Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour.

Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behaviour, such as spatial learning and memory. Here we show that meningeal immunity is also critical for social behaviour; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T-cell-derived cytokines suggest a strong interaction between social behaviour and interferon-γ (IFN-γ)-driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic (γ-aminobutyric-acid) currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behaviour. Meta-analysis of the transcriptomes of a range of organisms reveals that rodents, fish, and flies elevate IFN-γ/JAK-STAT-dependent gene signatures in a social context, suggesting that the IFN-γ signalling pathway could mediate a co-evolutionary link between social/aggregation behaviour and an efficient anti-pathogen response. This study implicates adaptive immune dysfunction, in particular IFN-γ, in disorders characterized by social dysfunction and suggests a co-evolutionary link between social behaviour and an anti-pathogen immune response driven by IFN-γ signalling.

Erosive pustular dermatosis of the scalp.

Erosive pustular dermatosis of the scalp (EPDS) is a rare inflammatory condition commonly associated with antecedent iatrogenic insult. EPDS may be diagnostically challenging owing to a lack of pathognomonic histologic findings and cutaneous manifestations that overlap with alternative dermatologic conditions. Therefore, EPDS may be more common than previously recognized. We present a 60-year-old woman with a four-year history of non-healing scalp erosions, progressive skin atrophy, and scarring alopecia despite intravenous antibiotics and intraoperative debridement who improved with systemic glucocorticoids. Our report emphasizes the importance of early recognition of EPDS when delayed wound healing and erosive disease occur in the setting of iatrogenic injury to the scalp. Timely treatment with systemic anti-inflammatory agents is paramount to prevent cicatricial alopecia and mitigate further scalp insult in EPDS.

Utility and Limitations of Transient Elastography to Monitor Hepatic Steatosis, Hepatic Fibrosis, and Methotrexate-Associated Hepatic Disease in Psoriasis: A Systematic Review.

OBJECTIVE: Psoriasis is associated with hepatic steatosis, fibrosis, and methotrexate-associated liver injury. There is a need for reliable methods to monitor liver disease in psoriasis. Transient elastography (TE) is a validated non-invasive method for assessing hepatic steatosis and fibrosis. Psoriasis-specific TE studies have been limited until recently. Here, we review the utility and limitations of TE to detect and monitor liver disease in the context of psoriasis. METHODS: A comprehensive search using OVID, PubMed, and gray literature was conducted (2005-November 2019) to identify studies of TE use in psoriasis for assessment of hepatic steatosis and fibrosis. RESULTS: Fifteen studies met inclusion criteria. A total of 1,536 patients with psoriasis or psoriatic arthritis were represented. TE-detected liver fibrosis is associated with age, diabetes, obesity, and severity of psoriasis. TE successfully evaluates hepatic steatosis and fibrosis. Elastography has a high negative predictive value and specificity in the context of methotrexate-associated liver fibrosis in psoriasis; however, reported associations between abnormal elastography results and cumulative methotrexate dose varied significantly despite methotrexate's association with hepatotoxicity and fibrosis. The presence of central adiposity is associated with increased TE failure rate. LIMITATION: The TE studies included in this review date from 2007 to 2019, which could contribute to publication bias, as the technique of TE has improved over this time period. CONCLUSION: TE is a useful and non-invasive modality to detect hepatic steatosis and fibrosis in psoriasis. Dermatologists might consider TE in psoriatic patients and concomitant risk factors for fibrosis with the understanding that failure rates may be higher in patients with central adiposity.

Multiple Plantar Poromas in a Stem Cell Transplant Patient.

Poromatosis, or the formation of multiple eccrine poromas, is associated with chronic immunosuppression, lymphoproliferative neoplasms, and stem cell transplantation, though the etiology and clinical significance remain poorly understood. Eccrine poromas are asymptomatic, may appear years after treatment, and overlap morphologically with other diagnoses, particularly human papillomavirus-associated verrucae, to which immunosuppressed patients may be predisposed and commonly occur in similar sites. We report a 47-year-old female on chronic immunosuppression who developed multiple plantar eccrine poromas three years after achieving acute myeloid leukemia (AML) remission following treatment with chemotherapy, total body irradiation, and allogenic stem cell transplantation. We propose that early recognition, timely treatment, and regular follow-up skin examinations are necessary in the setting of multiple poromas to reduce the risk of malignancy and avoid delays in diagnosis.

MiR-155 induction by microbes/microbial ligands requires NF-κB-dependent de novo protein synthesis.

MiR-155 regulates numerous aspects of innate and adaptive immune function. This miR is induced in response to Toll-like receptor ligands, cytokines, and microbial infection. We have previously shown that miR-155 is induced in monocytes/macrophages infected with Francisella tularensis and suppresses expression of the inositol phosphatase SHIP to enhance activation of the PI3K/Akt pathway, which in turn promotes favorable responses for the host. Here we examined how miR-155 expression is regulated during infection. First, our data demonstrate that miR-155 can be induced through soluble factors of bacterial origin and not the host. Second, miR-155 induction is not a direct effect of infection and it requires NF-κB signaling to up-regulate fos/jun transcription factors. Finally, we demonstrate that the requirement for NF-κB-dependent de novo protein synthesis is globally shared by microbial ligands and live bacteria. This study provides new insight into the complex regulation of miR-155 during microbial infection.

LyGDI, a novel SHIP-interacting protein, is a negative regulator of FcγR-mediated phagocytosis.

SHIP and SHIP-2 are inositol phosphatases that regulate FcγR-mediated phagocytosis through catalytic as well as non-catalytic mechanisms. In this study we have used two-dimensional fluorescence difference gel electrophoresis (DIGE) analysis to identify downstream signaling proteins that uniquely associate with SHIP or SHIP-2 upon FcγR clustering in human monocytes. We identified LyGDI as a binding partner of SHIP, associating inducibly with the SHIP/Grb2/Shc complex. Immunodepletion and competition experiments with recombinant SHIP domains revealed that Grb2 and the proline-rich domain of SHIP were necessary for SHIP-LyGDI association. Functional studies in primary human monocytes showed that LyGDI sequesters Rac in the cytosol, preventing it from localizing to the membrane. Consistent with this, suppression of LyGDI expression resulted in significantly enhanced FcγR-mediated phagocytosis.