Interleukin-12 and Th1 immune response in Crohn＇s disease： Pathogenetic relevance and therapeutic inplication

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD and UC result from a deregulated mucosal immune response to normal constituents of the gut microflora. Evidence, however, indicates that the main pathological processes in these two diseases are distinct. In CD, the tissue-damaging inflammatory reaction is driven by activated type 1 helper T-cell (Th1), whereas a humoral response predominates in UC. Consistently, a marked accumulation of macrophages making interleukin (IL)-12, the major Th1-inducing factor, is seen in CD but not in UC mucosa. Preliminary studies also indicate that administration of a monoclonal antibody blocking the IL-12/p40 subunit can be useful to induce and maintain clinical remission in CD patients. Notably, the recently described IL-23 shares the p40 subunit with IL-12, raising the possibility that the clinical benefit of the anti-IL-12/p40 antibody in CD may also be due to the neutralization of IL-23 activity. This review summarizes the current information on the expression and functional role of IL-12 and IL-12-associated signaling pathways both in patients with CD and experimental models of colitis, thus emphasizing major differences between IL-12 and IL-23 activity on the development of intestinal inflammation.     

Interleukin-12 and Th1 immune response in Crohn’s disease: Pathogenetic relevance and therapeutic inplication

INTRODUCTION Inflammatory bowel disease (IBD) is the general term indicating Crohn’s disease (CD) and ulcerative colitis (UC), two chronic inflammatory disorders of the intestine that have different morphological, immunological and clinical characteristi…     

Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease

Inflammatory bowel disease(IBD)includes Crohn’s disease and ulcerative colitis.The exact etiology and pathology of IBD remain unknown.Available evidence suggests that an abnormal immune response against the microorganisms in the intestine is responsible for the disease in genetically susceptible individuals.Dysregulation of immune response in the intestine plays a critical role in the pathogenesis of IBD,involving a wide range of molecules including cytokines.On the other hand,besides T helper(Th)1 and Th2 cell immune responses,other subsets of T cells,namely Th17 and regulatory T cells,are likely associated with disease progression.Studying the interactions between various constituents of the innate and adaptive immune systems will certainly open new horizons of the knowledge about the immunologic mechanisms in IBD.     

A functional interleukin-10 mutation in Dutch patients with Crohn''s disease

BACKGROUND AND AIMS: Interleukin-10 is an anti-inflammatory and immunomodulatory cytokine. Interleukin-10 deficient mice are prone to develop chronic colitis. Administration of recombinant human interleukin-10 has been proposed to have a beneficial effect in a subgroup of patients with Crohn's disease. Recently, we found an interleukin-10 Gly15Arg mutation in a family with Crohn's disease which is associated with reduced interleukin-10 secretion by in vitro stimulated monocytes and lymphocytes. We hypothesised that this interleukin-10 mutation plays a role in maintaining the inflammatory process in Crohn's disease in some families. PATIENTS AND METHODS: We evaluated interleukin-10 Gly15Arg in 379 patients with Crohn's disease, and 75 unrelated healthy controls. Also, first degree family members of interleukin-10 Gly15Arg carriers were evaluated. Additionally, mutation carriers and their relatives were evaluated for CARD15 R702W, G908R, and 1007fs. RESULTS: Two patients with Crohn's disease were heterozygous for the interleukin-10 Gly15Arg mutation. No homozygotes were found. The Gly15Arg mutation was not observed in the controls. In first degree family members of the Crohn's disease-affected interleukin-10 Gly15Arg carriers, the mutation was found in Crohn's disease-affected as well as in their apparently healthy individuals. All family members carried one or two CARD15 mutation(s). CONCLUSION: The interleukin-10 Gly15Arg mutation is rare in patients with Crohn's disease, and is not associated with the disease in the Netherlands.     

