Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function.

BACKGROUND & AIMS: Bacterial infections commonly occur in decompensated cirrhosis resulting from bacterial translocation from the intestine. We studied the role of intestinal macrophages and the epithelial barrier in cirrhosis. METHODS: Forty-four patients with NASH/ASH cirrhosis (decompensated n=29, compensated n=15) and nineteen controls undergoing endoscopy were recruited. Serum was obtained and LPS and LBP levels determined. Intestinal macrophages were characterized by flow cytometry, immunohistochemistry, and nitric oxide (NO) production measured in supernatant of cultured duodenal samples. Quantitative RT-PCR was performed on duodenal biopsies assessing 84 inflammatory genes. Protein levels of cytokines/chemokines were assessed in serum and supernatant. The duodenal wall was assessed by electron microscopy, tight junction protein expression determined by RT-PCR, immunohistochemistry, and Western blot and, functional analysis performed by transepithelial resistance measurement and permeability studies. RESULTS: Increased plasma LPS, LBP levels and higher numbers of duodenal CD33(+)/CD14(+)/Trem-1(+) macrophages, synthesizing iNOS and secreting NO were present in decompensated cirrhosis. Upregulation of IL-8, CCL2, CCL13 at the transcriptional level, and increased IL-8, and IL-6 were detected in supernatant and serum in cirrhosis. IL-6 and IL-8 co-localised with iNOS(+) and CD68(+), but not with CD11c(+) cells. Electron microscopy demonstrated an intact epithelial barrier. Increased Claudin-2 was detected by Western blot and immunohistochemistry, while decreased transepithelial resistance and increased duodenal permeability were detected in decompensated cirrhosis. CONCLUSIONS: Our study shows the presence of activated CD14(+)Trem-1(+)iNOS(+) intestinal macrophages, releasing IL-6, NO, and increased intestinal permeability in patients with cirrhosis, suggesting that these cells may produce factors capable of enhancing permeability to bacterial products.

Morphologic and immunohistochemical characterization of granulomas in the nucleotide oligomerization domain 2-related disorders Blau syndrome and Crohn disease.

BACKGROUND: Blau syndrome (BS) and Crohn disease (CD) are both characterized by granulomatous inflammation and related to nucleotide oligomerization domain 2 (NOD2) mutations. OBJECTIVE: This study aimed to define the morphologic and immunohistochemical characteristics of granulomas in patients with NOD2-related BS and CD. METHODS: Granuloma-containing biopsy specimens from 6 patients with BS and 7 pediatric patients with CD carrying NOD2 mutations or single nucleotide polymorphisms were studied for morphology, cellular composition, and cytokine expression by using hematoxylin and eosin staining and immunohistochemistry. RESULTS: Biopsy specimens from patients with BS typically showed polycyclic granulomas with large lymphocytic coronas, extensive emperipolesis of lymphocytes within multinucleated giant cells (MGCs), MGC death, and fibrinoid necrosis and fibrosis. In contrast, biopsy specimens from patients with CD showed simple granulomas with subtle/absent lymphocytic coronas, sclerosis of the surrounding tissue, and polymorphonuclear cells. Findings found to be similar in all granulomas were as follows: CD68 and HLA-DR expression by epithelioid cells, monocyte-macrophage lineage cells and MGCs, increased lymphocytic HLA-DR expression, increased CD4(+)/CD8(+) T-cell ratio, and CD20(+) B lymphocytes evenly distributed within and around granulomas. In both patient groups prominent IFN-γ expression was found in and around granulomas, and TNF-α and IL-23 receptor expression was moderate. IL-6, IL-17, and TGF-ß expression was prominent in granulomas from patients with BS but sporadic in granulomas from patients with CD. IL-10 expression was absent. CONCLUSION: Granulomas from patients with BS and granulomas from patients with NOD2-associated CD show distinct morphologic features and cytokine expression patterns, suggesting that the T(H)17 axis might be involved in the pathogenesis of BS, whereas T(H)1 is important in both patients with BS and patients with CD.

Budd-Chiari syndrome as presenting symptom of hepatic sarcoidosis in a child, with recurrence after liver transplantation.

A seven-yr-old boy presented with a severe Budd-Chiari syndrome, complicated by recurrent thrombosis of several successive TIPSs. Because of liver failure secondary to venous outflow tract obstruction and deterioration of his general condition, an emergency liver transplantation was performed. Steroids were discontinued three months after transplantation, and maintenance immunosuppressive therapy consisted of tacrolimus and azathioprine. Seven years later, this patient presented symptoms of recurrence of venous outflow obstruction in the transplant liver, comparable to the initial event. Histopathology of the liver revealed diffuse granulomatous inflammation with confluent non-caseating granulomas compressing the centrolobular veins. Extensive investigations excluded infections, immune deficiency, and systemic vasculitides. After treatment with a high dose of corticosteroids, the granulomas in the allograft disappeared completely. We report the first case of hepatic sarcoidosis, presenting with venous outflow obstruction and recurring after liver transplantation, in a child.

Granulomatous inflammation in cartilage-hair hypoplasia: risks and benefits of anti-TNF-α mAbs.

BACKGROUND: Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH. OBJECTIVE: We sought to describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency, and evaluate treatment options. METHODS: In a retrospective observational study we collected clinical data on 21 patients with CHH to identify and further characterize patients with granulomatous inflammation. RESULTS: Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) had epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti-TNF-α mAb therapy in 3 of these patients led to significant regression of granulomas. However, 1 treated patient had fatal progressive multifocal leukoencephalopathy caused by the JC polyomavirus. In 2 patients immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas. CONCLUSION: To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although TNF-α antagonists can effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients.