Presence Of Inflammatory Infiltrate Research Articles

Transcriptional Network Analysis Implicates Altered Hepatic Immune Function in NASH development and resolution.

Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. Presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of NASH patients before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed NAFLD reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity upon LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intra-hepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy.

Epidermal growth factor receptor 2 immunoexpression in gastric cells of domestic cats with H. heilmannii infection

The aim of this study was to evaluate the immunoexpression of HER-2 in gastric cells of cats infected with Non H. pylori Helicobacter (NHPH) and to investigate an association with the presence of inflammatory infiltrate. Forty-eight paraffin-embedded gastric samples were retrieved from the archives of the Veterinary Anatomic Pathology Laboratory that had previously been shown to be positive for NHPH with the rapid urease test and cytology. Infection by NHPH was confirmed by histopathology using the Warthin-Starry staining. Hematoxylin-eosin stained sections were reviewed to evaluate inflammatory cell infiltrates. Immunohistochemical analysis was done using anti- H. pylori antibody and anti-HER-2 antibody. Molecular analysis was performed by PCR to confirm the presence of Helicobacter. Statistical analysis was performed to determine whether there was an association between the presence of H. Heilmannii and HER-2 expression in gastric samples. All samples were positive for NHPH, by immunohistochemistry, and confirmed by PCR as H. Heilmannii. On histopathologic analysis, 56,3% of the samples had lymphocytes and plasma cells infiltrates, 52,1% of which were mild and 4,2% moderate. The intensity of the inflammatory infiltrate in the gastric mucosa was significantly greater in the complete plasma membrane of parietal cells of gastric glands that had greater HER-2 immunoexpression (p = 0.0001). A statistically significant association (p = 0.007) between the H. Heilmannii infection score and the expression of HER-2 in the lateral membrane of gastric surface cells was observed. HER-2 expression may be increased in feline gastric cells infected by H. Heilmannii and in parietal cells of gastric glands with an increased inflammatory infiltrate.

Lect2 Controls Inflammatory Monocytes to Constrain the Growth and Progression of Hepatocellular Carcinoma

Leukocyte cell-derived chemotaxin-2 (LECT2) was originally identified as a hepatocyte-secreted chemokine-like factor and a positive target of β-catenin signaling. Here, we dissected out the mechanisms by which LECT2 modulates hepatocellular carcinoma (HCC) development using both HCC mouse models and human HCC samples. We have demonstrated that LECT2 exhibits dual abilities as it has profound repercussions on the tumor phenotype itself and the immune microenvironment. Its absence confers Ctnnb-1-mutated tumor hepatocytes a stronger ability to undergo epithelial to mesenchymal transition and fosters the accumulation of pejorative inflammatory monocytes harboring immunosuppressive properties and strong tumor-promoting potential. Consistent with our HCC mouse model, a low level of LECT2 in human HCC is strongly associated with high tumor grade and the presence of inflammatory infiltrates, emphasizing the clinical value of LECT2 in human liver tumorigenesis. Conclusion: Our findings have demonstrated that LECT2 is a key player in liver tumorigenesis because its absence reshapes the tumor microenvironment and the tumor phenotype, revealing LECT2 as a promising immunotherapeutic option for HCC.

Involvement of neutrophils in Chagas disease pathology.

Chagas disease (CD) is a public health problem in Latin America. The acute phase presents nonspecific symptoms and most patients recover from acute parasitemia and undergo a prolonged asymptomatic phase. Several years later, about 30% of infected individuals develop chronic cardiopathy with progressive cardiomegaly, arrhythmia, thromboembolic events and heart failure. These symptoms suggest a persistent association with the presence of inflammatory infiltrate and tissue, and cellular destruction in the heart muscle. Nevertheless, few research studies have attempted to understand the role of inflammatory cells, such as neutrophils, in establishing the pathology and progression of CD. Only recently have some studies been performed with this intention. Despite this effort, the role of neutrophils in CD is still considered controversial. This review discusses the morphological and functional characteristics of neutrophils that describes their participation in the establishment and progression of Trypanosoma cruzi infection, through the development of its effector functions, such as release of lithic components, production of oxidative agents and release of inflammatory mediators capable of modulating the host immune response.

Immunohistochemical Evaluation of Peri-Implant Soft Tissues around Machined and Direct Metal Laser Sintered (DMLS) Healing Abutments in Humans.