Saliva Interleukin-6 in patients with inflammatory bowel disease

Objective. The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions that affect the gastrointestinal tract. In regulation of this inflammatory process, Interleukin-6 (IL-6) has a major role. Overproduction of IL-6 by immunocompetent cells contributes to development of the inflammatory condition. Elevated levels of IL-6 in saliva could be expected, because the saliva-producing cells are part of the digestive system. Material and methods. IL-6 concentrations in saliva and plasma were studied in patients with CD (n=15), UC (n=7) and reference persons (RP) (n=19) by use of an ELISA method. Results. A significant difference in saliva IL-6 concentration between CD patients (median 16.9 ng/L; p<0.05) and RP (median 6.3 ng/L) was found. A significant difference in plasma IL-6 concentration between CD (median 10.3 ng/L; p<0.001) or UC (median 7.8 ng/L; p<0.001) and RP (median 0.8 ng/L) was observed. In patients with CD, plasma IL-6 correlated significantly with C-reactive protein (CRP) as well as albumin. In patients with UC, saliva IL-6 and plasma IL-6 correlated significantly with AI (activity index) scores as well as albumin. In patients with UC, a significant correlation between the saliva and plasma IL-6 concentrations was found. Conclusions. IL-6 was found in saliva in patients with IBD, documenting the general involvement of the gastrointestinal tract extending to the mouth cavity, and measuring IL-6 may be an additional method for evaluating and monitoring the disease activity.     

白介素-10与炎症性肠病

炎症性肠病(inflammatory bowel disease,IBD)是一种慢性、复发性的肠道炎症疾病,其明确病因目前仍不清楚.肠道免疫功能异常导致过量炎症因子释放损伤肠道黏膜在IBD发病中起着关键作用,应用免疫抑制剂减少炎症因子的释放也被应用于IBD的治疗.近年来利用细胞因子调节机体免疫功能以治疗IBD的研究日渐...     

白细胞介素-23在炎症性肠病的表达升高并诱导促炎细胞因子分泌

目的 通过分析白细胞介素(IL)-23p19及其受体(IL-23R)在炎症性肠病(IBD)患者中的表达,研究IL-23对IBD患者外周血T细胞激活和效应应答的影响,探讨其在疾病发生过程中的免疫病理作用.方法 收集12例克罗恩病(CD)患者、25例溃疡性结肠炎(UC)患者和20名健康者外周血和肠黏膜组织活检标本,使用免疫组化染色和逆转录(RT)-PCR分析IL-23p19表达,分离外周血单个核细胞(PBMC)和肠黏膜固有层内单个核细胞(LPMC),利用流式细胞仪检测IL-23R在CD4+、CD8+T细胞和自然杀伤(NK)细胞表面表达.体外培养PBMC,使用IL-23和抗CD3单抗体外刺激,使用酶联免疫吸附试验检测肿瘤坏死因子(TNF)-α、干扰素(IFN)-γ和白细胞介素(IL)-2分泌.结果 IBD患者炎症肠黏膜组织内IL-23p19蛋白和mRNA表达水平比健康对照者显著升高(P<0.05).IL-23R在IBD患者外周血和肠黏膜固有层组织内CD4+、CD8+T细胞和NK细胞表达水平也比健康者显著升高(P<0.05).体外培养PBMC,使用IL-23刺激,发现IL-23可显著诱导IBD患者,尤其是CD患者PBMC激活,分泌高水平TNF-α、IFN-γ和IL-2(P<0.05).结论 IL-23及其受体在IBD患者炎症肠黏膜组织中表达升高,IL-23可诱导IBD患者淋巴细胞分泌高水平的炎性介质,提示IL-23参与了肠黏膜炎症损伤,阻断IL-23生物学效应可能治疗IBD.     

Th17/Treg失衡与炎症性肠病的关系

炎症性肠病(inflammatory bowel disease.IBD)的病因和发病机制尚未完全明确,肠道黏膜免疫系统异常反应所导致的炎症过程在发病中起重要作用.辅助性T细胞17(T helper 17 cells,Th17)可介导慢性炎症和自身免疫性疾病的发生,调节性T细胞(regulatory T cell,Treg)有抑制自身免疫的功能,二者存在相互转化的关系.有研究表明Th17/Treg转化平衡是维持肠道免疫稳态的重要因素,这可能是导致人类IBD的原因之一.最近研究表明TGF-β,IL-6和维甲酸(retinoic acid,RA)可能是调控二者平衡关系的重要因素.肠道菌群(intestinal flora)与IBD的发生发展关系密切,益生菌(probiotics)对IBD的治疗作用成为研究的热点.深化对Th17/Treg转化调控关系的研究是当前重要的研究课题.     

Th17 immune response in IBD: A new pathogenic mechanism

Although traditionally associated with exaggerated Th1 or Th2 cell response, the gut inflammation occurring in patients with IBD is also characterized by production of cytokines made by a distinct lineage of T helper cells, termed Th17 cells. The discovery that this new inflammatory T-cell subset drives immune-mediated pathology and that the antigen-presenting cell-derived IL-23 is necessary for amplifying Th17 cell-associated inflammation has contributed to elucidate new pathways of intestinal tissue damage as well as to open new avenues for development of therapeutic strategies in IBD.In this review, we discuss the available data regarding the involvement of Th17 cells and their interplay with other mucosal cell types in the modulation of intestinal tissue inflammation.     

Short- and long-term therapeutic efficacy of nutritional therapy and corticosteroids in paediatric Crohn''s disease

BACKGROUND: Comparative data on the therapeutic efficacy of different enteral nutrition formulas and corticosteroids to obtain clinical remission and to induce mucosal healing influencing long-term disease course in paediatric Crohn's disease are still scarce. AIMS: To investigate the efficacy of nutritional therapy using three different formulas versus corticosteroids to achieve clinical remission as well as to induce intestinal mucosal healing in active Crohn's disease children. Duration of remission and effect on growth recovery were also assessed. PATIENTS AND METHODS: Clinical, laboratory, endoscopic and histological data of all new diagnosed active Crohn's disease paediatric cases were retrospectively recorded and reviewed. Thirty-seven children (median age 12.1 years) received nutritional therapy (12 polymeric; 13 semi-elemental; 12 elemental diet) and 10 subjects (median age 12.4 years) received corticosteroids. RESULTS: Similar clinical remission rate were observed after 8 weeks of treatment: 86.5% children receiving nutritional therapy versus 90% treated with corticosteroids. Improvement in mucosal inflammation occurred in 26 out of 37 (64.8%) patients on nutritional therapy and in 4 out of 10 (40%) children on steroids (p < 0.05). Finally, seven subjects on nutritional therapy and none on corticosteroids achieved complete mucosal healing (p < 0.005) at the end of the treatment. Nutritional therapy was more effective than corticosteroids in improving nutritional status and linear growth recovery. Compared to corticosteroids, the duration of clinical remission was longer in the nutritional therapy groups without differences among the three different formulas. CONCLUSIONS: In children with active Crohn's disease, nutritional therapy is more effective than corticosteroids to improve intestinal inflammation and to maintain a more sustained clinical remission.     

Crohn''s disease in Stockholm County during 1990-201: An epidemiological update

AIM: To further assess of the incidence and localization of Crohn's disease (CD) in a well-defined population during the 1990s and to evaluate the prevalence of CD on the 1st of January 2002.METHODS: In a retrospective population based study, all 16-90 years old citizens of Stockholm County diagnosed as having CD according to Lennard Jones'criteria between 1990 and 2001 were included.Case identification was made by using computerized inpatient and outpatient registers. Moreover private gastroenterologists were asked for possible cases. The extent of the disease and the frequency of anorectal fistulae were determined as were the ages at diagnosis.Further, the prevalence of CD on the 1st of January 2002was assessed.RESULTS: All the 1389 patients, 689 men and 700women, fulfilled the criteria for CD. The mean incidence rate for the whole period was 8.3 per 105 (95%CI 7.9-8.8). There was no difference between the genders.The mean annual incidence of the whole study period for colorectal disease and ileocecal disease, was 4.4 (95%CI 4.0-4.7) and 2.4 (95%CI 2.1-2.6) per 105, respectively.Perianal disease occurred in 13.7% (95%CI 11.9-15.7 %)of the patients. The prevalence of CD was 213 per 100000 inhabitants.CONCLUSION: The incidence of CD has markedly increased during the last decade in Stockholm County and 0.2% of the population suffers from CD. The increase is attributed to a further increase of colorectal disease, while the incidence of ileocecal disease has remained stable.     

