Abstract
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene and characteristically leads to prominent lung and pancreatic malfunctions. Although an inflammatory reaction is normally observed in the CF airways, no studies have been performed to establish whether a chronic inflammatory response is also present in the CF intestine. We have investigated whether immunologic alterations and signs of inflammation are observed in CF small intestine. Fourteen CF, 20 negative, and four disease controls underwent duodenal endoscopy for diagnostic purposes. Two CF patients were rebiopsied, one after 3 mo of an elemental diet and the other after 2 wk of pancreatic enzyme withdrawal. In three CF and 10 controls, in vitro small intestine organ cultures were also performed. Expression of ICAM-1, IL-2 receptor, IL-2, IFN-γ, CD80, and transferrin receptor was studied by immunohistochemistry before and after in vitro organ culture. In CF small intestine, an increased number of lamina propria mononuclear cells express ICAM-1 [mean 114 (SD 82.8), p < 0.001 versus controls], CD25 [20.2 (18.7), p < 0.01], IL-2 [23.6 (13.7), p < 0.05], and IFN-γ [19 (15.9), p < 0.05], whereas villus enterocytes highly express transferrin receptor. Reduced expression of immunologic markers was observed after 24 h of in vitro culture in all three CF patients as well as in the patient kept on elemental diet for 3 mo. These results indicate that chronic inflammation is observed in CF duodenum and suggest that the perturbation of local mucosal immune response may contribute to the overall clinical picture in CF patients.
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CF is the most common single-gene lethal inherited disease in Caucasians, with an incidence of one in 2000 to 3000 births. CF is caused by mutations in the CFTR gene that result in its altered expression and lead to an impaired function of exocrine tissues such as lung and pancreas (1), the two most prominent sites of clinical disease manifestation.
An inflammatory process dominated by polymorphonuclear leukocytes is a characteristic trait of CF lung manifestation in response to environmental bacterial infection (2–6). In CF infants, it has also been reported that an early pulmonary inflammation (7) occurs even in the absence of detectable infection and that even infants without symptomatic lung disease have endobronchial bacterial infection associated with inflammation and a large number of neutrophils (7, 8). Recently, it has been demonstrated that CF airway epithelial cells that express the ΔF508 mutation have significantly increased localization of NF-kB in the nucleus (9), a key transcriptional factor involved in immunoinflammatory modulation (10). Furthermore, epithelial cells from CF patients produce less IL-10 (11), a key immunomodulatory cytokine (12), do not up-regulate L-selectin on neutrophils in response to IL-8 stimulation (13), and have an impaired T-cell function (14). All these findings indicate that the absence of wild-type CFTR per se interferes with the modulation of an inflammatory response and influences the host's ability to fight environmental challenges; in particular in CF, an intrinsic defect in responding at the mucosal level to antigenic threats appears to be present. Finally, it has been reported that CF airway epithelia fail to kill bacteria because of abnormal airway surface fluid (15).
Gastrointestinal manifestations are commonly observed in CF patients (16, 17), but, contrary to airways symptoms that are dominated by persistent infections, they are considered to be caused by primary exocrine pancreatic insufficiency (1). Thus, gastrointestinal symptoms are considered a simple “bystander” event caused by a primary alteration that takes place in another organ (pancreas). Impaired digestion leads to poor nutrition, which potentially causes a wide range of symptoms and clinical signs, particularly energy deficiency, steatorrhea and fat soluble vitamin deficiency, azotorrhea, and sometimes starch intolerance (1). Pancreatic insufficiency, however, does not provide a complete and satisfactory explanation for all the gastrointestinal CF manifestations. For instance, steatorrhea in CF does not normalize despite inhibition of intestinal acidity and administration of high doses of pancreatic enzymes (18).
Because chronic inflammation is a feature of CF airways, we investigated whether the small intestine may also be a site of a permanent inflammatory process, thus providing a further clue for the complex gastrointestinal patterns detected in CF. We have already reported that other specific alterations are taking place in CF small intestine, such as marked DNA fragmentation in villus enterocytes with likely dysregulation of the apoptotic pathway (19), which may also be caused by alteration of the NF-Kb nuclear distribution (20). In this article, we report that a chronic inflammation is observed in CF duodenum. Such inflammatory response is not dominated by polymorphonuclear leukocytes and apparently occurs without IL-8 up-regulated expression. Thus, as observed in the airways, an intrinsic incapacity to control an environmental challenge, bacterial in the lung and alimentary antigenic load in the gut, can influence the homeostasis of these organs and reflect on the clinical evolution of CF. The evidence of a chronic inflammatory reaction in CF duodenum suggests that the small intestine may play a more important role in CF nutritional alterations as well as in disease evolution than previously supposed.
