Mucocutaneous Tissues Research Articles

S1920 Pruritis & Dysphagia: Gastrointestinal Manifestations of Lichen Planus

INTRODUCTION: Lichen planus is an inflammatory disorder of the mucocutaneous tissues. Esophageal involvement is rare and is often asymptomatic early in disease course. Therefore, delay in diagnosis is common and may predispose patients to both failed symptom treatment and development of oral squamous cell carcinoma. Esophageal lichen planus (ELP) is a rare and underrecognized cause of dysphagia that has been reported almost exclusively in middle-aged to elderly women. We present a male patient with ELP and the uncommon endoscopic finding of esophageal pseudodiverticulosis and histology notable for Civatte bodies. CASE DESCRIPTION/METHODS: 36-year-old male presents with 4 years of dysphagia to solids that worsened following his fourth esophageal balloon dilatation for esophageal stenosis. He endorsed a pruritic rash on his torso, localized to his hands, arms, and abdomen (Figure A). EGD revealed multiple pseudodiverticula and a benign appearing stricture in the proximal esophagus at 15–18 cm from the incisors (Figure B). Random esophageal biopsies demonstrated increased intraepithelial lymphocytes with scattered Civatte bodies and rare eosinophils (Figure C). Patient’s hospital course was complicated by concurrent diarrhea; stool culture positive for Campylobacter and Clostridium difficile. Therefore, patient was started on topical steroids and oral antihistamine instead of the standard treatment of systemic steroids. DISCUSSION: ELP is a rare condition that often occurs in conjunction with other manifestations of lichen planus. Yet, ELP continues to be under-recognized due to misinterpretation of the endoscopic features. Predominant endoscopic finding of ELP include stricturing of the proximal esophagus as seen in our patient. The most suggestive evidence of ELP is the presence of atrophic epithelial changes, lymphohistiocytic inflammatory infiltrate, and scattered, degenerated and dyskeratotic cells also known as Civatte bodies. Mucosal changes from ELP varies, but in our patient, we found an uncommon endoscopic finding of esophageal pseudodiverticulosis. Based on previous case series and case reports, easy sloughing of the esophageal mucosa seems to be another characteristic sign of ELP. In conclusion, ELP is a rare condition that is commonly missed; the presence of esophageal pseudodiverticulosis may hint at ELP. It is critical to consider ELP in patients with dysphagia and dermatologic manifestations of lichen planus, as delayed diagnosis of ELP may result in oral squamous cell carcinoma.Figure 1.: Pruritic rash on torso, hands, arms, and abdomen with oral lesion on physical examination.Figure 2.: Image 1 & 2: EGD revealed multiple pseudodiverticula in the esophagus marked by arrows Image 3:Benign appearing stricture in the proximal esophagus at 15-18cm from the incisors.Figure 3.: Esophageal biopsy concerning for increased intraepithelial lymphocytes with scattered Civatte bodies and rare eosinophils. Arrows marking Civatte bodies.

S1930 Lisinopril-Induced Oroesophageal Pemphigus Vulgaris: A Previously Unreported Side Effect

