Nita H Salzman

Medical College of Wisconsin, Milwaukee, Wisconsin, United States

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Publications (62)456.04 Total impact

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    ABSTRACT: Background: To identify and develop novel targeted therapies for complex diseases such as Crohn's disease (CD), functional subtypes rooted in pathogenesis must be defined. One candidate method to subtype CD is to define the small intestinal Paneth cell phenotypes based on the intracellular distribution of antimicrobial proteins. We have previously shown that in CD patients, Paneth cell phenotype correlates with the patients' genotype, distinct gene expression signature, presence of granuloma (pathologic hallmark), and time to recurrence after surgery. However, the mechanism by which abnormal Paneth cells contribute to pathogenesis and sub-classify disease in the context of host-microbial interaction is unclear. We analyzed Paneth cell phenotype and its correlation with mucosal microbiome and transcriptome in a cohort of pediatric CD and non-inflammatory bowel disease (IBD) patients. Methods: We first retrospectively analyzed Paneth cell phenotypes using archived resection specimens from adult (n = 531) and pediatric (n = 73) CD patients. We next analyzed a prospectively recruited pediatric cohort, including CD (n = 44) and non-IBD (n = 62) patients aged 4 to 18. These patients were recruited at the time of routine endoscopy. Ileal mucosal biopsy samples were collected and analyzed for Paneth cell phenotype (lysozyme/defensin 5 immunofluorescence), mucosal microbiome (16S rRNA sequencing), and transcriptome (RNA-sequencing). Paneth cell phenotype was determined by the percentage of normal Paneth cells in each sample. Type I Paneth cell phenotype was defined as <80% normal Paneth cells, whereas Type II Paneth cell phenotype was defined as ≥80% normal Paneth cells. Results: The prevalence of type I Paneth cell phenotype in pediatric CD patients was higher than in adult CD cohorts (47% versus 18%; P < 0.0001). In pediatric CD patients, the type I Paneth cell phenotype was associated with significant changes in the ileal mucosal microbiome, characterized by reduced abundance of barrier-associated microbes (Faecalibacterium, Blautia, Ruminococcaceae, Porphyromonas, Lachnospira, Peptostreptococcus, Anaerostipes, and Odoribacteraceae) and enrichment of potentially pro-inflammatory microbes (Corynebacterium and Erysipelotrichaceae). In addition, pediatric CD patients with type I Paneth cell phenotype also displayed an altered epithelial gene expression profile, with significant reduction in oxidative phosphorylation gene cluster. Furthermore, the down regulation of oxidative phosphorylation gene cluster in CD was in turn associated with reduced abundance of Faecalibacterium, suggesting a complex network between Paneth cell function, epithelial energy/metabolism, and microbiome homeostasis. The connections between Paneth cell phenotypes, microbiome, and transcriptome profiles were not observed in non-IBD patients. Conclusions: These data support a functional role for Paneth cells in subtyping CD that is based on a specific pattern of metabolic dysregulation and mucosal dysbiosis.
    No preview · Article · Feb 2016 · Inflammatory Bowel Diseases
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    ABSTRACT: Objective: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in TGF-β signaling. Methods and results: We used a T cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naïve CD4 T cells from xIAP mice compared to colitis induced by naïve CD4 T cells from WT mice. We did not observe any significant difference in the induction of Treg cells in these studies. We next tested whether xIAP is required for Treg cell function by co-transferring xIAP or WT Treg cells with naïve WT CD4 cells in this model. We demonstrate that XIAP deficient Treg cells were able to prevent disease similarly to WT Treg cells. However, in these experiments we found a significantly decreased percentage of IL-17A producing CD4 T cells in mice receiving Tregs from xIAP mice. Conclusions: xIAP appears dispensable for the generation of induced Treg cells as well as function of natural Treg cells. There appeared to be a role of xIAP in generation of IL-17 producing cells from either naïve CD4 T cells or Treg cells. Further research is needed to explore the role of xIAP in generation of IL-17 producing cells.
    No preview · Article · Jan 2016 · Journal of Pediatric Gastroenterology and Nutrition
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    ABSTRACT: Background: The inflammatory state associated with Crohn's disease (CD) and ulcerative colitis (UC) remains incompletely defined. Methods: To better understand the extracellular milieu associated with inflammatory bowel disease (IBD), we employed a bioassay whereby plasma of treatment naïve pediatric IBD patients (n=22 CD, n=15 UC) and unrelated healthy controls (uHC, n=10) were used to induce transcriptional responses in a healthy leukocyte population. After culture, gene expression was comprehensively measured with microarrays and analyzed. Results: Relative to uHC, plasma of CD and UC patients induced distinct responses, respectively consisting of 985 and 895 regulated transcripts (|log2 ratio| ≥ 0.5 (1.4-fold); FDR ≤ 0.01). The CD:uHC and UC:uHC signatures shared a nonrandom, commonly regulated, intersection of 656 transcripts (χ(2) : p < 0.001) and were highly correlative (Pearson's Correlation Coefficient = 0.96, 95% CI [0.96, 0.97]). Despite sharing common genetic susceptibility loci, the IBD signature negatively correlated with that driven by plasma of Type 1 diabetes (T1D) patients (Pearson's Correlation Coefficient: -0.51). Ontological analyses revealed the presence of an immunoregulatory plasma milieu in IBD, as transcripts for cytokines/chemokines, receptors and signaling molecules consistent with immune activation were under expressed relative to uHC and T1D plasma. Multiplex ELISA and receptor blockade studies confirmed TGF-β and IL-10 as contributors to the IBD signature. Analysis of CD patient signatures detected a subset of transcripts associated with responsiveness to 6-mercaptopurine treatment. Conclusions: Through plasma induced signature analysis, we have defined a unique, partially TGF-β/IL-10 -dependent immunoregulatory signature associated with IBD that may prove useful in predicting therapeutic responsiveness. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Clinical & Experimental Immunology
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    ABSTRACT: Enterococcus faecalis is both a common commensal of the human gastrointestinal tract and a leading cause of hospital-acquired infections. Systemic infections with multidrug-resistant enterococci occur subsequent to gastrointestinal colonization. Preventing colonization by multidrug-resistant E. faecalis could therefore be a valuable approach towards limiting infection. However, little is known about the mechanisms E. faecalis uses to colonize and compete for stable gastrointestinal niches. Pheromone-responsive conjugative plasmids encoding bacteriocins are common among enterococcal strains and could modulate niche competition among enterococci or between enterococci and the intestinal microbiota. We developed a model of colonization of the mouse gut with E. faecalis, without disrupting the microbiota, to evaluate the role of the conjugative plasmid pPD1 expressing bacteriocin 21 (ref. 4) in enterococcal colonization. Here we show that E. faecalis harbouring pPD1 replaces indigenous enterococci and outcompetes E. faecalis lacking pPD1. Furthermore, in the intestine, pPD1 is transferred to other E. faecalis strains by conjugation, enhancing their survival. Colonization with an E. faecalis strain carrying a conjugation-defective pPD1 mutant subsequently resulted in clearance of vancomycin-resistant enterococci, without plasmid transfer. Therefore, bacteriocin expression by commensal bacteria can influence niche competition in the gastrointestinal tract, and bacteriocins, delivered by commensals that occupy a precise intestinal bacterial niche, may be an effective therapeutic approach to specifically eliminate intestinal colonization by multidrug-resistant bacteria, without profound disruption of the indigenous microbiota.
    No preview · Article · Oct 2015 · Nature

  • No preview · Article · Oct 2015 · Journal of the American College of Surgeons
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    ABSTRACT: It is clear that IL-10 plays an essential role in maintaining homeostasis in the gut in response to the microbiome. However, it is unknown whether IL-10 also facilitates immune homeostasis at distal sites. To address this question, we asked whether splenic immune populations were altered in IL-10-deficient (Il10(-) (/-)) mice in which differences in animal husbandry history were associated with susceptibility to spontaneous enterocolitis that is microbiome dependent. The susceptible mice exhibited a significant increase in splenic macrophages, neutrophils, and marginal zone (MZ) B cells that was inhibited by IL-10 signaling in myeloid, but not B cells. The increase in macrophages was due to increased proliferation that correlated with a subsequent enhancement in MZ B cell differentiation. Cohousing and antibiotic treatment studies suggested that the alteration in immune homeostasis in the spleen was microbiome dependent. The 16S rRNA sequencing revealed that susceptible mice harbored a different microbiome with a significant increase in the abundance of the bacterial genus Helicobacter. The introduction of Helicobacter hepaticus to the gut of nonsusceptible mice was sufficient to drive macrophage expansion and MZ B cell development. Given that myeloid cells and MZ B cells are part of the first line of defense against blood-borne pathogens, their increase following a breach in the gut epithelial barrier would be protective. Thus, IL-10 is an essential gatekeeper that maintains immune homeostasis at distal sites that can become functionally imbalanced upon the introduction of specific pathogenic bacteria to the intestinal track. Copyright © 2015 by The American Association of Immunologists, Inc.
    Full-text · Article · Aug 2015 · The Journal of Immunology
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    ABSTRACT: Otitis media is one of the most common diseases of early childhood. Susceptibility to otitis is influenced by a number of factors, including the actions of innate immune molecules secreted by the epithelia lining the nasopharynx, middle ear, and Eustachian tube. The SPLUNC1 (short palate, lung, nasal epithelial clone 1) protein is a highly abundant secretory product of the mammalian nasal, oral, and respiratory mucosa that is thought to play a multifunctional role in host defense. In this study we investigated Splunc1 expression in the ear of the mouse, and asked whether this protein contributes to overall host defense in the middle ear and/or Eustachian tube. We found that Splunc1 is highly expressed in both the surface epithelium and in submucosal glands in these regions in wild-type mice. In mice lacking Splunc1, we noted histologically an increased frequency of otitis media, characterized by accumulation of leukocytes (neutrophils with scattered macrophages), proteinaceous fluid, and mucus in the middle ear lumens. Further, many of these mice had extensive remodeling of the middle ear wall, suggesting a chronic course of disease. From these observations, we conclude that loss of Splunc1 predisposes mice to the development of otitis media. The Splunc1(-/-) mouse model should help investigators to better understand both the biological role of Splunc1 as well as host defense mechanisms in the middle ear. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Mar 2015 · Disease Models and Mechanisms
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    ABSTRACT: Establishment of a statistical association between microbiome features and clinical outcomes is of growing interest because of the potential for yielding insights into biological mechanisms and pathogenesis. Extracting microbiome features that are relevant for a disease is challenging and existing variable selection methods are limited due to large number of risk factor variables from microbiome sequence data and their complex biological structure. We propose a tree-based scanning method, Selection of Models for the Analysis of Risk factor Trees (referred to as SMART-scan), for identifying taxonomic groups that are associated with a disease or trait. SMART-scan is a model selection technique that uses a pre-defined taxonomy to organize the large pool of possible predictors into optimized groups, and hierarchically searches and determines variable groups for association test. We investigate the statistical properties of SMART-scan through simulations, in comparison to a regular single-variable analysis and three commonly-used variable selection methods, stepwise regression, least absolute shrinkage and selection operator (LASSO) and classification and regression tree (CART). When there are taxonomic group effects in the data, SMART-scan can significantly increase power by using bacterial taxonomic information to split large numbers of variables into groups. Through an application to microbiome data from a vervet monkey diet experiment, we demonstrate that SMART-scan can identify important phenotype-associated taxonomic features missed by single-variable analysis, stepwise regression, LASSO and CART. Availability: The SMART-scan approach is implemented in R and is available at https://dsgweb.wustl.edu/qunyuan/software/smartscan/ CONTACT: qunyuan@wustl.edu. © The Author (2015). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    No preview · Article · Jan 2015 · Bioinformatics
  • Edith Porter · Erika V Valore · Rabin Anouseyan · Nita H Salzman
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    ABSTRACT: Antimicrobial (poly)peptides (AMPs) are ancient key effector molecules of innate host defense and have been identified in mammals, insects, plants, and even fungi (Nakatsuji and Gallo, J Invest Dermatol, 132: 887-895, 2012). They exhibit a cationic net charge at physiological pH and are rich in hydrophobic amino acids (Dufourc et al., Curr Protein Pept Sci, 13: 620-631, 2012). Their mode of action has been best investigated in bacteria. When assuming secondary structure the cationic and hydrophobic amino acids are sequestered creating a bipartitioned molecule in which the cationic amino acids mediate initial electrostatic interaction with the negatively charged bacterial surface and the hydrophobic amino acids mediate embedding into the bacterial membranes followed by a multitude of effects interfering with bacterial viability (Nicolas, FEBS J, 276: 6483-6496, 2009; Padovan et al., Curr Protein Pept Sci, 11: 210-219, 2010). However, immunomodulatory, antitumor, and other effects have been added to the ever increasing list of AMP functions (Pushpanathan et al., Int J Pept, 2013: 675391, 2013). Several classes of AMPs have been distinguished based on structure, namely anti-parallel beta-sheet, alpha-helical, circular, as well as disulfide bridge connectivity (Bond and Khalid, Protein Pept Lett, 17: 1313-1327, 2010). Many of the AMPs undergo posttranslational modification including further proteolysis. Biochemical analysis at the protein level is of great interest for a wide range of scientists and important when studying host-pathogen interaction, for example Salmonella invasion of the small intestine. Acid-urea polyacrylamide gel electrophoresis (AU-PAGE) followed by Western immunoblotting is an important tool for the identification and quantification of cationic AMPs. The protocol for these procedures outlined here describes, in detail, the necessary steps; including pouring the AU-gels, preparing the test samples, performing the electrophoretic separation and protein transfer to the membrane, and conducting the immunodetection using an alkaline phosphatase/NBT/BCIP system. A standard SDS-PAGE in comparison with AU-PAGE and the corresponding Western immunoblot are depicted in Fig. 1.
    No preview · Article · Jan 2015 · Methods in Molecular Biology
  • Nita H Salzman

    No preview · Article · Dec 2014 · Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology
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    ABSTRACT: Background There is increasing evidence that intestinal inflammation plays a major role in gastrointestinal symptoms in cystic fibrosis (CF). Fecal calprotectin is a marker that is elevated in several gastrointestinal inflammatory diseases, but little is known about its value in CF. We aimed to look for associations of elevated fecal calprotectin among CF patients and whether its level correlates with the clinical manifestations of CF. Methods A single stool specimen was collected from 62 patients with CF. Fecal calprotectin was measured using the commercially available ELISA kits (PhiCal™ test). Clinical data were collected from patients’ records and CF registry. Results There were no significant differences between CF patients with normal and abnormal fecal calprotectin levels. However, patients who were not receiving inhaled antibiotics had higher fecal calprotectin levels than those who were. Conclusion Elevated fecal calprotectin may not accurately predict intestinal inflammation in CF. However, the fact that it was elevated in both pancreatic sufficient and insufficient groups supports the concept of “cystic fibrosis enteropathy” regardless of the pancreatic status.
    Full-text · Article · May 2014 · BMC Pediatrics
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    ABSTRACT: The innate and adaptive immune systems in the intestine cooperate to maintain the integrity of the intestinal barrier and to regulate the composition of the resident microbiota. However, little is known about the crosstalk between the innate and adaptive immune systems that contribute to this homeostasis. We find that CD4+ T cells regulate the number and function of barrier-protective innate lymphoid cells (ILCs), as well as production of antimicrobial peptides (AMPs), Reg3γ and Reg3β. RAG1-/- mice lacking T and B cells had elevated ILC numbers, interleukin-22 (IL-22) production, and AMP expression, which were corrected by replacement of CD4+ T cells. Major histocompatibility class II-/- (MHCII-/-) mice lacking CD4+ T cells also had increased ILCs, IL-22, and AMPs, suggesting that negative regulation by CD4+ T cells occurs at steady state. We utilized transfers and genetically modified mice to show that reduction of IL-22 is mediated by conventional CD4+ T cells and is T-cell receptor dependent. The IL-22-AMP axis responds to commensal bacteria; however, neither the bacterial repertoire nor the gross localization of commensal bacteria differed between MHCII+/- and MHCII-/- littermates. These data define a novel ability of CD4+ T cells to regulate intestinal IL-22-producing ILCs and AMPs.Mucosal Immunology advance online publication, 22 January 2014; doi:10.1038/mi.2013.121.
    Preview · Article · Jan 2014 · Mucosal Immunology
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    ABSTRACT: BACKGROUND: Increased susceptibility to Crohn's disease (CD) is associated with mutations in several genes that have roles in the functioning of Paneth cells (PCs). PCs produce and secrete antimicrobial peptides and proteins, which are critical for host defense against pathogens and regulation of intestinal homeostasis, notably in regulating the composition of the small intestinal biota. We hypothesize that a significant subset of patients with CD carry susceptibility genes that cause PC dysfunction, resulting in decreased expression of PC antimicrobials, leading to intestinal dysbiosis. We tested this by evaluating a cohort of pediatric patients with CD and non-IBD controls, for genotype, PC gene expression, and microbiota composition.METHODS: We recruited patients <19 years age from Children's hospital of Wisconsin. We obtained clinical data for disease phenotyping. We genotyped subjects for known CD susceptibility gene mutations by Immunochip. Total RNA was isolated from biopsy tissue and analyzed by RTqPCR for levels of PC product gene expression, including defensins HD5 and HD6, lysozyme, sPLA2, and RegIIIgamma. We evaluated differences in PC gene expression among patients with CD and non-inflamed controls. We also characterized the ileal microbiota for bacterial composition and diversity using 16S rRNA gene sequence analysis to determine associations between PC antimicrobial expression and biome composition.RESULTS: We recruited a total of 70 CD patients and 192 non-IBD controls. Control patients skewed younger than disease cohorts. There was male preponderance in CD cohort. Immunochip analysis, subsequently validated by qPCR SNP typing, demonstrated statistically significant correlations between SNP mutations and CD, most notably with the NOD2 insertion mutant (SNP13) (P = 0.0001272). Microbiota analysis showed no significant differences in alpha diversity between control and CD, however there were notable differences in composition. Various sub species of Firmicutes, Actinobacteria and Bacterioidetesare all reduced in CD samples compared to Control. Veillonellaceae (Firmicutes), Alcaligenaceae, Enterobacteriaceae, and Pasteurellaceae (Proteobacteria) are all increased in CD samples. PCA analysis suggested that Lachnospira and Enterobacteria are the main determinants of variance, with a smaller contribution by Prevotella. The relative abundance of bacterial families was significantly different in CD patients compared to controls (Adonis analysis, P < 0.001). The abundance of Lachnospiraceae is consistently higher in controls than CD, while the abundance of Enterobacteriaceae is consistently lower in controls than in CD samples. Ileal samples from CD patients show significantly altered expression of HD6, PSP/REG, and Lysozyme, when compared to controls (Kruskal-Wallis Test).CONCLUSIONS: There are statistically significant correlations between SNP mutations and CD, most notably with the NOD2 insertion mutant (SNP13). The ileal microbiota composition of CD samples differs significantly from control samples. Expression of PC antimicrobial peptides is dysregulated in CD ileal samples compared to controls, with significantly altered expression of human defensin 6, PSP/REG and lysozyme, which may contribute to dysbiosis at the ileal surface. PC morphology and location are abnormal in CD ileal samples compared to controls, which may contribute to abnormalities in mRNA expression.(C) Crohn's & Colitis Foundation of America, Inc.
    No preview · Article · Dec 2013 · Inflammatory Bowel Diseases
  • Nita H Salzman · Charles L Bevins
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    ABSTRACT: The complex community of colonizing microbes inhabiting the mucosal surfaces of mammals is vital to homeostasis and normal physiology in the host. When the composition of this microbiota is unfavorably altered, termed dysbiosis, the host is rendered more susceptible to a variety of chronic diseases. In the mammalian small intestine, specialized secretory epithelial cells, named Paneth cells, produce a variety of secreted antimicrobial peptides that fundamentally influence the composition of the microbiota. Recent investigations have identified numerous genetic and environmental factors that can disrupt normal Paneth cell function, resulting in compromised antimicrobial peptide secretion and consequent dysbiosis. These findings suggest that Paneth cell dysfunction should be considered a common cause of dysbiosis.
    No preview · Article · Nov 2013 · Seminars in Immunology
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    ABSTRACT: To study regulatory T (Treg) cell control of chronic autoimmunity in a lymphoreplete host, we created and characterized a new model of autoimmune lung inflammation that targets the medium and small airways. We generated transgenic mice that express a chimeric membrane protein consisting of hen egg lysozyme and a hemoglobin epitope tag under the control of the Clara cell secretory protein promoter, which largely limited transgene expression to the respiratory bronchioles. When Clara cell secretory protein-membrane hen egg lysozyme/hemoglobin transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the hemoglobin epitope, the bigenic progeny developed dense, pseudo-follicular lymphocytic peribronchiolar infiltrates that resembled the histological pattern of follicular bronchiolitis. Aggregates of activated IFN-γ- and IL-17A-secreting CD4(+) T cells as well as B cells surrounded the airways. Lung pathology was similar in Ifng(-/-) and Il17a(-/-) mice, indicating that either cytokine is sufficient to establish chronic disease. A large number of Ag-specific Treg cells accumulated in the lesions, and Treg cell depletion in the affected mice led to an interstitial spread of the disease that ultimately proved fatal. Thus, Treg cells act to restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease.
    No preview · Article · Oct 2013 · The Journal of Immunology

