Stephan R Targan

Cedars-Sinai Medical Center, Los Angeles, California, United States

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Publications (433)3957.49 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Inflammatory bowel diseases (IBD) are a collection of diseases characterized by chronic gastrointestinal inflammation resulting from an exuberant immune response to commensal flora in genetically susceptible individuals. Rapid advances in the field of genomics have resulted in the identification of at least 163 loci that contribute susceptibility to both Crohn's disease (CD) and ulcerative colitis (UC). Similar to other complex diseases, however, the "curse of missing heritability" remains a significant concern in understanding the mechanisms underlying IBD. While genetic discoveries, to date, only account for 7-14 % of disease variance for IBD, studies have increasingly demonstrated a role for environmental factors in disease pathogenesis. Furthermore, the use of animal models of IBD has led to a greater understanding of disease pathogenesis implicating various aspects of the innate immune response including the bacterial, fungal, and viral microbiome and adaptive immune response such as the interleukin (IL)-23/IL-17 pathway.
    Seminars in immunopathology. 09/2014;
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    ABSTRACT: Mucosal expression of interferon (IFN)-γ plays a pivotal role in the pathogenesis of inflammatory bowel disease (IBD) and IBD risk regions flank IFNG. The conserved IFNG rs1861494 T/C introduces a new CpG methylation site, is associated with disease severity and lack of therapeutic response in other infectious and immune-mediated disorders, and is in linkage disequilibrium with a ulcerative colitis (UC) disease severity region. It seems likely that CpG-altering single nucleotide polymorphisms modify methylation and gene expression. This study evaluated the association between rs1861494 and clinical, serologic, and methylation patterns in patients with IBD.
    Inflammatory Bowel Diseases 08/2014; · 5.12 Impact Factor
  • Katie L Alexander, Stephan R Targan, Charles O Elson
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    ABSTRACT: The human host has coevolved with the collective of bacteria species, termed microbiota, in a complex fashion that affects both innate and adaptive immunity. Differential regulation of regulatory T-cell and effector T-cell responses are a direct result of specific microbial species present within the gut, and this relationship is subject to dysregulation during inflammation and disease. The microbiota varies widely between individuals and has a profound effect on how one reacts to various environmental stimuli, particularly if a person is genetically predisposed to an immune-mediated inflammatory disorder such as inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Approximately, half of all CD patients have elevated antibodies to CBir1, a microbiota flagellin common to mice and humans, demonstrating flagellins as immunodominant antigens in the intestines. This review focuses on the use of flagellins as probes to study microbiota-specific responses in the context of health and disease as well as probes of innate and adaptive responses employed by the host to deal with the overwhelming bacterial presence of the microbiota.
    Immunological Reviews 07/2014; 260(1):206-20. · 12.16 Impact Factor
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    ABSTRACT: Assess the impact of preoperative serum antitumor necrosis factor-α (anti-TNFα) drug levels on 30-day postoperative morbidity in inflammatory bowel disease (IBD) patients.
    Annals of surgery. 06/2014;
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    ABSTRACT: NK cells are innate immune cells known for their cytolytic activities toward tumors and infections. They are capable of expressing diverse killer Ig-like receptors (KIRs), and KIRs are implicated in susceptibility to Crohn's disease (CD), a chronic intestinal inflammatory disease. However, the cellular mechanism of this genetic contribution is unknown. In this study, we show that the "licensing" of NK cells, determined by the presence of KIR2DL3 and homozygous HLA-C1 in host genome, results in their cytokine reprogramming, which permits them to promote CD4(+) T cell activation and Th17 differentiation ex vivo. Microfluidic analysis of thousands of NK single cells and bulk secretions established that licensed NK cells are more polarized to proinflammatory cytokine production than unlicensed NK cells, including production of IFN-γ, TNF-α, CCL-5, and MIP-1β. Cytokines produced by licensed NK augmented CD4(+) T cell proliferation and IL-17A/IL-22 production. Ab blocking indicated a primary role for IFN-γ, TNF-α, and IL-6 in the augmented T cell-proliferative response. In conclusion, NK licensing mediated by KIR2DL2/3 and HLA-C1 elicits a novel NK cytokine program that activates and induces proinflammatory CD4(+) T cells, thereby providing a potential biologic mechanism for KIR-associated susceptibility to CD and other chronic inflammatory diseases.
