S1173 Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in Crohn's Disease

Gathungu, Grace; Ferguson, John; Silverberg, Mark S.; Trapnell, Bruce C.; Denson, Lee A.; Cho, Judy H.; Radford‐Smith, Graham

doi:10.1016/s0016-5085(10)60889-x

Cited by 11 publications

(19 citation statements)

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“…Concentrations of anti-GM-CSF Ab obtained in this study were greater than observed in previous studies concentrations [14,16,[18][19][20]22] which could be related to a lack of specificity of the technique used or better sensitivity. Our study has several limitations as the cohort of IBD patients comes from a tertiary referral single-center leading to a selection bias; the relative small sample size of the population, that may have limited the identification of some associations with disease behavior; the criterion defining a severe disease course are composite, including heterogeneous parameters, and may be the subject of discussion; the determination of anti-GM-CSF Abs is based on a unique serum sample and hypothesized that these antibodies remain stable over the time.…”

Section: Discussioncontrasting

confidence: 84%

“…Thus, higher concentrations were found in ileocolonic CD and damages extended to the left colon in UC [18]. In another study of Gathungu et al an association was found between high levels of anti-GM-CSF Ab and stricturing and penetrating behaviors of CD [19]. In contrast to these studies, no significant difference was observed depending on the location, the disease behavior of CD, or depending on the extent of the disease in UC in our study.…”

Section: Discussioncontrasting

confidence: 83%

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Clinical Utility of Anti- Granulocyte Macrophage-Colony Stimulating Factor Antibodies in Inflammatory Bowel Disease

Paul¹

2017

JGPLD

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Section: Discussioncontrasting

confidence: 84%

Section: Discussioncontrasting

confidence: 83%

Clinical Utility of Anti- Granulocyte Macrophage-Colony Stimulating Factor Antibodies in Inflammatory Bowel Disease

Paul¹

2017

JGPLD

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“…5 This reduction in GM-CSF bioactivity was in turn associated with higher rates of stricturing complications. 3,4 We therefore asked whether disease location or complications would vary within CD patients stratified by both circulating GMAb and the neutrophil-intrinsic GMSI. We identified a progressive decrease in the frequency of colon-only disease location and an increase in the frequency of jejunal and proximal ileal location and perianal involvement in patients with both elevated GMAb and reduced GMSI.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 We therefore next asked whether these would also vary with the neutrophil GMSI as a measure of cell-intrinsic GM-CSF responsiveness. As shown in Table 3, age of onset, sex, race, and disease location did not vary within the CD or UC groups with the neutrophil GMSI.…”

Section: Clinical and Demographic Characteristics Of Ibd Patients Witmentioning

confidence: 99%

“…1,2 We discovered that pediatric and adult CD patients exhibit an acquired basis for neutrophil dysfunction, GM-CSF auto-antibodies (GMAb), which increase in titer with older age and suppress GM-CSF:STAT5 signaling in a cell-extrinsic manner. 3,4 GMAb carriage is associated with reduced neutrophil STAT5 activation, phagocytic capacity, and bacterial killing, and with high rates of antimicrobial serologies (AMS) and stricturing behavior. 5,6 Crohn's disease patients were found to exhibit increased levels of GMAb in the months preceding clinical relapses, suggesting a role in initiation of mucosal inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease

Denson

Jurickova

Karns

et al. 2018

Inflammatory Bowel Diseases

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Background: Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. Methods:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. Results:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). Conflicts of interest:The authors have no financial arrangements with any company whose product figures prominently in the submitted manuscript or with a company making a competing product. Dr. Denson has received grant support from Janssen and holds a patent for the use of GM-CSF auto-antibodies as a diagnostic doi: 10.1093/ibd/izy265 Published online 13 August 2018 test in inflammatory bowel disease. Dr. Dubinsky has served as a consultant for Abbvie, Takeda, Janssen, and Pfizer and has received research support from Abbvie, Janssen, and Prometheus. Dr. Guthery has received research support in the last year from Regeneron Pharmaceuticals. Dr. Leleiko or his immediate family have equity interests in Celgene, Vericel, Ionis, Vertex, and Alnylam, and he has served as a consultant for CRICO. The remaining authors have nothing to declare. 2Denson et al from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001).Conclusions: Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.

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Molecular Analysis of Inflammatory Bowel Disease: Clinically Useful Tools for Diagnosis, Response Prediction, and Monitoring of Targeted Therapy

Jiang

2015

Mol Diagn Ther

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Biomarkers of inflammatory bowel disease (IBD) are non-invasive or minimally invasive tests for IBD diagnosis and/or prognosis as well as assessment of disease activity and response to therapy. Here, we update the current status of IBD biomarkers, including serological, fecal, and genetic (DNA and microRNA [miRNA]) biomarkers. As an update, the classical serological biomarkers, including ASCA, pANCA, anti-OmpC, anti-Cbir, anti-I2, and other anti-glycan antibodies, are discussed only briefly. Emphasis in this article is given to those that have been recently identified or extensively characterized, as well as to the clinical utilities of biomarkers, with special attention to prediction of disease complication and activity assessment, mucosal healing, and response to therapies. In particular, we discuss the utilities of blood-based biomarkers predicting therapeutic response to anti-tumor necrosis factor (TNF)-α, such as anti-anti-TNFα antibodies or anti-drug antibodies (ADA) and trough level of anti-TNFα. Fecal biomarkers, which have recently attracted substantial attention, are also discussed extensively, including the well-characterized calprotectin and lactoferrin, as well as the recently characterized M2-PK, CHI3L1, neopterin, MMP-9, and HMGB1. Genome and exome sequencing enables the discovery of a number of rare yet disease-defining IBD-susceptible genes, particularly those involved in very early onset IBD, providing rare yet extremely useful biomarkers at genetic levels for IBD diagnosis/prognosis. Finally, we briefly summarize the discovery, characterization, and potential implications of miRNA as potential IBD biomarkers.

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S1173 Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in Crohn's Disease

Cited by 11 publications

References 0 publications

Clinical Utility of Anti- Granulocyte Macrophage-Colony Stimulating Factor Antibodies in Inflammatory Bowel Disease

Clinical Utility of Anti- Granulocyte Macrophage-Colony Stimulating Factor Antibodies in Inflammatory Bowel Disease

Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease

Molecular Analysis of Inflammatory Bowel Disease: Clinically Useful Tools for Diagnosis, Response Prediction, and Monitoring of Targeted Therapy

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