Innate and Th1/Th17 adaptive immunity in acute and convalescent Brazilian borreliosis disease

IntroductionBrazilian borreliosis (BB) disease is an infectious disease transmitted by ticks that mimics Lyme disease (LD) from the Northern Hemisphere. The BB clinical picture is characterized by a pathognomonic skin lesion (migratory erythema) and joint, neurological, cardiac and psychiatric symptoms. Innate and Th1/Th17 adaptive immunity seem to play an important role in the pathogenesis of Lyme disease.ObjectiveThe aim of this study was to characterize the role of innate and Th1/Th17 adaptive immunity in BB patients with acute (<3 months) and convalescent (>3 months) disease.MethodsFifty BB patients (28 with acute and 22 with convalescent disease) without treatment and 30 healthy subjects were evaluated. Levels of 20 cytokines or chemokines associated with innate and Th1/Th17 adaptive immunity were analyzed using Luminex (Millipore Corp., Billerica, MA).ResultsOverall, BB patients had increased levels of IL-8 (6.29 vs 2.12 p = 0.002) and MIP-1α/CCL3 (5.20 vs 2.06, p = 0.030), associated with innate immunity, and MIP3B/CCL19 (Th1; 297.86 vs 212.41, p = 0.031) and IL-17A (Th17; 3.11 vs 2.20, p = 0.037), associated with adaptive immunity, compared with the levels of healthy controls. When comparing acute BB vs. convalescent BB subjects vs. healthy controls, IL-1β, IL-8 and MIP-1α/CCL3 (innate mediators) levels were highest in patients in the acute phase of disease (p < 0.05). TNF-α was associated with disseminated symptoms and with humoral reactivity against Borrelia burgdorferi. IL-10 was significantly correlated with IL-6 (r = 0.59, p = 0.003), IL-8 (r = 0.51, p < 0.001), MIP-1α/CCL3 (r = 0.42, p < 0.001) and MIP-3β/CCL19 (r = 0.40, p = 0.002) in all BB patients.ConclusionsThis is the first study describing that innate and Th1/Th17 adaptive immunity play a crucial role in BB disease. Furthermore, innate mediators are particularly important in acute BB disease, and TNF-α is associated with evolution of BB symptoms.     

IL-35与炎症性疾病

IL-35是一种抑制性细胞因子,属于IL-12细胞因子家族的新成员,它是由调节性T细胞结构性分泌产生,由P35和EBI3两个亚基组成.研究发现,IL-35在自身免疫性疾病、炎症性疾病、肿瘤等治疗中有重要作用.在临床上,感染性疾病的控制一直是个难题,IL-35的应用也许为临床提供一种新的思路和方法.     

T淋巴细胞亚群在炎症性肠病中作用的研究

炎症性肠病(inflammatory bowel disease,IBD)主要包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn's disease,CD),是一种反复发作的慢性炎症性肠道疾病,通常认为IBD的发生、发展与自身免疫系统异常关系密切.胃肠道需要在耐受内容物及对病原体的免疫...     

Role of soluble triggering receptor expressed on myeloid cells in inflammatory bowel disease

AIM: To investigate the probable role of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in the pathogenesis of inflammatory bowel disease (IBD). METHODS: Fifty-eight patients were enrolled; nineteen healthy volunteers served as controls; 8 patients were diagnosed with Crohn's disease, and 31 with ulcerative colitis. Clinical and endoscopic activity indexes of patients with Crohn's disease and ulcerative colitis respectively were estimated. Upon admission blood was sampled; sTREM-1 and TNFαwere measured by an immunoassay and malondialdehyde (MDA) by the thiobarbitourate assay, after passage through an HPLC system. RESULTS: Median±SE of TNFαof controls, patients with Crohn's disease and patients with ulcerative colitis were 6.02±3.94, 7.98±5.08 (P = NS vs controls), and 8.45±4.15 ng/L (P = 0.018 vs controls) respectively. Respective values of sTREM-1 were 53.31±32.93, 735.10±197.17 (P = 0.008 vs controls) and 435.82±279.71 ng/L (P = 0.049 vs controls). sTREM-1 was positively correlated with Crohn's disease activity index and clinical and endoscopic activity indexes of ulcerative colitis (P = 0.002, 0.001 and 0.009, respectively). sTREM-1 of patients with ulcerative colitis was positively correlated with TNFa (P = 0.001). CONCLUSION: sTREM-1 seems to behave as a novel mediator in IBD in correlation with the degree of the inflammatory reaction of the intestinal mucosa.     

