[show abstract][hide abstract] ABSTRACT: Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. Although the cause of MS is unknown, microorganisms seem to be important for the onset and/or progression of disease. However, it is unclear how microbial colonization, either symbiotic or infectious, affects autoimmunity. Herein, we investigate a role for the microbiota during the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice maintained under germ-free conditions develop significantly attenuated EAE compared with conventionally colonized mice. Germ-free animals, induced for EAE, produce lower levels of the proinflammatory cytokines IFN-γ and IL-17A in both the intestine and spinal cord but display a reciprocal increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Mechanistically, we show that gut dendritic cells from germ-free animals are reduced in the ability to stimulate proinflammatory T cell responses. Intestinal colonization with segmented filamentous bacteria (SFB) is known to promote IL-17 production in the gut; here, we show that SFBs also induced IL-17A-producing CD4(+) T cells (Th17) in the CNS. Remarkably, germ-free animals harboring SFBs alone developed EAE, showing that gut bacteria can affect neurologic inflammation. These findings reveal that the intestinal microbiota profoundly impacts the balance between pro- and antiinflammatory immune responses during EAE and suggest that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases such as MS.
Proceedings of the National Academy of Sciences 03/2011; 108 Suppl 1:4615-22. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although microbes have been classically viewed as pathogens, it is now well established that the majority of host-bacterial interactions are symbiotic. During development and into adulthood, gut bacteria shape the tissues, cells, and molecular profile of our gastrointestinal immune system. This partnership, forged over many millennia of coevolution, is based on a molecular exchange involving bacterial signals that are recognized by host receptors to mediate beneficial outcomes for both microbes and humans. We explore how specific aspects of the adaptive immune system are influenced by intestinal commensal bacteria. Understanding the molecular mechanisms that mediate symbiosis between commensal bacteria and humans may redefine how we view the evolution of adaptive immunity and consequently how we approach the treatment of numerous immunologic disorders.
[show abstract][hide abstract] ABSTRACT: Vitamin D deficiency is implicated in autoimmune disease. We therefore evaluated the effects of 1α,25-dihydroxyvitamin D(3) (1,25-D(3)), the active form of vitamin D, on the development of T helper 1 (Th1), Th17, and Th9 cells, which are implicated in the pathogenesis of different types of autoimmunity. 1,25-D(3) compromised the development of Th17 and Th9 cells, including IL-22-expressing cells while simultaneously increasing the frequency of IL-10-competent cells. Relative to Th17 and Th9 cells, the effects of 1,25-D(3) on Th1 cells were modest, reflecting the significantly reduced levels of the receptor for vitamin D in this lineage. The use of cells deficient in IL-10 or antibodies that block IL-10 signaling abolished the inhibitory effect of 1,25-D(3) on Th9 cells but had no effect on inhibition of Th17 cell frequencies. Thus, the induction of IL-10 in cultures of Th9 cells is an important mechanism by which 1,25-D(3) compromises Th9 development but does not explain inhibition of Th17 cells. A survey of select representatives of the Th17 transcriptome revealed that the levels of mRNA that encode RORγt, IL-17A, IL-17F, IL-23R, and IL-22, were reduced by 1,25-D(3), whereas IL-21 and aryl hydrocarbon receptor mRNA remained unchanged. These data suggest that vitamin D deficiency may promote autoimmunity by favoring the inordinate production of Th17 and Th9 cells at the expense of regulatory IL-10-producing T cells.
Journal of Biological Chemistry 11/2010; 286(2):997-1004. · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Phenotypic plasticity of T helper 17 (Th17) cells suggests instability of chromatin structure of key genes of this lineage. We identified epigenetic modifications across the clustered Il17a and Il17f and the Ifng loci before and after differential IL-12 or TGF-beta cytokine signaling, which induce divergent fates of Th17 cell precursors. We found that Th17 cell precursors had substantial remodeling of the Ifng locus, but underwent critical additional modifications to enable high expression when stimulated by IL-12. Permissive modifications across the Il17a-Il17f locus were amplified by TGF-beta signaling in Th17 cells, but were rapidly reversed downstream of IL-12-induced silencing of the Rorc gene by the transcription factors STAT4 and T-bet. These findings reveal substantial chromatin instability of key transcription factor and cytokine genes of Th17 cells and support a model of Th17 cell lineage plasticity in which cell-extrinsic factors modulate Th17 cell fates through differential effects on the epigenetic status of Th17 cell lineage factors.
[show abstract][hide abstract] ABSTRACT: The emergence of Th17 cells as a distinct subset of effector CD4 T cells has led to a revised model of the adaptive immune system. Whereas the Th1-Th2 paradigm revolutionized our understanding of adaptive immunity by introducing the concept of alternative developmental pathways for naïve CD4 T cells induced by distinct cytokine cues from microbe-activated innate immune cells, delineation of Th17 cell differentiation has extended this concept and has led to a greater appreciation of the developmental plasticity of CD4 T cells. In contrast to Th1 and Th2 cells, which have been thought to represent terminal products of their respective developmental programs, recent studies suggest that Th17 cells are less rigid. In addition to early developmental links to induced regulatory T cells (Tregs) reflected in the shared requirement for TGF-beta, it is now apparent that there is substantial plasticity late in the Th17 program, which allows committed Th17 cells to transition from effectors that produce predominantly IL-17A and IL-17F, to effectors that produce predominantly IFNgamma. Tregs appear to have similar plasticity. This promises new insights into strategies for balancing antimicrobial defense with restraints on immune-mediated tissue injury, and raises new questions regarding the stability of epigenetic modifications that accompany induction of cytokine gene expression during T cell lineage development.
