Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are ubiquitously expressed. S1P-S1PR signaling has been well characterized in immune trafficking and activation in innate and adaptive immune systems. However, the full extent of its involvement in the pathogenesis of autoimmune diseases is not well understood. FTY720 (fingolimod), a non-selective S1PR modulator, significantly decreased annualized relapse rates in relapsing-remitting multiple sclerosis (MS). FTY720, which primarily targets S1P receptor 1 as a functional antagonist, arrests lymphocyte egress from secondary lymphoid tissues and reduces neuroinflammation in the central nervous system (CNS). Recent studies suggest that FTY720 also decreases astrogliosis and promotes oligodendrocyte differentiation within the CNS and may have therapeutic benefit to prevent brain atrophy. Since S1P signaling is involved in multiple immune functions, therapies targeting S1P axis may be applicable to treat autoimmune diseases other than MS. Currently, over a dozen selective S1PR and S1P pathway modulators with potentially superior therapeutic efficacy and better side-effect profiles are in the pipeline of drug development. Furthermore, newly characterized molecules such as apolipoprotein M (ApoM) (S1P chaperon) and SPNS2 (S1P transporter) are also potential targets for treatment of autoimmune diseases. Finally, the application of therapies targeting S1P and S1P signaling pathways may be expanded to treat several other immune-mediated disorders (such as post-infectious diseases, post-stroke and post-stroke dementia) and inflammatory conditions beyond their application in primary autoimmune diseases.

The significance of Th17 cells and interleukin- (IL-)17A signaling in host defense and disease development has been demonstrated in various infection and autoimmune models. Numerous studies have indicated that Th17 cells and its signature cytokine IL-17A are critical to the airway's immune response against various bacteria and fungal infection. Cytokines such as IL-23, which are involved in Th17 differentiation, play a critical role in controlling Klebsiella pneumonia (K. pneumonia) infection. IL-17A acts on nonimmune cells in infected tissues to strengthen innate immunity by inducing the expression of antimicrobial proteins, cytokines, and chemokines. Mice deficient in IL-17 receptor (IL-17R) expression are susceptible to infection by various pathogens. In this review, we summarize the recent advances in unraveling the mechanism behind Th17 cell differentiation, IL-17A/IL-17R signaling, and also the importance of IL-17A in pulmonary infection.

Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood–brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice (Pdgfbret/ret), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in Pdgfbret/ret mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti–ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfbret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in Pdgfbret/ret;2D2tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.

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The significance of Th17 cells and interleukin (IL)-17A signaling in host defense and disease development has been demonstrated in various infection and autoimmune models. In addition, the generation of Th17 cells is highly influenced by microbes. However, the specific bacterial components capable of shaping Th17 responses have not been well defined. The goals of this study are to understand how a bacterial toxin, cholera toxin (CT), modulates Th17-dominated response in isolated human CD4+ T cells, and what are the mechanisms associated with this modulation. The CD4+ cells isolated from human peripheral blood are treated with CT. The levels of cytokine production and specific T helper cell responses are determined by ELISA, Luminex assay, and flow cytometry. Along with the decreased production of other pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2), we found that CT could directly enhance the IL-17A production through a cAMP-dependent pathway. This enhancement is specific for IL-17A but not for IL-17F, IL-22 and CCL20. Interestingly, CT could increase IL-17A production only from Th17-committed cells, such as CCR6+ CD4+ T cells and in-vitro-differentiated Th17 cells. Furthermore, we also demonstrated that this direct effect occurs at a transcriptional level since CT stimulates the reporter activity in Jurkat and primary CD4+ T cells transfected with the IL-17A promoter-reporter construct. This is the first report to show that CT has the capacity to directly shape Th17 responses in the absence of antigen-presenting cells. Our findings highlight the potentials of bacterial toxins in the regulation of human Th17 responses.

