I linfociti TREG e TH17 nei pazienti con orticaria cronica spontanea

Background: the skin reactivity against Autologous Serum (SA) and the presence of anti-IgE and anti-IgE receptor, which are found in some patients with Chronic Spontaneous Urticaria (CSU), have suggested that this disease could have an autoimmune pathogenesis, although the actual causative mechanism is still unknown. It is well recognized, however, that mast cells play a key role in the pathogenesis, and recent studies show that they likely have a role in directing lymphocyte differentiation towards TH1 and TH17 subsets. Aim: to assess Treg and TH17 levels between CSU patients and healthy controls in different disease severity and different skin reactivity against SA. Methods: surface and intracellular antigens expression has been evaluated in peripheral blood mononuclear cells (PBMC) of CSU patients and healthy controls through flow cytometry, using monoclonal antibodies. Cells expressing CD4, CD25 and FOXP3 were considered Treg, while cells expressing CD4 and IL23R or IL17 or both were considered TH17. Results: no significant differences have been found between CSU patients and healthy controls regarding Treg levels, FOXP3 expression on Treg and ratio Treg/TH17. Furthermore, no significant differences have been found between the two groups regarding levels of IL23R+CD4+, IL23R+CD4+IL17+ and IL17+CD4+ cells. However, a remarkable increase of IL17+CD4+ cells level has been found in CSU patients comparing with healthy controls, with significant correlation between IL17+CD4+ cells levels and disease activity, estimated by the Urticaria Activity Score (UAS). Conclusions: IL17+CD4+ cells level is correlated with disease activity in CSU patients, thus suggesting a role of IL17+CD4+ cells in the pathogenesis of the disease

life expectancy in italian patients with hereditary angioedema due to c1 inhibitor deficiency

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The impact of puberty on the onset, frequency, location, and severity of attacks in hereditary angioedema due to C1-inhibitor deficiency: A survey from the Italian Network for Hereditary and Acquired Angioedema (ITACA)

IntroductionHereditary angioedema due to C1-inhibitor deficiency is influenced by hormonal factors, with a more severe course of disease in women. Our study aims to deepen the impact of puberty on onset, frequency, location and severity of attacks.MethodsRetrospective data were collected through a semi-structured questionnaire and shared by 10 Italian reference centers of the Italian Network for Hereditary and Acquired Angioedema (ITACA).ResultsThe proportion of symptomatic patients increased significantly after puberty (98.2% vs 83.9%, p=0.002 in males; 96.3% vs 68,4%, p<0.001 in females); the monthly mean of acute attacks was significantly higher after puberty, and this occurred both in females (median (IQR) = 0.41(2) in the three years before puberty vs 2(2.17) in the three years after, p<0.001) and in males (1(1.92) vs 1.25(1.56) respectively, p<0.001). The increase was greater in females. No significant differences were detected in attack location before and after puberty.DiscussionOverall, our study confirms previous reports on a more severe phenotype in the female gender. Puberty predisposes to increased numbers of angioedema attacks, in particular in female patients

Активность микрофлоры как показатель токсичности морских донных отложений шельфовой зоны Черного моря и Керченского пролива

Изучена потенциальная активность донной микрофлоры в местах утечки остатков химических токсикантов, затопленных в период Второй Мировой войны ХХ в. Отмечены особенности восстановления жизнедеятельности микрофлоры при различных уровнях загрязнения донных отложений мышьяком и хлорированными органическими сульфидами. Полученные результаты перспективно использовать при оценке экологического состояния донных отложений в загрязненных прибрежных акваториях