INTRODUCTION: Pemphigoid diseases (PD) are a group of blistering autoimmune pathologies including pemphigus vulgaris (PV) and pemphigus foliaceous (PF), which affect mucocutaneous tissues. NSAIDs, penicillamine, and angiotensin-converting enzyme inhibitors (ACEI) such as captopril and enalapril are associated with drug-induced pemphigoid (DIP). We present a case of lisinopril-associated PV which has not been previously reported. CASE DESCRIPTION/METHODS: A 35-year-old male with essential hypertension presented with multiple oral ulcers associated with dysphagia, odynophagia, and a 20-lb weight loss in six weeks since starting lisinopril. Multiple white-colored lesions were noted along the buccal mucosa (Figure 1) and posterior pharynx. Tests for ANA, HIV, and a chronic hepatitis panel were negative. Fluconazole, Nystatin, and Valganciclovir were initiated without improvement. As such, he subsequently underwent an intralesional incisional biopsy of the buccal mucosa which revealed changes compatible with PV (Figure 2). On EGD, two blood-filled blisters in the mid-esophagus were noted (Figure 3). Considering a pre-established diagnosis of PV, they were not biopsied. Lisinopril was discontinued and the patient was started on prednisone and mycophenolate with a subsequent resolution of symptoms. DISCUSSION: PD are characterized by IgG antibodies directed against epithelial antigens, desmoglein 1 and 3, leading to separation of keratinocytes (acantholysis) and formation of intraepidermal bullae. ACEI such as captopril, enalapril, and cilazapril have been associated with DIP. One case report of lisinopril induced PF has been reported. However, mucinous nor cutaneous PV secondary to its use has not been previously detailed. The etiology of lisinopril-induced DIP is not fully understood. All ACEI contain an amide-group which is noted to modify keratinocyte proteins to make neoantigens and can stimulate acantholysis. Patients on ACEI are also noted to have circulating autoantibodies against keratinocyte surface antigens which can be contributory. Cessation of ACEI is essential to halt progression while immunotherapy with steroids and other immunomodulators such as rituximab, azathioprine, or mycophenolate are the mainstay of management. A thorough drug reconciliation should be performed on presentation to allow for possibly early discontinuation of the offending agent(s), limit duration, and decrease side-effects of subsequent immunomodulatory therapy.Figure 1.: Well circumscribed, whitish ulceration of the buccal mucosa with adjacent erythema and swelling.Figure 2.: Hematoxylin-eosin (HE) stain of the buccal mucosa showing mucosal epithelium exhibiting a suprabasal split and associated acanthloysis with an underlying relatively brisk perivascular and interstitial lymphoplasmacytic infiltrate; with 40X (A) and 100X (B) magnification.Figure 3.: Two blood-filled blisters of the mucosa in the mid-esophagus, each measuring 6-7 mm in length.

Assessing Gammapapillomavirus infections of mucosal epithelia with two broad-spectrum PCR protocols

BackgroundHuman papillomaviruses (HPVs) have been divided into mucosal and cutaneous types according to their primary epithelial tissue tropism. However, recent studies showed the presence of several cutaneous types in mucosal lesions and healthy mucosa from different anatomical sites.MethodsHere, the HPV prevalence and type-specific distribution were assessed in a variety of mucosal samples from 435 individuals using a combination of two established broad-spectrum primer systems: Gamma-PV PCR and CUT PCR.ResultsOverall HPV prevalence in anal canal swabs, cervical cancer biopsies, genital warts and oral swabs was 85, 47, 62 and 4%, respectively. In anal canal swabs, Alpha-PVs were most frequently found (59%), followed by Gamma- (37%) and Beta-PVs (4%). The prevalence and persistence of HPV infection in the anal canal of 226 individuals were further explored. Overall HPV, Gamma-PVs and multiple HPV infections were significantly higher in men vs. women (p = 0.034, p = 0.027 and p = 0.003, respectively); multiple HPV infections were more common in individuals ≤40 years (p = 0.05), and significantly higher prevalence of Gamma-PVs and multiple HPV infections was observed in HIV-1-positive vs. HIV-1-negative individuals (p = 0.003 and p = 0.04, respectively). Out of 21 patients with follow-up anal swabs, only one persistent infection with the same type (HPV58) was detected.ConclusionsOur findings suggest that Gamma-PVs (except species Gamma-6) are ubiquitous viruses with dual muco-cutaneous tissue tropism. Anal canal Gamma-PV infections may be associated with sexual behavior and the host immune status. This study expands the knowledge on Gamma-PVs’ tissue tropism, providing valuable data on the characteristics of HPV infection in the anal canal.

Cytolethal distending toxin-induced release of interleukin-1β by human macrophages is dependent upon activation of glycogen synthase kinase 3β, spleen tyrosine kinase (Syk) and the noncanonical inflammasome.

Cytolethal distending toxins (Cdt) are a family of toxins produced by several human pathogens which infect mucocutaneous tissue and induce inflammatory disease. We have previously demonstrated that the Aggregatibacter actinomycetemcomitans Cdt induces a pro-inflammatory response from human macrophages which involves activation of the NLRP3 inflammasome. We now demonstrate that in addition to activating caspase-1 (canonical inflammasome), Cdt treatment leads to caspase-4 activation and involvement of the noncanonical inflammasome. Cdt-treated cells exhibit pyroptosis characterised by cleavage of gasdermin-D (GSDMD), release of HMGB1 at 24 hr and LDH at 48 hr. Inhibition of either the canonical (caspase-1) or noncanonical (caspase-4) inflammasome blocks both Cdt-induced release of IL-1β and induction of pyroptosis. Analysis of upstream events indicates that Cdt induces Syk phosphorylation (activation); furthermore, blockade of Syk expression and inhibition of pSyk activity inhibit both Cdt-induced cytokine release and pyroptosis. Finally, we demonstrate that increases in pSyk are dependent upon Cdt-induced activation of GSK3β. These studies advance our understanding of Cdt function and provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt-producing organisms such as A. actinomycetemcomitans.

Dermatomiositis anti-MDA5 (CADM-140) positiva: manifestaciones mucocutáneas y de partes blandas

Dermatomiositis anti-MDA5 (CADM-140) positiva: manifestaciones mucocutáneas y de partes blandas

6089Increased vascular endothelial growth factor signalling following loss of endothelial endoglin leads to peripheral arteriovenous shunting and high output heart failure

Abstract Background Endoglin is a co-receptor for TGFbeta/BMP9/10 signalling and ENG mutations lead to the vascular disorder hereditary haemorrhagic telangiectasia type I (HHT). Endoglin is also required for normal vascular development and angiogenesis, but little is known about endoglin's role in quiescent adult vascular endothelium. Purpose The goal of this present study is to determine how endoglin maintains vessel calibre in adult life to prevent AVM formation and thereby protect heart function. Methods To investigate this role, tamoxifen was administered to adult Cdh5(PAC)-CreERT2; Engfl/fl mice to generate endothelial-specific depletion of endoglin (Eng-iKOe). Cardiac magnetic resonance imaging, myography, vascular casting, microsphere injection, immunohistology, qPCR and aortic telemetry were used to evaluate cardiovascular changes after endoglin knockdown. Results Endothelial-specific loss of endoglin leads to an enlarged heart and cardiomyocyte hypertrophy within 5 weeks, progressing to high output heart failure (HOHF). In vivo aortic telemetry revealed significant loss of aortic pressure within a few days of endoglin depletion. Increased cardiac size and reduced cardiac afterload were confirmed by ventricular pressure loop analysis. As HOHF could result from arteriovenous malformations (AVMs), and these are found primarily in mucocutaneous and pulmonary tissues in HHT, we systematically screened for AVMs using microspheres and vascular casting. Although AVMs were absent in the majority of tissues, they were observed in the pelvic region and may account for the rapid increase in cardiac output. The pelvic cartilaginous symphysis is a noncapsulated cartilage with a naturally high endogenous expression of vascular endothelial growth factor (VEGF). Development of pelvic AVMs in this region of high VEGF expression occurred because loss of endoglin in endothelial cells leads to increased sensitivity to VEGF and a hyper-proliferative response. Finally, we found that inhibition of VEGFR2 was protective against AVMs development, enlargement of the heart and dilatation of the ventricles. Conclusion Our results showed the essential role of endoglin in the maintenance of adult cardio-vasculature through crosstalk with the VEGF signalling pathway. Acknowledgement/Funding British Heart Foundation, Cure HHT, The Swedish Research Council, The Cardiovascular Programme at Karolinska Institutet, The Swedish Cancer Society

Behçet's syndrome: clinical presentation and prevalence in Switzerland.

