Regulation of mast cell-mediated innate immunity during early response to bacterial infection

Summary Although the area of research on the role of MCs in innate immunity is relatively new, a number of studies that are reviewed here provide substantial evidence that MCs play a critical role in host immune defense against gram-negative bacteria. The studies show that mast cells have the ability to recognize and engulf bacteria and they release a number of inflammatory mediators including interleukin (IL)-4, IL-6, IL-10, TNFα, and leukotrienes in response to bacterial challenge. MC-derived TNFα and leukotrienes are shown to be important for bacterial clearance and early recruitment of phagocytic help at the site of infection. Studies directed at elucidating the molecular mechanisms associated with mast cell recognition of bacteria and subsequent events leading to mast cell mediator release revealed that GPI anchored CD48 molecule present on the cell surface of mast cells serves as a receptor for the bacterial adhesion molecule, FimH. The ligation of CD48 receptor by FimH-expresing bacteria results in bacterial uptake into caveolar chambers. This distinct mechanism of bacterial uptake promot es bacteral survival inside the cytosol of the mast cells. Although the exact mechanism(s) of how MC-dependent inflammatory responses are regulated is currently not known, recent studies have shown that complement, CD11β/CD18 (Mac-1) and protein tyrosine kinase JAK3, and TLR4 are important for the full expression of MC-dependent innate immunity in mice.     

Profil clinico-biologique et immunohématologique des patients atteints de β-thalassémie en Tunisie : à propos de 26 cas

Aim of the studyTo study the clinical and biological profile of β-thalassemic patients in our region, reflecting the quality of their care.Patients and methodsA retrospective study (2010–2011) on 26 β-thalassemic patients followed in the pediatrics service at CHU Farhat Hached Sousse, Tunisia. Epidemiological, clinical and biological data were collected from medical records and transfusion files of patients. The transfusion protocol adopted was to maintain a hemoglobin level > 10 g/dL by regular transfusions every 3–4 weeks. Iron chelation therapy, in order to maintain serum ferritin < 1500 ng/mL, was introduced when serum ferritin exceeded 800–1000 ng/mL.ResultsThe mean age of patients at diagnosis was 15 months. The clinical impact of anemia had resulted in failure to thrive in 54% of patients and facial dysmorphism in 23%. The average transfusion requirement was estimated at 311.02 mL/kg/year with 6 cases of hyperconsumption. The immunohaematological monitoring showed the appearance of anti-RBC alloimmunization in one patient and 4 cases of autoimmunization. Poor adherence of chelation therapy was 62% and causing 5 cases of cardiac complications, 4 cases of liver injury and 14 cases of endocrine complications.ConclusionImproving the therapeutic care of β-thalassemic children requires better monitoring of transfusion recovery and improved adherence to chelation therapy.     

Identification of novel markers for mouse CD4+ T follicular helper cells

CD4⁺ T follicular helper (T_FH) cells are central for generation of long‐term B‐cell immunity. A defining phenotypic attribute of T_FH cells is the expression of the chemokine R CXCR5, and T_FH cells are typically identified by co‐expression of CXCR5 together with other markers such as PD‐1, ICOS, and Bcl‐6. Herein, we report high‐level expression of the nutrient transporter folate R 4 (FR4) on T_FH cells in acute viral infection. Distinct from the expression profile of conventional T_FH markers, FR4 was highly expressed by naive CD4⁺ T cells, was downregulated after activation and subsequently re‐expressed on T_FH cells. Furthermore, FR4 expression was maintained, albeit at lower levels, on memory T_FH cells. Comparative gene expression profiling of FR4^hi versus FR4^lo Ag‐specific CD4⁺ effector T cells revealed a molecular signature consistent with T_FH and T_H1 subsets, respectively. Interestingly, genes involved in the purine metabolic pathway, including the ecto‐enzyme CD73, were enriched in T_FH cells compared with T_H1 cells, and phenotypic analysis confirmed expression of CD73 on T_FH cells. As there is now considerable interest in developing vaccines that would induce optimal T_FH cell responses, the identification of two novel cell surface markers should be useful in characterization and identification of T_FH cells following vaccination and infection.     

The diagnostic value of the bronchoalveolar lavage in interstitial lung diseases

Objective

Bronchoalveolar lavage (BAL) is a diagnostic tool often used during the management of interstitial lung diseases (ILD). However, its diagnostic value in discrimination between entities comprising the very heterogenous group of ILD, is still a controversial issue. The objective of our study is to assess the diagnostic value of BAL in the management of ILD, by comparing the cytological findings in BAL fluid among the different diseases of this group.

Methods

It was a retrospective, observational study of 151 patients between January 2012 and December 2015. BAL fluid cytology was performed to analyse the distribution of leucocytes population subsets in patients with ILD.

Results

The mean age was 52.78 years; 74.83% were women. The analysis of the following main groups of diseases was performed : sarcoïdosis (n?=?30), idiopathic pulmonary fibrosis (IPF; n?=?22), other idiopathic interstitial pneumonia (non specific interstitial pneumonia, cryptogenic organising pneumonia and respiratory bronchiolitis interstitial lung disease; n?=?20) and connective tissue disease (n?=?14).Overall, out of 141 patients, 22% had sarcoïdosis, 15.6% had idiopathic pulmonary fibrosis (IPF), 14.18% had other idiopathic interstitial pneumonia (IIP) and 9.9% had connective tissue disease (CTD). Mixed alveolitis was common in the 4 groups, sarcoïdosis had higher proportion of lymphocytes and IPF had higher neutrophils count. However, there was no significant statistical difference of BAL cellular count among these diseases (p?>?0.05). Also, the prevalence of studied diseases did not change with variation of BAL cellular count (p?>?0.05).

Conclusion

Alone, the BAL cytological analysis has a limited value to provide substantial information that could lead to discriminate between diseases that form ILD. Thus, it must be always associated with other diagnostic methods.

     

Diffusion-weighted MR imaging of the liver of hepatitis C patients

Magnetic resonance diffusion-weighted imaging (DWI) of the liver was investigated to determine whether this method could be used to differentiate between the stages of fibrosis and inflammation for hepatitis C viral infection. DWI data were recorded for 18 hepatitis C patients and 10 control subjects using a modified pulse sequence allowing a 52 ms echo time delay. Acquisitions were performed with breath holding using five different b gradient factor values ranging between 50 and 250 s/mm(2) and in the three axes. Apparent diffusion coefficient (ADC) values were measured from a 5.7 cm(2) area in the central region of the liver. The inflammation and fibrosis grades were evaluated histologically on a biopsy sample. The mean ADC values were 2.30 +/- 1.28 x 10(-3) and 1.79 +/- 0.25 x 10(-3) mm(2)/s for hepatitis C patients and control subjects, respectively. Using our technique, no correlation could be found between the ADC values and the inflammation or fibrosis scores, indicating that tissue changes produced by hepatitis C do not appear to be quantifiable by DWI.     

Retrospective-prospective study of safety and efficacy of sofosbuvir-based direct-acting antivirals in HIV/HCV-coinfected participants with decompensated liver disease pre– or post–liver transplant

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre– or post–liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6–29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre–LT and 26 post–LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre–LT and three post–LT. Overall, transplant free survival was 42.8% at 4 years and post–LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post–LT, with post–LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients.     

Peripheral nervous system pathology in fragile X tremor/ataxia syndrome (FXTAS)

Fragile X tremor/ataxia syndrome (FXTAS) occurs in individuals with moderate CGG expansion of the fragile X mental retardation 1 (FMR1) gene and is associated with intranuclear inclusions in neurons and astrocytes. Although the neuropathologic findings in the brain and spinal cord were described, pathological features in the peripheral nervous system were not reported. Here, we report on novel neuropathological findings in the peripheral nervous system and especially in autonomic ganglia at autopsy in a man with FXTAS. In addition to the characteristic brain and spinal cord findings, typical intranuclear inclusions were identified in the ganglion cells of adrenal medulla, dorsal root ganglia, paraspinal sympathetic ganglia, myenteric ganglia of the stomach and subepicardial autonomic ganglion of the heart. Our findings indicate that FXTAS diffusely involves the central and peripheral nervous systems, which explains the protean neurological symptoms ranging from dementia to dysautonomia.