  • No preview · Article · Aug 2013 · Zeitschrift für Gastroenterologie
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    ABSTRACT: Variants of the multidrug resistance gene (MDR1/ABCB1) have been associated with increased susceptibility to severe ulcerative colitis (UC). In this study, we investigated the role of TLR/IL-1R signaling pathways including the common adaptor MyD88 in the pathogenesis of chronic colonic inflammation in MDR1A deficiency. Double- or triple-null mice lacking TLR2, MD-2, MyD88, and MDR1A were generated in the FVB/N background. Deletion of TLR2 in MDR1A deficiency resulted in fulminant pancolitis with early expansion of CD11b(+) myeloid cells and rapid shift toward TH1-dominant immune responses in the lamina propria. Colitis exacerbation in TLR2/MDR1A double-knockout mice required the unaltered commensal microbiota and the LPS coreceptor MD-2. Blockade of IL-1β activity by treatment with IL-1R antagonist (IL-1Ra; Anakinra) inhibited colitis acceleration in TLR2/MDR1A double deficiency; intestinal CD11b(+)Ly6C(+)-derived IL-1β production and inflammation entirely depended on MyD88. TLR2/MDR1A double-knockout CD11b(+) myeloid cells expressed MD-2/TLR4 and hyperresponded to nonpathogenic Escherichia coli or LPS with reactive oxygen species production and caspase-1 activation, leading to excessive cell death and release of proinflammatory IL-1β, consistent with pyroptosis. Inhibition of reactive oxygen species-mediated lysosome degradation suppressed LPS hyperresponsiveness. Finally, active UC in patients carrying the TLR2-R753Q and MDR1-C3435T polymorphisms was associated with increased nuclear expression of caspase-1 protein and cell death in areas of acute inflammation, compared with active UC patients without these variants. In conclusion, we show that the combined defect of two UC susceptibility genes, MDR1A and TLR2, sets the stage for spontaneous and uncontrolled colitis progression through MD-2 and IL-1R signaling via MyD88, and we identify commensally induced pyroptosis as a potential innate immune effector in severe UC pathogenesis.
    Full-text · Article · May 2013 · The Journal of Immunology

