Junctional adhesion molecule-A deficient mice are protected from severe experimental autoimmune encephalomyelitis.

In multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), early pathological features include immune cell infiltration into the central nervous system (CNS) and blood-brain barrier (BBB) disruption. We investigated the role of junctional adhesion molecule-A (JAM-A), a tight junction protein, in active EAE (aEAE) pathogenesis. Our study confirms JAM-A expression at the blood-brain barrier and its luminal redistribution during aEAE. JAM-A deficient (JAM-A-/-) C57BL/6J mice exhibited milder aEAE, unrelated to myelin oligodendrocyte glycoprotein-specific CD4+ T-cell priming. While JAM-A absence influenced macrophage behavior on primary mouse brain microvascular endothelial cells (pMBMECs) under flow in vitro, it did not impact T-cell extravasation across primary mouse brain microvascular endothelial cells. At aEAE onset, we observed reduced lymphocyte and CCR2+ macrophage infiltration into the spinal cord of JAM-A-/- mice compared to control littermates. This correlated with increased CD3+ T-cell accumulation in spinal cord perivascular spaces and brain leptomeninges, suggesting JAM-A absence leads to T-cell trapping in central nervous system border compartments. In summary, JAM-A plays a role in immune cell infiltration and clinical disease progression in aEAE.

The Genetic Background of Mice Influences the Effects of Cigarette Smoke on Onset and Severity of Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults leading to severe disability. Besides genetic traits, environmental factors contribute to MS pathogenesis. Cigarette smoking increases the risk of MS in an HLA-dependent fashion, but the underlying mechanisms remain unknown. Here, we explored the effect of cigarette smoke exposure on spontaneous and induced models of experimental autoimmune encephalomyelitis (EAE) by evaluating clinical disease and, when relevant, blood leukocytes and histopathology. In the relapsing-remitting (RR) transgenic model in SJL/J mice, we observed very low incidence in both smoke-exposed and control groups. In the optico-spinal encephalomyelitis (OSE) double transgenic model in C57BL/6 mice, the early onset of EAE prevented a meaningful evaluation of the effects of cigarette smoke. In EAE models induced by immunization, daily exposure to cigarette smoke caused a delayed onset of EAE followed by a protracted disease course in SJL/J mice. In contrast, cigarette smoke exposure ameliorated the EAE clinical score in C57BL/6J mice. Our exploratory studies therefore show that genetic background influences the effects of cigarette smoke on autoimmune neuroinflammation. Importantly, our findings expose the challenge of identifying an animal model for studying the influence of cigarette smoke in MS.

MK2 and Fas receptor contribute to the severity of CNS demyelination.

Models of inflammatory or degenerative diseases demonstrated that the protein-kinase MK2 is a key player in inflammation. In this study we examined the role of MK2 in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In MK2-deficient (MK2-/-) mice we found a delayed onset of the disease and MK2-/- mice did not recover until day 24 after EAE induction. At this day a higher number of leukocytes in the CNS of MK2-/- mice was found. TNFα was not detectable in serum of MK2-/- mice in any stage of EAE, while high TNFα levels were found at day 16 in wild-type mice. Further investigation revealed an increased expression of FasR mRNA in leukocytes isolated from CNS of wild-type mice but not in MK2-/- mice, however in vitro stimulation of MK2-/- splenocytes with rmTNFα induced the expression of FasR. In addition, immunocomplexes between the apoptosis inhibitor cFlip and the FasR adapter molecule FADD were only detected in splenocytes of MK2-/- mice at day 24 after EAE induction. Moreover, the investigation of blood samples from relapsing-remitting multiple sclerosis patients revealed reduced FasR mRNA expression compared to healthy controls. Taken together, our data suggest that MK2 is a key regulatory inflammatory cytokines in EAE and multiple sclerosis. MK2-/- mice showed a lack of TNFα and thus might not undergo TNFα-induced up-regulation of FasR. This may prevent autoreactive leukocytes from apoptosis and may led to prolonged disease activity. The findings indicate a key role of MK2 and FasR in the regulation and limitation of the immune response in the CNS.

Exploring the MHC-peptide matrix of central tolerance in the human thymus.

Ever since it was discovered that central tolerance to self is imposed on developing T cells in the thymus through their interaction with self-peptide major histocompatibility complexes on thymic antigen-presenting cells, immunologists have speculated about the nature of these peptides, particularly in humans. Here, to shed light on the so-far unknown human thymic peptide repertoire, we analyse peptides eluted from isolated thymic dendritic cells, dendritic cell-depleted antigen-presenting cells and whole thymus. Bioinformatic analysis of the 842 identified natural major histocompatibility complex I and II ligands reveals significant cross-talk between major histocompatibility complex-class I and II pathways and differences in source protein representation between individuals as well as different antigen-presenting cells. Furthermore, several autoimmune- and tumour-related peptides, from enolase and vimentin for example, are presented in the healthy thymus. 302 peptides are directly derived from negatively selecting dendritic cells, thus providing the first global view of the peptide matrix in the human thymus that imposes self-tolerance in vivo.