Behçet's syndrome is a rare systemic autoimmune/autoinflammatory disease affecting mucocutaneous tissues, the skin and the eyes, as well as the joints, the central nervous system, the gastrointestinal tract and blood vessels. Because of the lack of clinical data in Switzerland, the aims of this cohort study were to calculate the disease prevalence and to analyse the disease manifestations and the immune-suppressive medication. Data were extracted from 52 patient charts. Thereafter, all patients were interviewed with a questionnaire and 46 had an additional physical examination and laboratory analyses. For calculation of prevalence, data of the national statistical bureau were used. A disease prevalence of 4.03/100,000 inhabitants was calculated. The mean delay between first disease manifestation and diagnosis was 8 years. It was 2 years longer for Swiss than for non-Swiss individuals (p = 0.45). The time intervals between diagnosis and occurrence of different organ manifestations ranged from +8 to -11 years. There was no difference in organ involvement between different ethnicities. Colchicine was prescribed for 52% of patients only, whereas tumour necrosis factor (TNF) inhibitors and glucocorticoids were most frequently prescribed (80 and 64%, respectively). In almost half of the patients, TNF blockers could be stopped and replaced by conventional immunosuppressive drugs. The data from this cohort of Behçet's syndrome patients, the largest in Switzerland, documents a prevalence higher than anticipated. The diagnostic delay underlines an urgent need to improve awareness of the disease and allow timely treatment.

Therapeutic Mucosal Vaccination of Herpes Simplex Virus 2-Infected Guinea Pigs with Ribonucleotide Reductase 2 (RR2) Protein Boosts Antiviral Neutralizing Antibodies and Local Tissue-Resident CD4+ and CD8+ TRM Cells Associated with Protection against Recurrent Genital Herpes.

Reactivation of herpes simplex virus 2 (HSV-2) from latency causes viral shedding that develops into recurrent genital lesions. The immune mechanisms of protection against recurrent genital herpes remain to be fully elucidated. In this preclinical study, we investigated the protective therapeutic efficacy, in the guinea pig model of recurrent genital herpes, of subunit vaccine candidates that were based on eight recombinantly expressed HSV-2 envelope and tegument proteins. These viral protein antigens (Ags) were rationally selected for their ability to recall strong CD4+ and CD8+ T-cell responses from naturally "protected" asymptomatic individuals, who, despite being infected, never develop any recurrent herpetic disease. Out of the eight HSV-2 proteins, the envelope glycoprotein D (gD), the tegument protein VP22 (encoded by the UL49 gene), and ribonucleotide reductase subunit 2 protein (RR2; encoded by the UL40 gene) produced significant protection against recurrent genital herpes. The RR2 protein, delivered either intramuscularly or intravaginally with CpG and alum adjuvants, (i) boosted the highest neutralizing antibodies, which appear to cross-react with both gB and gD, and (ii) enhanced the numbers of functional gamma interferon (IFN-γ)-producing CRTAM+ CFSE+ CD4+ and CRTAM+ CFSE+ CD8+ TRM cells, which express low levels of PD-1 and TIM-3 exhaustion markers and were localized to healed sites of the vaginal mucocutaneous (VM) tissues. The strong B- and T-cell immunogenicity of the RR2 protein was associated with a significant decrease in virus shedding and a reduction in both the severity and frequency of recurrent genital herpes lesions. In vivo depletion of either CD4+ or CD8+ T cells significantly abrogated the protection. Taken together, these preclinical results provide new insights into the immune mechanisms of protection against recurrent genital herpes and promote the tegument RR2 protein as a viable candidate Ag to be incorporated in future genital herpes therapeutic mucosal vaccines.IMPORTANCE Recurrent genital herpes is one of the most common sexually transmitted diseases, with a global prevalence of HSV-2 infection predicted to be over 536 million worldwide. Despite the availability of many intervention strategies, such as sexual behavior education, barrier methods, and the costly antiviral drug treatments, eliminating or at least reducing recurrent genital herpes remains a challenge. Currently, no FDA-approved therapeutic vaccines are available. In this preclinical study, we investigated the immunogenicity and protective efficacy, in the guinea pig model of recurrent genital herpes, of subunit vaccine candidates that were based on eight recombinantly expressed herpes envelope and tegument proteins. We discovered that similar to the dl5-29 vaccine, based on a replication-defective HSV-2 mutant virus, which has been recently tested in clinical trials, the RR2 protein-based subunit vaccine elicited a significant reduction in virus shedding and a decrease in both the severity and frequency of recurrent genital herpes sores. This protection correlated with an increase in numbers of functional tissue-resident IFN-γ+ CRTAM+ CFSE+ CD4+ and IFN-γ+ CRTAM+ CFSE+ CD8+ TRM cells that infiltrate healed sites of the vaginal tissues. Our study sheds new light on the role of TRM cells in protection against recurrent genital herpes and promotes the RR2-based subunit therapeutic vaccine to be tested in the clinic.