    Journal of immunology (Baltimore, Md. : 1950). 06/2014;
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    ABSTRACT: Patients with inflammatory bowel disease (IBD), namely ulcerative colitis (UC) and Crohn's disease (CD), have worse outcomes with Clostridium difficile infection (CDI) including increased readmissions, colectomy and death. Oral vancomycin is recommended for the treatment of severe CDI while metronidazole is standard of care for non-severe infection. We aimed to assess treatment outcomes of CDI in IBD.
    Antimicrobial Agents and Chemotherapy 06/2014; · 4.57 Impact Factor
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    ABSTRACT: Intestinal fibrostenosis is among the hallmarks of severe Crohn's disease. Patients with certain TNFSF15 (gene name for TL1A) variants over-express TL1A and have a higher risk of developing strictures in the small intestine. In addition, sustained Tl1a expression in mice leads to small and large intestinal fibrostenosis under colitogenic conditions. The aim of this study was to determine whether established murine colonic fibrosis could be reversed with Tl1a antibody (Ab). Treatment with neutralizing Tl1a Ab reversed colonic fibrosis back to the original pre-inflamed levels, potentially as a result of lowered expression of connective tissue growth factor, Il31Ra, transforming growth factor β1 and insulin-like growth factor-1. In addition, blocking Tl1a function by either neutralizing Tl1a Ab or deletion of death domain receptor 3 (Dr3) reduced the number of fibroblasts and myofibroblasts, the primary cell types that mediate tissue fibrosis. Primary intestinal myofibroblasts expressed Dr3 and functionally responded to direct Tl1a signaling by increasing collagen and Il31Ra expression. These data demonstrated a direct role for TL1A-DR3 signaling in tissue fibrosis and that modulation of TL1A-DR3 signaling could inhibit gut fibrosis.Mucosal Immunology advance online publication, 21 May 2014; doi:10.1038/mi.2014.37.
    Mucosal Immunology 05/2014; · 7.54 Impact Factor
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    ABSTRACT: Pyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis. We performed a case-control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG-) and EN (EN-). Data on clinical features were obtained by chart review. IBD-related serology was determined using enzyme-linked immunosorbent assay and genome-wide data generated using Illumina technology. Standard statistical tests for association were used. We identified a total of 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN cases were available for serological analyses. Fewer male subjects were identified in the PG(+) (odds ratio 0.6, P = 0.009) and EN(+) groups (odds ratio 0.31, P = 0 < 0.0001). Colonic disease, previous IBD-related surgery, and noncutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared with controls. PG(+) was associated with anti-nuclear cytoplasmic antibody seropositivity (P = 0.03) and higher anti-nuclear cytoplasmic antibody level (P = 0.02) in Crohn's disease. Genetic associations with PG included known IBD loci (IL8RA [P = 0.00003] and PRDM1 [0.03]) as well as with USP15 (4.8 × 10) and TIMP3 (5.6 ×10). Genetic associations with EN included known IBD susceptibility genes (PTGER4 [P = 8.8 × 10], ITGAL [0.03]) as well as SOCS5 (9.64 × 10), CD207 (3.14 × 10), ITGB3 (7.56 × 10), and rs6828740 (4q26) (P < 5.0 × 10). Multivariable models using clinical, serologic, and genetic parameters predicted PG (area under the curve = 0.8) and EN (area under the curve = 0.97). Cutaneous manifestations in IBD are associated with distinctive genetic characteristics and with the similar clinical characteristics, including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies.
    Inflammatory Bowel Diseases 01/2014; · 5.12 Impact Factor
  • Michelle Vu, Gil Y Melmed, Stephan R Targan
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 11/2013; · 5.64 Impact Factor
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    ABSTRACT: Genetic susceptibility loci for Crohn's disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and the presence of granuloma. Moreover, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.