METHODS
Patients.
Fourteen patients (eight male, mean age 11.3 y, range 3–23 y) (Table 1) affected by CF underwent duodenal endoscopy for diagnostic purposes. For each patient, height and weight were standardized for decimal age and sex and expressed as z-score deviation; the weight for height value expressed as a percentage of the predicted value was calculated (Table 1). Eleven of the 14 patients showed recurrent pulmonary infections with Pseudomonas colonization and mild to moderate lung disease; all had evidence of pancreatic insufficiency requiring enzyme replacement therapy (1000 U lipase/g fat), but, in two of them (cases 10 and 11, Table 1), intestinal biopsy was performed before diagnosis of CF and before pancreatic enzyme supplementation.
Only one patient (case 14, Table 1) showed chronic diarrhea and persistent vomiting at the time of biopsy. This patient had a weight for height value <75% of predicted and clinical and biochemical evidences of malnutrition despite pancreatic enzyme replacement therapy. This patient underwent an elemental diet over 3 mo with improvement of nutritional status and weight for height value >90% (Table 1).
Nine of 14 patients underwent endoscopy because of recurrent vomiting; in the other five patients, intestinal biopsy was performed to exclude diagnosis of celiac disease because of increased serum levels of anti-gliadin IgA antibodies associated with chronic diarrhea (case 14) or failure to grow before diagnosis of CF (cases 10 and 11). One patient (case 5) received a second biopsy after 15 d of pancreatic enzyme withdrawal and one (case 14) after 3 mo of elemental diet. Celiac disease was excluded on the basis of absence of antiendomysium antibodies (EMA) in the patient's serum (21, 22).
Twenty subjects (eight male, mean age 16.4 y, range 3–42 y) suffering from esophagitis (n = 9), gastritis (n = 3), and chronic nonspecific diarrhea (n = 8) were used as non-CF controls. Four non-CF patients with chronic pancreatitis and exocrine pancreatic insufficiency (two male, mean age 27 y, range 16–35 y) were also investigated.
Fully informed consent was obtained from all subjects, and the study was approved by the Ethical Committee of Regione Campania Health Authority.
Intestinal tissues.
Intestinal biopsy specimens obtained by endoscopy at the duodenal-jejunal flexure were embedded in optimal cutting temperature (OCT) compound (Tissue Tek, Miles Laboratories, Elkhart, IN), snap-frozen in liquid nitrogen, and stored at −70°C until cryosectioning.
In vitro tissue culture.
Duodenal biopsies from three CF patients (cases 5, 8, and 11) and 10 controls were also cultured in vitro for 24 h. Mucosal samples from each patient were placed on a stainless steel mesh positioned over the central well of an organ culture dish with the villus surface of the biopsy specimens uppermost. The cultures took place as previously reported in the presence of the sole culture medium (23). After incubation, the specimens were harvested, snap-frozen in liquid nitrogen, and prepared for cryosectioning as described earlier.
Immunohistochemistry and morphometric analysis.
Cryostat sections (3 μm) of each sample were tested individually using MAb (MoAbs) against CD3 (Dako, Copenhagen, Denmark, 1:100), CD8 (Dako, 1:100), CD4 (Dako, 1:100), ICAM-1 (Dako, 1:200), IL-2 receptor (CD25) (Dako, 1:30), CD80 (Becton Dickinson, Mountain View, CA, 1:40), and transferrin receptor (TFR) (Dako, 1:30) as previously described (23). The detection of IFN-γ and IL-2 in LPMNC was performed as previously reported (24) by anti-IFN-γ (mouse MoAb 166.5, 1:200) or anti-IL-2 (rat MoAb 13A6, 1:200). The experiments were carried out according to our previous reports (21, 23, 24). Detection of CD3, CD4, CD8, and ICAM-1 was performed by peroxidase/antiperoxidase (PAP) staining technique; the expression of the other markers was detected by alkaline phosphatase/antialkaline phosphatase method (APAAP). Control experiments were performed as previously described (21, 23, 24).