Background: Direct metal laser Sintering (DMLS) is an additive manufacturing technique that allows fabrication of dental implants and related components with a highly porous surface. To date, no human studies have investigated the soft tissue adhesion and presence of inflammatory infiltrate with porous DMLS healing abutments (HAs), nor have they compared these with the classic machined ones. Purpose: To evaluate the degree of cell adhesion (integrin expression) and the quantity/quality of inflammatory infiltrate, on HAs with different surfaces; full DMLS, full machined, and hybrid (half DMLS and half machined). Methods: Fifty implant patients were randomly assigned to receive one of these different Has: T1, full DMLS (11 subjects); T2, machined in the upper portion and DMLS in the lower one (10 subjects); T3, DMLS in the upper portion and machined in the lower one (19 subjects); T4, full machined (10 patients). Thirty days after placement, circular sections of soft tissues around HAs were retrieved for immunohistochemical evaluation. Results: With regard to the adhesion molecules, the samples showed different intensity of integrin expression, with a statistically significant difference (p < 0.001) between T1 and the other groups. All the samples were positive for the different clusters related to the inflammatory infiltrate (T lymphocytes, CD3; B lymphocytes, CD20; and macrophages, CD68), but a lower infiltrate was found in T1, with statistically significant differences (p < 0.001) among the groups. Conclusions: The HA surface seems to influence the degree of cell adhesion and the inflammatory infiltrate of the surrounding soft tissues.

BALB/c mice infected with DENV-2 strain 66985 by the intravenous route display injury in the central nervous system

Dengue is a mild flu-like arboviral illness caused by dengue virus (DENV) that occurs in tropical and subtropical countries. An increasing number of reports have been indicating that dengue is also associated to neurological manifestations, however, little is known regarding the neuropathogenesis of the disease. Here, using BALB/c mice intravenously infected with DENV-2 strain 66985, we demonstrated that the virus is capable of invading and damaging the host’s central nervous system (CNS). Brain and cerebellum of infected animals revealed histological alterations such as the presence of inflammatory infiltrates, thickening of pia matter and disorganization of white matter. Additionally, it was also seen that infection lead to altered morphology of neuroglial cells and apoptotic cell death. Such observations highlighted possible alterations that DENV may promote in the host’s CNS during a natural infection, hence, helping us to better understand the neuropathological component of the disease.

Histopathological evaluation of dental follicles associated with impacted third molars

Aim: To histologically evaluate dental follicles of impacted third molars with no radiographic evidence of pathology. Methods: We carried out both a quantitative and qualitative analysis of pericoronal follicles removed from impacted third molars and investigated the association with clinical data. The sample included 36 extracted dental follicles of impacted third molars, obtained from 28 patients, which presented with no radiographic evidence of pathologies. Results: None of the follicles analyzed showed any pathological entity. The epithelial lining was observed in 61.1% of samples, being identified as reduced enamel epithelium. We found a significant relation between the the presence of inflammatory infiltrate and the group aged over 21 years (64.3%; p&lt;0.05). Conclusions: Considering the absence of pathological lesions, we suggest that impacted third molars should only be extracted in young-aged individuals due to specific pathologies or indications.

Adipose-derived stem cells improve full-thickness skin grafts in a rat model

To investigate the effects of heterologous adipose-derived stem cells (ADSCs) on autologous full-thickness skin grafts, we designed a first-intention healing model using Wistar rats. We harvested and sutured two full-thickness skin grafts in the dorsal recipient beds of 15 rats, randomized into three groups. In the treatment group, 1 × 106 ADSCs resuspended in saline solution (200 μL) were administered subcutaneously to the skin graft. The control group received only saline solution subcutaneously, whereas the negative control group did not receive any treatment. Compressive dressings were maintained until postoperative day 5. The grafts were assessed by two observers, who checked for the presence of epidermolysis on day 14. Planimetry showed the relative areas of normal skin, redness, ulceration, and contraction. Graft samples were obtained on day 14 and stained with hematoxylin and eosin and Masson's trichrome. Epidermal analysis evaluated thickening, keratosis, acanthosis, hydropic degeneration, and inflammatory infiltrate. Dermal evaluation investigated the absence of hair follicles, granulation tissue formation, presence of inflammatory infiltrate, and collagen deposition. Immunohistochemistry was performed for dermal anti-VEGF and epidermal anti-Ki-67 staining. The ADSC group presented better macroscopic aspects, lower incidence of epidermolysis, and less loss of hair follicles. In addition, the ADSC group presented the lowest frequency of histopathological changes in the dermis and epidermis, as well as the largest subcutaneous and granulation tissue VEGF averages and the weakest Ki-67 staining of the epidermal basal layer. Subcutaneous administration of ADSCs may improve the integration of skin grafts, reducing the deleterious effects of ischemia and reperfusion injury.