    Gastroenterology 09/2013; · 12.82 Impact Factor
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    ABSTRACT: BACKGROUND:: The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables. METHODS:: Genotyping was performed on 1,115 subjects using Illumina-based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genome-wide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. RESULTS:: Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. CONCLUSIONS:: Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.
    Inflammatory Bowel Diseases 05/2013; · 5.12 Impact Factor
  • Rivkah Gonsky, Richard L Deem, Stephan R Targan
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    ABSTRACT: TL1A/TNFSF15 has been associated with IBD (inflammatory bowel disease) in GWAS (genome-wide association study) and plays a role mediating mucosal inflammation in IBD. Higher TL1A expression is associated with disease severity in both patients and mouse models. Although TL1A has been studied extensively for IBD-associated SNPs, the cis/trans-regulatory regions are poorly defined. Herein we identify response elements regulating TNFSF15 in primary human myeloid cells. Peripheral mononuclear cells transfected with TNFSF15 promoter constructs displayed 30-fold enhanced promoter activity in a minimal -74bp region. Transactivation was mediated partly by AP-1, since mutation of the AP-1 site resulting in loss of promoter activity. Monocytes transfected with c-Jun siRNA or treated with TAT-TI-JIP (JNK Inhibitor VII TAT-TI-JIP) demonstrated reduced TL1A mRNA and protein levels. Surprisingly, constructs larger than -74bp did not increase promoter expression (expression of -1275bp construct was 25% of -74bp activity), suggesting the presence of both activating and repressing TL1A promoter elements. In fact, mutation of the -210bp NFκB site enhanced promoter activity (60-fold) suggesting a repressive role for this site. DNA-protein binding to the TL1A AP-1 and NFκB elements was inhibited by excess consensus or TL1A oligonucleotides and binding and confirmed by chromatin immuno-precipitation analysis. Yet, despite the fact that the -210bp NFκB site acts as a suppressor element, overall mRNA and protein expression were inhibited in monocytes treated with MG132 (NFκB/proteasome inhibitor) or SN50 (NFκB-p50 blocking peptide), suggesting that NFκB acts as both an activator and silencer of TL1A expression. These data suggest that modulation of TL1A expression involves a complex interplay between positive and negative signals, binding to distinct regulatory regions.
    Cytokine 04/2013; · 2.52 Impact Factor
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    ABSTRACT: Clostridium difficile infection (CDI) is a common and debilitating nosocomial infection with high morbidity and mortality. C. difficile mediates diarrhea and colitis by releasing two toxins, toxin A and toxin B. Since both toxins stimulate proinflammatory signaling pathways in human colonocytes and both are involved in the pathophysiology of CDI, neutralization of toxin A and B activities may represent an important therapeutic approach against CDI infection. Recent studies indicate that human monoclonal antibodies (mAbs) against toxin A and B reduced their cytotoxic and secretory activities, and prevented CDI in hamsters. Moreover, anti-toxin A and anti-toxin B mAbs together with antibiotics also effectively reduced recurrent CDI in humans. However, whether these mAbs neutralize toxin A- and toxin B-associated immune responses in human colonic mucosa or human peripheral blood monocytes (PBMCs) has never been examined. We used fresh human colonic biopsies and peripheral blood monocytes to evaluate the effects of these antibodies against toxin A- and B-associated cytokine release, proinflammatory signaling and histologic damage. Incubation of anti-toxin A (MK3415) or anti-toxin B (MK6072) mAbs with human PBMCs significantly inhibited toxin A- and toxin B-mediated TNFα and IL-1β expression. MK3415 and MK6072 also diminished toxin A- and toxin B- mediated NF-κB p65 phosphorylation in human monocytes, respectively and significantly reduced toxin A- and B- induced TNFα and IL-1β expression as well as histological damage in human colonic explants. Our results underline the effectiveness of MK3415 and MK6072 in blocking C. difficile toxin A- and toxin B-mediated inflammatory responses and histological damage.
