Spontaneous Autoimmune Encephalomyelitis Research Articles

Learning-dependent dendritic spine plasticity is impaired in spontaneous autoimmune encephalomyelitis.

Cognitive impairment is often observed in multiple sclerosis and its animal models, experimental autoimmune encephalomyelitis (EAE). Using mice with immunization-induced EAE, we have previously shown that the stability of cortical synapses is markedly decreased before the clinical onset of EAE. In this study, we examined learning-dependent structural synaptic plasticity in a spontaneous EAE model. Transgenic mice expressing myelin basic protein-specific T cell receptor genes develop EAE spontaneously at around 8weeks of age. Using in vivo two-photon microscopy, we found that the elimination and formation rates of postsynaptic dendritic spines in somatosensory and motor cortices increased weeks before detectable signs of EAE and remained to be high during the disease onset. Despite the elevated basal spine turnover, motor learning-induced spine formation was reduced in presymptomatic EAE mice, in line with their impaired ability to retain learned motor skills. Additionally, we found a substantial elevation of IFN-γ mRNA in the brain of 4-week-old presymptomatic mice, and treatment of anti-IFN-γ antibody reduced dendritic spine elimination in the cortex. Together, these findings reveal synaptic instability and failure to form new synapses after learning as early brain pathology of EAE, which may contribute to cognitive and behavioral deficits seen in autoimmune diseases.

Dietary non-fermentable fiber prevents autoimmune neurological disease by changing gut metabolic and immune status

The autoimmune neurological disease, Multiple Sclerosis (MS), have increased at alarming rates in the Western society over the last few decades. While there are numerous efforts to develop novel treatment approaches, there is an unmet need to identify preventive strategies. We explored whether central nervous system (CNS) autoimmunity can be prevented through dietary manipulation using a spontaneous autoimmune encephalomyelitis mouse model. We report that the nutritional supplementation of non-fermentable fiber, common components of a vegetarian diet, in early adult life, prevents autoimmune disease. Dietary non-fermentable fiber alters the composition of the gut microbiota and metabolic profile with an increase in the abundance of long-chain fatty acids. Immune assays revealed that cecal extracts and a long chain fatty acid but not cecal lysates promoted autoimmune suppressive TH2 immune responses, demonstrating that non-fermentable fiber-induced metabolic changes account for the beneficial effects. Overall, these findings identify a non-invasive dietary strategy to prevent CNS autoimmunity and warrants a focus on nutritional approaches in human MS.

Impact of dietary metabolism by gut microbiota on the pathogenesis of spontaneous autoimmune encephalomyelitis

Impact of dietary metabolism by gut microbiota on the pathogenesis of spontaneous autoimmune encephalomyelitis

Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells

Foxp3 activity is essential for the normal function of the immune system. Two types of regulatory T (T reg) cells express Foxp3, thymus-generated natural T reg (nT reg) cells, and peripherally generated adaptive T reg (iT reg) cells. These cell types have complementary functions. Until now, it has not been possible to distinguish iT reg from nT reg cells in vivo based solely on surface markers. We report here that Neuropilin 1 (Nrp1) is expressed at high levels by most nT reg cells; in contrast, mucosa-generated iT reg and other noninflammatory iT reg cells express low levels of Nrp1. We found that Nrp1 expression is under the control of TGF-β. By tracing nT reg and iT reg cells, we could establish that some tumors have a very large proportion of infiltrating iT reg cells. iT reg cells obtained from highly inflammatory environments, such as the spinal cords of mice with spontaneous autoimmune encephalomyelitis (EAE) and the lungs of mice with chronic asthma, express Nrp1. In the same animals, iT reg cells in secondary lymphoid organs remain Nrp1(low). We also determined that, in spontaneous EAE, iT reg cells help to establish a chronic phase of the disease.

