17 in EAE mice. We also showed that the loss of diversity of gut microbiota induced by EAE was largely restored by L. reuteri treatment. Taxonomy-based analysis of gut microbiota showed that three "beneficial" genera Bifidobacterium, Prevotella, and Lactobacillus were negatively correlated with EAE clinical severity, whereas the genera Anaeroplasma, Rikenellaceae, and Clostridium were positively correlated with disease severity. Notably, L. reuteri treatment coordinately altered the relative abundance of these EAE-associated taxa. In conclusion, probiotic L. reuteri changed gut microbiota to modulate immune responses in EAE, making it a novel candidate in future studies to modify the severity of MS.