Markus Kleinewietfeld

Technische Universität Dresden, Dresden, Saxony, Germany

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Publications (26)331.12 Total impact

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    ABSTRACT: Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.
    No preview · Article · Oct 2015 · Immunity
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    ABSTRACT: FOXP3+ Tregs are central for the maintenance of self-tolerance and can be defective in autoimmunity. In multiple sclerosis and type-1 diabetes, dysfunctional self-tolerance is partially mediated by a population of IFNγ-secreting Tregs. It was previously reported that increased NaCl concentrations promote the induction of proinflammatory Th17 cells and that highsalt diets exacerbate experimental models of autoimmunity. Here, we have shown that increasing NaCl, either in vitro or in murine models via diet, markedly impairs Treg function. NaCl increased IFNγ secretion in Tregs, and reducing IFNγ — either by neutralization with anti-IFNγ antibodies or shRNA-mediated knockdown — restored suppressive activity in Tregs. The heightened IFNγ secretion and loss of Treg function were mediated by the serum/glucocorticoid-regulated kinase (SGK1). A high-salt diet also impaired human Treg function and was associated with the induction of IFNγ-secreting Tregs in a xenogeneic graft-versus-host disease model and in adoptive transfer models of experimental colitis. Our results demonstrate a putative role for an environmental factor that promotes autoimmunity by inducing proinflammatory responses in CD4 effector cells and Treg pathways.
    Preview · Article · Oct 2015 · The Journal of clinical investigation
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    ABSTRACT: A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.
    No preview · Article · Oct 2015 · The Journal of clinical investigation
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    ABSTRACT: The (pro)renin receptor (PRR) was originally thought to be important for regulating blood pressure via the renin-angiotensin system. However, it is now emerging that PRR has instead a generic role in cellular development. Here, we have specifically deleted PRR from T cells. T cell-specific PRR-knockout mice had a significant decrease in thymic cellularity, corresponding with a 100-fold decrease in the number of CD4(+) and CD8(+) thymocytes, and a large increase in double negative (DN) precursors. Gene expression analysis on sorted DN3 thymocytes indicated that PRR-deficient thymocytes have perturbations in key cellular pathways essential at the DN3 stage, including transcription and translation. Further characterisation of DN T cell progenitors leads us to propose that PRR deletion affects thymocyte survival and development at multiple stages; from DN3 through to DN4, DP and single positive CD4 and CD8. Our study thus identifies a new role for PRR in T cell development. Copyright © 2015 American Society of Hematology.
    No preview · Article · Jun 2015 · Blood
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    Full-text · Article · Jan 2015 · Nature
  • Katrina J Binger · Ralf A Linker · Dominik N Muller · Markus Kleinewietfeld
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    ABSTRACT: The incidence of autoimmune diseases in Western civilizations is increasing rapidly, suggesting an influence of environmental factors, such as diet. The pathogenesis of several of these autoimmune diseases is characterized by aberrant activation of T helper 17 (Th17) cells. Recent reports have shown that the differentiation of Th17 cells is sensitive to changes in local microenvironments, in particular salt (NaCl) concentrations, in a molecular mechanism centered around the serum- and glucocorticoid-inducible kinase 1 (SGK1). In this review, we summarize the recently disclosed mechanisms by which salt has been shown to affect SGK1 and, subsequently, Th17 activation.
    No preview · Article · Dec 2014 · Pflügers Archiv - European Journal of Physiology
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    ABSTRACT: Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.
    Full-text · Article · Oct 2014 · Nature
  • Markus Kleinewietfeld · David A. Hafler
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    ABSTRACT: Regulatory T cells are the central element for the maintenance of peripheral tolerance. Several subtypes of regulatory T (Treg) cells have been described, and most of them belong to the CD4+ T-helper (Th) cell lineage. These specific subtypes can be discriminated according to phenotype and function. Forkhead box protein 3 (FoxP3)-expressing natural Treg cells (Tregs) and IL-10-producing, T-regulatory type 1 cells (Tr1) are the best-studied types of CD4+ regulatory T cells in humans and experimental animal models. It was shown that they play a crucial role during autoimmune neuroinflammation. Both cells types seem to be particularly important for multiple sclerosis (MS). Here, we discuss the role of CD4+ regulatory T cells in autoimmune neuroinflammation with an emphasis on Tregs and Tr1 cells in MS.
    No preview · Article · May 2014 · Immunological Reviews
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    Theofilos Poutahidis · Markus Kleinewietfeld · Susan E Erdman
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    ABSTRACT: It is recently shown that beneficial environmental microbes stimulate integrated immune and neuroendocrine factors throughout the body, consequently modulating regulatory T-lymphocyte phenotypes, maintaining systemic immune balance, and determining the fate of preneoplastic lesions toward regression while sustaining whole body good health. Stimulated by a gut microbiota-centric systemic homeostasis hypothesis, we set out to explore the influence of the gut microbiome to explain the paradoxical roles of regulatory T-lymphocytes in cancer development and growth. This paradigm shift places cancer prevention and treatment into a new broader context of holobiont engineering to cultivate a tumor-suppressive macroenvironment.
    Preview · Article · Apr 2014 · Frontiers in Immunology
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    ABSTRACT: Interleukin 17 (IL-17)-producing helper T cells (T[subscript H]17 cells) are often present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that T[subscript H]17 cells are main drivers of autoimmune tissue injury. However, not all T[subscript H]17 cells are pathogenic; in fact, T[subscript H]17 cells generated with transforming growth factor-β1 (TGF-β1) and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we found that the production of TGF-β3 by developing T[subscript H]17 cells was dependent on IL-23, which together with IL-6 induced very pathogenic T[subscript H]17 cells. Moreover, TGF-β3-induced T[subscript H]17 cells were functionally and molecularly distinct from TGF-β1-induced T[subscript H]17 cells and had a molecular signature that defined pathogenic effector T[subscript H]17 cells in autoimmune disease.
    Full-text · Article · Mar 2014
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    ABSTRACT: Developed societies, although having successfully reduced the burden of infectious disease, constitute an environment where metabolic, cardiovascular, and autoimmune diseases thrive. Living in westernized countries has not fundamentally changed the genetic basis on which these diseases emerge, but has strong impact on lifestyle and pathogen exposure. In particular, nutritional patterns collectively termed the "Western diet", including high-fat and cholesterol, high-protein, high-sugar, and excess salt intake, as well as frequent consumption of processed and 'fast foods', promote obesity, metabolic syndrome, and cardiovascular disease. These factors have also gained high interest as possible promoters of autoimmune diseases. Underlying metabolic and immunologic mechanisms are currently being intensively explored. This review discusses the current knowledge relative to the association of "Western diet" with autoimmunity, and highlights the role of T cells as central players linking dietary influences to autoimmune pathology.
    No preview · Article · Jan 2014 · Current Allergy and Asthma Reports
  • Markus Kleinewietfeld · David A Hafler
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    ABSTRACT: CD4(+) T helper cells are a central element of the adaptive immune system. They protect the organism against a wide range of pathogens and are able to initiate and control many immune reactions in combination with other cells of the adaptive and the innate immune system. Starting from a naive cell, CD4(+) T cells can differentiate into various effector cell populations with specialized function. This subset specific differentiation depends on numerous signals and the strength of stimulation. However, recent data have shown that differentiated CD4(+) T cell subpopulations display a high grade of plasticity and that their initial differentiation is not an endpoint of T cell development. In particular, FoxP3(+) regulatory T cells (Treg) and Th17 effector T cells demonstrate a high grade of plasticity, which allow a functional adaptation to various physiological situations during an immune response. However, the plasticity of Treg and Th17 cells might also be a critical factor for autoimmune disease. Here we discuss the recent developments in CD4(+) T cell plasticity with a focus on Treg and Th17 cells and its role in human autoimmune disease, in particular multiple sclerosis (MS).
    No preview · Article · Nov 2013 · Seminars in Immunology
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    ABSTRACT: A recent epidemiological study showed that eating 'fast food' items such as potato chips increased likelihood of obesity, whereas eating yogurt prevented age-associated weight gain in humans. It was demonstrated previously in animal models of obesity that the immune system plays a critical role in this process. Here we examined human subjects and mouse models consuming Westernized 'fast food' diet, and found CD4(+) T helper (Th)17-biased immunity and changes in microbial communities and abdominal fat with obesity after eating the Western chow. In striking contrast, eating probiotic yogurt together with Western chow inhibited age-associated weight gain. We went on to test whether a bacteria found in yogurt may serve to lessen fat pathology by using purified Lactobacillus reuteri ATCC 6475 in drinking water. Surprisingly, we discovered that oral L. reuteri therapy alone was sufficient to change the pro-inflammatory immune cell profile and prevent abdominal fat pathology and age-associated weight gain in mice regardless of their baseline diet. These beneficial microbe effects were transferable into naïve recipient animals by purified CD4(+) T cells alone. Specifically, bacterial effects depended upon active immune tolerance by induction of Foxp3(+) regulatory T cells (Treg) and interleukin (Il)-10, without significantly changing the gut microbial ecology or reducing ad libitum caloric intake. Our finding that microbial targeting restored CD4(+) T cell balance and yielded significantly leaner animals regardless of their dietary 'fast food' indiscretions suggests population-based approaches for weight management and enhancing public health in industrialized societies.
    Full-text · Article · Jul 2013 · PLoS ONE
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    ABSTRACT: There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4+ helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23-TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.
    No preview · Article · Mar 2013 · Nature
  • Ralf Linker · Arndt Manzel · Markus Kleinewietfeld · David Hafler · Dominik Muller