At least five slides for each sample were evaluated. The number of stained cells in the lamina propria (per mm2 of lamina propria) as well as intraepithelial lymphocyte counts (per 100 enterocytes) was performed according to our previous reports (21, 23, 24). Briefly, the total number of cells that expressed different immunologic markers was evaluated within a total area of 1 mm2. Small areas of lamina propria corresponding to the villus axis were evaluated independently and pooled to reach the standard reference area of 1 mm2. The counts were performed at the microscope with a calibrated ocular graticular aligned parallel to the muscularis mucosae and independently analyzed in a blind manner by two observers; the results were compared afterward. The expression of TFR was graded 0 to 2+ on the basis of the intensity of staining and blindly analyzed by two observers; the results were compared afterward (23).
Antigliadin and EMA.
Serum levels of antigliadin and EMA were determined as previously reported (22).
Statistical analysis.
Two-tailed t test for independent samples was used to compare CF with control samples. Nonparametric tests (Wilcoxon 2-tailed) also were applied, and the results were concordant with those obtained using parametric tests. Fisher test was applied to compare CF and control individuals for the expression of TFR [low (0, 1+) versus intense (2+)] on the villus enterocytes.
RESULTS
Duodenal morphology.
All the mucosal samples showed normal morphology, and in all cases the villus height as well as the crypt depth were normal (25) with villus height/crypt depth ratio higher than 3. The enterocyte height was within normal ranges, and intraepithelial lymphocyte counts, defined as CD3+ cells per 100 enterocytes, were lower than 30/100. Only hyperplasia of goblet cells was observed at routine morphologic analysis in CF patients and in two controls suffering from chronic pancreatitis.
Immunomorphologic features.
The number of LPMNC that express ICAM-1 and CD25 was significantly increased in CF patients with respect to the pattern observed in controls [number of stained LPMNC per mm2 of lamina propria: ICAM-1, p < 0.001 versus controls (Table 1, Fig. 1A, Fig. 2, A and B); CD25, p < 0.01 versus controls (Table 1, Fig. 1A)]. The altered values were detected in 10 out of 14 tested patients (number of stained cells per mm2 of lamina propria higher than mean +2 SD of control population, Table 1). Conversely, the expression of CD80 molecules was similar to that observed in controls (mean 3.14, SD 1.9 versus mean 3, SD 1.4 in controls, p = NS).
The number of LPMNC that express IL-2 and IFN-γ was increased in the CF group of patients as a whole although not all had increased expression of IL-2 or IFN-γ–positive LPMNC (p < 0.05 versus controls) (Table 1, Fig. 1A). No significant differences in the expression of IL-10 and IL-8 were found between CF and non-CF tissues (Fig. 1A). None of the tested cytokines was detected in epithelial cells.
Only a mild increase in the number of total lamina propria CD3+ cells was found in CF tissues with respect to controls (median 350, range 210–400, versus median 310, range 195–370 in controls), whereas the CD4/CD8 ratio was unchanged. No differences were observed in the number of neutrophils in the intestinal mucosa between CF and control samples (data not shown).
These changes were present also in two CF patients (cases 10 and 11) who underwent intestinal biopsy before pancreatic enzyme supplementation.
No changes in the expression of all the tested immunologic markers were observed after 2 wk of pancreatic enzyme withdrawal in case 5 with respect to the pattern observed during pancreatic enzyme replacement therapy.
A reduction in the number of LPMNC that express ICAM-1, CD25, IL-2, and IFN-γ was observed in a patient (case 14) who was kept for 3 mo on an elemental diet (Table 1).
No inflammation was detected in the four patients with non-CF chronic pancreatitis or in the other 20 healthy controls [number of stained cells/mm2 of lamina propria, mean (SD): ICAM-1 34.5 (7.4); CD25 3.7 (1.5); IFN-γ 8.2 (6.5); IL-2 12.1 (4.3)]. In all but four CF subjects (cases 4, 7, 12, and 13), the expression of TFR in villus enterocytes was intense (2+) (Table 1), whereas in all controls it was very low. The expression of TFR was evident in the cytoplasm as well as on cell membranes (Fig. 3, A and B). TFR expression was highly reduced after elemental diet in patient 14 (Table 1).
