A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases.

The presence of donor-specific HLA antibodies before or after transplantation may have different implications based on the antibody strength. Yet, current approaches do not provide information regarding the true antibody strength as defined by antigen-antibody dissociation rate. To assess currently available methods, we compared between neat mean fluorescence intensity (MFI) values, C1q MFI values, ethylenediaminetetraacetic acid (EDTA)-treated samples, as well as titration studies and peak MFI values of over 7000 Luminex-based single-antigen HLA antibody data points. Our results indicate that neat MFI values do not always accurately depict antibody strength. We further showed that EDTA treatment (6%) does not always remove all inhibitory factors compared with C1q or titration studies. In this study of patients presenting with multiple antibody specificities, a prozone effect was observed in 71% of the cohort (usually not affecting all antibody specificities within a single serum sample, though). Similar to titration studies, the C1q assay was able to address the issue of potential inhibition; however, its limitation is its low sensitivity and inability to detect the presence of weak antibodies. Titration studies are the only method among the approaches used in this study to provide information suggesting antigen-antibody dissociation rates and are, therefore, likely to provide better indication of true antibody strength.Abbreviations: AMR, antibody-mediated rejection; DSA, donor-specific antibody; EDTA, ethylenediaminetetraacetic acid; MFI, mean fluorescence intensity; SAB, single antigen beads; SPA, solid phase assays

b Viral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-␣ and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-␣ than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.

Clinicopathological paradox has significantly hampered the effective assessment of the efficacy of therapeutic intervention of multiple sclerosis. The neuroimaging biomarkers of tissue injury could guide a more effective treatment by accurately reflecting the underlying subclinical pathologies. Diffusion tensor imaging-derived directional diffusivity and anisotropy indices have been applied to characterize white matter disorders. However, these biomarkers are sometimes confounded by complex pathologies seen in multiple sclerosis and its animal models. Recently, a novel diffusion basis spectrum imaging has been developed to quantitatively assess axonal injury, demyelination, and inflammation in a mouse model of inflammatory demyelination. Lenaldekar, which inhibits T-cell expansion in a non-cytolytic manner, has been shown to suppress relapses and preserve white matter integrity in mice with experimental autoimmune encephalomyelitis. In this study, relapsing-remitting experimental autoimmune encephalomyelitis was induced through active immunization of SJL/J mice with a myelin proteolipid protein peptide. We evaluated the therapeutic efficacy of Lenaldekar treatment via daily clinical score, cross-sectional ex vivo diffusion basis spectrum imaging examination, and histological analysis. Lenaldekar greatly reduced relapse severity and protected white matter integrity in these experimental autoimmune encephalomyelitis mice. Diffusion basis spectrum imaging-derived axial diffusivity, radial diffusivity and restricted diffusion tensor fraction accurately reflected axon, myelin integrity and inflammation associated cellularity change, respectively. These results support the potential use of diffusion basis spectrum imaging as an effective outcome measure for preclinical drug evaluation.

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system (CNS). Although the etiology of MS is unknown, genetic and environmental factors play a role. Infectious pathogens are the likely environmental factors involved in the development of MS. Pathogens associated with the development or exacerbation of MS include bacteria, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, the Staphylococcus aureus-produced enterotoxins that function as superantigens, viruses of the herpes virus (Epstein-Barr virus and human herpesvirus 6) and human endogenous retrovirus (HERV) families and the protozoa Acanthamoeba castellanii. Evidence, from studies with humans and animal models, supporting the association of these various pathogens with the development and/or exacerbation of MS will be discussed along with the potential mechanisms including molecular mimicry, epitope spreading and bystander activation. In contrast, infection with certain parasites such as helminthes (Schistosoma mansoni, Fasciola hepatica, Hymenolepis nana, Trichuris trichiura, Ascaris lumbricoides, Strongyloides stercolaris, Enterobius vermicularis) appears to protect against the development or exacerbation of MS. Evidence supporting the ability of parasitic infections to protect against disease will be discussed along with a brief summary of a recent Phase I clinical trial testing the ability of Trichuris suis ova treatment to improve the clinical course of MS. A complex interaction between the CNS (including the blood-brain barrier), multiple infections with various infectious agents (occurring in the periphery or within the CNS), and the immune response to those various infections may have to be deciphered before the etiology of MS can be fully understood.

We report here the presence of specific plasma membrane calcium pumps (PMCAs) in mouse olfactory sensory neurons. All 4 isoforms are present as shown by deconvolution microscopy, and the specific splice variants are identified by reverse transcriptase (RT)-polymerase chain reaction (PCR). The PMCAs are present on the cell body, dendrite, knob, and cilia, but the different isoforms of PMCAs are not identical in their distributions. The PMCAs are positioned to play a role in calcium clearance after stimulation.

Purpose of review This review will explore two new aspects of the involvement of viruses in multiple sclerosis pathogenesis. The first aspect is the complex interactions between viruses. The second aspect is the proposal of a mechanism by which autoreactive T cells are able to escape thymic selection and potentially recognize self and a pathogen. Recent findings With regard to viruses, recent work has demonstrated that one virus may enhance the replication of another virus, potentially leading to an increase in inflammation and disease progression. Also, interactions between human endogenous retroviruses, which likely do not replicate, and certain herpes viruses, may also play a role in disease pathogenesis. Mechanistically, T cells expressing dual T-cell receptors would be able to recognize self and a foreign antigen specifically. Therefore, human endogenous retroviruses potentially play a role in multiple sclerosis pathogenesis, and both interactions between multiple viruses and autoreactive CD8+ T cells with dual T-cell receptors may play a role in the pathogenesis of the disease. Summary The complex interactions between multiple viral infections, either within the central nervous system or in the periphery, and the host immune response to viral infection may be such that a variety of viral specificities result in the activation of T cells that recognize self and induce multiple sclerosis. Therefore, it is unlikely that any one microbe will be determined to be the causative agent of multiple sclerosis as reflected by the number of potential triggering mechanisms of the disease.

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