Assessment of the correlation between histological degeneration and radiological and clinical parameters in a series of patients who underwent lumbar disc herniation surgery

Background and objectiveThe use of histological degeneration scores in surgically-treated herniated lumbar discs is not common in clinical practice and its use has been primarily restricted to research. The objective of this study is to evaluate if there is an association between a higher grade of histological degeneration when compared with clinical or radiological parameters. Patients and methodRetrospective consecutive analysis of 122 patients who underwent single-segment lumbar disc herniation surgery. Clinical information was available on all patients, while the histological study and preoperative magnetic resonance imaging were also retrieved for 75 patients. Clinical variables included age, duration of symptoms, neurological deficits, or affected deep tendon reflex. The preoperative magnetic resonance imaging was evaluated using Modic and Pfirrmann scores for the affected segment by 2 independent observers. Histological degeneration was evaluated using Weiler's score; the presence of inflammatory infiltrates and neovascularization, not included in the score, were also studied. Correlation and chi-square tests were used to assess the association between histological variables and clinical or radiological variables. Interobserver agreement was also evaluated for the MRI variables using weighted kappa. ResultsNo statistically significant correlation was found between histological variables (histological degeneration score, inflammatory infiltrates or neovascularization) and clinical or radiological variables. Interobserver agreement for radiological scores resulted in a kappa of 0.79 for the Pfirrmann scale and 0.65 for the Modic scale, both statistically significant. ConclusionsIn our series of patients, we could not demonstrate any correlation between the degree of histological degeneration or the presence of inflammatory infiltrates when compared with radiological degeneration scales or clinical variables such as the patient's age or duration of symptoms.

Effect of Increased Intra-abdominal Pressure on Liver Histology and Hemodynamics: An Experimental Study.

While reduction of portal venous (PV) blood flow has been described in animal models of intra-abdominal hypertension, reports on compensatory changes in hepatic arterial (HA) flow, known as the hepatic arterial buffer response are controversial. Pneumoperitoneum with helium was induced in 13 piglets. Hemodynamic measurements and pathological assessment were conducted at baseline and during the three subsequent phases: Phase A: 45 minutes with a stable intra-abdominal pressure of 25 mmHg; phase B: 45 minutes with a stable intra-abdominal pressure of 40 mmHg; and phase C during which the abdomen was re-explored and reperfusion of the liver was allowed to take place. Phase B pressure was significantly greater than phase A pressure in both the PV and the inferior vena cava, demonstrating a positive association between escalating intra-abdominal hypertension and the pressure in these two vessels (all p<0.001). In contrast, HA pressure was comparable between baseline and phase A, while it tended to decrease in phase B. Regarding histology, the most notable abnormality was the presence of inflammatory infiltrates and hepatocyte necrosis. Helium-insufflation increased PV pressure with a partial compensatory decrease of HA pressure. Nonetheless, findings consistent with hepatic ischemia were observed on pathology.

Effect of atenolol pre-treatment in heart damage in a model of intestinal ischemia-reperfusion.

To investigate the effects of atenolol in inflammatory mediator and oxidative stress in a myocardial injury by intestinal ischemia/reperfusion in rat model. Adult Wistar male rats were randomly (n=8), anesthetized and divided in: Sham: submitted to operation only; group SS+IR: intravenous saline infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); group AT+IR: intravenous atenolol infusion (2 mg/kg) following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); and group AT+I+AT+R: intravenous atenolol infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and in the time 45 minutes other atenolol doses were administrated and the artery was open for 120 minutes (reperfusion), all animals were submitted to muscular relaxation for mechanical ventilation. In the end of experiment the animals were euthanized and the hearts tissue were morphology analyzed by histology and malondialdehyde by ELISA, and the plasma were analyzed for tumor necrosis factor-alpha by ELISA. The group SS+IR demonstrated the higher malondialdehyde levels when compared with the atenolol treated-groups (p=0.001) in the heart tissue. The tumor necrosis factor-alpha level in plasma decrease in the treated groups when compared with SS+IR group (p=0.001). Histology analyses demonstrate pyknosis, edema, cellular vacuolization, presence of inflammatory infiltrate and band contraction in the heart tissue of the rats. Atenolol significantly reduce the degree of cardiac damage after intestinal ischemia-reperfusion.