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21Brain endothelium possesses several organ-specific features collectively known as the blood-22 brain barrier (BBB). In addition, trafficking of immune cells in the healthy central nervous 23 system (CNS) is tightly regulated by CNS vasculature. In CNS autoimmune diseases such as 24 multiple sclerosis (MS), these homeostatic mechanisms are overcome by autoreactive 25 2 lymphocyte entry into the CNS causing inflammatory demyelinating immunopathology. 26Previous studies have shown that pericytes regulate the development of organ-specific 27 characteristics of brain vasculature such as the BBB and astrocytic end-feet. Whether pericytes 28 are involved in the control of leukocyte trafficking remains elusive. Using adult, pericyte-29 deficient mice (Pdgfb ret/ret ), we show here that brain vasculature devoid of pericytes shows 30 increased expression of VCAM-1 and ICAM-1, which is accompanied by increased leukocyte 31 infiltration of dendritic cells, monocytes and T cells into the brain, but not spinal cord 32 parenchyma. Regional differences enabling leukocyte trafficking into the brain as opposed to 33 the spinal cord inversely correlate with the pericyte coverage of blood vessels. Upon induction 34 of experimental autoimmune encephalitomyelitis (EAE), pericyte-deficient mice succumb to 35 severe neurological impairment. Treatment with first line MS therapy -fingolimod significantly 36 reverses EAE, indicating that the observed phenotype is due to the massive influx of immune 37 cells into the brain. Furthermore, pericyte-deficiency in mice that express myelin 38 oligodendrocyte glycoprotein peptide (MOG35-55) specific T cell receptor (Pdgfb ret/ret ; 2D2 Tg ) 39 leads to the development of spontaneous neurological symptoms paralleled by massive influx 40 of leukocytes into the brain, suggesting altered brain vascular immune quiescence as a prime 41 cause of exaggerated neuroinflammation. Thus, we show that pericytes indirectly restrict 42 immune cell transmigration into the CNS under homeostatic conditions and during 43 autoimmune-driven neuroinflammation by inducing immune quiescence of brain endothelial 44 cells. 45 46 leukocytes into brain parenchyma, thus contributing to immune privilege of the CNS. BBB 51 function is induced by neural tissue and established by all cell types constituting the 52 neurovascular unit (NVU). Pericytes and mural cells residing on the abluminal side of 53 capillaries and post-capillary venules, regulate several features of the BBB 1, 2 . Studies on Pdgfb 54and Pdgfrb mouse mutants, which exhibit variable pericyte loss, have demonstrated that 55 pericytes negatively regulate endothelial transcytosis which, if not suppressed, leads to 56 increased BBB permeability to plasma proteins 1, 2 . In addition, pericyte-deficient vessels show 57 abnormal astrocyte end-feet polarization 1 . Thus, pericytes regulate several characteristics of 58 brain vasculature during development and in the adult organism 1, 2 . Whether the non-59 permissive properties of brain vasculature to leukocyte traffic...

Numerous studies have shown that TH17 cells and their signature cytokine IL-17A are critical to host defense against various bacterial and fungal infections. The protective responses mediated by TH17 cells and IL-17A include the recruitment of neutrophils, release of antimicrobial peptides and chemokines, and enhanced tight junction of epithelial cells. Due to the importance of TH17 cells in infections, efforts have been made to develop TH17-based vaccines. The goal of vaccination is to establish a protective immunological memory. Most currently approved vaccines are antibody-based and have limited protection against stereotypically different strains. Studies show that T-cell–based vaccines may overcome this limitation and protect hosts against infection of different strains. Two main strategies are used to develop TH17 vaccines: identification of TH17-specific antigens and TH17-skewing adjuvants. Studies have revealed that cholera toxin (CT) induces a potent Th17 response following vaccination. Antigen vaccination along with CT induces a robust TH17 response, which is sometimes accompanied by TH1 responses. Due to the toxicity of CT, it is hard to apply CT in a clinical setting. Thus, understanding how CT modulates TH17 responses may lead to the development of successful TH17-based vaccines.