Possible role for IL-40 and IL-40-producing cells in the lymphocytic infiltrated salivary glands of patients with primary Sjögren's syndrome.

OBJECTIVES: Aim of this study was to investigate the expression of interleukin (IL)-40, a new cytokine associated with B cells homoeostasis and immune response, in primary Sjögren syndrome (pSS) and in pSS-associated lymphomas. METHODS: 29 patients with pSS and 24 controls were enrolled. Minor salivary gland (MSG) biopsies from patients, controls and parotid gland biopsies from pSS-associated lymphoma were obtained. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-40 were performed on MSG. MSG cellular sources of IL-40 were determined by flow-cytometry and immunofluorescence. Serum concentration of IL-40 was assessed by ELISA and cellular sources of IL-40 were determined by flow-cytometry. An in vitro assay with recombinant IL-40 (rIL-40) was performed to detect the effect on cytokine production from peripheral blood mononuclear cells (PBMCs). RESULTS: IL-40 was significantly increased in the lymphocytic infiltrated MSG of patients with pSS and correlated with focus score and with IL-4 and transforming growth factor-ß expression. In addition, IL-40 was increased in the serum of pSS and its levels correlated with the EULAR Sjögren's Syndrome Disease Activity Index score. B cells from patients were shown to be the major source of IL-40 at both tissue and peripheral level. PBMCs from patients, exposed to rIL-40 in vitro, released proinflammatory cytokines, specifically interferon-γ from B cells and T-CD8+ and tumour necrosis factor-α and IL-17 from both T-CD4+ and T-CD8+. IL-40 expression in parotid glands of pSS-associated lymphomas was also increased. Moreover, IL-40-driven NETosis was evidenced in neutrophils obtained from pSS. CONCLUSION: Our results suggest that IL-40 may play a role in pSS pathogenesis and pSS-associated lymphomas.

Interleukin 9 neutralisation reduces collagen-induced arthritis severity in mouse models.

OBJECTIVES: Interleukin 9 (IL-9) is a mediator of tissue damage in several inflammatory diseases. In this study we aimed to evaluate the effects of in vivo IL-9 neutralisation in mice developing collagen induced arthritis (CIA). METHODS: DBA/1 were immunised with collagen in Freund's complete adjuvant (CFA) to induce arthritis. Anti-IL-9 mAb was injected in mice after the onset of arthritis (Group A) or on the same day as sensitisation and again on the day of the challenge (Group B). Histological analysis was performed in joints of mice and spleen cells were also analysed by flow cytometry. A geneset analysis was carried out on whole tarsal joint tissue transcriptomes. RESULTS: IL-9 was over-expressed in swollen joints of mice developing arthritis. Treatment with anti-IL-9 mAb after arthritis onset efficiently down-modulated the severity of joint inflammation. Similarly, anti-IL-9 mAb administered on the same day as sensitisation and on the day of challenge also delayed the onset of arthritis. Anti-IL-9 mAb injection after the onset of arthritis was associated with a decrease of CD4+ TNF-α+ cells and an increase of CD4+ FoxP3+ IL-10+ cells. Geneset analysis in CIA showed an up-regulation of GATA3 with no significant direct interactions between IL-9 and GATA3, which instead was mediated by IL-5 through STAT6. CONCLUSIONS: Our results suggest that IL-9 is involved in the immunopathogenesis of CIA. Further implications for the clinical translation of our findings are discussed.

IgA nephropathy in a child: Crohn's disease-associated or adalimumab induced?

In pediatric patients with Inflammatory Bowel Disease renal parenchymal disease is infrequent. There are only two reports about the association between IgA Nephropathy and Pediatric Crohn Disease. IgA Nephropathy is a rather uncommon complication of Tumor Necrosis Factor-alpha (TNF-α) inhibition. We describe a case of IgA Nephropathy which has arisen in a 11-year-old child 2 years after Crohn disease diagnosis, during therapy with anti-TNF-α. An ileal e jejunal Crohn disease was diagnosed at 9 years old, initially treated with prednisone, followed by biological therapy with anti-TNF-α (Adalimumab) due to severe disease activity, with gradual improvement of clinical conditions until clinical remission is achieved. Two years after the diagnosis, the child suddenly presented macroscopic hematuria. Subsequent laboratory examinations showed acute renal failure. So kidney biopsy was performed and IgA Nephropathy diagnosis was made. Adalimumab was discontinued and the child has been treated with steroids for sixth months associated with angiotensin-converting enzyme inhibitor resulted in clinical improvement over the following year and remission was maintained. To our knowledge the association of IgA Nephropathy and pediatric IBD during therapy with anti-TNF-α has never been reported. Careful monitoring of renal function, proteinuria, and autoantibodies is advised in patients treated with anti-TNF-α agents.

Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery.

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.

Hsp27 and Hsp60 in human submandibular salivary gland: Quantitative patterns in healthy and cancerous tissues with potential implications for differential diagnosis and carcinogenesis.