    Antimicrobial Agents and Chemotherapy 04/2013; · 4.57 Impact Factor
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    ABSTRACT: TL1A is a member of the TNF superfamily, and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, patients with certain TNFSF15 variants over-express TL1A and have a higher risk of developing strictures in the small intestine. Consistently, mice with sustained Tl1a expression in either lymphoid or myeloid cells develop spontaneous ileitis and increased intestinal collagen deposition. Transgenic (Tg) mice with constitutive Tl1a expression in both lymphoid and myeloid cells were generated to assess their in vivo consequence. Constitutive expression of Tl1a in both lymphoid and myeloid cells showed increased spontaneous ileitis and collagen deposition than WT mice. T cells with constitutive expression of Tl1a in both lymphoid and myeloid cells were found to have a more activated phenotype, increased gut homing marker CCR9 expression, and enhanced Th1 and Th17 cytokine activity than WT mice. Although no differences in T cell activation marker, Th1 or Th17 cytokine activity, ileitis, or collagen deposition were found between constitutive Tl1a expression in lymphoid only, myeloid only, or combined lymphoid and myeloid cells. Double hemizygous Tl1a-Tg mice appeared to have worsened ileitis and intestinal fibrosis. Our findings confirm that TL1A-DR3 interaction is involved in T cell-dependent ileitis and fibrosis.
    European journal of microbiology & immunology. 03/2013; 3(1):11-20.
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    ABSTRACT: : Extracts of the plant Andrographis paniculata have been used to treat inflammatory diseases in Asian countries. A recent double-blind, placebo-controlled trial of HMPL-004 (A. paniculata extract) has demonstrated its safety and effectiveness for induction of clinical response, remission, and mucosal healing in patients with mild to moderate ulcerative colitis (UC). We aimed to determine if HMPL-004 could prevent the development of T-cell-dependent murine colitis and to define its in vivo mechanism(s) of action. : CD4CD45RB T cells were transferred into Rag1 mice and gavaged daily with HMPL-004 or methyl cellulose (MC). Severity of colitis was evaluated by weight loss, histology, and cytokine expression. : Mice treated with MC developed colitis within 4-7 weeks, as evaluated by weight loss, and severe intestinal inflammation. HMPL-004-treated mice did not lose weight and displayed only very mild intestinal inflammation. Tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, interferon-gamma (IFN-γ), and IL-22 expression were significantly decreased in HMPL-004-treated mice. We observed higher percentages of naïve CD4 T cells in the lamina propria of HMPL-004-treated mice. At early timepoints HMPL-004-treated mice have significantly reduced splenic cell counts, reduced CD4, and IL-17, and IFN-γ T cells. Furthermore, HMPL-004 inhibited the proliferation of CD4 T cells and differentiation into TH1/TH17 cells in vitro. : HMPL-004 inhibits the development of chronic colitis by affecting early T-cell proliferation, differentiation, and TH1/TH17 responses in a T-cell-driven model of colitis, presenting a unique mechanism of action. Our data suggest that HMPL-004 could be an attractive herbal therapeutic for inflammatory bowel disease.
    Inflammatory Bowel Diseases 01/2013; 19(1):151-64. · 5.12 Impact Factor
  • Michelle Vu, Gil Y. Melmed, Stephan R. Targan
    Clinical Gastroenterology and Hepatology. 01/2013;
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    ABSTRACT: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) share genetic and clinical features. IBD is associated with the presence of antibodies to a variety of commensal microorganisms including anti-Saccharomyces cerevesiae antibodies (ASCA), antineutrophil cytoplasmic antibodies (ANCA), anti-I2 (associated with anti-Pseudomonas activity), anti-Eschericia coli outer membrane porin C (anti-OmpC) and anti-flagellin antibodies (anti-CBir1). Subclinical intestinal inflammation may be present in up to 65% of patients with AS. This study evaluated the presence of antimicrobial antibodies in patients with AS alone, patients with AS and concomitant IBD (AS-IBD) and a control group of patients with mechanical back pain (MBP). Sera were tested by ELISA for ASCA IgG and IgA, anti-OmpC, anti-CBir1 and ANCA in 76 patients with AS alone, 77 patients with AS-IBD and 48 patients with MBP. Antibody positivity rates, median quantitative antibody levels and the proportion of patients with antibody levels in the 4th quartile of a normal distribution were compared between the three groups of patients. Patients with AS alone demonstrated higher anti-CBir1 antibody positivity rates and median antibody levels than MBP patients. Anti-CBir1 positivity in AS was associated with elevation of acute phase reactants. AS-IBD patients demonstrated elevated responses when compared to AS alone for ASCA, anti-OmpC and anti-CBir1. Quartile analysis confirmed the findings. These data suggest that adaptive immune responses to microbial antigens occur in AS patients without clinical IBD and support the theory of mucosal dysregulation as a mechanism underlying the pathophysiology of AS.
    Arthritis research & therapy 01/2013; 15(5):R166. · 4.27 Impact Factor
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    ABSTRACT: BACKGROUND: Current instruments used to measure disease activity and health-related quality of life in patients with Crohn's disease (CD) and ulcerative colitis (UC) are often cumbersome, time-consuming, and expensive; although used in clinical trials, they are not convenient for clinical practice. A numeric rating scale (NRS) is a quick, inexpensive, and convenient patient-reported outcome that can capture the patient's overall perception of health. AIMS: The aim of this study was to assess the validity, reliability, and responsiveness of an NRS and evaluate its use in clinical practice in patients with CD and UC. METHODS: We prospectively evaluated patient-reported NRS scores and measured correlations between NRS and a range of severity measures, including physician-reported NRS, Crohn's disease activity index (CDAI), Harvey-Bradshaw index (HBI), inflammatory bowel disease questionnaire (IBDQ), and C-reactive protein (CRP) in patients with CD. Subsequently, we evaluated the correlation between the NRS and standard measures of health status (HBI or simple colitis clinical activity index [SCCAI]) and laboratory tests (sedimentation rate [ESR], CRP, and fecal calprotectin) in patients with CD and UC. RESULTS: The patient-reported NRS showed excellent correlation with CDAI (R (2) = 0.59, p < 0.0001), IBDQ (R (2) = 0.66, p < 0.0001), and HBI (R (2) = 0.32, p < 0.0001) in patients with CD. The NRS showed poor, but statistically significant correlation with SCCAI (R (2) = 0.25, p < 0.0001) in patients with UC. The NRS did not correlate with CRP, ESR, or calprotectin. The NRS was reliable and responsive to change. CONCLUSIONS: The NRS is a valid, reliable, and responsive measure that may be useful to evaluate patients with CD and possibly UC.
    Digestive Diseases and Sciences 12/2012; · 2.26 Impact Factor
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    ABSTRACT: INTRODUCTION: Inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) are similar chronic inflammatory diseases whose definitive etiology is unknown. Following recent clinical and genetic evidence supporting an intertwined pathogenic relationship, we conducted a pilot study to measure fecal Calprotectin (fCAL) and IBD related serologies in AS patients. METHODS: Consecutive AS patients were recruited from a long term prospectively collected longitudinal AS cohort at Cedars-Sinai Medical Center (CSMC). Controls were recruited from CSMC employees or spouses of patients with AS. Sera were tested by enzyme-linked immunosorbent assay (ELISA) for IBD-associated serologies (antineutrophil cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA) IgG and IgA, Anti-I2, Anti-OmpC, and Anti-CBir1). The Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), and Bath ankylosing spondylitis radiology index (BASRI) were completed for AS patients. RESULTS: A total of 81 subjects (39 AS and 42 controls) were included for analysis. Average age of AS patients was 47 years and average disease duration was 22 years. AS patients were predominantly male; 76% were HLA-B27 positive. Median fCAL levels were 42micrograms/g and 17micrograms/g in the AS group and controls, respectively (p < 0.001). When using the manufacturer's recommended cut off for positivity of 50micrograms/g, stool samples of 41% of AS patients and 10% of controls were positive for fCAL (p = 0.0016). With the exception of ANCA, there were no significant differences in antibody levels between patients and controls. Median ANCA EU was 6.9 in AS patients and 4.3 in the controls. Among AS patients stratified by fCAL level, there were statistically significant differences between patients and controls for multiple IBD associated antibodies. CONCLUSIONS: Calprotectin levels were elevated in 41% of patients with AS with a cut off for positivity of 50micrograms/g. fCAL positive AS patients displayed higher medians of most IBD specific antibodies when compared to healthy controls or fCAL negative AS patients. Further studies are needed to determine if fCAL can be used to identify and characterize a subgroup of AS patients whose disease might be driven by subclinical bowel inflammation.