Dynamic thiol/disulfide homeostasis in patients with lichen planus.

Lichen planus (LP) is an autoimmune inflammatory disease of the mucocutaneous tissue, whose exact pathological course remains unclear. Abnormal thiol/disulfide homeostasis has been postulated to be responsible for a number of diseases predominated by chronic inflammation. To be able to contribute complicated and unclear pathogenesis of LP, we aimed to investigate dynamic thiol/disulfide homeostasis in patients with LP, using an original automated method developed by Erel and Neselioglu in this study. The study group consisted of 81 unrelated patients with LP and 80 unrelated healthy controls with no LP lesions in their personal history or on clinical examination. Thiol/disulphide homeostasis tests have been measured with a novel automatic spectrophotometric method developed and the results have been compared statistically. Native thiol and total thiol levels were found as significantly higher in patients with LP than the control group (P=0.026 and 0.035, respectively). There was no significant difference between the disulfide levels of the patients with LP and the control group. We provide evidence that that thiol/disulphide homeostasis impaired in favor of thiol levels in LP patients compared to the control group based on the data of our study. To the best of our knowledge, the present study is the first examination on the correlation between thiol and disulfide homeostasis in patients with LP.

Laser Adjuvant-Assisted Peptide Vaccine Promotes Skin Mobilization of Dendritic Cells and Enhances Protective CD8+ TEM and TRM Cell Responses against Herpesvirus Infection and Disease.

There is an urgent need for chemical-free and biological-free safe adjuvants to enhance the immunogenicity of vaccines against widespread viral pathogens, such as herpes simplex virus 2 (HSV-2), that infect a large proportion of the world human population. In the present study, we investigated the safety, immunogenicity, and protective efficacy of a laser adjuvant-assisted peptide (LAP) vaccine in the B6 mouse model of genital herpes. This LAP vaccine and its laser-free peptide (LFP) vaccine analog contain the immunodominant HSV-2 glycoprotein B CD8+ T cell epitope (HSV-gB498-505) covalently linked with the promiscuous glycoprotein D CD4+ T helper cell epitope (HSV-gD49-89). Prior to intradermal delivery of the LAP vaccine, the lower-flank shaved skin of B6 or CD11c/eYFP transgenic mice received a topical skin treatment with 5% imiquimod cream and then was exposed for 60 s to a laser, using the FDA-approved nonablative diode. Compared to the LFP vaccine, the LAP vaccine (i) triggered mobilization of dendritic cells (DCs) in the skin, which formed small spots along the laser-treated areas, (ii) induced phenotypic and functional maturation of DCs, (iii) stimulated long-lasting HSV-specific effector memory CD8+ T cells (TEM cells) and tissue-resident CD8+ T cells (TRM cells) locally in the vaginal mucocutaneous tissues (VM), and (iv) induced protective immunity against genital herpes infection and disease. As an alternative to currently used conventional adjuvants, the chemical- and biological-free laser adjuvant offers a well-tolerated, simple-to-produce method to enhance mass vaccination for widespread viral infections.IMPORTANCE Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect a large proportion of the world population. There is an urgent need for chemical-free and biological-free safe adjuvants that would advance mass vaccination against the widespread herpes infections. The present study demonstrates that immunization with a laser-assisted herpes peptide vaccine triggered skin mobilization of dendritic cells (DCs) that stimulated strong and long-lasting HSV-specific effector memory CD8+ T cells (TEM cells) and tissue-resident CD8+ T cells (TRM cells) locally in the vaginal mucocutaneous tissues. The induced local CD8+ T cell response was associated with protection against genital herpes infection and disease. These results draw attention to chemical- and biological-free laser adjuvants as alternatives to currently used conventional adjuvants to enhance mass vaccination for widespread viral infections, such as those caused by HSV-1 and HSV-2.

