Gut Feeling – intestinal microbes influence immune system tolerance of central nervous system

Multiple Sclerosis (MS: Wikipedia, PubMedHealth) is an autoimmune disease wherein lymphocytes attack the central nervous system (CNS), including the brain and spinal cord, leading to relapsing, progressive loss of neurons. Lesions containing B and T lymphocytes develop in the CNS. The cause of MS is unknown.

A mouse model of MS, called experimental autoimmune encephalomyelitis (EAE), can be induced when mice of certain strains are immunized with spinal cord proteins, or it can occur spontaneously in genetically engineered strains in which many CD4+ “helper” T cells express a transgenic T cell receptor specific for myelin oligodendrocyte glycoprotein (MOG), a protein abundant on the surface of key non-neuronal cells of the CNS.

These authors observed that depending on the animal housing facility, between 35-90% of MOG-specific-TCR-transgenic mice spontaneously develop EAE at between 3-8 months of age. The wide range in the disease incidence reminded the authors of a 1993 report by Goverman that mice with T cells expressing transgenic antigen receptors specific for another nerve protein, MBP, developed EAE ‘spontaneously’ in non-sterile housing but not in sterile housing.

They compared EAE incidence in mice that possess normal gut microbes but harbor no known pathogens, termed Specific Pathogen Free (SPF), and mice that possess no microbes at all, termed “germ free” (GF), and found that GF mice were protected (Fig 1a, shown, left panel).

Gut microbes are known to contribute to lymphocyte maturation, stimulated by , e.g., segmented filamentous bacteria) or polysaccharides of Bacteroides fragilis. However, the authors argue this does not explain protection because GF mice colonized with “conventional commensal” microbes developed EAE “promptly”, starting about a month later (Fig 1b, shown, right panel). They add that colonization with segmented filamentous bacteria – shown to trigger autoimmunity in another model – conferred EAE susceptibility only inefficiently. They also argue that GF mice immunized with MOG in complete adjuvant develop EAE (though again with a delay of about a month) and produce specific antibodies (though measured crudely, not titered), demonstrating that their lymphocytes are mature.

Instead, the authors argue that some lymphocyte activities are reduced in GF mice, particularly T cell production of the pro-inflammatory interleukin-17 and spontaneous B cell production of MOG-specific antibodies (which is also “promptly” albeit only partially corrected by colonization, Fig 3a). Moreover, MOG-specific B cells – but not polyclonal normal B cells – transferred into MOG-specific-TCR-transgenic mice – but not MOG-deficient mice – home to germinal centers where they mature and make antibodies that are IgG2a class-switched, and therefore implicitly effective in cooperating with specific T cells to induce EAE. They conclude that commensal gut microbes activate autoreactive T cells that recruit autoreactive B cells, which together mediate disease.

Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, Wekerle H, Krishnamoorthy G. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011 Oct 26;479(7374):538-41. doi: 10.1038/nature10554. PubMed PMID: 22031325