Tumors of the submandibular salivary gland (SMG) are uncommon but sufficiently frequent for the physician to consider them in routine examinations and for the pathologist to be prepared to differentiate them from other tissue abnormalities. However, scarcity of specimens makes training difficult, a situation compounded by the lack of accepted universal diagnostic guidelines. Furthermore, there is little information on the chaperone system (CS) of the gland, despite the increasing evidence of its participation in carcinogenesis as a biomarker for diagnosis and patient follow up, and in the mechanisms by which the tumor cells thrive. We are investigating this aspect of various tumors, and here we describe standardized methods for assessing the tissue levels of two chaperones, Hsp27 and Hsp60, in normal SMG and its tumors. We present illustrative results obtained with immunohistochemistry (IHC) and immunofluorescence-confocal microscopy (IF-CM), which we propose as a platform onto which a data base could be built by adding new information and which would provide material for developing guidelines for tumor identification and monitoring. The initial findings are encouraging in as much as the tumors surveyed showed quantitative patterns of Hsp27 and Hsp60 that distinguished tumoral from normal tissue and certain tumors from the others, and the results from IHC were confirmed by IF-CM.

Burkitt's lymphoma in pregnant woman: Difficult management of a rare case.

INTRODUCTION: Burkitt's lymphoma (BL), an aggressive subtype of non-Hodgkin lymphoma (NHL), is extremely rare during pregnancy. In the case of bowel localization, diagnosis can be very difficult. Moreover, signs and symptoms of the primary small intestine lymphoma are nonspecific, mostly attributable to the "mass effect" of the tumor. The most frequent symptom is abdominal cramp-like pain, associated with nausea and vomiting. PRESENTATION OF CASE: We report a rare case of a 37-year-old pregnant woman, at the 33rd week of gestation, with an abdominal-pelvic mass of uncertain nature. Surgical strategy consisted of a two-step procedure, which involved a cesarean section and typing of the mass: extemporaneous examination hypothesized intestinal lymphoma. The definitive histological examination confirmed the diagnosis of rare case of BL in pregnancy. DISCUSSION: The clinical case reported, representing a rare occurrence of BL in pregnancy, was associated with difficult interpretation and complex management. Lymphoma of the small intestine is often overlooked in the early stages of the disease, due to the fact that symptoms are non-specific and consequently underestimated. In our case, based on gestational age, it was possible to perform a multidisciplinary approach, a cesarean section with surgical intestinal exploration, achieving at the same time delivery of the child and a definitive diagnosis of BL with intestinal involvement. CONCLUSION: The involvement of multiple professionals is undoubtedly the best way to deal with the above referred to situation, with the main point being to keep in mind the possibility of this type of occurrence.

Molecular chaperones in tumors of salivary glands.

The salivary glands are key components of the mouth and play a central role in its physiology. Their importance may be appreciated considering their number, occurrence in pairs, and distribution in the mouth: two parotids, two submandibular, two sublingual, and many other small ones scattered throughout the mouth. They produce saliva, without which ingestion of non-liquid nutrients and speech would be practically impossible. Nevertheless, the physiology and pathology of salivary glands are poorly understood. For instance, tumors of salivary glands occur, and their incidence is on the rise, but their etiology and pathogenesis are virtually unknown, although some risk factors have been identified. Likewise, the role of the chaperoning system in the development, normal functioning, and pathology, including carcinogenesis, remains to be determined. This scarcity of basic knowledge impedes progress in diagnosis, disease monitoring, and therapeutics of salivary gland tumors. We are currently involved in examining the chaperoning system of human salivary glands and we performed a search of the literature to determine what has been reported relating to oncology. We found data pertaining to six components of the chaperone system, namely HSP27, HSP60, HSP70, HSP84, HSP86, and GRP78, and to another HSP, the heme-oxygenase H-O1, also named HSP32, which does not belong in the chaperoning system but seemed to have potential as a biomarker for diagnostic purposes as much as the HSP/chaperones mentioned above. The reported quantitative variations of the six chaperones were distinctive enough to distinguish malignant from benign tumors, suggesting that these molecules hold potential as biomarkers useful in differential diagnosis. Also, the quantitative variations described accompanying tumor development, as observed in cancers of other organs, encourages research to elucidate whether chaperones play a role in the initiation and/or progression of salivary gland tumors.

Could JC virus be linked to chronic idiopathic intestinal pseudo-obstruction?

JC virus is a member of the Polyomavirus family, infects humans worldwide, and 90% of the population carry antibodies to the virus by adult life. The initial infection is asymptomatic, but it may become persistent. JC virus DNA is frequently present in the upper and lower gastrointestinal tracts of healthy adults. Chronic idiopathic intestinal pseudo-obstruction, one of the most severe gastrointestinal motility disorders, is a condition characterized by a clinical picture mimicking small bowel occlusion with related symptoms and signs in the absence of demonstrable mechanical obstruction. Because of the known neuropathic capability of this virus, and its frequent presence in the gut, it has been proposed that JCV might be detectable in tissues of patients with chronic idiopathic intestinal pseudo-obstruction, and possibly be involved in the pathogenesis of this disease, because the virus may actively infect the enteroglial cells of the myenteric plexuses of the patients with chronic idiopathic intestinal pseudo-obstruction. We report two cases of upper idiopathic intestinal pseudo-obstruction associated with JCV infection.