    Arthritis research & therapy 11/2012; 14(6):R261. · 4.27 Impact Factor
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    ABSTRACT: The transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) plays important roles in embryonic development and immunity. Blimp-1 is required for the differentiation of plasma cells, and mice with T cell-specific deletion of Blimp-1 (Blimp-1CKO mice) develop a fatal inflammatory response in the colon. Previous work demonstrated that lack of Blimp-1 in CD4(+) and CD8(+) T cells leads to intrinsic functional defects, but little is known about the functional role of Blimp-1 in regulating differentiation of Th cells in vivo and their contribution to the chronic intestinal inflammation observed in the Blimp1CKO mice. In this study, we show that Blimp-1 is required to restrain the production of the inflammatory cytokine IL-17 by Th cells in vivo. Blimp-1CKO mice have greater numbers of IL-17-producing TCRβ(+)CD4(+)cells in lymphoid organs and in the intestinal mucosa. The increase in IL-17-producing cells was not restored to normal levels in wild-type and Blimp-1CKO-mixed bone marrow chimeric mice, suggesting an intrinsic role for Blimp-1 in constraining the production of IL-17 in vivo. The observation that Blimp-1-deficient CD4(+) T cells are more prone to differentiate into IL-17(+)/IFN-γ(+) cells and cause severe colitis when transferred to Rag1-deficient mice provides further evidence that Blimp-1 represses IL-17 production. Analysis of Blimp-1 expression at the single cell level during Th differentiation reveals that Blimp-1 expression is induced in Th1 and Th2 but repressed by TGF-β in Th17 cells. Collectively, the results described here establish a new role for Blimp-1 in regulating IL-17 production in vivo.
    The Journal of Immunology 11/2012; · 5.52 Impact Factor

Publication Stats

24k Citations
3,957.49 Total Impact Points


  • 1989–2014
    • Cedars-Sinai Medical Center
      • • Cedars Sinai Medical Center
      • • Department of Medicine
      Los Angeles, California, United States
  • 2013
    • Hebei Medical University
      Chentow, Hebei, China
  • 1987–2013
    • University of California, Los Angeles
      • • Division of Digestive Diseases
      • • Department of Medicine
      • • Department of Pathology and Laboratory Medicine
      • • Center for Culture and Health
      Los Angeles, CA, United States
  • 2011
    • University of Manitoba
      Winnipeg, Manitoba, Canada
    • Keck School of Medicine USC
      Los Angeles, California, United States
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States
  • 1995–2010
    • Children's Hospital Los Angeles
      • Division of Medical Genetics
      Los Angeles, California, United States
    • Mayo Clinic - Rochester
      • Department of Gastroenterology and Hepatology
      Rochester, Minnesota, United States
  • 2009
    • Charité Universitätsmedizin Berlin
      Berlín, Berlin, Germany
  • 2008
    • VA Greater Los Angeles Healthcare System
      Los Angeles, California, United States
  • 1984–2008
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 2007
    • University of California, Davis
      Davis, California, United States
  • 2003–2006
    • University of Alabama at Birmingham
      • Division of Gastroenterology & Hepatology
      Birmingham, AL, United States
  • 2002
    • Mayo Foundation for Medical Education and Research
      • Division of Gastroenterology and Hepatology
      Scottsdale, AZ, United States
    • Arizona State University
      Phoenix, Arizona, United States
  • 1998–2001
    • Université de Montréal
      • Department of Pediatrics
      Montréal, Quebec, Canada
  • 2000
    • Children's Hospital Oakland Research Institute
      Oakland, California, United States
  • 1999
    • Universitair Ziekenhuis Leuven
      • Department of Gastroenterology
      Leuven, VLG, Belgium
  • 1994
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 1986
    • Barnes Jewish Hospital
      San Luis, Missouri, United States