  • No preview · Article · Dec 2012 · Inflammatory Bowel Diseases
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    ABSTRACT: "Natural" regulatory T cells (nTregs) that express the transcription factor Foxp3 and produce IL-10 are required for systemic immunological tolerance. "Induced" regulatory T cells (iTregs) are nonredundant and essential for tolerance at mucosal surfaces, yet their mechanisms of suppression and stability are unknown. We investigated the role of iTreg-produced IL-10 and iTreg fate in a treatment model of inflammatory bowel disease. Colitis was induced in Rag1(-/-) mice by the adoptive transfer of naive CD4(+) T cells carrying a nonfunctional Foxp3 allele. At the onset of weight loss, mice were treated with both iTregs and nTregs where one marked subset was selectively IL-10 deficient. Body weight assessment, histological scoring, cytokine analysis, and flow cytometry were used to monitor disease activity. Transcriptional profiling and TCR repertoire analysis were used to track cell fate. When nTregs were present but IL-10 deficient, iTreg-produced IL-10 was necessary and sufficient for the treatment of disease, and vice versa. Invariably, ∼85% of the transferred iTregs lost Foxp3 expression (ex-iTregs) but retained a portion of the iTreg transcriptome, which failed to limit their pathogenic potential upon retransfer. TCR repertoire analysis revealed no clonal relationships between iTregs and ex-iTregs, either within mice or between mice treated with the same cells. These data identify a dynamic IL-10-dependent functional reciprocity between regulatory T cell subsets that maintains mucosal tolerance. The niche supporting stable iTregs is limited and readily saturated, which promotes a large population of ex-iTregs with pathogenic potential during immunotherapy.
    Full-text · Article · Nov 2012 · The Journal of Immunology
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    Article: Response.

    Preview · Article · Nov 2012 · The FASEB Journal

Publication Stats

4k Citations
456.04 Total Impact Points

Institutions

  • 2006-2015
    • Medical College of Wisconsin
      • Department of Pediatrics
      Milwaukee, Wisconsin, United States
  • 2014
    • Children's Hospital of Wisconsin
      Madison, Wisconsin, United States
  • 2008
    • University of Groningen
      • Department of Cell Biology
      Groningen, Groningen, Netherlands
  • 2003
    • California State University, Los Angeles
      • Department of Biological Sciences
      Los Ángeles, California, United States
  • 1998
    • The Children's Hospital of Philadelphia
      • Division of Human Genetics and Molecular Biology
      Philadelphia, Pennsylvania, United States