Evaluation of Mandibular Bone After Dental Extraction in Rats Treated With Antiresorptive Drugs

Zoledronic acid (ZOL) and denosumab (Dmab) are commonly used to treat bone pathologies. Because these drugs suppress bone metabolism, this study sought to compare their effect on bone repair after tooth extraction. Four-week-old male Wistar rats were randomly assigned to 1 of 3 groups: ZOL 0.125mg/kg, Dmab 0.25mg/kg, or saline solution 10mL/kg (control). After 1week of treatment, the first left molar was extracted; the rats were euthanized at 28days. The jaws were removed and photographed for macroscopic analysis of wound healing and then subjected to tomographic and histologic analyses. Immunohistochemistry was carried out against the receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG). No difference in wound healing, presence of inflammatory infiltrate and bone sequestration, or osteocyte expression of RANKL and OPG was found among groups. Tomographic analysis showed that the ZOL group had less alveolar resorption and more complete alveolar repair compared with the other groups. There was a statistically significant difference in the OPG marker in the control (P=.008) and ZOL (P=.05) groups when comparing the extracted and non-extracted sides. Systemic use of ZOL can improve alveolar bone healing; however, the potential risk for the development of osteonecrosis should be considered. Higher expression of OPG seems to be associated with the control of osteoclastogenesis during bone repair.

Intestinal toxicity evaluation of long-circulating and pH-sensitive liposomes loaded with cisplatin

Cisplatin (CDDP) is a chemotherapeutic agent widely used in several anticancer protocols for instance head and neck, testicle, ovarian, lung and peritoneal carcinomatosis. According to the literature, the use of CDDP is associated with several side effects; among them, we highlighted the mucositis. CDDP, when administered by IP, promoted significant intestinal epithelium alterations in an experimental model. Our research group has proposed that the incorporation of CDDP into long-circulating and pH-sensitive liposomes (SpHL-CDDP) could help to overcome some side effects induced by this drug. Thus, we evaluated signs of intestinal toxicity 24h and 72h after the administration of a single i.p dose of free CDDP or SpHL-CDDP to healthy Swiss mice. Twenty-four hours after administration of free CDDP, the mice showed signs of intestinal toxicity, principally weight loss, increased intestinal permeability associated with a decrease in expression of tight junctions, and histological damage with the presence of inflammatory infiltrates and activation of ERK1/2 and NF-κB. These changes persisted after 72h. While signs of intestinal toxicity were also observed 24h after administration of SpHL-CDDP, after 72h body weight and intestinal permeability of mice in this group were similar to those of mice in the control group. In comparison with the free CDDP treatment group, 72h after treatment mice in the SpHL-CDDP group showed better histological parameters, lower levels of inflammatory infiltrate with increased IL-10 and IgA levels, and less activation of caspase-3, ERK1/2 and NF-κB. These differences could account for the recovery of the intestinal epithelium observed in mice treated with SpHL-CDDP but not in mice treated with free CDDP. In conclusion, here we show that encapsulation of CDDP in SpHL lessens intestinal damage and that, as such, SpHL-CDDP is a promising candidate for clinical use.

Agreement between postmortem endometrial cytology, biopsy and bacteriology in culled dairy cows

The objectives of this study were to determine: a) the agreement between postmortem endometrial cytology, uterine biopsy and presence of intrauterine fluid in apparently normal genital tracts collected from culled dairy cows; b) the agreement between results obtained from paired uterine horns using the different diagnosis methods; and c) the microorganisms isolated from uteri with cytological endometritis. One hundred grossly normal genital tracts from Holstein cows were collected at a local slaughterhouse. Samples for cytology, histopathology and bacteriology were obtained from both uterine horns, and presence of any intrauterine content was determined after opening the tracts. Cut-offvalues used for positive cytology were ≥5% PMN (polymorphonuclear neutrophils). Data were analyzed by ROC curve analysis, Cohen's Kappa method and Chi-square tests. Presence of inflammatory infiltrate and its endometrial distribution were the only histological parameters significantly correlated with cytology results (AUC: 0.780 and 0.694, respectively). Agreement between histology and cytology was moderately high for presence of infiltrate (kappa = 0.55) and low for infiltrate distribution (kappa = 0.33). Other histological parameters (status of endometrial epithelium, endometrial glands or fibrosis), intrauterine content or bacteriology were not correlated with cytology. Presence of intrauterine content was significantly (P = 0.036) related with biopsy results. Moderately high agreement was observed between paired uterine horns for cytology (kappa = 0.65) and biopsy (kappa = 0.74). Bacteriology was not related with cytology or biopsy, but different bacteria were isolated from cytology negative or positive uteri. It was concluded that endometrial cytology, although less sensitive than biopsy, is a useful tool for diagnosing subclinical endometrial inflammation.

