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Genetic factors associated with the development of inflammatory bowel disease

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World Journal of Gastroenterology 2007年第42期13卷 5594-5597页

作者： jesus k yamamoto-furusho Inflammatory Bowel DiseaseClinic Department of Gastroenterology Instituto Nacional deCiencias Médicas y Nutrición Vasco de Quiroga 15 ColoniaSección XVI Tlalpan C.P. 14000 México D.F. México

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 *** 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.

关键词： Genetic Susceptibility Inflammatory bowel disease Ulcerative colitis Crohn's disease

Innovative therapeutics for inflammatory bowel disease

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World Journal of Gastroenterology 2007年第13期13卷 1893-1896页

作者： jesus k yamamoto-furusho Inflammatory Bowel Diseas Clinic Department of Gastroenterology Instituto Nacional d Ciencias Médicas y Nutrición. Vasco de Quiroga 15 Coloni Sección XVI Tlalpan México CP 14000 DF México

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.

关键词： Novel agents Inflammatory bowel diseases Biologic therapy Future agents

Innate immunity in inflammatory bowel disease

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World Journal of Gastroenterology 2007年第42期13卷 5577-5580页

作者： jesus k yamamoto-furusho Daniel k Podolsky Gastrointestinal Unit and Center for the Study of Inflammatory BowelDisease Massachusetts General Hospital and Harvard MedicalSchool Boston MA 02114 United States

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.

关键词： Innate Immunity Toll-like receptors Inflammatory bowel disease

Crohn’s disease:Innate immunodeficiency?

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World Journal of Gastroenterology 2006年第42期12卷 6751-6755页

作者： jesus k yamamoto-furusho Joshua R korzenik Gastro-intestinal Unit and Center for the Study of Inflammatory Bowel Disease Massachusetts General Hospital and Harvard Medical School Boston MA 02114 United States

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.

关键词： Crohn's disease Innate immunity Immunodeficiency NOD2

Role of cytokines in inflammatory bowel disease

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World Journal of Gastroenterology 2008年第27期14卷 4280-4288页

作者： Fausto Sanchez-Muoz Aaron Dominguez-Lopez jesus k yamamoto-furusho Inflammatory Bowel Disease Clinic Department of Gastroenterology Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Vasco de Quiroga 15 colonia Sección XVI

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.

关键词： Cytokines Inflammatory bowel disease Crohn's disease Ulcerative colitis Inflammation

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

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World Journal of Gastroenterology 2006年第10期12卷 1617-1620页

作者： jesus k yamamoto-furusho Luis Uscanga-Domínguez Alondra Lopez-Martinez Julio Granados Department of Gastroenterology Institute Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.México D FMéxico Department of Immunology Institute Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.México D FMéxico

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 ***： The HLA-DRB1＊07 is associated with p-ANCA positive UC Mexican patients.

关键词： HLA-DR p-ANCA Ulcerative colitis Mexicans

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

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World Journal of Gastroenterology 2006年第21期12卷 3406-3409页

作者： jesus k yamamoto-furusho Takeshi Takahashi-Monroy Omar Vergara-Fernandez Edgardo Reyes Luis Uscanga Departments of Gastroenterology. Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Mexico City Mexico Departments of Surgery. Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Mexico City Mexico Departments of Pathology. Institute Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Mexico City Mexico

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.

关键词： Ulcerative colitis Inflammatory bowel disease Perinuclear anti-neutrophil cytoplasmic antibodies

Basic and clinical aspects of osteoporosis in inflammatory bowel disease

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World Journal of Gastroenterology 2007年第46期13卷 6156-6165页

作者： Lorena Rodríguez-Bores JosuéBarahona-Garrido Jesús k yamamoto-furusho IBD Clinic Department of GastroenterologyInstituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.Vasco de Quiroga 15 colonia Sección ⅩⅥTlalpanCP 14000México

Low bone mineral density and the increased risk of fracture in gastrointestinal diseases have a multifactorial pathogenesis. Inflammatory bowel disease （IBD） has been associated with an increased risk of osteoporosis and osteopenia and epidemiologic studies have reported an increased prevalence of low bone mass in patients with IBD. Certainly, genetics play an important role, along with other factors such as systemic inflammation, malnutrition, hypogonadism, glucocorticoid therapy in IBD and other lifestyle factors. At a molecular level the proinflammatory cytokines that contribute to the intestinal immune response in IBD are known to enhance bone resorption. There are genes influencing osteoblast function and it is likely that LRP5 may be involved in the skeletal development. Also the identification of vitamin D receptors （VDRs） and some of its polymorphisms have led to consider the possible relationships between them and some autoimmune diseases and may be involved in the pathogenesis through the exertion of its immunomodulatory effects during inflammation. Trying to explain the physiopathology we have found that there is increasing evidence for the integration between systemic inflammation and bone loss likely mediated via receptor for activated nuclear factor kappa-B （RANk）, RANk-ligand, and osteoprotegerin, proteins that can affect both osteoclastogenesis and T-cell activation. Although glucocorticoids can reduce mucosal and systemic inflammation, they have intrinsic qualities that negatively impact on bone mass. It is still controversial if all IBD patients should be screened, especially in patients with preexisting risk factors for bone disease. Available methods to measure BMD include single energy x-ray absorptiometry, DXA, quantitative computed tomography （QCT）, radiographic absorptiometry, and *** is the establish method to determine BMD, and routinely is measured in the hip and the lumbar spine. There are several treatments options that have

关键词： Inflammatory bowel disease Osteoporosis

Novel genetic markers in inflammatory bowel disease

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World Journal of Gastroenterology 2007年第42期13卷 5560-5570页

作者： Lorena Rodríguez-Bores Gabriela C Fonseca Marco A Villeda Jesús k yamamoto-furusho IBD Clinic Department of Gastroenterology Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Vasco de Quiroga 15 colonia Sección XVI Tlalpan CP 14000 México

Genetic factors play a significant role in determining inflammatory bowel disease(IBD)*** data support genetic contribution to the pathogenesis of IBD,which include familial aggregation,twin studies,racial and ethnic differences in disease *** studies have identified several susceptibility genes contained in different genomic regions named IBD1 to *** oligomerization domain(NOD2)and human leukocyte antigen(HLA)genes are the most extensively studied genetic regions(IBD1 and IBD3 respectively)in *** of the NOD2 gene are associated with Crohn's disease(CD)and several HLA genes are associated with ulcerative colitis(UC)and *** like receptors(TLRs)have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial *** single-nucleotide polymorphisms(SNPs)in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of ***,numerous new genes have been identified to be involved in the genetic susceptibility to IBD:NOD1/Caspase-activation recruitment domains 4(CARD4),Chemokine ligand 20(CCL20),IL-11,and IL-18 among *** characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.

关键词： Genetic Inflammatory bowel disease Human leukocyte antigen Nucleotide oligomerizationdomain Toll like receptors Susceptibility