59-Year-Old Woman With Fatigue, Dyspnea, and Lower Extremity Edema

59-Year-Old Woman With Fatigue, Dyspnea, and Lower Extremity Edema

Complex disposition of an enigmatic pathogen: rare electron microscopic manifestations in nasal rhinosporidiosis

Abstract Rhinosporidiosis is a polypoidal disease of the nose and mucocutaneous tissues, the diagnosis of which is based on the presence of round bodies believed to be causative agents of the disease. Historically, the round body has been considered to be a sporangium of a fungus Rhinosporidium seeberi but without any convincing evidence. Round bodies contain numerous daughter cells, which are likely in the infective stage and are shed through a rupture in the wall of the round body. The released single-celled organisms eventually develop into round bodies on availability of suitable transformative trigger and favourable environment. Surgical excision of the polyp by electrocautery is the only effective treatment; however, recurrence may occur due to spillage of infective endospores in the surrounding mucosa during removal. There are many enigmatic features of the causative agent of this disease, which have been baffling researchers for more than a century. Here we present some rare electron microscopic and previously unreported features of the coat of the round body and single-celled organism in nasal rhinosporidiosis.

IL-17-producing \u03b3\u03b4 T cells switch migratory patterns between resting and activated states

Interleukin 17-producing γδ T (γδT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being fundamental to γδT17-driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling γδT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that γδT17 cells constitutively express chemokine receptors CCR6 and CCR2. While CCR6 recruits resting γδT17 cells to the dermis, CCR2 drives rapid γδT17 cell recruitment to inflamed tissues during autoimmunity, cancer and infection. Downregulation of CCR6 by IRF4 and BATF upon γδT17 activation is required for optimal recruitment of γδT17 cells to inflamed tissue by preventing their sequestration into uninflamed dermis. These findings establish a lymphocyte trafficking model whereby a hierarchy of homing signals is prioritized by dynamic receptor expression to drive both tissue surveillance and rapid recruitment of γδT17 cells to inflammatory lesions.

Pulmonary Kaposi Sarcoma with Osseous Metastases in an Human Immunodeficiency Virus (HIV) Patient: A Remarkable Response to Highly Active Antiretroviral Therapy

Patient: Male, 34Final Diagnosis: Pulmonary Kaposi’s sarcoma with bony metastatsesSymptoms: Cough • weight lossMedication: —Clinical Procedure: —Specialty: Infectious DiseasesObjective:Rare diseaseBackground:Kaposi sarcoma (KS) is known to involve the mucocutaneous tissues and the aero-digestive tracts. In acquired immune deficiency syndrome (AIDS) patients, KS has an aggressive course and carries poor prognosis. We present a case of pulmonary KS with osseous metastases as the first presentation of human immunodeficiency virus (HIV) infection in a young male. The lesions impressively decreased in size and numbers following initiation of highly active antiretroviral therapy (HAART).Case Report:A 34-year-old heterosexual male presented with a one month history of cough and 15–20 pound weight loss within six months. Examination revealed oral thrush, decreased breath sounds and crackles on the right lower lung base. Imaging showed a large right perihilar mass with multiple lytic lesions involving thoracic and lumber vertebrae, ribs, sternum, and clavicles. Blood and sputum cultures, smears for acid fast bacilli, and a QUANTIferon gold test were all negative. He tested positive for HIV and his CD4 count was 7 cells/uL. Bronchoscopy with biopsy was unrevealing. Pathology of the right hilar mass was diagnostic of KS. Following initiation of antiretroviral therapy his condition dramatically improved; repeat chest CT scan showed marked regression of the bony and pulmonary lesions.Conclusions:The dual action of HAART on the recovery of the immune system and against human herpes virus 8 (HHV-8) may essentially cause regression of KS lesions.