Immune Regulatory Mechanisms Influence Early Pathology in Spinal Cord Injury and in Spontaneous Autoimmune Encephalomyelitis

Injuries to the central nervous system (CNS) trigger an inflammatory reaction with potentially devastating consequences. In this report we compared the characteristics of the inflammatory response on spinal cord injury (SCI) caused by a stab wound between the T7 and T9 vertebrae and spontaneous experimental autoimmune encephalomyelitis (EAE). SCI and EAE were compared in two types of myelin basic protein Ac1-11-specific T-cell receptor transgenic mice: T/R+ mice harbor regulatory T cells, and T/R- mice lack regulatory T cells. Our results show that 8 days after SCI, T/R- mice developed a strong T-cell infiltrate in the spinal cord, with remarkable down-modulation of CD4 expression that was accompanied by a local increase in Mac-3+ and F4/80+ reactivity and diffuse local and distal astrogliosis. In contrast, T/R+ mice exhibited a modest increase in CD4+ cells localized to the site of injury, without CD4 down-modulation; focal astrogliosis was restricted to the site of the lesion, although Mac-3+ and F4/80+ cells were also present. Similarly to T/R- mice that underwent SCI, T cells displaying down-modulated CD4 expression were found in the CNS of older T/R- mice afflicted by spontaneous EAE. Overall, our results suggest that common mechanisms regulate T-cell accumulation in CNS lesions of different causes, such as mechanic lesion or autoimmune-mediated damage.

Regulatory T cells in spontaneous autoimmune encephalomyelitis.

Spontaneous experimental autoimmune encephalomyelitis (EAE) develops in 100% of mice harboring a monoclonal myelin basic protein (MBP)-specific CD4+ alphabeta T-cell repertoire. Monoclonality of the alphabeta T-cell repertoire can be achieved by crossing MBP-specific T-cell receptor (TCR) transgenic mice with either RAG-/- mice or TCR alpha-/-/TCR beta-/- double knockout mice. Spontaneous EAE can be prevented by a single administration of purified CD4+ splenocytes or thymocytes obtained from wild-type syngeneic mice. The regulatory T cells (T-reg) that protect from spontaneous EAE need not express the CD25 marker, as effective protection can be attained with populations depleted of CD25+ T cells. Although the specificity of the regulatory T cells is important for their generation or regulatory function, T cells that protect from spontaneous EAE can have a diverse TCR alpha and beta chain composition. T-reg cells expand poorly in vivo, and appear to be long lived. Finally, precursors for T-reg are present in fetal liver as well as in the bone marrow of aging mice. We propose that protection of healthy individuals from autoimmune diseases involves several layers of regulation, which consist of CD4+CD25+ regulatory T cells, CD4+CD25- T-reg cells, and anti-TCR T cells, with each layer potentially operating at different stages of T-helper cell-mediated immune responses.

Differential roles of Fas ligand in spontaneous and actively induced autoimmune encephalomyelitis.

To determine the roles of Fas/Fas ligand (FasL) in autoimmunity, we studied spontaneous and actively induced autoimmune encephalomyelitis in 541 myelin basic protein-specific T cell receptor transgenic mice. We found that spontaneous autoimmune encephalomyelitis, which was initiated by unidentified microbial factors, was dramatically exacerbated in mice carrying Fas or FasL gene mutation. The exacerbation of autoimmune encephalomyelitis was reflected primarily by an increase in disease incidence and a decrease in spontaneous disease recovery. By contrast, actively induced encephalomyelitis, which was initiated by pertussis toxin, was significantly inhibited by Fas or FasL gene mutation. These results suggest that environmental factors that trigger autoimmune disease may determine not only whether disease will occur but also whether an immune molecule such as FasL will promote or inhibit the autoimmune process.

CD28 Costimulation Is Crucial for the Development of Spontaneous Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE.

Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis.

