Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-β present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.

Influenza virus causes a heterogeneous respiratory infectious disease ranging from self-limiting symptoms to non-resolving pathology in the lungs. Worldwide, seasonal influenza infections claim ~500,000 lives annually. Recent reports describe pathologic pulmonary sequelae that result in remodeling the architecture of lung parenchyma following respiratory infections. These dysfunctional recovery processes that disproportionately impact the elderly have been understudied. Macrophages are involved in tissue remodeling and are critical for survival of severe influenza infection. Here, we found intrinsic deficiency of the nuclear receptor PPAR-γ in myeloid cells delayed the resolution of pulmonary inflammation following influenza infection. Mice with myeloid cell-specific PPAR-γ deficiency subsequently presented with increased influenza-induced deposition of pulmonary collagen compared to control mice. This dysfunctional lung remodeling was progressive and sustained for at least 3 months following infection of mice with myeloid PPAR-γ deficiency. These progressive changes were accompanied by a pro-fibrotic gene signature from lung macrophages and preceded by deficiencies in activation of genes involved with damage repair. Importantly similar aberrant gene expression patterns were also found in a secondary analysis of a study where macrophages were isolated from patients with fibrotic interstitial lung disease. Quite unexpectedly, mice with PPAR-γ deficient macrophages were more resistant to bleomycin-induced weight loss whereas extracellular matrix deposition was unaffected compared to controls. Therefore PPAR-γ expression in macrophages may be a pathogen-specific limiter of organ recovery rather than a ubiquitous effector pathway in response to generic damage.

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BackgroundCutaneous adverse drug reactions (ADRs) are the most common adverse reactions attributed to drugs. A systematic and effective approach to a patient with suspected drug eruption allows for prompt recognition, classification and treatment of cutaneous ADRs. A standardized and effective approach for objective causality assessment is necessary to make consistent and accurate identification of ADRs.ObjectiveAlthough the Naranjo algorithm is the most widely used assessment tool, it contains many components which are not suitable for clinical assessment of ADRs in Korea. The purpose of this study is to compare correlations of the Naranjo algorithm and the Korean algorithm to evaluate usefulness of both algorithms in order to make a causal link between drugs and cutaneous ADRs. In addition, this study classifies the clinical types and causative agents of cutaneous ADRs.MethodsThe authors retrospectively reviewed the clinical types and laboratory findings of patients who were diagnosed with cutaneous ADRs in the dermatology clinic at Gil hospital. One hundred forty-one patients were enrolled in this evaluation. The causal relationship of ADRs was assessed by using the Naranjo algorithm and Korean algorithm (version 2.0).ResultsA cross-tabulation analysis was applied to the Naranjo algorithm and Korean algorithm (version 2.0). Simple correlation analysis and a Bland-Altman plot were used for statistical analysis. Correlation analysis confirmed that the two assessment algorithms were significantly correlated. Exanthematous eruptions (68.8%), Stevens- Johnson syndrome (10.6%), and urticaria (8.5%) were the most common types of cutaneoues ADRs. The most common causative agents were antibiotics/antimicrobials, antipyretics/non-steroidal anti-inflammatory drugs, and central nervous system depressants.ConclusionThe Naranjo algorithm and Korean algorithm (version 2.0) were significantly correlated with each other, and thus reliable assessment methods to determine cutaneous ADRs.

The two nuclear hormone receptor ligands progesterone and vitamin D (vit.D) each play important roles in regulating T cells. The mechanism that connects these two hormones in regulating T cells has not been established. We report here that progesterone is a novel inducer of vit.D receptor (VDR) in T cells and makes T cells highly sensitive to calcitriol. At the molecular level, the induction by progesterone is mediated by two progesterone receptor binding elements in the intron region after the first non-coding exon of the human VDR gene. Increased expression of VDR by progesterone allows highly sensitive regulation of T cells by vit.D even when vit.D levels are suboptimal. This novel regulatory pathway allows enhanced induction of Tregs but suppression of Th1 and Th17 cells by the two nuclear hormones. The results have significant ramifications in effective regulation of T cells to prevent adverse immune responses during pregnancy.

The basidiomycete Laetiporus sulphureus var. miniatus belongs to the Aphyllophorales, Polyporaceae, and grows on the needleleaf tree. The fruiting bodies of Laetiporus species are known to produce N-methylated tyramine derivatives, polysaccharides, and various lanostane triterpenoids. As part of our ongoing effort to discover biologically active compounds from wood-rotting fungi, an anti-inflammatory triterpene, LSM-H7, has been isolated from the fruiting body of L. sulphureus var. miniatus and identified as acetyl eburicoic acid. LSM-H7 dose-dependently inhibited the NO production in RAW 264.7 cells without any cytotoxicity at the tested concentrations. Furthermore it suppressed the production of proinflammatory cytokines, mainly inducible nitric oxide synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6 and tumor necrosis factor α, when compared with glyceraldehyde 3-phosphate dehydrogenase. These data suggest that LSM-H7 is a crucial component for the anti-inflammatory activity of L. sulphureus var. miniatus.

Chromoblastomycosis is a chronic fungal disease of the skin and subcutaneous tissues caused by a group of dematiaceous (black) fungi. The most common etiologic agents are Fonsecaea pedrosoi and Cladophialophora carrionii, both of which can be isolated from plant debris. The infection usually follows traumatic inoculation by a penetrating thorn or splinter wound. Several months after the injury, painless papules or nodules appear on the affected area; these papules then progress to scaly and verrucose plaques. We report a case of chromoblastomycosis caused by Phialophora richardsiae, which has been rarely associated with chromoblastomycosis. The case involved a 43-year-old male, who for the past 2 months had noted an erythematous, pustulous plaque that was somewhat dark brown in color on his right shin; the plaque also had intermittent purulent discharge and crust formation. On histopathological examination, chronic granulomatous inflammation and sclerotic cells were seen. The tissue fungus culture grew out the typical black fungi of P. richardsiae, which was confirmed by polymerase chain reaction. The patient has been treated with a combination of terbinafine and itraconazole for 3 months with a good clinical response. (Ann Dermatol 22(3) 362∼366, 2010)

Pemphigus vegetans is a rare variant of pemphigus vulgaris and is characterized by vegetating lesions in the inguinal folds and mouth and by the presence of autoantibodies against desmoglein 3. Two clinical subtypes of pemphigus vegetans exist, which are initially characterized by flaccid bullae and erosions (the Neumann subtype) or pustules (the Hallopeau subtype). Both subtypes subsequently develop into hyperpigmented vegetative plaques with pustules and hypertrophic granulation tissue at the periphery of the lesions. Oral administration of corticosteroids alone does not always induce disease remission in patients with pemphigus vegetans. We report here on a 63-year-old woman with pemphigs vegetans. She had a 2-year history of vegetating, papillomatous plaques on the inguinal folds and erosions of the oral mucosa. The enzyme-linked immunosorbent assay was positive for anti-desmoglein 3, but it was negative for anti-desmoglein 1. She was initially treated with systemic steroid, but no improvement was observed. The patient was then successfully treated with a combination of systemic steroid and dapsone with a good clinical response.