Sclerodermatous GVHD after Allogeneic Bone Marrow Transplant: a Review

Chronic graft versus host disease (cGVHD) is the leading cause of non-relapse mortality after allogeneic hematopoietic bone marrow transplantation (HCT) for blood malignancy in patients who survive for more than two years. cGVHD can significantly affect quality of life and cause decreased mobility amongst other grave consequences such as end-organ damage, contributing to morbidity and mortality rates for recipients of HCT. Unlike acute GVHD (aGVHD), the chronic variant of graft versus host disease (GVHD) has complex immunopathology involving both humoral and cell immunity. It typically affects the integumentary system, though is known to also affect myofascial, mucocutaneous tissues as well as cause end organ damage ultimately resulting in death. Sclerodermatous cGVHD is a type of cGVHD characterized by involvement of the skin, subcutaneous tissue and fascia without evidence of disease in the viscera. Manifestations of this disease are often evocative of autoimmune disease, which is a self-directed inflammatory reaction to the innate and adaptive immune system in various tissues or multiple organ systems. This inflammatory reaction gives rise to autoantibodies as well as B-cell and T-cell mediated direct toxicity which can cause chronic inflammatory changes of tissues ultimately resulting in tissue scarring and end organ dysfunction. We aim to review the literature on this grave disease and elucidate aspects of the immunopathology of chronic sclerodermatous GVHD in hopes that it may lead to revelations inspiring novel therapies after its diagnosis or preventative measures before stem cell transplantation for malignancy.

Innate defense mechanisms against HSV-1 infection in the target tissues, skin and brain.

Herpes simplex virus type 1 (HSV-1) initiates productive infection in mucocutaneous tissues to cause cold sores and establishes latent infection in the trigeminal ganglia. Under certain circumstances, HSV-1 may cause encephalitis. Here, we compared host innate defenses against HSV-1 in the two clinically relevant tissues, skin and brain, using a unique ex vivo system of organ culture. Upon HSV-1 infection and spread, apoptosis induction was observed in the skin, but not in brain tissues. While the two tissues elicited interferon (IFN-β) response upon HSV1 infection, IFN induction was more robust in the skin compared to the brain. Moreover, antiviral response to exogenous IFNβ treatment was much stronger in the skin compared to brain tissues. This observation was not related to the availability of the IFN receptor on cells' surface. Taken together, our study demonstrates differential innate antiviral responses to HSV-1 infection that may be exploited in future development of selective and tissue-specific anti-viral treatments.

Pathogenesis of Behçet's disease: autoinflammatory features and beyond.

Behçet's disease (BD) is an inflammatory disorder of unknown aetiology characterised by recurrent attacks affecting the mucocutaneous tissues, eyes, joints, blood vessels, brain and gastrointestinal tract. It is a multifactorial disease classified as a variable vessel vasculitis, and several environmental triggers may induce inflammatory episodes in genetically susceptible individuals. BD has several autoinflammatory features including recurrent self-limited clinical manifestations overlapping with monogenic autoinflammatory disorders, significant host predisposition and abnormally increased inflammatory response, with a robust innate component. Human leukocyte antigen (HLA)-B*51 is the strongest susceptibility factor described so far affecting the disease risk and typical phenotype. Non-HLA genetic associations such as endoplasmic reticulum aminopeptidase 1 (ERAP1), interleukin 23 receptor (IL23R) and IL10 variations suggest that BD shares susceptibility genes and inflammatory pathways with spondyloarthritis. Although genomewide association studies revealed an increased risk associated with recessively inherited ERAP1 variations in HLA-B*51 positive patients, it is not clear yet whether certain peptide-HLA allele combinations result in an adaptive response by a self-antigen-directed cytotoxic response or an innate response by modulating an NK cell activity or causing an unfolded protein response. Understanding of major histocompatibility complex (MHC) Class I-driven inflammatory response is expected to provide insights for the development of better treatment and remission-induction options in BD as well as in ankylosing spondylitis (AS) and psoriasis.

Scleroderma : a case report

Scleroderma is an autoimmune connective tissue disorder which is characterized by fibrosis of visceral organs, skin and blood vessels. This condition can be localized or systemic. Its estimated prevalence is 250 cases in a million and it is more common in women than in men. Resorption of the mandibular angle and coronoid process can be observed in patients with scleroderma. Pressure of fibrous mucocutaneous tissues is thought to be the cause of the resorption. Decreased number of wrinkles due to sclerosis and distinct facial features because of the atrophy of ala nasi are among common clinical characteristics of this condition. The aim of this case report is to present a 40-year-old female patient with scleroderma who presented with signs of resorption at the angle of mandible, coronoid process, as well as widening of the periodontal space.

Cost analysis of prophylaxis with activated prothrombin complex concentrate vs. on-demand therapy with activated factor VII in severe haemophilia A patients with inhibitors, in Spain.

A cost analysis model was developed to compare annual cost of prophylaxis with activated prothrombin complex concentrate (aPCC) vs. on-demand therapy with activated recombinant factor VII (rFVIIa) in severe haemophilia A patients with inhibitors for the Spanish National Health System (NHS). Model inputs were drug cost for prophylaxis (aPCC) and for on-demand treatment (rFVIIa or aPCC); bleeding episodes management (excluding bypassing agent cost); surgical costs and disease management (excluding bleeding episodes). Annual bleeding episodes treated on-demand was assumed to be 25, whereas breakthrough bleeds on prophylaxis was 8. Dose for prophylaxis was 75.72 U kg(-1) , three times per week. The total on-demand dose/bleeding episode was 679.66 μg kg(-1) (rFVIIa) and 235.28 U kg(-1) (aPCC). The average bleeding cost (€2998) considered different bleeding sites (62.5% joints, 28.6% muscles and soft tissues, 3.6% mucocutaneous tissues and 5.4% other areas). A 7.5% deduction was applied to ex-factory drug prices. Unitary costs (€2013) derived from local databases. Sensitivity analyses (SA) were performed. Annual cost of aPCC prophylaxis (€524,358) was 16% lower than on-demand treatment with rFVIIa (€627,876). Yearly drug costs were €497,017 for aPCC (€73,166 for on-demand treatment and €423,850 for prophylaxis), and €548,870 for rFVIIa. Disease management cost (€2645 per year) and surgical procedures (€708 per year) were common for both strategies. In the SA prophylactic treatment led to savings between €26,225 and €-1,008,960. Prophylaxis with aPCC reduces number of bleeding episodes in severe haemophilia A patients with inhibitors. aPCC prophylaxis resulted in savings in excess of €100,000 per-patient per year, being 16% less costly than on-demand treatment with rFVIIa, for the Spanish NHS.

PO-0921 Recurrent Inguinal Hernias : Think Metabolic !

Introduction There is little available evidence on the differential etiologic diagnosis of recurrent inguinal hernia, particularly if the original causative disorder is a storage disease... Material and methods The examination of un affected boy, at first consulting in surgery for a recurrent inguinal hernia, reveals in addition a marked dysmorphism with a peculiar umbilical hernia; uncommon for a 23 months infant... Careful palpation notes a mild hepato-splenomegaly; rising the suspicion of a Mucopolysaccharidosis –MPS- Prompt Dry Blood Test for enzymatic essay, combined to urinary glycosaminoglycans – GAG- collection and molecular genetic testing, confirm the diagnosis of MPS 2 – Hunter disease. Immediate enzyme replacement therapy is ordered, as well as referring to haematology consultancy for a rapid bone marrow transplant Management is differed after ERT and a possible bone marrow transplant; with a special attention to the anaesthetic dangers for such a condition. Results and discussion Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder characterised by glycosaminoglycans (GAG) accumulation. The latter gives an hyperlaxity aspect to the mucocutaneous tissues leading to such recurrent hernias Surgeons ought to be aware of this peculiar presentation of attenuated mucopolysaccharidosis, in time of onset and types of clinical related features. Conclusion Recurrent inguinal hernias, specially if associated to dysmorphic features and visceromegaly, should be promptly managed as a probable metabolic – lysosomal storage disease, chiefly a mucopolysaccharidosis.