Granulocyte–Macrophage Colony-Stimulating Factor Autoantibodies

Abstract

Background & Aims Neutralizing auto-antibodies (Ab) against granulocyte-macrophage colony-stimulating factor (GM-CSF Ab) have been associated with stricturing ileal Crohn’s disease (CD) in a largely pediatric patient cohort (total 394, adult CD 57). The aim of this study was to examine this association in two independent predominantly adult inflammatory bowel disease patient cohorts. Methods Serum samples from 745 subjects from the NIDDK IBD Genetics Consortium and 737 patients from Australia were analyzed for GM-CSF Ab and genetic markers. We conducted multiple regression analysis with backwards elimination to assess the contribution of GM-CSF Ab levels, established CD risk alleles and smoking on ileal disease location in the 477 combined CD subjects from both cohorts. We also determined associations of GM-CSF Ab levels with complications requiring surgical intervention in combined CD subjects in both cohorts. Results Serum samples from CD patients expressed significantly higher concentrations of GM-CSF Ab when compared to Ulcerative Colitis or controls in each cohort. Non-smokers with ileal CD expressed significantly higher GM-CSF Ab concentrations in the Australian cohort (p= 0.002). Elevated GM-CSF Ab, ileal disease location and disease duration greater than 3 years were independently associated with stricturing/penetrating behavior and intestinal resection for CD. Conclusions The expression of high GM-CSF Ab is a risk marker for aggressive CD behavior and complications including surgery. Modifying factors include environmental exposure to smoking and genetic risk markers.

Serum Cytokine Profiles in Children with Crohn’s Disease

“…A similar observation was published by Gathungu et al, where CD patients with elevated anti-GM-CSF antibody exhibited increased bowel permeability as compared to those with lower levels of this antibody [62]. It has been suggested that GM-CSF neutralization promotes ileac disease by modulating expression of CCL25 by intestinal epithelium and CCR9 by T lymphocytes via Nod2-dependent and -independent pathways [62]. Therefore, increased GM-CSF levels in adult CD may contribute to inhibition of bowel inflammation and prevention of tissue damage.…”

“…Further, these authors demonstrated that elevated anti-GM-CSF antibody levels were associated with intestinal stricture, penetration, and resection in CD patients. A similar observation was published by Gathungu et al, where CD patients with elevated anti-GM-CSF antibody exhibited increased bowel permeability as compared to those with lower levels of this antibody [62]. It has been suggested that GM-CSF neutralization promotes ileac disease by modulating expression of CCL25 by intestinal epithelium and CCR9 by T lymphocytes via Nod2-dependent and -independent pathways [62].…”

“…These authors suggested that GM-CSF-activated macrophages facilitate differentiation of Th2 lymphocytes by upregulating production of IL-4, IL-10, and IL-13 in lamina propria resident leukocytes, which may decrease local inflammation, improve bacterial clearance, and promote healing. In another study, Gathungu et al have shown that the presence of anti-GM-CSF antibody can serve as marker for the severity of CD [62]. Further, these authors demonstrated that elevated anti-GM-CSF antibody levels were associated with intestinal stricture, penetration, and resection in CD patients.…”

Predicting Outcomes to Optimize Disease Management in Inflammatory Bowel Diseases

“…Disease located in the small bowel [ileal/ileocolonic disease] has been consistently identified as an independent risk factor for surgery in adult populations, 21,38,45,46,47,48 possibly because small bowel disease is more frequently associated with penetrating and stenosing behaviour. 22 Disease located in the jejunum and upper GI tract [L4] is also indicative of higher surgical risk for similar reasons, 11,12,13,14,15,49 while colonic disease [L2] is protective against major surgery. 22,42,49,50,51 …”

Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis

“…GM-CSF receptor is a heterodimer composed of α and β subunits20. A reduction of macrophages in synovial tissue has been correlated with improvement in the disease activity score, thus antagonizing GM-CSF was found to markedly reduce established disease in mouse models of RA2122. In order to protect the synovial tissue from inflammatory cell infiltration, a synergistic effect will be expected with the combined treatment of paroxetine and GM-CSF inhibitor for RA patients.…”