The interactions of viruses with the skin immune system are not well understood. The interface of poxviruses with skin is especially intriguing, given that (i) skin infection and disfigurement are prominent features of smallpox disease; (ii) successful smallpox immunization is achieved by intentional skin infection with vaccinia virus; and (iii) eczema vaccinatum is a major severe complication of vaccination in people with atopic dermatitis (AD), a condition associated with defects in skin barrier function and antiviral innate immunity (25,26,69). Concerns about smallpox as a bioterrorism threat against an unvaccinated population, the persistence of monkeypox in Africa and episodes of its extracontinental spread, and the imperative to improve smallpox vaccination strategies all focus attention on poxvirus-host dynamics, particularly with skin. A recent case of life-threatening eczema vaccinatum in a child with AD who became infected by mere household contact with a smallpox vaccinee and then passed the infection on to a third party (68) highlights just how delicate the balance is between poxvirus virulence and skin immunity.Keratinocytes comprise the predominant cell type in the epidermis. Liu et al. (43) reported that vaccinia virus had limited replicative capacity in human keratinocytes and that infection induced keratinocytes to produce the Th2 cytokines transforming growth factor ␤, interleukin-10 (IL-10), and IL-13, which suggested that vaccinia virus might downregulate skin immune responses. Human keratinocytes express Toll-like receptors (TLRs) that initiate innate immune signaling by binding to ligands referred to as pathogen-associated molecular patterns (30,40,47,49). Human keratinocytes produce a repertoire of cytokines, chemokines, and antimicrobial peptides in response to TLR stimulation (6,40,66). Such cytokines and chemokines augment innate and acquired immunity mediated by dendritic cells, neutrophils, macrophages, NK cells, and T cells, which reside in the skin or are recruited to the skin in the setting of infection or inflammation (39).The type I interferons (IFN-␣ and IFN-␤) are key mediators of antiviral innate immunity (65). Double-stranded RNA (dsRNA) introduced during virus infection is a potent inducer of the type I IFN response. dsRNA can trigger distinct signaling pathways by engaging either (i) the endosomal membrane-bound receptor TLR3 (42), (ii) the soluble cytoplasmic receptors 29,31,73), or (iii) the dsRNA-dependent protein kinase PKR (16). Signaling through TLR3 leads to activation of the transcription factors IFN regulatory factor 3 (IRF3) and NF-B via the adaptor molecule TRIF. As a consequence, IRF3 is phosphorylated and then moves to the nucleus to activate IFN-␤ expression (59). In contrast, cytoplasmic dsRNA produced during replication of RNA viruses binds to RIG-I or MDA5 and triggers activation of IRF3 and NF-B through the mitochondrial antiviral signaling protein, MAVS

Poxviruses are large DNA viruses that replicate in the cytoplasm of infected cells. Myxoma virus is a rabbit poxvirus that belongs to the Leporipoxvirus genus. It causes a lethal disease called myxomatosis in European rabbits but cannot sustain any detectable infection in nonlagomorphs. Vaccinia virus is a prototypal orthopoxvirus that was used as a vaccine to eradicate smallpox. Myxoma virus is nonpathogenic in mice, whereas systemic infection with vaccinia virus can be lethal even in immunocompetent mice. Plasmacytoid dendritic cells (pDCs) are potent type I interferon (IFN)-producing cells that play important roles in antiviral innate immunity. How poxviruses are sensed by pDCs to induce type I IFN production is not well understood. Here we report that infection of primary murine pDCs with myxoma virus, but not with vaccinia virus, induces IFN-␣, IFN-␤, tumor necrosis factor (TNF), and interleukin-12p70 (IL-12p70) production. Using pDCs derived from genetic knockout mice, we show that the myxoma virus-induced innate immune response requires the endosomal DNA sensor TLR9 and its adaptor MyD88, transcription factors IRF5 and IRF7, and the type I IFN positive-feedback loop mediated by IFNAR1. It is independent of the cytoplasmic RNA sensing pathway mediated by the mitochondrial adaptor molecule MAVS, the TLR3 adaptor TRIF, or the transcription factor IRF3. Using pharmacological inhibitors, we demonstrate that myxoma virus-induced type I IFN and IL-12p70 production in murine pDCs is also dependent on phosphatidylinositol 3-kinase (PI3K) and Akt. Furthermore, our results reveal that the N-terminal Z-DNA/RNA binding domain of vaccinia virulence factor E3, which is missing in the orthologous M029 protein expressed by myxoma virus, plays an inhibitory role in poxvirus sensing and innate cytokine production by murine pDCs.Plasmacytoid dendritic cells (pDCs) are potent type I interferon (IFN)-producing cells that play critical roles in antiviral immunity. Human and murine pDCs are present in the blood, bone marrow, spleen, lymph nodes, and various other tissues (2, 7, 9, 40). pDCs express endosomal localized receptors TLR7 and TLR9 to detect viral RNA and DNA. Upon ligand binding, these receptors utilize a coadaptor molecule, MyD88, to form complexes resulting in the recruitment and activation of transcription factors, leading to the production of type I IFN and proinflammatory cytokines (22). Myxoma virus is a rabbit-specific poxvirus that belongs to the Leporipoxvirus genus. It causes a rapidly disseminating lethal myxomatosis in European rabbits (Oryctolagus cuniculus) and a benign localized infection in its natural evolutionary host in South American rabbits (Sylvilagus brasiliensis) but is nonpathogenic in humans and mice. In contrast, systemic infection with vaccinia virus is lethal in mice, and even vaccination

Amyopathic dermatomyositis (ADM) is characterized by the presence of dermatomyositis (DM) for 6 months or more in individuals who have normal muscle enzymes and no clinically significant muscle weakness. The aim of the study was to investigate the initial laboratory data, clinical manifestations, complications, and clinical outcomes of patients with the diagnosis of ADM. We reported 16 cases with the cutaneous findings of dermatomyositis without clinical or laboratory evidence of muscle disease for at least 2 years after onset of the skin manifestations in the Department of Dermatology and Rheumatology at Shanghai Ruijin Hospital between 1998 and 2004. All patients had Gottron's papules, periungual erythema/telangiectasia, and violaceous discoloration of the face, neck, upper chest, and back at some time during the course of their disease. Follow-up of 1 to 10 years after diagnosis found muscle weakness in three patients (18.75%) within 5 years of diagnosis. One patient (6.15%) was rediagnosed as chronic cutaneous lupus erythematosus (CCLE). Four patients (25%) had associated malignancies. Twelve patients (75%) had radiographic evidence indicative of interstitial fibrosis irrespective of respiratory symptoms. Patients with ADM appear to be at risk for developing the same potentially fatal disease complications as those patients with DM (e.g., interstitial lung disease and internal malignancy). These cases further emphasize that the cutaneous manifestations of dermatomyositis are pathognomonic for DM and we propose the term dermatomyositis-like skin disease as a better designation than amyopathic dermatomyositis to describe this distinctive subset of cutaneous symptoms. Dermatomyositis-like skin disease is a complex syndrome, which includes the characteristic cutaneous eruption of dermatomyositis without clinical evidence of muscle disease. Our findings suggest that patients diagnosed with this syndrome are at risk for fatal interstitial lung disease, malignancy, and/or delayed onset of DM or CCLE. Cautious systematic clinical trials should be considered for this group of patients.

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Introduction: Thyroid storm (TS) is a rare, but critical illness that can cause multiorgan failure and carries a high risk of mortality. We describe a case of refractory TS successfully treated with SPAD. Case: A 48 y/o lady was evaluated for sustained ventricular tachycardia (SVT) in the setting of newly diagnosed thyroid storm. She received a left ventricular assist device (LVAD) 4 years ago for cardiomyopathy (EF< 20%). Exam: SVT and florid CHF. Biochemical evaluation following amiodarone infusion for 18 hours: TSH < 0.05 (0.4 - 4 UIU/ml), FT4 7.87(0.76-1.46ng/dl), TT3 181 (60-180 ng/dl). TPO, TRAB and TSI antibodies were negative. Thyroid sonogram showed heterogeneous normal sized gland, no nodules or hyper vascularity. She received methimazole (MMI) 60 mg orally twice daily, Lugol’s iodine 10 drops orally three times daily and hydrocortisone 100mg intravenously 3 times daily. Beta-blockers were deferred due to cardiogenic shock. Amiodarone (400 mg orally twice daily)) was continued for ongoing episodes of SVT. She developed shock liver limiting the continuation of maximum doses of MMI. Continuous veno-venous hemofiltration (CVVH) was initiated for anuric renal failure. She required ventilator and pressor support on day 7 (D7) of hospitalization as urgent preparations were being made for LVAD exchange (given LVAD malfunction). TFts obtained on D7 showed a suboptimal response to maximal therapy: FT4 3.86, TT3 146. She underwent emergent SPAD using modified CVVH with dialysate containing 4% human albumin for 12 hrs. pre-operatively. It led to a fall in the FT4 to 1.71 and TT3 to 90. She received a new LVAD without further episodes of SVT. TFTs subsequent to 8 additional sessions of SPAD (as a bridge to definitive thyroidectomy) were as follows: FT4 1.56, TT3 76, thereby allowing for a dose reduction in MMI. Thyroidectomy was considered but deferred since the family opted for comfort measures when the patient developed cardiac tamponade Conclusions: TS can be recalcitrant to therapy with MMI, beta blockade, cold iodine and steroids. Adjunct therapy such as lithium, cholestyramine, and plasmapheresis, in addition to conventional therapy may have limited benefit, and comes with potential side effects. SPAD offers a safe and effective therapeutic alternative for refractory TS that can be performed continuously for a sustained response. In our case, with SPAD, thyroid hormones dropped to permissible levels, thus allowing for successful completion of emergent high risk cardiac surgery. Additionally, SPAD may provide a window for definitive surgical intervention and should be considered in refractory TS.