Granulocyte-macrophage colony stimulating factor blockade promotes ccr9+ lymphocyte expansion in Nod2 deficient mice

Samson, Charles M.; Jurickova, Ingrid; Molden, Erin K.; Schreiner, William J.; Colliver, Joshua; Bonkowski, Erin; Han, Xiaonan; Trapnell, Bruce C.; Denson, Lee A.

doi:10.1002/ibd.21672

Cited by 13 publications

(11 citation statements)

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“…Analysis of the CCL25/GM-CSF ratio indicates that H. pylori positive and negative gastroduodenitis are unrelated clinical entities. Our data support the observation made by Samson et al suggesting a role for GM-CSF and CCL25 in the pathogenesis of inflammatory gastrointestinal disease (Samson et al, 2011). These authors demonstrated that CD patients with high serum level of GM-CSF neutralizing antibodies had increased number of iliac epithelial cells expressing CCL25.…”

Section: Discussionsupporting

confidence: 93%

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Serum Cytokine Signature That Discriminates Helicobacter pylori Positive and Negative Juvenile Gastroduodenitis

et al. 2016

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Gastroduodenitis caused by H. pylori, often acquired in early childhood, is found in about 50% of the adult population. Although H. pylori infections can remain asymptomatic, its virulence factors usually trigger epithelial vacuolization and degeneration, loss of microvilli, disintegration of cytoplasm, and leukocyte accumulation. It is believed that leukocyte infiltration is driven by cytokines produced locally in infected tissue. However, so far little is known about changes in serum cytokines in juvenile patients infected with H. pylori. Serum cytokine profiles were analyzed in 62 juvenile patients diagnosed with gastroduodenitis using the Bio-Plex multiplex assay. H. pylori infection was confirmed in 32 patients, while 30 patients were H. pylori-free. Cytokines CXCL5 and CXCL6, potent neutrophil chemoattractants, were upregulated in all patients diagnosed with gastroduodenitis. Serum levels of IL8, a prototype neutrophil attractant, remained unchanged in subjects with gastroduodenitis relative to controls. Therefore, our data suggest that CXCL5 and CXCL6 play a role in directing neutrophil trafficking into inflamed gastroduodenal tissue. In addition, the CCL25/GM-CSF ratio differed significantly between H. pylori-positive and -negative juveniles. Further, study is needed to evaluate the role of CCL25 and GM-CSF in the pathogenesis of the different etiologies of gastroduodenitis.

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Section: Discussionsupporting

confidence: 93%

“…In Crohn's disease altered expression of GM-CSF and CCL25 has been suggested to play a role in the pathogenesis of inflammatory gastrointestinal disease (Samson et al, 2011). Therefore, we sought to determine whether these two cytokines were involved in the pathogenesis of H. pylori -related gastroduodenitis.…”

Section: Resultsmentioning

confidence: 99%

Serum Cytokine Signature That Discriminates Helicobacter pylori Positive and Negative Juvenile Gastroduodenitis

et al. 2016

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“…7 Our studies in animal models have shown that GM-CSF promotes intestinal barrier function and effective responses to mucosal injury, suggesting a direct role for genetic or acquired variation in GM-CSF bioactivity in more aggressive CD disease behavior. 4,8 However, a role for neutrophil-intrinsic variation in GM-CSF signaling in cell function and disease complications in pediatric CD has not previously been explored.…”

Section: Introductionmentioning

confidence: 99%

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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“…We discovered that GM-CSF Ab are present in a subset of CD patients, and that titers increase with increasing age of onset, from VEO to EO pediatric disease, and further with adult-onset disease 21 . Overall, approximately fifty percent of CD patients exhibit high levels of GM-CSF Ab which are associated with reduced neutrophil phagocytic capacity, increased intestinal permeability and reactivity to the enteric flora, and expansion of effector T cells expressing the gut homing receptor CCR9 21-23 . This is of potential therapeutic interest, as an oral small molecule inhibitor of CCR9 is entering phase 3 clinical trials for CD, and we have found that CD patients with elevated GM-CSF Ab who are treated with current therapies progress more rapidly to stricturing behavior requiring surgery 24 .…”

Section: A More Common Cause For Reduced Innate Function In Pediatricmentioning

confidence: 99%

The Role of the Innate and Adaptive Immune System in Pediatric Inflammatory Bowel Disease

Denson

2013

Inflammatory Bowel Diseases

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Recent translational studies have provided new insights into the pathogenesis of pediatric-onset Inflammatory Bowel Disease (IBD). Registry studies have identified distinct clinical phenotypes with increasing age of onset; this has led to a revision of the clinical phenotyping system, now termed the Paris classification system. It is recognized that there are infantile (age <1 years), very early onset (VEO, age 1-10), and early onset (EO, age 10-17) forms of disease. Rare genetic mutations affecting anti-microbial and anti-inflammatory pathways have been discovered in infantile and VEO forms, while genetic pathways identified in EO disease have been similar to adult-onset IBD. An increasing incidence in the infantile and VEO forms has suggested an important environmental influence. This is likely ultimately expressed via alterations in the enteric flora (dysbiosis) and dysregulated immune responses to the flora which are recognized as a critical trigger for mucosal inflammation. These data should ultimately guide new pathogenic models of disease which will inform both therapy in individual patients, and disease prevention in their at-risk family members.

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Granulocyte-macrophage colony stimulating factor blockade promotes ccr9+ lymphocyte expansion in Nod2 deficient mice

Cited by 13 publications

References 59 publications

Serum Cytokine Signature That Discriminates Helicobacter pylori Positive and Negative Juvenile Gastroduodenitis

Serum Cytokine Signature That Discriminates Helicobacter pylori Positive and Negative Juvenile Gastroduodenitis

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

The Role of the Innate and Adaptive Immune System in Pediatric Inflammatory Bowel Disease

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