Lymphocytic Colitis With Increased Apoptosis: A Marker of Mutation in T-Cell-Mediated Immunity?

Lymphocytic colitis is a subtype of microscopic colitis that is mostly seen in adults. It presents mainly as chronic nonbloody diarrhea, with the hallmark of normal or near-normal endoscopy. In this case series, we are presenting 4 pediatric patients with lymphocytic colitis with prominent apoptosis of the colonic gland epithelium. Remarkably, all the patients have genetic mutations known to be associated with autoimmune enteropathy. Three patients have a CTLA4 mutation, and 1 patient has an STAT3 mutation. These mutations were previously reported in association with inflammatory bowel disease, but a specific connection with lymphocytic colitis has not been described. This report investigates the histopathology of such lesions in children and adolescents.

Diagnosis and Management of Microscopic Colitis.

Microscopic colitis (MC) is a relatively common cause of chronic watery diarrhea, especially in older persons. Associated symptoms, including abdominal pain and arthralgias, are common. The diagnosis is based upon characteristic histological findings in the presence of diarrhea. The two types of MC, collagenous and lymphocytic colitis, share similar clinical features, with the main difference being the presence or absence of a thickened subepithelial collagen band. There are several treatment options for patients with MC, although only budesonide has been well studied in multiple controlled clinical trials. This review will describe the clinical features, epidemiology, pathophysiology, diagnostic criteria, and treatment of patients with MC.

Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment.

Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX3CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX3CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

Clinical features and treatment responses in pediatric lymphocytic and collagenous colitis.

OBJECTIVE: Microscopic colitis (MC) is prevalent in adults investigated for chronic watery diarrhea, yet characterization of pediatric MC is limited. METHODS: Our pathology database was searched from 1995 to 2011 for pediatric cases of lymphocytic colitis (LC) or collagenous colitis (CC). Those with diarrhea persisting for >2 weeks and visually normal colonoscopy were accepted as cases. Demographics, laboratory results, medication use within 3 months of presentation, medical and family history of autoimmune disease, and response to treatment were abstracted. RESULTS: A total of 27 cases were histologically consistent with MC on biopsy; 5 with concomitant enteric infection or isolated abdominal pain were excluded. Twenty-two cases of MC (female patients, 59%; median age at diagnosis, 15.3 years) were included (19 LC and 3 CC). Two had type 1 diabetes mellitus, 2 were anti-nuclear antibody positive, and 2 had common variable immunodeficiency. Of 20 patients who underwent an esophagogastroduodenoscopy, 1 had collagenous sprue and 4 had celiac disease. One presented after the clearance of recurrent Clostridium difficile infection. Previous drug exposures included nonsteroidal anti-inflammatory drugs (n = 7), proton pump inhibitors (n = 6), and selective serotonin reuptake inhibitors (n = 3). Common symptoms in addition to diarrhea included abdominal pain (77.3%) and weight loss (27.3%). Of 17 patients with follow-up, all of the 8 treated with steroids had some response: 57.1% (4/7) responded to mesalamine and 42.9% (3/7) responded to bismuth subsalicylate. CONCLUSIONS: In this cohort of pediatric patients, LC was much more common than CC. As described in adults, we observed associations with celiac disease, type 1 diabetes mellitus, and medications; we additionally saw an association with immunodeficiency. Our patients showed greater response to steroids than mesalamine or bismuth.

Lymphocytic colitis and collagenous colitis: a review of clinicopathologic features and immunologic abnormalities.

Lymphocytic colitis (LC) and collagenous colitis (CC), 2 histologic forms of microscopic colitis, were recognized as rare disease entities 4 decades ago. An increasing body of evidence accumulated in the past 40 years reveals increasing incidence and prevalence rates, a wide spectrum of clinical presentations, and several histologic variants. Although several recent randomized clinical trials confirmed the efficacy of oral budesonide in treating LC and CC, disease relapse after a short-duration treatment is common. Despite their common clinical presentations and well-defined histologic diagnostic criteria, there are only few studies on the immunologic abnormalities in colonic tissue. The aim of this review is to (1) familiarize the pathologists in general practice with histomorphology of LC and CC, including the rare histologic variants and the clinical implication associated with these 2 diagnoses, (2) summarize the data from recent randomized clinical trials of oral budesonide, and (3) review immunological studies on colonic tissue. Overall, immunologic abnormalities of colonic tissue seem to explain for the histomorphologic features and the clinical symptomatology of LC and CC. Advances in the understanding of the underlying immunologic abnormalities in the colonic tissue may help develop novel and effective therapies for these 2 diseases.

Lymphocytic and collagenous colitis in children and adolescents: Comprehensive clinicopathologic analysis with long-term follow-up.

Microscopic colitis (MC) is characterized by chronic watery diarrhea, endoscopically normal findings, and abnormal histology. While mostly encountered in adults, pediatric cases are rare and may show varying presentations. Our pathology data system was searched from 1984 to 2019 for patients ≤18 years of age with a lymphocytic colitis (LC) or collagenous colitis (CC) pattern of injury. Twenty-seven cases (23 LC and 4 CC) were retrieved. LC was more prevalent than CC (85% vs 15%, respectively) and affected slightly younger individuals (mean, 9.8 years versus 12.25 years). Immune dysregulation was documented in 11 (41%) patients. Most patients presented with watery diarrhea (n = 26, 96%) and either abdominal pain (n = 18, 67%), nausea/vomiting (n = 5, 19%), flatulence (n = 6, 22%), and/or weight loss (n = 1, 4%). A subset of patients (n = 10, 37%) demonstrated endoscopic abnormalities. Histologically, some patients with LC and CC displayed focal cryptitis or crypt abscess formation (n = 7, 26%) and focally increased crypt apoptosis (n = 9, 33%) in the absence of chronic injury. Clinical follow-up data were available for 23 (85%) patients with variable clinical responses recorded. Only 8 patients experienced complete symptom resolution. Twelve patients (11 LC and 1 CC) had subsequent biopsy material; of which, one developed histologic features of inflammatory bowel disease and another was found to have a CTLA-4 deficiency. Our study shows that pediatric patients with MC may have atypical clinical, histologic, and endoscopic findings and variable clinical responses. Underlying inflammatory and/or genetic conditions may be eventually unmasked, and genetic testing may be helpful in a small subset of patients.

Clinicopathological significance of lymphocytic colitis/collagenous colitis in inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) may occasionally present with lymphocytic colitis/collagenous colitis (LC/CC) either before or after the onset of IBD. Although a few reports have described a small number of such cases, the relationship between these 2 disorders is still unclear. We evaluated 27 patients with diagnosis of either ulcerative colitis (UC) or Crohn disease (CD) and LC/CC. Clinical, endoscopic, and pathological features were reviewed. Ten patients with initial diagnoses of LC (n = 2)/CC (n = 8) evolved into UC (n = 7) or CD (n = 3) after a median interval of 14 months (range, 2-44 months). Among these, 4 patients with LC/CC evolving into IBD also had recurrent CC in a quiescent phase of IBD. Seventeen patients with initial diagnosis of UC (n = 11) or CD (n = 6) developed LC (n = 6)/CC (n = 11) after a median interval of 108 months (range, 15-548 months). IBD patients with initial presentation of LC/CC were significantly older than those who developed LC/CC after onset of IBD (66.5 versus 34.0 years old, P = .001). The interval time between LC/CC to IBD was significantly shorter than that of IBD to LC/CC (14 versus 108 months, P = .007). Quiescent UC with superimposed CC was the most common pattern (n = 8). Patients with CD had shorter interval time to develop LC/CC than UC patients, although it was not statistically significant (60.5 versus 139 months, P = .14). Endoscopically, most patients that started with LC/CC had unremarkable findings, but 11 of 17 patients who developed LC/CC after IBD showed quiescent chronic colitis. Histologically, LC/CC patients with diagnosis of IBD, either before or after, more frequently show active inflammation. Chronicity was more commonly seen in biopsy of LC/CC patients with a history of IBD. Our study found that IBD patients with initial presentation of LC/CC tend to occur in older age, with shorter interval time and frequent active inflammation in initial LC/CC. These findings suggest that LC/CC may be a spectrum of IBD as the initial presentation in a subset of older IBD patients. On the other hand, IBD patients can develop LC/CC associated with chronic mucosal injury many years after the onset of IBD (typically with >10 years interval time while patients are in remission phase), for which these 2 processes seem unrelated to each other.

Paucicellular lymphocytic colitis: is it a minor form of lymphocytic colitis? A clinical pathological and immunological study.