No correlation was observed between duodenal inflammation and Pseudomonas colonization in airways of CF patients.
In vitro tissue culture.
In the three tested CF patients (cases 5, 8, and 11), a reduction in the number of LPMNC that express ICAM-1, CD25, IFN-γ, and IL-2 was observed after 24 h of in vitro culture in the presence of the medium alone with respect to the pattern observed before culture (Fig. 1B) (number of stained LPMNC per mm2 of lamina propria: mean values −2 SD before culture higher than mean values +2 SD after culture with medium alone). In all three tested cases, epithelial expression of TFR was strongly reduced after in vitro culture. No modifications were detected after in vitro culture of control biopsies [mean (SD): ICAM-1, 36 (11.7); CD25, 4.5 (2.5); IFN-γ, 5.7 (2.6); IL-2, 7.7 (2.4) versus samples before culture, ICAM-1, 32.8 (12.4); CD25, 4.1 (2.0); IFN-γ, 5.4 (2.0); IL-2, 7.2 (2.4), p > 0.1; expression of TFR unchanged in all tested cases].
Serum antibody levels.
Seven out of eight tested CF patients showed high levels of IgG antigliadin antibodies, and five of them also showed the high levels of IgA antigliadin antibodies previously reported in many CF patients (26), but none had EMA in serum. None of the controls had increased serum levels of either antigliadin antibodies or EMA.
DISCUSSION
In CF, there are evidences that an underlying alteration of the immune response contributes to the overall evolution of this pathology. This is poignantly proven by continuous and persistent lung infections with an inflammatory process dominated by polymorphonuclear leukocyte infiltration; these infections are the main cause or morbidity and mortality in CF patients (1, 27). Although this dysregulation of the immune response is considered to be involved in the inability to fight respiratory infections, no consistent studies have been performed to address whether signs of inflammatory reactions are present in other mucosae. Here, we provide evidence that an inflammatory process is a common trait of the small intestine of CF patients; moreover, the high expression of ICAM-1, IL-2 receptor, IL-2, and IFN-γ indicates that a local but persistent activation of the immune system is detected although no mucosal injury is observed.
If, in the lungs, the main immunologic challenge is composed of infectious (bacterial) challenges, the inflammation in CF duodenum is likely due to the alimentary antigenic challenge. Pancreatic enzyme replacement therapy seems to have little role, because inflammation occurred in those two patients (cases 10 and 11) studied before diagnosis of CF as well as in one patient (case 5) who was examined after pancreatic enzyme withdrawal.
Furthermore, the inflammation observed in CF duodenum is not directly related to pancreatic insufficiency, although it may still play a role, because no inflammatory response was observed in the four non-CF chronic pancreatitis patients with associated pancreatic insufficiency. In CF, small intestine inflammation likely reflects an abnormal mucosal response to the large load of dietary antigens as a consequence of the impaired protein luminal digestion and an underlying impaired immune response. The increased expression of TRF in CF villus enterocytes, a well-known marker of epithelial activation (23), supports this supposition. Moreover, the increased intestinal permeability observed in CF patients (28, 29), which allows macromolecules to have access to the immunocompetent compartments of small bowel mucosa, is likely to contribute to such abnormal mucosal response. Because IFN-γ can affect epithelial barrier function, as described in cultured intestinal epithelial monolayers (30), the increased intestinal LPMNC IFN-γ expression will contribute to the enhanced aberrant transport of the dietary antigens across the intestinal epithelium, thus amplifying the mucosal inflammatory process.
Therefore, two factors seem to contribute to duodenal inflammation in CF: the high antigenic load, a consequence of pancreatic insufficiency with defective luminal digestion, and an intrinsic abnormal immune response. That these two factors, one genetic and the other environmental, are essential to induce inflammation is supported by several evidences as discussed above. Thus, mucosal inflammation is strongly reduced after antigen withdrawal as described in the CF patients maintained on an elemental diet for 3 mo, indicating that an environmental component (antigen burden) has a triggering role in CF individuals. The studies performed with the organ culture system of duodenal explants provided the definitive data to support such a conclusion. This model has been successfully used to validate in vitro the effects of various mixtures of dietary antigens on the duodenal mucosa (21–24, 31). Using this in vitro organ culture model, we demonstrated that in the absence of any antigen challenge, the features of mucosal inflammation decrease after 24 h, thus indicating that a continuous antigenic challenge drives the mucosal inflammatory process.