    No preview · Conference Paper · Feb 2013
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    ABSTRACT: Angiotensin (Ang) II induces vascular injury in part by activating innate and adaptive immunity; however, the mechanisms are unclear. We investigated the role of interferon (IFN)-γ and interleukin (IL)-23 signaling. We infused Ang II into IFN-γ receptor (IFN-γR) knockout mice and wild-type controls, as well as into mice treated with neutralizing antibodies against IL-23 receptor and IL-17A. Ang II-treated IFN-γR knockout mice exhibited reduced cardiac hypertrophy, reduced cardiac macrophage and T-cell infiltration, less fibrosis, and less arrhythmogenic electric remodeling independent of blood pressure changes. In contrast, IL-23 receptor antibody treatment did not reduce cardiac hypertrophy, fibrosis, or electric remodeling despite mildly reduced inflammation. IL-17A antibody treatment behaved similarly. In the kidney, IFN-γR deficiency reduced inflammation and tubulointerstitial damage and improved glomerular filtration rate. Nonetheless, albuminuria was increased compared with Ang II-treated wild-type controls. The glomeruli of Ang II-treated IFN-γR knockout mice exhibited fewer podocytes, less nephrin and synaptopodin staining, and impaired podocyte autophagy. Thus, IFN-γ blockade, but not IL-23 receptor antibody treatment, protects from Ang II-induced cardiac damage and electric remodeling. In the kidney, IFN-γ signaling acts in a cell type-specific manner. Glomerular filtration rate is preserved in the absence of the IFN-γR, whereas podocytes may require the IFN-γR in the presence of Ang II for normal integrity and function.
    Preview · Article · Oct 2012 · Hypertension
  • Lee Y · Awasthi A · Yosef N · F. J. Quintana · Xiao S · Peters A · Wu C · Kleinewietfeld M · Kunder S · Hafler DA · Sobel RA · Regev A · V. K. Kuchroo
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    ABSTRACT: Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are often present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that T(H)17 cells are main drivers of autoimmune tissue injury. However, not all T(H)17 cells are pathogenic; in fact, T(H)17 cells generated with transforming growth factor-β1 (TGF-β1) and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we found that the production of TGF-β3 by developing T(H)17 cells was dependent on IL-23, which together with IL-6 induced very pathogenic T(H)17 cells. Moreover, TGF-β3-induced T(H)17 cells were functionally and molecularly distinct from TGF-β1-induced T(H)17 cells and had a molecular signature that defined pathogenic effector T(H)17 cells in autoimmune disease.
    No preview · Article · Sep 2012 · Nature Immunology
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    ABSTRACT: Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are often present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that T(H)17 cells are main drivers of autoimmune tissue injury. However, not all T(H)17 cells are pathogenic; in fact, T(H)17 cells generated with transforming growth factor-β1 (TGF-β1) and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we found that the production of TGF-β3 by developing T(H)17 cells was dependent on IL-23, which together with IL-6 induced very pathogenic T(H)17 cells. Moreover, TGF-β3-induced T(H)17 cells were functionally and molecularly distinct from TGF-β1-induced T(H)17 cells and had a molecular signature that defined pathogenic effector T(H)17 cells in autoimmune disease.
    Full-text · Article · Sep 2012 · Nature Immunology
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    Dominik N Müller · Markus Kleinewietfeld · Heda Kvakan

