The role of genetics, proteinases, and interleukins in Anti-Tumor Necrosis Factor alpha unresponsiveness in Crohn’s Disease
Introduction: Crohn’s Disease is a chronic inflammatory bowel condition that involves any part of the gastrointestinal tract.1, 2 Tumor necrosis factor alpha (TNF-alpha) plays a role in Crohn’s as it is a cytokine tasked for regulation of immune cells but may cause increased inflammation in high concentrations.2 Current treatments focus on reverse signaling to reduce TNF-alpha release or by blocking TNF-alpha binding with receptors. Loss of response to anti-TNF results in 1/4 to 1/3 of patients having no improvements with therapy to Crohn’s.3 Additional research is needed in determining methods in targeting genes, proteinases, and interleukins to improve outcomes in unresponsiveness of Crohn’s patients to anti-TNF-alpha.4 Methods: Mouse models were used to observe various presentations of Crohn’s due to TNF-alpha overexpression.5 To study the genetic component of Crohn’s, whole-genome transcriptional analysis compared the subjects using or not using anti-TNF treatments.6 RNA isolation, microarrays, and RT-PCR was then used to analyze these samples. To observe proteinase cleavage of anti-TNF agents, colon biopsy was performed and examined through histology or phosphate-buffered saline and sonication.7 Interleukin and cytokine expressions were examined with ELISA and intracellular staining.8 Results: Mouse models showed that gut manifestations of Crohn’s stem from TNF-alpha derived from intestinal epithelium and increased cytokines.5 Increased expression of IL-2 was significant in Crohn’s compared to non-Crohn’s subjects while IL-17 was unchanged. IL-2 stimulates the Th1 pathway of interferon-gamma, Treg cells, B-cell, and natural killer cells that facilitate Crohn’s inflammation. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene activates cytokines and leads to inflammation. Studies also show that certain genes were differently regulated when comparing anti-TNF responsive and unresponsive patients.6 Deregulation of genes responsible for the inflammatory mediators have been studied in Crohn’s unresponsiveness to anti-TNF therapy. Matrix metalloproteinases (MMP 3 and 12) are able to degrade anti-TNF agents. These MMPs cleave the IgG Fc component of the Etanercept (TNF-inhibitor) within the study.7 Conclusion: Unresponsiveness to anti-TNF agents stem from a variety of factors ranging from genetics to the activated proteinases and interleukins. The genetic polymorphisms may result in overproductions of the inflammatory mediators that causes further inflammation of the GI tract or may cleave the current Crohn’s treatments. These mechanistic studies showed that future assessments could be based on treatments that inhibit overproduction of these inflammatory agents and regulating the genes responsible for these mediators to circumvent the unresponsiveness of Crohn’s subjects to current anti-TNF agents.
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- Peake STC, Bernardo D, Mann ER, Al-Hassi HO, Knight SC, Hart AL. Mechanisms of Action of Anti–tumor Necrosis Factor α Agents in Crohn’s Disease. Inflammatory Bowel Diseases. 2013;19(7):1546-1555.
- Qiu Y, Chen B-li, Mao R, et al. Systematic review with meta-analysis: loss of response and requirement of anti-TNFα dose intensification in Crohn’s disease. Journal of Gastroenterology. 2017;52(5):535-554.
- Sands BE, Feagan BG, Rutgeerts P, et al. Effects of Vedolizumab Induction Therapy for Patients With Crohn’s Disease in Whom Tumor Necrosis Factor Antagonist Treatment Failed. Gastroenterology. 2014;147(3):618-627.
- Bamias G, Dahman MI, Arseneau KO, et al. Intestinal-Specific TNFα Overexpression Induces Crohn’s-Like Ileitis in Mice. Plos One. 2013;8(8):e72594-e72594.
- Leal RF, Planell N, Kajekar R, et al. Identification of inflammatory mediators in patients with Crohn’s disease unresponsive to anti-TNFα therapy. Gut. 2014;64(2):233-242
- Biancheri P, Brezski RJ, Di Sabatino A, et al. Proteolytic Cleavage and Loss of Function of Biologic Agents That Neutralize Tumor Necrosis Factor in the Mucosa of Patients With Inflammatory Bowel Disease. Gastroenterology. 2015;149(6):1564-1574.
- Katz LH, Kopylov U, Fudim E, et al. Expression of IL-2, IL-17 and TNF-alpha in patients with Crohn’s disease treated with anti-TNF antibodies. Clinics and Research in Hepatology and Gastroenterology. 2014;38(4):491-498.