Role of cytokines in inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), rep- resents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal mac- rophages play an important role in the mucosal im- mune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major con- tributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD. Therefore, several cyto- kine therapies have been developed and tested for the treatment of IBD patients.

Innate immunity in inflammatory bowel disease

The human intestinal tract is home to an enormous bacterial flora. The host defense against microorganisms can be divided into innate and adaptive immunity. The former is the most immediate line of response to immunologic challenges presented by bacteria, viruses, and fungi. The mucosal immune system has evolved to balance the need to respond to pathogens while co-existing with commensal bacteria and food antigens. In inflammatory bowel disease （IBD）, this hyporesponsiveness or tolerance breaks down and inflammation supervenes driven by the intestinal microbial flora. Bacteria contain compounds and are recognized by a variety of receptors, including Toll-like receptors （TLRs） and NODs （a family of intracellular bacterial sensors） and are potent stimuli of innate immune responses. Several mutations in these receptors have been associated with development of IBD.

Genetic factors associated with the development of inflammatory bowel disease

Crohn's disease(CD)and ulcerative colitis(UC)are complex polygenic disorders,characterized by several genes together with environmental factors contributing to the development of inflammatory bowel disease(IBD).Recent advances in research on genetic susceptibility have allowed the identification of diverse genes at different levels:(1)Innate immunity;(2)Antigen presentation molecules;(3)Epithelial integrity;(4)Drug transporter;(5)Cell adhesion.The application of genetic testing into clinical practice is close and all genetic markers may have several clinical implications:prediction of disease phenotype,molecular classification,prevention of complications,and prognosis.

Innovative therapeutics for inflammatory bowel disease

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract, which clinically present as one of two disorders, Crohn's disease or ulcerative colitis. Mainstays of drug treatments for IBD include aminosalicylates, corticosteroids and immunosuppressants such as azathioprine, methotrexate and cyclosporin. Advances in basic research of the pathophysiological process in IBD have been applied to generate a variety of new therapeutics targeting at different levels of the inflammatory processes. New therapies are classified as: (1) Anti-TNFα antibodies; (2) Recombinant cytokines; (3) Selective adhesion blockade; (4) Growth factors; (5) Innate immunostimulation; (6) Nucleic acid based therapies; (7) Gene therapy; (8) Autologous bone-marrow transplantation; (9) Helminths and (10) Extracorporeal immunomodulation. All treatments have the potential to provide more effective and safe treatment for IBD.

Association of the HLA-DRB1*0701 allele with perinuclear anti-neutrophil cytoplasmatic antibodies in Mexican patients with severe ulcerative colitis

AIM： To determine the association between the HLADRB1 alleles and perinuclear anti-neutrophil cytoplasmatic antibodies （p-ANCA） positive in Mexican patients with ulcerative colitis （UC）. METHODS： Ninety Mexican mestizo patients （45 females） with UC, confirmed by biopsy, were studied. High resolution HLA typing was performed by PCR-SSO reverse dot blot and PCR-SSP. Molecular typing techniques were applied to define HLA-DRB1 alleles. Enzyme-linked immunosorbent assay and immunofluorescence techniques were used to detect p-ANCA. RESULTS： Forty-eight （53%） UC patients were positive for p-ANCA by ELISA and IF. We found that p-ANCA- positive UC patients had a significantly increased frequency of HLA-DR7 compared with p-ANCA-negative controls （22% vs 5.1%; pC=0.02, OR=5.2, CI 95%： 1.06-37.82）. Disease activity was scored as severe in 20 patients, moderate in 8, mild in 14 and no activity in the remaining 38 patients according to the Truelove and Witts criteria. Subgroup analysis showed a significantly increased frequency of the HLA-DRB1＊07 allele in 15 of 20 UC patients with severe activity of UC and p-ANCA positivity [100% vs 0%; pC=0.0000001; OR=35]. No significant differences were found between p-ANCA positive patients, HLA-DR alleles and other clinical features such as extraintestinal manifestations, proctocolectomy and extension.CONCLUSION： The HLA-DRB1＊07 is associated with p-ANCA positive UC Mexican patients.

Crohn’s disease:Innate immunodeficiency?

In the past, Crohn’s disease (CD) has been understood primarily as an immunologic disorder characterized by an abnormal T-cell response. Recent in vitro and in vivo data suggests that CD may instead be precipitated by innate immune dysfunction resulting from a combination of genetic and environmental factors. Some reports have demonstrated a defective immune response in a variety of other cellular components, including neutrophils, monocytes and dendritic cells. Recent studies of granulocyte-macrophage colony-stimulating factor (GM- CSF) in CD, aiming to stimulate the innate immune system with the conception that an innate immune defect underlies the development of the disease, have been demonstrated a clinical benefit and reinforce this evolving understanding of the disease.

Perinuclear anti-neutrophil cytoplasmic antibodies (p-anca) in chronic ulcerative colitis: Experience in a Mexican institution

AIM： To assess the prevalence and clinical value of p-ANCA in a sample of Mexican ulcerative colitis （UC） patients. METHODS： In a prospective, IRB-approved protocol, p-ANCA was determined in 80 patients with UC （mean age, 32 ± 12.9 years）. The severity and extension of disease were determined by clinical methods, searching a statistical association with p-ANCA status. RESULTS： p-ANCA were detected in 41 （51%） patients. Severity of disease was the only clinical variable statistically associated with their presence （P 〈 0.0001; OR = 9; CI 95% = 3.2-24.7）. CONCLUSION： The prevalence of p-ANCA was similar to that reported in other countries. Their presence was associated to UC severity, but offered no more information than the obtained by clinical methods.

Emerging therapeutic options in inflammatory bowel disease

Inflammatory bowel disease(IBD)is a chronic disease that requires chronic treatment throughout the evolution of the disease,with a complex physiopathology that entails great challenges for the development of new and specific treatments for ulcerative colitis and Crohn's disease.The anti-tumor necrosis factor alpha therapy has impacted the clinical course of IBD in those patients who do not respond to conventional treatment,so there is a need to develop new therapies and markers of treatment response.Various pathways involved in the development of the disease are known and the new therapies have focused on blocking the inflammatory process at the gastrointestinal level by oral,intravenous,subcutaneous,and topical route.All these new therapies can lead to more personalized treatments with higher success rates and fewer relapses.These treatments have not only focused on clinical remission,but also on achieving macroscopic changes at the endoscopic level and microscopic changes by achieving mucosal healing.These treatments are mainly based on modifying signaling pathways,by blocking receptors or ligands,reducing cell migration and maintaining the integrity of the epithelial barrier.Therefore,this review presents the efficacy and safety of the new treatments that are currently under study and the advances that have been made in this area in recent years.