OBJECTIVES: It has been suggested that paucicellular lymphocytic colitis (PLC) should be considered to be part of the morphological spectrum of microscopic colitis. The aim of the study was to evaluate whether PLC may be considered to be a true microscopic colitis, and in this case, whether it is a minor form of lymphocytic colitis (LC) or a different entity. METHODS: All incident cases of PLC, LC, and collagenous colitis (CC) during the period 2004-2006 were included. The incidence rate and the clinical, histopathological, and immunological features of PLC were assessed and compared with those of both LC and CC. Immunoreactivities to CD25, c-Kit, and FOXP3 in lamina propria were assessed. RESULTS: In all, 19 patients with CC, 19 with LC, and 26 with PLC were identified. CD25+FOXP3+ expression was seen only in classical forms of microscopic colitis: 12 of 19 LC, 14 of 20 CC, and none of 20 PLC cases (P < 0.0001). Diarrhea ceased in 21 of the 26 patients, with a decrease in the daily stool number from 5.08 +/- 0.44 to 1.7 +/- 0.2 (P < 0.005). The five patients with no response to therapy fulfilled the Rome II criteria of irritable bowel syndrome (IBS). CONCLUSIONS: The incidence rate of PLC, identified using objective histological criteria, was higher than those of CC and LC. The lack of expression of CD25+FOXP3+ cells in PLC, in contrast to those seen in both LC and CC, would suggest the existence of different pathophysiological mechanisms and does not support that PLC is a minor form of LC.

Histopathologic Features of Colitis Due to Immunotherapy With Anti-PD-1 Antibodies.

Programmed cell death protein 1 (PD-1) blocking agents are novel immunotherapeutics used for treatment of advanced-stage malignancies. They have shown promise in the treatment of several malignancies, with greater efficacy and better tolerability than cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking agents. However, as with anti-CTLA-4 agents, clinically significant colitis remains an important complication. Although there is growing awareness of the histopathologic features of anti-CTLA-4 therapy, there is little information on the pathologic features of anti-PD-1 colitis. We describe here the histopathologic findings in 8 patients who developed colitis while on anti-PD-1 monotherapy. The most common pattern of injury observed (5/8 cases) was an active colitis with neutrophilic crypt microabscesses and with prominent crypt epithelial cell apoptosis and crypt atrophy/dropout. These latter features are reminiscent of other colitides with prominent apoptosis such as acute graft-versus-host disease or certain drug-induced colitides. The remainder of cases (3/8) showed a lymphocytic colitis-like pattern, characterized by increased intraepithelial lymphocytes and surface epithelial injury. Apoptosis was also often increased in these cases but crypt atrophy/dropout was not present. In patients who experienced recurrence of anti-PD-1 colitis, histologic features were similar to the initial insult but, in addition, features of chronicity developed that mimicked inflammatory bowel disease (basal lymphoplasmacytosis and crypt architectural irregularity, and Paneth cell metaplasia in 1 case). Awareness of the clinical scenario, however, should allow pathologists to suggest anti-PD-1 colitis. Interestingly, recurrent colitis was observed in patients who had been off anti-PD-1 therapy for many months. As anti-PD-1 agents are increasingly used in oncology, we present this series to increase awareness of anti-PD-1 colitis among pathologists, to facilitate its timely diagnosis and treatment.

Immunological Differences between Lymphocytic and Collagenous Colitis.

BACKGROUND: Lymphocytic (LC) and collagenous (CC) colitis are the two major forms of microscopic colitis (MC). The aim of this study was to identify similarities and differences in their mucosal immune characteristics. METHODS: Colonic biopsies from 15 CC, 8 LC, and 10 healthy controls were collected. Mucosal lymphocytes were assessed by flow cytometry. Tissue gene expression and protein levels were determined by real-time PCR and ELISA, respectively. RESULTS: LC patients had lower numbers of CD4(+) and double-positive CD4(+)CD8(+)mucosal T lymphocytes, and higher numbers of CD8(+) and CD4(+)TCRγδ(+) mucosal T cells, compared with controls and CC patients. Regulatory Treg (CD4(+)CD25(+)FOXP3(+)) and double-negative (CD3(+)CD4(-)CD8(-)) T cell percentages were higher in both CC and LC compared with controls, coupled with higher levels of the anti-inflammatory IL-10, both at mRNA and protein levels. By contrast, Th1 and Th17 cells were lower in both CC and LC, although gene expression of Th1/Th17 cytokines was higher in both. CONCLUSION: CC and LC share some regulatory and effector mechanisms, but not others. Higher IL-10 levels and higher Treg and double-negative T cell percentages, found in both CC and LC, could be responsible for the lack of progression of structural damage and the blockade of proinflammatory cytokine production. However, CC and LC are revealed as separate, independent entities, as they show clearly different mucosal lymphocyte profiles, which could be caused by different luminal triggers of the two diseases. Hence, CC and LC are two closely related but independent intestinal disorders.

Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis.

AIM: To investigate Toll-like receptor (TLR) signaling regulators in microscopic and ulcerative colitis patients. METHODS: Total RNA and microRNA were isolated from fresh frozen colonic biopsies of non-inflamed controls and patients with active or in-remission collagenous colitis (CC), lymphocytic colitis (LC), or ulcerative colitis (UC). We compared expressions of interleukin-1 receptor-associated kinase (IRAK)-2, IRAK-M, interleukin (IL)-37, microRNA (miR)-146a, miR-155, and miR-21 using quantitative real time reverse transcription polymerase chain reaction. RESULTS: IRAK-M expression was increased in LC patients with active disease in histopathological remission (LC-HR; P = 0.02) and UC patients (P = 0.01), but no differences in IRAK-2 expression were detected compared to controls. miR-146a, -155 and -21 expressions were increased in LC-HR (P = 0.04, 0.07, and 0.004) and UC (P = 0.02, 0.04 and 0.03) patients. miR-146a and miR-21 expressions were significantly enhanced in UC patients compared to UC remission (UC-R; P = 0.01 and 0.04). Likewise, active CC patients showed significantly increased expression of miR-155 (P = 0.003) and miR-21 (P = 0.006). IL-37 expression was decreased in both CC (P = 0.03) and LC (P = 0.04) patients with a similar trend in UC patients but not statistically significant, whilst it was increased in UC-R patients compared to controls (P = 0.02) and active UC (P = 0.001). CONCLUSION: The identification of differentially expressed miRNAs, IL-37, and IRAK-M suggests different pathophysiologic mechanisms in various disease stages in LC, CC, and UC.

Microscopic colitis.

Microscopic colitis is a frequent cause of chronic watery diarrhea, especially in older persons. Common associated symptoms include abdominal pain, arthralgias, and weight loss. The incidence of microscopic colitis had been increasing, although more recent studies have shown a stabilization of incidence rates. The diagnosis is based on characteristic histologic findings in a patient with diarrhea. Microscopic colitis can occur at any age, including in children, but it is primarily seen in the elderly. Several treatment options exist to treat the symptoms of microscopic colitis, although only budesonide has been well studied in randomized clinical trials.

Immunohistochemical characterization of lymphocytes in microscopic colitis.

BACKGROUND AND AIMS: Microscopic colitis (MC), encompassing the subgroups collagenous colitis (CC) and lymphocytic colitis (LC), is characterized by macroscopically normal or near-normal colonic mucosa, and an increased number of intraepithelial lymphocytes (IELs) and mononuclear cell infiltration in the underlying lamina propria (LP), in addition to an increased collagen layer in CC. This study aimed to characterize the inflammatory cells involved in mucosal inflammation, using immunohistochemistry. METHODS: Paraffin-embedded biopsies from 23 untreated patients with MC (CC=13, LC=10) and 17 controls were stained with antibodies against CD3, CD4, CD8, CD20, CD30, Foxp3, CD45RO and Ki67. Computerized image analysis was used to calculate areas of stained lymphocytes in the surface and crypt epithelia as well as in the LP. RESULTS: In CC and LC, an increase of predominantly CD8(+) lymphocytes was seen in both the epithelium and the lamina propria, whereas a decreased amount of CD4(+) lymphocytes was found in the lamina propria. CD45RO(+) and Foxp3(+) cells were more abundant in all areas in both patient groups compared to controls, as were CD20(+) areas, although more scarce. Ki67(+) areas were only more abundant in the epithelium, whereas CD30(+) areas were more abundant in the lamina propria of both patient groups compared to controls. CONCLUSIONS: This study confirms an increased amount of CD8(+) lymphocytes in the epithelium. Lymphocytic proliferation and activation markers were more abundant, whereas a decreased amount of CD4(+) lymphocytes was seen in the LP. Further studies are needed to reveal the underlying mechanism(s).

Microscopic colitis patients have increased proportions of Ki67(+) proliferating and CD45RO(+) active/memory CD8(+) and CD4(+)8(+) mucosal T cells.

BACKGROUND: Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic inflammatory bowel disorders of unknown etiology. This study investigated phenotypic characteristics of the mucosal lymphocytes in CC and LC. METHODS: Lamina propria and intraepithelial lymphocytes (LPLs, IELs) isolated from mucosal biopsies from CC (n=7), LC (n=6), as well as LC or CC patients in histopathological remission, (LC-HR) (n=6) and CC-HR (n=4) and non-inflamed controls (n=10) were phenotypically characterized by four-color flow cytometry. RESULTS: The proportions of CD8(+) IELs were increased in CC and LC (p<0.01) compared to controls. Increased proportions of CD45RO(+)CD8(+) IELs and LPLs were observed in LC and even more in CC patients (p<0.01). Both CC (p<0.05) and LC patients had elevated proportions of CD4(+)8(+) IELs and LPLs compared to controls. The proportions of CD45RO(+) cells were increased in CD4(+)8(+) IELs and LPLs (p<0.05) in CC and LC patients compared to controls. Both CC (p<0.05) and LC patients had higher proportions of Ki67(+)CD8(+) IELs and LPLs compared to controls. In contrast, decreased proportions of CD4(+) LPLs were observed in CC and LC as well as CD4(+) IELs in LC compared to controls. Increased proportions of Ki67(+)CD4(+) IELs and LPLs (p<0.05) were observed in CC and LC patients. CC-HR but not LC-HR patients demonstrated normalized proportions of both IELs and LPLs compared to CC and LC patients respectively. CONCLUSION: LC and CC patients have differences in mucosal lymphocyte subsets, with increased proportions of Ki67(+) and CD45RO(+) CD8(+) and CD4(+)8(+) mucosal T cells.

Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile.

BACKGROUND: Microscopic colitis (MC) is a chronic inflammatory bowel disorder of unknown aetiology comprising collagenous colitis (CC) and lymphocytic colitis (LC). Data on the local cytokine profile in MC is limited. This study investigated the T helper (Th) cell and cytotoxic T lymphocyte (CTL) mucosal cytokine profile at messenger and protein levels in MC patients. METHODS: Mucosal biopsies from CC (n=10), LC (n=5), and CC or LC patients in histopathological remission (CC-HR, n=4), (LC-HR, n=6), ulcerative colitis (UC, n=3) and controls (n=10) were analysed by real-time PCR and Luminex for expression/production of IL-1ß, -4, -5, -6, -10, -12, -17, -21, -22, -23, IFN-γ, TNF-α, T-bet and RORC2. RESULTS: Mucosal mRNA but not protein levels of IFN-γ and IL-12 were significantly up regulated in CC, LC as well as UC patients compared to controls. Transcription of the Th1 transcription factor T-bet was significantly enhanced in CC but not LC patients. mRNA levels for IL-17A, IL-21, IL-22 and IL-6 were significantly up regulated in CC and LC patients compared to controls, albeit less than in UC patients. Significantly enhanced IL-21 protein levels were noted in both CC and LC patients. IL-6 protein and IL-1ß mRNA levels were increased in CC and UC but not LC patients. Increased mucosal mRNA levels of IFN-γ, IL-21 and IL-22 were correlated with higher clinical activity, recorded as the number of bowel movements per day, in MC patients. Although at lower magnitude, IL-23A mRNA was upregulated in CC and LC, whereas TNF-α protein was increased in CC, LC as well as in UC patients. Neither mRNA nor protein levels of IL-4, IL-5 or IL-10 were significantly changed in any of the colitis groups. LC-HR and especially CC-HR patients had normalized mRNA and protein levels of the above cytokines compared to LC and CC patients. No significant differences were found between LC and CC in cytokine expression/production. CONCLUSION: LC and CC patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile.

Reduced T cell receptor excision circle levels in the colonic mucosa of microscopic colitis patients indicate local proliferation rather than homing of peripheral lymphocytes to the inflamed mucosa.

Dysregulated T cell responses in the intestine may lead to chronic bowel inflammation such as collagenous colitis (CC) and lymphocytic colitis (LC), together known as microscopic colitis (MC). Having demonstrated increased local T cell responses in the intestinal mucosa of MC patients, we investigated the recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic biopsies from CC (n = 8), LC (n = 5), and CC or LC patients in histopathological remission (CC-HR, n = 3) (LC-HR, n = 6), non-inflamed diarrhoea patients (n = 17), and controls (n = 10) by real-time PCR. We observed lower median TREC levels in both CC and LC patients as well as in LC-HR patients compared to controls. In contrast to MC patients, non-inflamed diarrhoea patients presented with enhanced TREC levels compared to controls. None of the recorded differences did, however, reach statistical significance. A trend towards increased relative expression of CD3 was noted in all MC subgroups examined and reached statistical significance in LC patients compared to controls. In conclusion, reduced TRECs level in the colonic mucosa, together with our previously demonstrated enhanced expression of Ki67(+) T cells, suggests local expansion of resident T lymphocytes in the inflamed mucosa of MC patients.

Lymphocytic and collagenous colitis: an overview of so-called microscopic colitis.

The entity of 'microscopic colitis' is being diagnosed with increasing frequency and is a well-established clinicopathological diagnosis that is underpinned by a triad of watery diarrhea, normal results on endoscopy and characteristic microscopic findings. Careful histopathological evaluation and awareness of its numerous associations (especially with drugs and celiac disease) and mimics will lead to the correct diagnosis of microscopic colitis. The etiology of microscopic colitis remains enigmatic and is multifactorial with different elements being more influential in different individuals. Treatment includes antidiarrheal agents and anti-inflammatory drugs (including steroids). The purpose of this article is to provide some clarity on nomenclature, discuss the multitude of conditions that can occur synchronously or metachronously with microscopic colitis and their role in the etiopathogenesis of this condition, provide a detailed review of the pathological aspects of the disease and to briefly discuss treatment trends.

Foxp3 expression patterns in microscopic colitides: a clinicopathologic study of 69 patients.

Microscopic colitides, including lymphocytic (LC) and collagenous colitis (CC), are well-described pathologic conditions. An altered immune response is implicated in the pathogenesis of both entities. CD8+ T lymphocytes (CTLs) secrete interleukin 2 which stimulates proliferation of regulatory T cells (Tregs), and Tregs, in turn, inhibit CTLs, inducing cytotoxic tissue damage. In Tregs, Foxp3 regulates T-cell-related immune responses. The distribution of Tregs and CTLs in microscopic colitides has remained underexplored. To characterize differences in the distribution pattern of Foxp3 in biopsy specimens from patients with LC and CC, 71 colonic biopsy specimens from 69 consecutive patients were categorized into 1 of 3 diagnoses: no significant histopathologic abnormality (NSHPA), LC, or CC. Further immunohistochemical evaluation of all biopsy specimens was conducted using a panel of markers including CD8 and Foxp3. Our study demonstrated that CTL distribution pattern differences exist among these 2 colitides and that differences in the immunologic recruitment of Foxp3+ Tregs in the colonic mucosa correlate with differences in the spectrum of morphologic changes seen in patients with either LC or CC.

Differences in the T-bet and GATA-3 expression patterns between lymphocytic colitis and coeliac disease.

Lymphocytic colitis (LC) is a disease of unknown aetiology. Among other pathogenetic possibilities, an abnormal reaction to a luminal antigen has been discussed. To clarify this fact, we characterized the inflammatory infiltrate in LC and compared it with the Th1 response-related coeliac disease (CD). Biopsies from 10 LC and 10 CD patients were analyzed by immunohistochemistry for detection of T-bet, the master regulator of Th1 response and its antagonist GATA-3 in T cells employing double labellings. In LC, 10-20% of intraepithelial lymphocytes (IEL) expressed GATA-3 and the remaining T-bet, whereas in CD, all IEL were T-bet-positive. The T cells in the lamina propria of LC (65-70% CD4+; 30-35% CD8+) showed a mixed expression pattern of T-bet and GATA-3. The majority of the CD4+ T cells were GATA-3+, while T-bet and GATA-3 were expressed at a similar frequency by the CD8+ T cells. Most of the T cells in the lamina propria of CD specimens were CD4+, showing a predominant T-bet expression. Also, most of the CD8+ lamina propria T cells in CD were T-bet+. We conclude that in contrast to CD, which exhibits immunophenotypical features of a Th1-response, LC shows features of a mixed Th1/Th2 immune response.

Autoimmune hepatitis in association with lymphocytic colitis.

Autoimmune hepatitis is a rare, chronic inflammatory disorder which has been associated with a number of other auto-immune conditions. However, there are no reports in the medical literature of an association with microscopic (lymphocytic) colitis. We report the case of a 53-year-old woman with several autoimmune conditions, including lymphocytic colitis, who presented with an acute hepatitis. On the basis of the clinical features, serology, and histopathology, we diagnosed autoimmune hepatitis. To our knowledge, this is the first report of autoimmune hepatitis in association with lymphocytic colitis, and lends support to the theory of an autoimmune etiology for lymphocytic colitis.