The potential of urinary metabolites for diagnosing multiple sclerosis

A definitive diagnostic test for multiple sclerosis (MS) does not exist; instead physicians use a combination of medical history, magnetic resonance imaging, and cerebrospinal fluid analysis (CSF). Significant effort has been employed to identify biomarkers from CSF to facilitate MS diagnosis; however none of the proposed biomarkers have been successful to date. Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, non-invasive, inexpensive, and efficient diagnostic tool for various human diseases. Nevertheless, urinary metabolites have not been extensively explored as a source of biomarkers for MS. Instead, we demonstrate that urinary metabolites have significant promise for monitoring disease-progression, and response to treatment in MS patients. NMR analysis of urine permitted the identification of metabolites that differentiate experimental autoimmune encephalomyelitis (EAE)-mice (prototypic disease model for MS) from healthy and MS drug-treated EAE mice

Association of Autophagy in the Cell Death Mediated by Dihydrotestosterone in Autoreactive T Cells Independent of Antigenic Stimulation

Gender disparity is well documented in the mouse model of experimental autoimmune encephalomyelitis (EAE) induced with proteolipid protein (PLP) 139–151, in which female, but not male, SJL mice show a chronic relapsing-remitting paralysis. Furthermore, dihydrotestosterone (DHT) has been shown to ameliorate the severity of EAE, but the underlying mechanisms of its protective effects are unclear. Using major histocompatibility complex (MHC) class II dextramers for PLP 139-151, we tested the hypothesis that DHT selectively modulates the expansion and functionalities of antigen-specific T cells. Unexpectedly, we noted that DHT induced cell death in antigen-specific, autoreactive T cells, but the effects were not selective, because both proliferating and non-proliferating cells were equally affected independent of antigenic stimulation. Furthermore, DHT-exposed PLP 139- 151-specific T cells did not show any shift in cytokine production; rather, frequencies of cytokine-producing PLP-specific T cells were significantly reduced, irrespective of T helper (Th) 1, Th2, and Th17 subsets of cytokines. By evaluating cell death and autophagy pathways, we provide evidence for the induction of autophagy to be associated with cell death caused by DHT. Taken together, the data provide new insights into the role of DHT and indicate that cell death and autophagy contribute to the therapeutic effects of androgens in autoreactive T cells. Includes Supplementary Materials. An Erratum for this article is attached (below)

Differential Regulation of T-cell mediated anti-tumor memory and cross-protection against the same tumor in lungs versus skin

A major advantage of immunotherapy of cancer is that effector cells induced at one site should be able to kill metastatic cancer cells in other sites or tissues. However, different tissues have unique immune components, and very little is known about whether effector T cells induced against tumors in one tissue can work against the same tumors in other tissues. Here, we used CT26 murine tumor models to investigate anti-tumor immune responses in the skin and lungs and characterized cross-protection between the two tissues. Blockade of the function of Treg cells with anti-CD25 allowed for T cell-dependent rejection of s.c. tumors. When these mice were simultaneously inoculated i.v. with CT26, they also rejected tumors in the lung. Interestingly, in the absence of s.c. tumors, anti-CD25 treatment alone had no effect on lung tumor growth. These observations suggested that T cell-mediated anti-tumor protective immunity induced against s.c. tumors can also protect against lung metastases of the same tumors. In contrast, NKT cell-deficiency in CD1d(-/-) mice conferred significant protection against lung tumors but had no effect on the growth of tumors in the skin, and tumor rejection induced against the CT26 in the lung did not confer protection for the same tumor cells in the skin. Thus, effector cells against the same tumor do not work in all tissues, and the induction site of the effector T cells is critical to control metastasis. Further, the regulation of tumor immunity may be different for the same tumor in different anatomical locations

Relevance of Molecular Mimicry in the Mediation of Infectious Myocarditis

Heart disease, the leading cause of death in humans, is estimated to affect one in four American adults in some form. One predominant cause of heart failure in young adults is myocarditis, which can lead to the development of dilated cardiomyopathy, a major indication for heart transplantation. Environmental microbes, including viruses, bacteria, and fungi that are otherwise innocuous, have the potential to induce inflammatory heart disease. As the list is growing, it is critical to determine the mechanisms by which microbes can trigger heart autoimmunity and, importantly, to identify their target antigens. This is especially true as microbes showing structural similarities with the cardiac antigens can predispose to heart autoimmunity by generating cross-reactive immune responses. In this review, we discuss the relevance of molecular mimicry in the mediation of infectious myocarditis