    Preview · Article · Jun 2011 · Journal of Renin-Angiotensin-Aldosterone System
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    ABSTRACT: Hypertensive target organ damage, especially cardiac hypertrophy with heart failure and arrhythmia, is a major source of morbidity and mortality. Angiotensin II, a major mediator of hypertension and cardiac damage, has proinflammatory properties. Inflammation and activation of the immune system play a pivotal role in pathogenesis of hypertensive target organ damage. However, the role of immunosuppressive CD4+CD25+ regulatory T (Treg) cells in the pathogenesis of hypertensive target organ damage is unexplored. We conducted adoptive transfer of Treg cells into angiotensin II-infused hypertensive mice. Treg cell recipients exhibited improved cardiac hypertrophy and less cardiac fibrosis despite sustained hypertension. Amelioration of cardiac morphology was accompanied by an improvement in arrhythmogenic electric remodeling, indicating the functional significance of the enhanced cardiac morphology. Delocalization of the connexin 43 gap junction protein is one of the major pathomechanisms in electric remodeling. Pronounced connexin 43 immunoreactivity was found at the lateral borders of cardiomyocytes in angiotensin II-treated mice. In contrast, connexin 43 was restricted to the intercalated disk regions in sham controls. Surprisingly, angiotensin II+Treg-treated mice showed normal connexin 43 gap junction protein localization. Adoptive Treg cell transfer resulted in a marked reduction in cardiac CD4+, CD8+, and CD69+ cell and macrophage infiltration. Immunosuppressive effects of transferred Treg cells ameliorated cardiac damage and accounted for the improved electric remodeling independently of blood pressure-lowering effects. Our results provide new insights into the pathogenesis of hypertensive cardiac damage and could therefore lead to new therapeutic approaches that involve manipulation of the immune system.
    Preview · Article · Jul 2009 · Circulation

Publication Stats

2k Citations
331.12 Total Impact Points

Institutions

  • 2014-2015
    • Technische Universität Dresden
      Dresden, Saxony, Germany
  • 2012-2015
    • Yale University
      New Haven, Connecticut, United States
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 2013-2014
    • Harvard University
      Cambridge, Massachusetts, United States
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
  • 2006-2009
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany