Macrophage migration inhibitory factor promotes eosinophil accumulation and tissue remodeling in eosinophilic esophagitis.

Macrophage migration inhibitory factor (MIF) is involved in eosinophil biology and in type 2 inflammation, contributing to allergic and helminthic diseases. We hypothesized that MIF participates in the pathogenesis of eosinophilic esophagitis (EoE), an allergic condition characterized by esophageal eosinophilic inflammation. MIF is highly expressed in esophageal mucosa of patients with EoE, compared with gastro-esophageal reflux disease and control patients, where it co-localizes predominantly with eosinophils. In vitro, recombinant MIF promotes human eosinophil chemotaxis, while MIF antagonist and CXCR4 antagonist, AMD3100, revert this effect. In a model of EoE induced by ovalbumin, Mif-deficient mice have reduced inflammation and collagen deposition compared with wild-type (WT) mice. Importantly, treatment of WT mice with anti-MIF or with AMD3100 during the challenge phase prevents accumulation of eosinophils and tissue remodeling. Conversely, recombinant MIF promoted tissue eosinophil inflammation in allergic mice. Together, these results implicate MIF in the pathogenesis of esophageal inflammation and suggest that targeting MIF might represent a novel therapy for EoE.

Expression of lymphocyte-endothelial receptor-ligand pairs, alpha4beta7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease.

BACKGROUND: The interaction between leucocytes and vascular endothelial cells is essential for leucocyte migration into inflammatory sites. AIMS: To study the local expression of the pairs of complementary molecules, alpha4beta7/mucosal addressin cell adhesion molecule (MAdCAM-1) and OX40/OX40 ligand in the lamina propria of the colon and jejunum of patients with inflammatory bowel disease. METHODS: Ten patients with active ulcerative colitis (UC), nine with active Crohn's disease (CD), and seven irritable bowel syndrome (IBS) controls were submitted to endoscopic and peroral jejunal biopsies. Specimens were immunostained by indirect alkaline phosphatase using antibodies against CD3, intercellular adhesion molecule (ICAM) 1, alpha4beta7, MAdCAM-1, and OX40. An OX40-mouse-IgG fusion protein was used to detect OX40 ligand on frozen sections. Immunohistological analysis was carried out by optical microscopy using a computer assisted image analyser. RESULTS: Colonic lamina propria of patients with CD and UC showed increased density of CD3+, alpha4beta7+, and OX40+ cells compared with IBS controls. ICAM-1, MAdCAM-1, and OX40 ligand positive vessels were also increased compared with IBS controls. No significant difference was found in the density of any of these cells in the jejunal mucosa of patients compared with IBS controls. CONCLUSIONS: The expression of MAdCAM-1 and OX40 ligand on gut endothelial and OX40+ cells is increased in sites of mucosal inflammation in patients with inflammatory bowel disease. No evidence was found for increased lamina propria T cells or increased vascular adhesion molecule expression in the proximal intestine of patients with distal inflammatory bowel disease.

Small-bowel involvement in systemic lupus erythematosus: a morphometric and immunohistochemical study.

BACKGROUND: We have investigated the intestinal mononuclear cell subpopulations in patients with systemic lupus erythematosus (SLE) and correlated these with the disease activity. METHODS: Eighteen female outpatients were studied; in 10 of them lupus activity was measured with the Lupus Activity Criteria Count and the SLE Disease Activity Index. Eight patients were in lupus remission. The control group consisted of 10 healthy volunteers. Peroral jejunal biopsy was performed in all individuals, at the angle of Treitz, using a Watson capsule, under X-ray control. Histologic studies analysed the villous to crypt ratio, lamina propria cells, and intraepithelial lymphocyte count. Immunohistochemical evaluation was carried out with the indirect immunoperoxidase technique, using monoclonal antibodies against CD3, CD4, CD8, D1, D7, D9, and M1. RESULTS: Lamina propria CD3+, CD8+, D7+, and M1+ cells from patients with SLE did not differ significantly from those of controls. CD4+ cells were decreased in all patients with SLE, especially in the clinically inactive patients. D1+ and D9+ cells were also decreased in all patients. CONCLUSION: The finding of quantitative abnormalities in the cell-mediated immunity of the intestinal mucosa may reflect systemic defects of the immune system in SLE.

Intestinal immune cells in Strongyloides stercoralis infection.

BACKGROUND: Strongyloides stercoralis can cause a wide spectrum of disease in man, ranging from a chronic asymptomatic infection to a hyperinfective, often fatal syndrome. In rodents, spontaneous expulsion of Strongyloides spp occurs after experimental infection. Mast cells, goblet cells, and eosinophils have been identified as possible effectors of this expulsion. AIMS: To investigate intestinal histopathology and mucosal immunity in immunocompetent patients with chronic S stercoralis infection. METHODS: Jejunal biopsies were performed in 19 immunocompetent patients with a positive stool examination for S stercoralis and few or no symptoms, and in seven healthy controls. Specimens were processed for histopathological analysis and stained by the immunoperoxidase technique, using the following monoclonal antibodies: CD2, CD3, CD4, CD8, anti-T cell receptor (TcR) gamma/delta, RFD1 and RFD7 (two different macrophage markers), Ki67+ (proliferating) cells, antihuman leucocyte antigen (HLA)-DR, and anticollagen IV. In addition, CD25+ cells, mast cells, IgE expressing cells, calprotectin containing cells, and neutrophil elastase positive cells were stained by the alkaline phosphatase method. RESULTS: Jejunal morphology and the numbers of different T cell subsets, mast cells, IgE expressing cells, eosinophils, and goblet cells were unaffected by S stercoralis infection. Conversely, the numbers of mature macrophages and dividing enterocytes in the crypts were reduced significantly. Crypt enterocytes did not express HLA-DR in both groups. The expression of HLA-DR by villus enterocytes was also comparable in patients and controls. There were no activated (CD25+) cells in the mucosa of either patients or controls. CONCLUSIONS: Compared with seven healthy uninfected volunteers, a group of 19 Brazilians with clinically mild strongyloides infection showed no abnormality of mucosal structure and no increase in non-specific inflammatory cells. Likewise, there was no increase in mucosal T cells or macrophages.

Role of different methods for the detection of diarrhoeal pathogens in HIV-infected patients in Brazil.

To evaluate the ability of different diagnostic methods for the detection of AIDS-related diarrhoeal pathogens in developing countries, we studied 40 HIV-infected patients with diarrhoea. All patients were subjected to stool examinations for parasites, stool culture and peroral jejunal biopsy. Jejunal specimens were processed for histological examination with several stains and for transmission electron microscopy (TEM). Jejunal juice and mucosa were cultured. An aetiologic agent was found in twenty patients. Eleven stool specimens were positive for parasites and stool culture was positive in three patients. The enteropathogens detected by these two methods included every microorganism amenable to treatment. Histological examination revealed four agents not previously identified. TEM added to diagnosis in only two patients. All cultures of jejunal mucosa and jejunal juice were negative, even when stool culture was positive. We conclude that a minimal investigation consisting of stool examination for parasites and stool culture is a cost-effective strategy in the management of AIDS-related diarrhoea in developing countries.

PIP: The authors report findings from their evaluation of the ability of different diagnostic methods to detect AIDS-related diarrheal pathogens in developing countries. 40 HIV-infected patients with diarrhea participated in the study, having their stools examined for parasites and submitting to stool culture and peroral jejunal biopsy. Jejunal specimens were processed for histological examination with several stains and for transmission electron microscopy (TEM). Jejunal juice and mucosa were cultured. An etiologic agent was found in 20 patients, with 11 stool specimens positive for parasites and stool culture positive in three patients. The enteropathogens detected by these two methods included every microorganism amenable to treatment. Histological examination revealed four agents not previously identified. TEM added to diagnosis in only two patients. All cultures of jejunal mucosa and jejunal juice were negative, even when stool culture was positive. The authors conclude that a minimal investigation consisting of stool examination for parasites and stool culture is a cost-effective strategy in the management of AIDS-related diarrhea in developing countries.

Jejunal biopsy in HIV-infected patients.

Forty-nine HIV-infected patients were submitted to peroral jejunal biopsy in order to evaluate the presence of microorganisms and the histomorphometric aspects of the enteric mucosa with subsequent correlation of these findings to the appropriate clinical stage of the disease. Thirty-seven patients fulfilled the CDC criteria for AIDS, of whom 23 presented with diarrhea. Of the 12 patients who had not yet been given an AIDS diagnosis. 3 had persistent generalized lymphadenopathy and 9 were asymptomatic carriers. Flat mucosa was observed in two patients (8.7%) with diarrhea and coccidea. Subtotal villous atrophy and severe lamina propria (LP) mononuclear infiltrate (13%) were found only in patients with diarrhea. Moderate to severe histologic changes were more frequently observed in this group, not always related to the presence of microorganisms. Crypt hyperregeneration was a constant finding. Intraepithelial lymphocyte (IEL) count was decreased in patients with diarrhea. Specific infectious agents were unexpectedly rare for the tropical developing country population studied. The organism most commonly associated with diarrhea was Cryptosporidium sp. (21.7%). The etiology of diarrhea in a significant number of patients remains unclear.