Life Span of a Parapoxvirus Ovis Vector and Local Immune Activation in a Non-Permissive Host

Objective: Promising vector vaccine candidates derive from parapoxvirus ovis (PPVO) strain D1701. Thorough analysis of their safety is therefore of great relevance. We investigated the safety of and the immune response induced by the reporter gene β-galactosidase-expressing vector PPVO D1701-VrV. It is important to define the life span of the vector in vaccinated hosts. We chose non-permissive mice for a first study of PPVO longevity and clearence. Methods: Mice were inoculated i.m. with a TCID50 of 106.5 PPVO D1701-VrV and with PBS into the quadriceps and contralateral quadriceps muscle, respectively. The muscles were analyzed for viral genome, infective virus particles and infiltrating leukocytes. Day 21 was fixed as a late vector virus clearance option. The immune cell content of the draining lymph nodes, IFN-γ production by in vitro restimulated splenocytes, and expression of β- galactosidase in myoblasts in vitro was characterized. Results: Upon i.m. application infective PPVO D1701-VrV particles were detectable at the inoculation site for at least seven days but cleared at the fixed late time point. Among the re-isolated vector virus aberrantly shaped PPVO particles were detected, but the reporter gene expression remained stable. The PPVO D1701-VrV-induced local immune activation was characterized by the presence of inflammatory infiltrates and, even more important for the priming capability of the viral vector, significantly enhanced numbers of CD11c+ B220- conventional DC, CD11c+ B220+ plasmacytoid DC, CD4+ T cells, CD8+ T cells, and B220+ B cells in the muscle-draining inguinal lymph nodes. Elevated interferon-gamma (IFN-γ) production by splenocytes of PPVO D1701-VrV-inoculated mice indicated a systemic immunostimulatory effect. The detection of β-galactosidase expression by inoculated myoblasts shows that PPVO D1701-VrV is able to enter murine myoblasts and express the foreign antigen. Conclusions: Our data support the safety of PPVO D1701 as a vector virus under non-permissive conditions.

Immune-Mediated Heart Disease.

The heart involvement in systemic autoimmune diseases represents a growing burden for patients and health systems. Cardiac function can be impaired as a consequence of systemic conditions and manifests with threatening clinical pictures or chronic myocardial damage. Direct injuries are mediated by the presence of inflammatory infiltrate which, even though unusual, is one of the most danger manifestations requiring prompt recognition and treatment. On the other hand, a not well-managed inflammatory status leads to accelerated atherosclerosis that precipitates ischemic disease. All cardiac structures may be damaged with different grades of intensity; moreover, lesions can appear simultaneously or more frequently at a short distance from each other leading to the onset of varied clinical pictures. The pathogenesis of heart damages in systemic autoimmune conditions is not yet completely understood for the great part of situations, even if several mechanisms have been investigated. The principal biochemical circuits refer to the damaging role of autoantibodies on cardiac tissues and the precipitation of immune complexes on endocardium. These events are finally responsible of inflammatory infiltration which leads to subsequent worsening of the previous damage. For these reasons, it appears of paramount importance a regular and deepened cardiovascular assessment to prevent a progressive evolution toward heart failure in patient affected by autoimmune diseases.

Physiopathology of Malaria-Associated Acute Respiratory Distress Syndrome

Malaria is a major global health problem, affecting mainly tropical and subtropical areas. In Brazil, in most cases, it was caused by Plasmodium vivax and Plasmodium falciparum, respectively. Malaria can lead to severe complications like severe anemia, placental malaria, cerebral malaria and others. When associated with lung, severe malaria can cause Acute Respiratory Distress Syndrome (ARDS). The main problems of this syndrome are the presence of inflammatory infiltrate, hemorrhages and edema. It is not known what starts the development of malaria associated ARDS, but it could be related to adhesion molecules expressed by the parasite on the surface of the erythrocyte membrane, or with the inflammatory responses of the host. However, latest researches show new mechanisms involving neutrophils are the key to the establishment of this syndrome.

Histopathological lesions in encephalon and heart of mice infected with Toxoplasma gondii increase after Lycopodium clavatum 200dH treatment

In many cases, symptoms of toxoplasmosis are mistaken for the ones of other infectious diseases. Clinical signs are rare in immunocompetent people. However, when they arise, in the acute phase of infection, several organs are affected due to the rapid spread of tachyzoites through the bloodstream. In the present study, the reduction of tachyzoites in peripheral blood of mice of G72 (infected 72h after treatment) and G48 (infected 48h after treatment and treated three more times), when compared with IC (infected and non-treated), suggests protective effect exerted by Lycopodium clavatum. If on the one hand L. clavatum brought benefits, reducing parasitemia, on the other hand, the parasitism became exacerbated. Histopathological analysis demonstrated focal, multifocal and diffuse inflammatory infiltrates, ranging from absent, discreet, moderate to intense, in heart and encephalon of mice of NIC (non-infected and non-treated), IC, G48 and G72 groups, respectively. In the perivascular region and meninges, the injuries were enlarged. The presence of tachyzoites was demonstrated through immunohistochemical (IHC) assay in myocardium. Toxoplasma gondii induced increase of collagen fibers in myocardium of mice of G72 and G48 groups, compared with IC (p<0.05) and NIC (p<0.001). The presence of inflammatory infiltrates, as well as the progressive fibrosis, caused myocardial remodeling in animals treated with L. clavatum. Counterstaining with H&E suggests TGF-β expression by mononuclear cells in the inflammatory infiltrate. Based on our results, we can conclude that the adopted regimen and potency exerted a protective effect, reducing parasitemia. However, it intensified the histopathological lesions in encephalon and heart of mice infected with T. gondii.

Chronic pancreatitis and lipomatosis are associated with defective function of ciliary genes in pancreatic ductal cells

Genetic diseases associated with defects in primary cilia are classified as ciliopathies. Pancreatic lesions and ductal cysts are found in patients with ciliopathic polycystic kidney diseases suggesting a close connection between pancreatic defects and primary cilia. Here we investigate the role of two genes whose deletion is known to cause primary cilium defects, namely Hnf6 and Lkb1, in pancreatic ductal homeostasis. We find that mice with postnatal duct-specific deletion of Hnf6 or Lkb1 show duct dilations. Cells lining dilated ducts present shorter cilia with swollen tips, suggesting defective intraciliary transport. This is associated with signs of chronic pancreatitis, namely acinar-to-ductal metaplasia, acinar proliferation and apoptosis, presence of inflammatory infiltrates, fibrosis and lipomatosis. Our data reveal a tight association between ductal ciliary defects and pancreatitis with perturbed acinar homeostasis and differentiation. Such injuries can account for the increased risk to develop pancreatic cancer in Peutz-Jeghers patients who carry LKB1 loss-of-function mutations.

Advances in serological diagnostics of inflammatory myopathies.

Inflammatory myopathies are rare diseases. Their diagnosis criteria are historically based on their clinical phenotype (topography of the muscle weakness, presence of skin lesions and/or of extra-skin/muscle signs) and the presence of inflammatory infiltrates on muscle biopsy. However, the recent discovery of different myositis-specific antibodies (MSA) or myositis-associated antibodies (MAA) permitted to revisit these old classifications. This review covers recent findings in clinical and pathological phenotypes regarding prognosis, associated cancer and response to the treatment based on MSA/MAA categorization. Since the mid-1970s, about 20 MSA or MAA were discovered year after year (by immunoprecipitation). Now commercial kits (mainly dot line assays) permit their detection routinely which is clearly a help for the diagnosis but also give some key indications on clinical features, risk of associated cancers and response to the treatments. Overlap myositis is associated with antisynthetase antibodies (Abs) or those associated with sclerodermia (anti-RNP, Ku and PM-ScL). Dermatomyositis is associated with anti-Mi2, small ubiquitin-like modifier activating enzyme (SAE), nuclear matrix protein-2 (NXP2), TIF-1γ or melanoma differentiation-associated gene 5 (MDA5) Abs. Immune-mediated necrotizing myopathies are associated with anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) Abs. One third of inclusion body myositis' patients also presented anti-cytosolic 5'-nucleotidase 1A (cN1A) Abs. The risk of associated cancers is elevated with anti-TIF-1γ, NXP2 or HMGCR Abs.