Kerstin Berer

Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination

Active multiple sclerosis lesions show inflammatory changes suggestive of a combined attack by autoreactive T and B lymphocytes against brain white matter. These pathogenic immune cells derive from progenitors that are normal, innocuous components of the healthy immune repertoire but become autoaggressive upon pathological activation. The stimuli triggering this autoimmune conversion have been commonly attributed to environmental factors, in particular microbial infection. However, using the relapsing–remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis, here we show that the commensal gut flora—in the absence of pathogenic agents—is essential in triggering immune processes, leading to a relapsing–remitting autoimmune disease driven by myelin-specific CD4+ T cells. We show further that recruitment and activation of autoantibody-producing B cells from the endogenous immune repertoire depends on availability of the target autoantigen, myelin oligodendrocyte glycoprotein (MOG), and commensal microbiota. Our observations identify a sequence of events triggering organ-specific autoimmune disease and these processes may offer novel therapeutic targets.

Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells

We describe new T cell receptor (TCR) transgenic mice (relapsing-remitting [RR] mice) carrying a TCR specific for myelin oligodendrocyte glycoprotein (MOG) peptide 92–106 in the context of I-As. Backcrossed to the SJL/J background, most RR mice spontaneously develop RR experimental autoimmune encephalomyelitis (EAE) with episodes often altering between different central nervous system tissues like the cerebellum, optic nerve, and spinal cord. Development of spontaneous EAE depends on the presence of an intact B cell compartment and on the expression of MOG autoantigen. There is no spontaneous EAE development in B cell–depleted mice or in transgenic mice lacking MOG. Transgenic T cells seem to expand MOG autoreactive B cells from the endogenous repertoire. The expanded autoreactive B cells produce autoantibodies binding to a conformational epitope on the native MOG protein while ignoring the T cell target peptide. The secreted autoantibodies are pathogenic, enhancing demyelinating EAE episodes. RR mice constitute the first spontaneous animal model for the most common form of multiple sclerosis (MS), RR MS.

From classic to spontaneous and humanized models of multiple sclerosis: impact on understanding pathogenesis and drug development.

Multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), presents as a complex disease with variable clinical and pathological manifestations, involving different pathogenic pathways. Animal models, particularly experimental autoimmune encephalomyelitis (EAE), have been key to deciphering the pathophysiology of MS, although no single model can recapitulate the complexity and diversity of MS, or can, to date, integrate the diverse pathogenic pathways. Since the first EAE model was introduced decades ago, multiple classic (induced), spontaneous, and humanized EAE models have been developed, each recapitulating particular aspects of MS pathogenesis. The advances in technologies of genetic ablation and transgenesis in mice of C57BL/6J background and the development of myelin-oligodendrocyte glycoprotein (MOG)-induced EAE in C57BL/6J mice yielded several spontaneous and humanized EAE models, and resulted in a plethora of EAE models in which the role of specific genes or cell populations could be precisely interrogated, towards modeling specific pathways of MS pathogenesis/regulation in MS. Collectively, the numerous studies on the different EAE models contributed immensely to our basic understanding of cellular and molecular pathways in MS pathogenesis as well as to the development of therapeutic agents: several drugs available today as disease modifying treatments were developed from direct studies on EAE models, and many others were tested or validated in EAE. In this review, we discuss the contribution of major classic, spontaneous, and humanized EAE models to our understanding of MS pathophysiology and to insights leading to devising current and future therapies for this disease.

Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice

Significance Studies using experimental models have indicated that multiple sclerosis (MS)-like disease can be triggered in the gut following interactions of brain autoimmune T lymphocytes with local microbiota. Here we studied the gut microbiota from monozygotic human twin pairs discordant for multiple sclerosis. When we transferred human-derived microbiota into transgenic mice expressing a myelin autoantigen-specific T cell receptor, we found that gut microbiota from multiple sclerosis-affected twins induced CNS-specific autoimmunity at a higher incidence than microbiota from healthy co-twins. Our results offer functional evidence that human microbiome components contribute to CNS-specific autoimmunity. There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twin-derived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.

Microbial view of central nervous system autoimmunity

Not much is known about the initial events leading to the development of the central nervous system (CNS)‐specific autoimmune disorder Multiple Sclerosis (MS). Environmental factors are suspected to trigger the pathogenic events in people with genetic disease susceptibility. Historically, many infectious microbes were linked to MS, but no infection has ever been demonstrated to be the cause of the disease. Recent emerging evidence from animal models of MS suggests a causal link with resident commensal bacteria. Microbial organisms may trigger the activation of CNS‐specific, auto‐aggressive lymphocytes either through molecular mimicry or via bystander activation. In addition, several gut microbial metabolites and bacterial products may interact with the immune system to modulate CNS autoimmunity.

Commensal gut flora and brain autoimmunity: a love or hate affair?