Current opinion in immunology 07/2009; 21(3):274-80. · 10.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: Development of T helper (Th) 17 cells requires transforming growth factor (TGF)-beta and interleukin (IL)-6 and is independent of the Th1 pathway. Although T cells that produce interferon (IFN)-gamma are a recognized feature of Th17 cell responses, mice deficient for STAT4 and T-bet-two prototypical Th1 transcription factors-are protected from autoimmunity associated with Th17 pathogenesis. To examine the fate and pathogenic potential of Th17 cells and origin of IFN-gamma-producing T cells that emerge during Th17 immunity, we developed IL-17F reporter mice that identify cells committed to expression of IL-17F and IL-17A. Th17 cells required TGF-beta for sustained expression of IL-17F and IL-17A. In the absence of TGF-beta, both IL-23 and IL-12 acted to suppress IL-17 and enhance IFN-gamma production in a STAT4- and T-bet-dependent manner, albeit with distinct efficiencies. These results support a model of late Th17 developmental plasticity with implications for autoimmunity and host defense.
[show abstract][hide abstract] ABSTRACT: Aqueous extracts or juice from unripened fruit of Momordica charantia (bitter melon) has traditionally been used in the treatment of diabetes and its complications. Insulin resistance is characterized by significant down-regulation of hepatic insulin signalling as documented by attenuated phosphorylation of insulin receptor (IR), IR substrates 1 and 2, phosphoinositide-3 kinase, protein kinase B, and over-expression of phosphotyrosine phosphatase 1B. We recently demonstrated that bitter melon juice (BMJ) is a potent inhibitor of apoB secretion and TAG synthesis and secretion in human hepatoma cells, HepG2, that may be involved in plasma lipid- and VLDL-lowering effects observed in animal studies. The aim of this study was to evaluate the effects of BMJ on plasma apoB levels and hepatic insulin signalling cascade in mice fed high-fat diet (HFD). Female C57BL/6 mice (4-6 weeks old) were randomized into three groups receiving regular rodent chow, HFD and HFD+BMJ. The data indicate that BMJ not only improves glucose and insulin tolerance but also lowers plasma apoB-100 and apoB-48 in HFD-fed mice as well as modulates the phosphorylation status of IR and its downstream signalling molecules. Investigating the biochemical and molecular mechanisms involved in amelioration of diabetic dyslipidaemia by BMJ may lead to identification of new molecular targets for dietary/alternative therapies.
The British journal of nutrition 04/2008; 100(4):751-9. · 3.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recently, a paradigm shift has emerged in T-cell-mediated adaptive immunity. On the heels of the discovery of T cells with immunosuppressive function, so-called regulatory T cells (Tregs), the diversity of effector cells has expanded to include a third helper T cell, termed Th17. The appreciation that Th17 cells are products of a distinct effector pathway depended critically on observations made during investigations of mouse models of autoimmunity, advanced by discovery of the cytokines IL-17 and IL-23. These studies understandably led investigators to highlight the role played by Th17 cells in autoimmunity. Yet while the dysfunctional behavior of this phenotype as a contributor to inflammatory disease remains a central issue, this pathway evolved to meet a need for host protection against potential pathogens. It has become apparent that the Th17 pathway promotes host defense against certain extracellular bacteria and fungi, but more recent studies also implicate a role in protection against some protozoa and viruses. Here we review the experimental history that ultimately uncovered the existence and nature of Th17 cells, and then turn the reader's attention to what is currently known about Th17 cells as a bulwark against pathogens.
Advances in Immunology 02/2008; 99:115-63. · 7.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: 1. Hyperlipidemic effects of HIV-1-protease inhibitors (PI) are associated with increased hepatic production of triglyceride (TG)-rich lipoproteins, rather than lipoprotein clearance. PI are known to increase apolipoprotein B (apoB) secretion, apoC-III mRNA expression and decrease apoA-1 secretion. Nutritional therapy remains an important strategy to manage PI-associated hyperlipidemia. 2. This study investigated the in vitro efficacy of Asian vegetable, Momordica charantia or bitter melon (BM) to ameliorate PI-associated apoB and lipid abnormalities in HepG2 cells. 3. Our study demonstrates that bitter melon juice (BMJ) significantly reduced apoB secretion and apoC-III mRNA expression and normalized apoA-I expression in PI-treated HepG2 cells. BMJ also significantly reduced cellular TG and microsomal TG transfer protein, suggesting that lipid bioavailability and lipidation of apoB assembly may play a role in decreased apoB secretion. 4. Identifying molecular targets of BM may offer alternative dietary strategies to decrease PI-associated hyperlipidemia and improve quality of life among HIV-1-infected patients.
British Journal of Pharmacology 09/2006; 148(8):1156-64. · 5.07 Impact Factor