Mannose-binding lectin (MBL) is a soluble lectin of the innate immune system that is produced by the liver and secreted into the circulation where it activates the lectin complement pathway, enhances phagocytosis of microorganisms by leukocytes, and modulates inflammation. MBL can recognize patterns on the surface of different pathogens, including Candida albicans. Our aims were to investigate whether MBL is expressed in the gut epithelium and to examine its effect on the modulation of intestinal inflammation and C. albicans elimination. Using reverse transcriptase-PCR, MBL transcripts were highly expressed in different parts of the mouse gut. MBL expression was also detected by immunoblotting and immunolocalization in response to C. albicans colonization of the gut; the highest expression of MBL was detected in the stomach. Blocking MBL by administering mannans to mice increased C. albicans colonization. MBL-deficient mice had a higher level of colonization than wild-type mice. Dextran sodium sulfate-induced colitis promoted C. albicans dissemination to the kidneys and lungs of MBL-deficient mice. MBL-deficient mice exhibited elevated expression of interleukin (IL)-17, IL-23, dectin-1, and Toll-like receptor-4. This study shows that MBL expression is induced in the gut in response to C. albicans sensing and is required for intestinal homeostasis and host defense against C. albicans.
Alcoholic individuals are predisposed to respiratory infections. However, mechanisms of perturbations leading to increased susceptibility to lung infections of individuals with alcoholic liver cirrhosis (ALC) are not fully understood. We studied the antibacterial activity and oxidant generation (before and after stimulation by phorbol myristate acetate or opsonized zymosan) of alveolar macrophages from 16 patients with ALC. Our results were compared with those obtained from 12 healthy control subjects, from 8 patients with primary biliary cirrhosis (PBC), and from 8 alcoholic individuals without cirrhosis. All were nonsmokers, had normal chest X-rays, and did not present evidence of lung infection 3 months before. The total number of cells recovered by bronchoalveolar lavage did not significantly differ between control subjects and patients. The cellular viability of alveolar macrophages (trypan blue exclusion) was greater than 90% in all cases. The antibacterial activity of alveolar macrophages versus Staphylococcus aureus was severely impaired in ALC (-21 +/- 8.2%) whereas it was normal in PBC (52 +/- 4.2%), in alcoholic subjects (44.6 +/- 5.4%), and in control subjects (60 +/- 5.5%). The same pattern of results was observed versus Escherichia coli (-47.7 +/- 10,28 +/- 8,28 +/- 12, and 29 +/- 8.5%, respectively). Previous incubation of normal alveolar macrophages with serum or BAL fluid from ALC patients or with normal serum or normal BAL fluid did not result in a significant decrease in antibacterial activity of normal alveolar macrophages. To distinguish ingested bacteria from adherent extracellular bacteria, cells that had been incubated with bacteria for 90 min were then incubated with lysostaphin (1 microgram/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
Reply. We thank Drs Uemura and coworkers for their interest in our recently published systematic review and meta-analysis that showed clinical remission and response rates were similar among patients with Crohn's disease undergoing induction therapy with an anti-tumor necrosis factor (TNF) agent who were treated with and without concomitant steroid therapy.Dr Uemura and colleagues accurately highlighted the heterogeneity in steroid-weaning protocols across clinical trials. Indeed, there is still a lack of standardization of steroid therapy weaning and cessation in clinical trials. Detailed information on disease severity at the time of steroid initiation is also unknown, and dose and duration of therapy before clinical trial entry are largely at the discretion of the treating physician. It is worth mentioning that the possible utility of initiating steroids in patients with Crohn's disease undergoing induction with anti-TNF therapy remains unknown. This combination effect was suspected after high success rates were observed in the COMMIT study, in which participants who were recently initiated on prednisone were then randomized to induction therapy with infliximab alone or in combination with methotrexate. 1 On a separate note, we respectfully disagree with Dr Uemura and colleagues' interpretation of the study performed by the GETAID group in 2006. 2 This study aimed to determine the usefulness of short-term infliximab as a "bridge" therapy to azathioprine maintenance in patients with steroid-dependent Crohn's disease. This study did not investigate or demonstrate superiority of concomitant corticosteroid use with anti-TNF therapy, or triple immunosuppression therapy, compared with anti-TNF monotherapy.Again, we appreciate the interest and insights of Dr Uemura and colleagues and hope that future work will help define the optimal use of steroids and appropriate weaning strategies in patients with Crohn's disease.
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