Chronic Inflammatory Demyelinating Polyneuropathy is a debilitating autoimmune disease characterized by peripheral nerve demyelination and dysfunction. How the autoimmune response is initiated, identity of provoking antigens, and pathogenic effector mechanisms are not well-defined. The Autoimmune Regulator (Aire) plays a critical role in central tolerance by promoting thymic expression of self-antigens and deletion of self-reactive T cells. Here, we utilized mice with hypomorphicAire function and two patients with Aire mutations to define how Aire deficiency results in spontaneous autoimmune peripheral neuropathy. Autoimmunity against peripheral nerves in both mice and humans targets Myelin Protein Zero (P0), an antigen whose expression is Aire-regulated in the thymus. Consistent with a defect in thymic tolerance, CD4+ T cells are sufficient to transfer disease in mice and produce IFN-gamma in infiltrated peripheral nerves. Our findings suggest that defective Aire-mediated central tolerance to P0 initiates an autoimmune Th1 effector response toward peripheral nerves.

The role of mouse strain and the influence of gender on demyelination were explored for the first time in SJL mice using the cuprizone intoxication model. We document here that SJL mice display a unique pattern of demyelination that did not follow the profile that is well-characterized in C57BL/6 mice. The SJL mice did not readily demyelinate at the midline within the corpus callosum but showed greater demyelination immediately lateral to midline. During continuous exposure to cuprizone, demyelination was not complete and appeared to plateau after week 7. Importantly, female mice were partially resistant to demyelination, whereas male mice were more severely demyelinated. Differences in the number of mature oligodendrocytes were consistent with the extent of demyelination; however, microglia, astrocyte and oligodendrocyte precursor cell populations did not differ between male and female mice. Thus, genetic factors and gender influence susceptibility to demyelinating disease in the cuprizone model, which may provide additional insights into the variability observed in human demyelinating diseases such as multiple sclerosis.

Multiple sclerosis is a demyelinating neurological disease that is influenced by gender, primarily reflected in greater susceptibility to disease development in women than in men. Cuprizone intoxication, an animal model that is used to study demyelination and remyelination, has been extensively characterized in male C57BL/6 mice. Here, we have undertaken a comprehensive characterization of the morphological and cellular processes that occur in female C57BL/6J mice during cuprizone-induced demyelination and subsequent remyelination and compared them with age-matched male mice. We find that the pattern of demyelination and remyelination is similar between genders and that there is little or no difference in the loss or repopulation of mature oligodendrocytes or accumulation of reactive glia. Furthermore, examination of alphaERKO and betaERKO mice suggests that estrogen receptors do not affect the outcome for demyelination or remyelination. Interestingly, we found that cuprizone treatment disrupts estrous cyclicity in female mice, possibly interfering with potential hormone influences on demyelination and remyelination. Therefore, cuprizone-induced demyelination in C57BL/6J mice may have limitations as a model for the study of sex differences.

Cuprizone intoxication is one of several animal models used to study demyelination and remyelination. Early treatment protocols exposed mice to cuprizone for 6 weeks to induce demyelination; however, more recent reports have varied exposure times from 4 to 5 weeks. The goal of this study was to determine the minimal exposure of cuprizone in C57BL/6 mice that would induce a pathology of robust demyelination and gliosis similar to that described for a 5- or 6-week treatment. We found that an abbreviated insult of only 2 weeks of exposure to cuprizone induced significant demyelination 3 weeks later (5-week time point) but was somewhat variable. Three weeks of exposure to cuprizone produced extensive demyelination by week 5, equivalent to that observed with 5 weeks of exposure. The depletion of mature oligodendrocytes, as well as microglia and astrocyte accumulation, showed trends similar to those with 5-week exposure to cuprizone. Once mature oligodendrocytes are perturbed after a 3-week treatment, the progression to demyelination occurs without requiring further exposure. Furthermore, the early removal of cuprizone did not accelerate remyelination, suggesting that other sequences of events must follow before repair can occur. Thus, a short, "hit and run" CNS insult triggers a cascade of events leading to demyelination 2-3 weeks later.

In addition to regulating reproductive functions in the brain and periphery, estrogen has trophic and neuroprotective functions in the central nervous system (CNS). Estrogen administration has been demonstrated to provide protection in several animal models of CNS disorders, including stroke, brain injury, epilepsy, Parkinson’s disease, Alzheimer’s disease, age-related cognitive decline and multiple sclerosis. Here, we use a model of toxin-induced oligodendrocyte death which results in demyelination, reactive gliosis, recruitment of oligodendrocyte precursor cells and subsequent remyelination to study the potential benefit of 17β-estradiol (E2) administration in male mice. The results indicate that E2 partially ameliorates loss of oligodendrocytes and demyelination in the corpus callosum. This protection is accompanied by a delay in microglia accumulation as well as reduced mRNA expression of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα), and insulin-like growth factor-1 (IGF-1). E2 did not significantly alter the accumulation of astrocytes or oligodendrocyte precursor cells, or remyelination. These data obtained from a toxin-induced, T cell-independent model using male mice provide an expanded view of the beneficial effects of estrogen on oligodendrocyte and myelin preservation.