Several lessons can be learned from our study, some directly associated with CF and others of more general pathophysiologic gastroenterologic significance. For instance, in CF, duodenum mucosal inflammation with clear mucosal T-cell activation occurs without any alteration of villus architecture, whereas in other intestinal conditions such as celiac disease, with significant mucosal T-cell activation and persistent inflammation, mucosal damage takes place (32). However, in celiac disease, mucosal inflammation is strictly dependent on a gluten challenge that initiates a cascade of events considered to be driven by gluten/gliadin-specific T cells (33, 23, 24). Even in some celiac patients, those with the so-called latent celiac disease, no apparent mucosal damage is detected (21).
In celiac disease, apoptosis of epithelial cells may be involved in the induction of the flat mucosa (34), and it is likely that pathogenic T cells are involved in this process. In this context, we have recently reported that an abnormal apoptotic status is observed in small intestine epithelial CF cells (19); therefore, we do not know whether mucosal damage is not observed in CF because the epithelial apoptotic machinery is altered. In epithelial cells, which lack the CFTR gene, a significantly increased amount of NF-kB is detected in the nucleus (9), and NF-kB activation has been reported to control induction of apoptosis (20).
The ability to mount an abnormal immune response to exogenous stimuli appears, therefore, to be a generalized characteristic of different CF tissues. However, the inflammation taking place in CF duodenum is histopathologically different from that occurring in airways in which infectious agents or their products constitute the exogenous challenge (1, 2, 9). In the latter condition, neutrophil infiltration, release of neutrophil elastase (35), and increased epithelial production of IL-8 (3, 9, 35) occur. In CF duodenum, in which the putative exogenous stimulus is represented by dietary antigens, no increased expression of IL-8 is observed and no neutrophil infiltration is found.
An abnormal regulation of host CF immune response may explain, at least in part, the association between CF and some forms of immunologic food intolerances, such as cow's milk enteropathy (36), as well as the high levels of serum antibodies to various dietary antigens (26). It has also been reported that CF patients have an increased vulnerability to develop inflammatory bowel lesions such as Crohn's disease (37) and severe noninfectious colitis with or without stricture formation (38, 39). That the intestine must be an important organ in CF is supported by the evidence that the CFTR gene is central to the action of intestinal bacterial toxins such as heat labile enterotoxin of toxinogenic strains of Escherichia coli and cholera toxin from Vibrio cholerae (40). These toxins cause their harmful effects via a Cl− efflux that is mediated by the opening of the CFTR Cl− channel (40); moreover, Salmonella typhi uses CFTR to enter intestinal epithelial cells (41, 42). The strict correlation between that lack of the CFTR gene and these intestinal pathologies is, therefore, intuitive.
This study provides the first evidence that chronic inflammation is found in CF duodenum. Duodenal inflammation is likely to have a significant impact on the nutritional problems typically observed in CF children and, consequently, on the evolution of the disease because malnutrition contributes to the progression of lung disease (43, 44). We also cannot exclude that an altered host intestinal immune response may play a role in the increased risk of digestive-tract cancer observed in the CF population (45). Our findings further indicate that the small intestine may be a more prominent organ target in CF than normally accepted and that control of the inflammatory process may represent a further important therapeutic challenge in treating CF patients.
Abbreviations
- CF:
-
cystic fibrosis
- CFTR:
-
cystic fibrosis transmembrane conductance regulator
- IFN:
-
interferon
- LPMNC:
-
lamina propria mononuclear cells
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Acknowledgements
The authors thank Prof. Giuseppe Castaldo, Centro di Ingegneria Genetica and Dipartimento di Biochimica e Biotecnologie Mediche, University Federico II of Naples, for genetic analysis.
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Supported by grant 2902(10/06/1992) “Prevenzione, diagnosi e cura della Fibrosi Cistica” from Regione Campania, Italy.
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Raia, V., Maiuri, L., de Ritis, G. et al. Evidence of Chronic Inflammation in Morphologically Normal Small Intestine of Cystic Fibrosis Patients. Pediatr Res 47, 344–350 (2000). https://doi.org/10.1203/00006450-200003000-00010
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DOI: https://doi.org/10.1203/00006450-200003000-00010
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