Familial exudative vitreoretinopathy with TGFBR2 mutation without signs of Loeys-Dietz syndrome.

Background: Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disorder with high genetic heterogeneity, and it is characterized by a defect in the development of the retinal vascular system. Loeys-Dietz syndrome (LDS) is an autosomal dominant systemic connective tissue disorder that is caused by mutations in the genes related to transforming growth factor signaling systems including the TGFBR2 gene. Two earlier studies reported that patients with LDS from mutations in the TGFBR2 gene were associated with FEVR-like retinal phenotype. The purpose of this study was to determine the characteristics of a case of FEVR without systemic abnormalities who had a mutation in the TGFBR2 gene.Materials and Methods: The clinical appearances and surgical outcomes were determined from the medical records. Genetic analysis was performed by whole exome sequencing.Results: A 15-year-old boy was diagnosed with FEVR by the appearance of the peripheral retina of both eyes and a retinal detachment in the left eye. Whole exome sequencing revealed a heterozygous deletion mutation in the TGFBR2 gene. A de novo mutation was confirmed by examining the family members. No systemic abnormalities were detected in the patient including those associated with LDS.Conclusions: FEVR can be associated with a TGFBR2 mutation without showing signs of LDS.

Possible Involvement of Sphingosine-1-Phosphate/G(i)/RhoA pathways in adherence of eosinophils to pulmonary endothelium.

BACKGROUND: Sphingosine-1-phosphate (S1P), a lysophospholipid released from inflammatory cells, causes cell migration by increasing cytokines and chemokines. This study was designed to determine whether S1P causes adherence of eosinophils to pulmonary endothelial cells via enhancement of adhesion molecule expression. METHODS: Expression of VCAM-1 and ICAM-1 was assessed by RT-PCR and Western blot analysis in human pulmonary microvasucular endothelial cells (HPMVECs). The number of adherent eosinophils to HPMVECs was calculated according to adhesion assay. RESULTS: Pre-treatment of HPMVECs with S1P increased mRNA and protein expression of VCAM-1, in contrast, did not dramatically increase those expression of ICAM-1. The maximal expression of these adhesion molecules in mRNA and protein was observed 4 and 8h after exposure to S1P, respectively. Pre-treatment with S1P also activated RhoA, a monomeric G protein; the ability of S1P to enhance the expression of VCAM-1 was attenuated by RhoA related inhibitors such as Y-27632, C3 exoenzyme, and GGTI-286. The effects of S1P on VCAM-1 were attenuated by pre-incubation with pertussis toxin, which catalyzes the ADP-ribosylation of G(i), a heterotrimeric G protein. After HPMVECs were treated with S1P, adhesion of human eosinophilic leukemic cell line (EoL-1) cells to HPMVECs was enhanced in a concentration-dependent manner. Augmented adherence of EoL-1 cells by S1P was also attenuated by Y-27632 and pertussis toxin. S1P causes adherence of eosinophils to pulmonary endothelium via RhoA activation. CONCLUSIONS: S1P may act as a lipid mediator in asthma. The RhoA/Rho-kinase pathway may be a therapeutic target for preventing eosinophil infiltration to the airway.

Thalidomide attenuates airway hyperresponsiveness and eosinophilic inflammation in a murine model of allergic asthma.

Asthma is characterized by chronic eosinophilic inflammation and hyperresponsiveness of the airways. We hypothesized that thalidomide, which has numerous immunomodulatory properties, may have anti-inflammatory effects in allergic asthma. BALB/c mice sensitized and challenged with ovalbumin (OVA) were treated orally with thalidomide (30, 100, or 300 mg/kg) or a vehicle. When thalidomide was administered to OVA-challenged mice, the number of eosinophils in bronchoalveolar lavage fluid (BALF) was significantly decreased. The numbers of inflammatory cells other than eosinophils were not reduced by thalidomide. Thalidomide inhibited the elevated levels of interleukin-5 (IL-5) and tumor necrosis factor-alpha (TNF-alpha) in BALF by OVA challenges. Histological analysis of the lung revealed that both the infiltration of inflammatory cells and the hyperplasia of goblet cells were significantly suppressed by thalidomide treatment. Furthermore, thalidomide significantly inhibited the response to methacholine induced by OVA challenges. Taken together, thalidomide treatment decreased airway inflammation and hyperresponsiveness in a murine model of allergic asthma. These results might provide an opportunity for the development of novel therapeutics to treat severe asthma.

[A case of pulmonary inflammatory pseudotumor accompanied with increased serum immunoglobulin G levels and autoimmune pancreatitis].

A 77-year-old man with increased serum immunoglobulin G levels and autoimmune pancreatitis was found to have a chest X-ray abnormality. The chest X-ray and CT films showed a mass shadow in the right lower lobe and lymphadenopathy. Since transbronchial tumor biopsy did not obtain diagnostic material, CT-guided cutting needle biopsy was performed. The microscopic findings showed plasma cells and lymphocytes infiltrating the pleura and alveolar interstitium. A diagnosis of inflammatory pseudotumor was suspected, but it was difficult to exclude malignancy. Therefore, wedge resection of the right lower lobe including the mass and incisional biopsy of mediastinal lymph nodes were performed. Histopathologic examination of the resected specimen revealed inflammatory pseudotumor that was predominantly composed of mature plasma cells infiltrating in the bronchiolar wall, peribronchiolar interstitial tissue, alveolar wall, visceral pleura, the diaphragmatic area of the parietal pleura and mediastinal lymph nodes. Immunohistochemical staining revealed many IgG4-positive plasma cells diffusely infiltrated in the resected mass and lymph nodes. In this case, there is a possibility that patient developed autoimmune pancreatitis, pulmonary inflammatory pseudotumor and lymphadenopathy as part of systemic IgG4-related

[Prevalence of myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) in patients with interstitial pneumonia].

Myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) is an autoantibody that is frequently found in patients with vasculitides. We encountered some MPO-ANCA positive patients with interstitial pneumonia who lacked vasculitides, but its meaning remains unclear. We measured MPO-ANCA titers in 69 patients with interstitial pneumonia (IP) who did not have collagen vascular diseases and observed their outcome. MPO-ANCA was positive in 5 patients and its prevalence was 7.2%. Patients with MPO-ANCA positive showed higher positivity in rheumatoid factor (RF) than patients with MPO-ANCA negative. The sensitivity and specificity of a combination of anti-nuclear antibody-negative and RF-positive were 80.0% and 87.7%, respectively. Two patients were accompanied by microscopic polyangiitis and the 3-year survival rate was 40% in all patients with MPO-ANCA. Measurement of MPO-ANCA titers in patients with IPs is meaningful for determining therapeutic strategy.

[A case of primary pulmonary MALT lymphoma with diffuse micronodules and anemia].

A 52-year-old woman presented with low grade fever and fatigue. She had diffuse micronodules in both lung fields on chest X-ray. Chest CT showed diffuse multiple small nodules. Laboratory examination revealed high values for C-reactive protein, together with anemia and polyclonal hyper-immunoglobulinemia and an elevated interleukin-6 level. Although we suspected multicentric Castleman's disease, thoracoscopic lung biopsy revealed primary pulmonary MALT lymphoma by immunohistochemical analysis of tissue specimens. After COP and rituximab therapy, partial remission was obtained.