The development of T cell-mediated autoimmune diseases hinges on the balance between effector and regulatory mechanisms. Using two transgenic mouse lines expressing identical myelin basic protein (MBP)-specific T cell receptor (TCR) genes, we have previously shown that mice bearing exclusively MBP-specific T cells (designated T/R-) spontaneously develop experimental autoimmune encephalomyelitis (EAE), whereas mice bearing MBP-specific T cells as well as other lymphocytes (designated T/R+) did not. Here we demonstrate that T/R- mice can be protected from EAE by the early transfer of total splenocytes or purified CD4(+) T cells from normal donors. Moreover, whereas T/R+ mice crossed with B cell-deficient, gamma/delta T cell-deficient, or major histocompatibility complex class I-deficient mice did not develop EAE spontaneously, T/R+ mice crossed with TCR-alpha and -beta knockout mice developed EAE with the same incidence and severity as T/R- mice. In addition, MBP-specific transgenic mice that lack only endogenous TCR-alpha chains developed EAE with high incidence but reduced severity. Surprisingly, two-thirds of MBP-specific transgenic mice lacking only endogenous TCR-beta chains also developed EAE, suggesting that in T/R+ mice, cells with high protective activity escape TCR-beta chain allelic exclusion. Our study identifies CD4(+) T cells bearing endogenous alpha and beta TCR chains as the lymphocytes that prevent spontaneous EAE in T/R+ mice.

The Fate of T Cells in the Brain: Veni, Vidi, Vici and Veni, Mori

Since the dawn of modern immunology, immune responses within the central nervous system (CNS) have puzzled immunologists. On one hand, the immune-privileged status of the CNS has been known for a long time; along with the eye, the gonads, and the placenta, the CNS is among the few organs that accept grafted foreign cells more readily than the rest of the body. 1 On the other hand, the CNS has been known to be particularly susceptible to autoimmune disease. The first and best characterized autoimmune model, experimental allergic encephalomyelitis (EAE), which resembles multiple sclerosis (MS), is the result of an autoimmune attack by T lymphocytes on the CNS. 2 A report on EAE in this issue 3 by Bauer et al provides data of exceptional clarity that should help in understanding this apparent contradiction. Neuroantigen-specific T cells, which can mount an autoimmune attack against the CNS, are detectable in healthy individuals. This is particularly well established for T cells that are specific for myelin basic protein (MBP), the best-characterized target antigen in the CNS. Studies using MBP-specific T cell receptor-transgenic mice suggested that these T cells normally ignore the autoantigen. 4-6 Like lymphocytes that have not encountered their antigen before, they retain a naive/resting phenotype. Such T cells dramatically change their behavior as soon as they become activated in the course of an immune response; they start to infiltrate the CNS and cause inflammatory damage there. In experimental models EAE is initiated either by immunization with a CNS antigen (for active EAE) or by in vitro injection of activated CNS antigen-specific T cells (for passive EAE, the model used by Bauer et al). In MS, infections with crossreactive microorganisms are thought to initiate the autoimmune attack. It remains unclear why activated myelin-reactive T cells “see” and attack the autoantigen that resting T cells with the same specificity had ignored. The information needed to promote resolution of this question pertains to the rules that govern the entry of lymphocytes into CNS tissue. This issue was addressed by Bauer et al. They injected into rats congenic T cells specific for either various CNS “self” antigens (Bauer et al, Table 1) or for the irrelevant “foreign” antigen ovalbumin (OVA). To distinguish clearly between injected T cells with a defined specificity and activation state and recruited host-derived T cells of unknown specificity and activation state, the authors took advantage of a TK-tsa-transgenic model. The detection of the TK-tsA transgene by in situ hybridization facilitated reliable discrimination of the injected T cells from those of the host.

High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice

We have generated TCR transgenic mice ( T R + ) specific for myelin basic protein (MBP) and crossed them to RAG-1-deficient mice to obtain mice ( T R − ) that have T cells expressing the transgenic TCR but no other lymphocytes. Both T R + and T R − mice carry, in the lymph nodes and spleen, large numbers of the potentially encephalitogenic CD4 + anti-MBP T cells. These cells respond to MBP in vitro but show no signs of activation in vivo. Nevertheless, ∼ 14% of H-2 u T R + and 100% of H-2 u T R − mice developed spontaneous experimental autoimmune encephalomyelitis (EAE) within 12 months. These data indicate that EAE can be mediated by CD4 + anti-MBP T cells in the absence of any other lymphocytes and that nontransgenic lymphocytes that are present in T R + but absent in T R − mice have a protective effect. The data also suggest that spontaneous EAE may be triggered by an in situ activation of CD4 + anti-MBP cells in the nervous system.