Multiple sclerosis (MS) and other chronic inflammatory autoimmune diseases represent major public health challenges in industrialised Western society. MS results from an autoimmune attack against myelin structures by self-reactive lymphocytes, which are normal components of the healthy immune repertoire. The nature of the triggers that convert the innocuous self-reactive lymphocytes into an autoaggressive phenotype is poorly understood. In the past, it was primarily suspected that pathogenic infections trigger MS. However, so far, none of the incriminated pathogenic microbes were firmly associated with the disease. A growing body of evidence in animal models of MS implicates the gut microbiota in the induction of central nervous system (CNS) autoimmunity. The mammalian gut harbors a diverse population of microbial organisms which are essential for our well being. There is an increasing understanding that the gut microbiota not only modulates the local immune functions but also affects the systemic immune system. We are only just beginning to understand the nature of the interactions of the gut microbiota with the host’s immune system especially in the context of autoimmune diseases. This review will address the influence of intestinal microbiota on immune homeostasis and on the development of autoimmune responses at sites distal to the intestine with a particular emphasis placed on a discussion about CNS autoimmunity.

The Immunoregulator Soluble TACI Is Released by ADAM10 and Reflects B Cell Activation in Autoimmunity

BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF–APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-κB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF–APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation.

B cells in spontaneous autoimmune diseases of the central nervous system

B cells and their secreted products participate in the intricate network of pathogenic and regulatory immune responses. In human autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes, a role for B cells and antibodies is well established. However, in multiple sclerosis (MS), despite the presence of autoantibodies, B cells were less considered as a major participant of autoimmune processes, until recently. Several lines of evidence now indicate a more active role for B cells in disease pathogenesis. In this review, we discuss the diverse roles of B cells in autoimmune diseases with particular focus on multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE) as well as the recently generated spontaneous EAE mouse models.

Treg cells mediate recovery from EAE by controlling effector T cell proliferation and motility in the CNS

Regulatory T cells are crucial in controlling various functions of effector T cells during experimental autoimmune encephalomyelitis. While regulatory T cells are reported to exert their immunomodulatory effects in the peripheral immune organs, their role within the central nervous system (CNS) during experimental autoimmune encephalomyelitis is unclear. Here, by combining a selectively timed regulatory T cells depletion with 2-photon microscopy, we report that regulatory T cells exercise their dynamic control over effector T cells in the CNS. Acute depletion of regulatory T cells exacerbated experimental autoimmune encephalomyelitis severity which was accompanied by increased pro-inflammatory cytokine production and proliferation of effector T cells. Intravital microscopy revealed that, in the absence of regulatory T cells, the velocity of effector T cells was decreased with simultaneous increase in the proportion of stationary phase cells in the CNS. Based on these data, we conclude that regulatory T cells mediate recovery from experimental autoimmune encephalomyelitis by controlling cytokine production, proliferation and motility of effector T cells in the CNS.

Deficiency of the Stroke Relevant HDAC9 Gene Attenuates Atherosclerosis in Accord With Allele-Specific Effects at 7p21.1

Background and Purpose— Recent genome-wide association studies identified the histone deacetylase 9 (HDAC9) gene region as a major risk locus for large-vessel stroke and coronary artery disease. However, the mechanisms linking variants at this locus to vascular risk are poorly understood. In this study, we investigated the candidacy and directionality of HDAC9 in atherosclerosis and analyzed associations between risk alleles at 7p21.1 and plaque characteristics. Methods— Allele-dependent expression of HDAC9 was analyzed in human peripheral blood mononuclear cells of healthy donors. Effects of HDAC9 deficiency on atherosclerotic plaques were investigated in 18- and 28-week-old ApoE−/− mice by histology and immunohistochemistry. We further performed detailed plaque phenotyping and genotyping of rs2107595, the lead single-nucleotide polymorphism for large-vessel stroke, in carotid endarterectomy samples of 1858 subjects from the Athero-Express study. Results— Gene expression studies in peripheral blood mononuclear cells revealed increased mRNA levels of HDAC9 but not of neighboring genes (TWIST1/FERD3L) in risk allele carriers of rs2107595. Compared with HDAC9+/+ApoE−/− mice, HDAC9−/−ApoE−/− mice exhibited markedly reduced lesion sizes throughout atherosclerotic aortas and significantly less advanced lesions. The proportion of Mac3-positive macrophages was higher in plaques from HDAC9−/−ApoE−/− mice, but this was largely because of a lower proportion of advanced lesions. Analysis of human atherosclerotic plaques revealed no association between rs2107595 and specific plaque characteristics. Conclusions— Our results suggest that HDAC9 represents the disease-relevant gene at the stroke and coronary artery disease risk locus on 7p21.1, and that risk alleles in this region mediate their effects through increased HDAC9 expression. Targeted inhibition of HDAC9 might be a viable strategy to prevent atherosclerosis.