白介素8与慢性阻塞性肺疾病

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是呼吸系统的常见病、多发病,COPD患病人数多、病死率高,近年来发病率呈明显上升的趋势.COPD的确切发病机制尚不完全清楚,目前认为炎症是COPD发生发展的主要机制.白介素8(IL-8)是主要的炎症介质之一,在COPD患者多种因素可以导致其明显增高,IL-8有强力的中性粒细胞、T细胞及嗜碱粒细胞趋化作用,并可激活中性粒细胞,产生中性粒细胞反应,破坏肺泡,产生多种炎症效应.对IL-8的干预可能影响COPD的炎症过程.     

炎症性肠病患者外周血辅助性T细胞1和辅助性T细胞17水平及其临床意义

 目的 探讨炎症性肠病（IBD）患者外周血Th1和Th17细胞水平对IBD发病及活动度的意义。方法 收集2011年5月至2012年7月健康对照者40例和IBD患者81例［其中克罗恩病（CD）39例,溃疡性结肠炎（UC）42例］,采集外周血标本。分离外周血单个核细胞,经PMA及伊屋诺霉素联合刺激、培养后,利用流式细胞仪检测Th1和Th17细胞在外周血CD⁺₄T细胞中的百分比,并结合临床资料分析其临床意义。结果 （1）CD组及UC组Th1细胞百分比［(38.32±16.18)%和(34.23±11.60)%］均明显高于健康对照组［(24.58±10.02)%］（P值均<0.01）,而CD组及UC组的差异无统计学意义;CD及UC缓解期患者的Th1细胞百分比均低于活动期患者［(26.50±9.24)%比(48.46±13.83)%,P<0.01;(30.05±7.41)%比(37.68±13.35)%,P<0.05］。（2）CD组及UC组Th17细胞百分比［(2.51±1.59)%和(4.15±2.75)%］均高于健康对照组［(1.44±0.73)%］（P值均<0.01）,且UC组这一比例高于CD组（P<0.01）;CD及UC活动期患者的Th17细胞百分比明显高于缓解期患者［(3.39±1.56)%比(1.48±0.81)%,(5.77±2.77)%比(2.18±0.59)%,P值均<0.01］。（3）UC组外周血Th17/Th1比值（0.14±0.11）高于CD组（0.08±0.06）和健康对照组（0.07±0.06）,P值均<0.01。结论 IBD患者外周血中Th1、Th17细胞占CD⁺₄T细胞比例较健康人群明显升高,且与IBD活动度密切相关。Th1和Th17细胞在IBD发病中可能具有重要作用。     

三硝基苯磺酸和噁唑酮诱导肠炎小鼠脾脏中Th1/Th2类细胞因子基因表达的动态研究

目的 对比研究三硝基苯磺酸（TNBS）和 唑酮（OXZ）诱导的实验性小鼠肠炎模型脾脏中Th1／Th2类细胞因子基因表达的动态变化。方法 雌性BALB／c小鼠，随机分为50％乙醇对照组，OXZ诱导肠炎模型组，TNBS诱导肠炎模型组（保证每组小鼠取材时6只以上）。采用RT—PCR方法观察OXZ和TNBS诱导肠炎后小鼠脾脏于3及7d IFN-γ、IL-4 mRNA的表达变化。结果 TNBS模型组小鼠在造模后3及7d脾脏中IFN-γ mRNA的表达量均高于OXZ模型组（P〈0．05），IL-4 mRNA的表达量低于OXZ模型组（P〈0．05）。结论 在造模后3和7d TNBS模型小鼠的外周免疫皆以Th1型为主，OXZ模型小鼠的外周免疫以Th2型为主，可代表肠道局部免疫类型。