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (PPeer reviewe

I linfociti TREG e TH17 nei pazienti con orticaria cronica spontanea

Background: the skin reactivity against Autologous Serum (SA) and the presence of anti-IgE and anti-IgE receptor, which are found in some patients with Chronic Spontaneous Urticaria (CSU), have suggested that this disease could have an autoimmune pathogenesis, although the actual causative mechanism is still unknown. It is well recognized, however, that mast cells play a key role in the pathogenesis, and recent studies show that they likely have a role in directing lymphocyte differentiation towards TH1 and TH17 subsets. Aim: to assess Treg and TH17 levels between CSU patients and healthy controls in different disease severity and different skin reactivity against SA. Methods: surface and intracellular antigens expression has been evaluated in peripheral blood mononuclear cells (PBMC) of CSU patients and healthy controls through flow cytometry, using monoclonal antibodies. Cells expressing CD4, CD25 and FOXP3 were considered Treg, while cells expressing CD4 and IL23R or IL17 or both were considered TH17. Results: no significant differences have been found between CSU patients and healthy controls regarding Treg levels, FOXP3 expression on Treg and ratio Treg/TH17. Furthermore, no significant differences have been found between the two groups regarding levels of IL23R+CD4+, IL23R+CD4+IL17+ and IL17+CD4+ cells. However, a remarkable increase of IL17+CD4+ cells level has been found in CSU patients comparing with healthy controls, with significant correlation between IL17+CD4+ cells levels and disease activity, estimated by the Urticaria Activity Score (UAS). Conclusions: IL17+CD4+ cells level is correlated with disease activity in CSU patients, thus suggesting a role of IL17+CD4+ cells in the pathogenesis of the disease.Introduzione: la reattività cutanea nei riguardi del siero autologo (SA) e la presenza di anticorpi anti - IgE ed anti -recettore per le IgE che caratterizzano alcuni pazienti con orticaria cronica spontanea (CSU) hanno suggerito una patogenesi autoimmunitaria della malattia, ma l’effettivo meccanismo causale resta oscuro. E’ comunque noto che i mastociti rivestono un ruolo fondamentale nella patogenesi , e recenti lavori suggeriscono un loro probabile ruolo di polarizzazione dei linfociti T helper in senso TH1 e TH17. Scopo dello studio: valutare l’andamento di Treg e TH17 nei pazienti con CSU rispetto a controlli sani nelle diverse fasi cliniche e in relazione alla reattività cutanea nei confronti del siero autologo. Metodi: l’espressione degli antigeni di superficie e intracitoplasmatici di Treg e TH17 sulle cellule mononucleate del sangue periferico (PBMC) dei pazienti con CSU e dei controlli è stata valutata mediante citometria a flusso. Per identificare i Treg sono stati utilizzati anticorpi monoclonali (AcM) rivolti verso CD4, CD25 e il fattore di trascrizione Forkhead box P3 (FOXP3), mentre per identificare i TH17 sono stati utilizzati AcM rivolti verso CD4, il recettore per l’Interleuchina 23 (IL23R) e l’Interleuchina 17 (IL17). Risultati: non sono emerse differenze significative tra i due gruppi per quanto riguarda il numero di linfociti Treg circolanti, la loro espressione di FOXP3 e il rapporto Treg/TH17. Per quanto riguarda i TH17 non sono emerse differenze significative nei gruppi cellulari analizzati (IL23R+CD4+, IL23R+CD4+IL17+, IL17+CD4+), ma abbiamo osservato un rilevante aumento della percentuale di cellule IL17+CD4+ nei pazienti affetti da CSU rispetto ai controlli, con una significativa correlazione tra % di cellule IL17+CD4+ e grado di severità di malattia calcolata con l’Urticaria Activity Score (UAS). Conclusioni : L’aumento di cellule IL17+CD4+ correla con il grado di attività di malattia e suggerisce un coinvolgimento dei TH17 nella patogenesi della CSU

Melkersson-Rosenthal syndrome: A case report of a rare disease with overlapping features 11 Medical and Health Sciences 1107 Immunology 11 Medical and Health Sciences 1103 Clinical Sciences

Background: Melkersson-Rosenthal syndrome (MRS) is a rare, neuro-mucocutaneous disease which presents as orofacial swelling, facial palsy and fissured tongue. These symptoms may occur simultaneously or, more frequently, with a oligosymptomatic or monosymptomatic pattern. Swelling, that is the most common initial finding, may mimic hereditary or acquired angioedema, a disorder caused by histamine or bradykinin-mediated plasma-leakage affecting subcutaneous and/or submucosal tissue. The differential diagnosis of MRS includes also chronic inflammatory and infective diseases characterized by granulomatous infiltration, as well as rosacea, contact dermatitis, allergic reactions and Bell's palsy. Case presentation: A 71-year old, non-allergic female patient with no familial and personal history of angioedema presented, a few days after a possible herpes simplex or varicella-zoster virus infection, with monolateral facial paraesthesia and lower lip edema. After temporary remission of symptoms on oral steroids and antihistamines, she showed swelling recurrence refractory to valaciclovir therapy and a subsequent course of antihistamines. The clinical picture and a previous history of non-Hodgkin lymphoma prompted us to rule out an acquired form of paraneoplastic, C1-inhibitor (C1-INH) deficiency: C1q and both antigen and functional C1-INH tested normal, whilst we found low plasma levels of C3 and C4 possibly related to the parallel detection of antiphospholipid antibodies. Thus, we hypothesized a non-histaminergic, idiopathic form of angioedema and planned further therapy with tranexamic acid and the leukotriene receptor antagonist montelukast. Treatment failure with both drugs finally suggested a Melkersson-Rosenthal syndrome, which was confirmed by histologic findings of non caseating granulomas on lip biopsy. Conclusion: Melkersson-Rosenthal syndrome may occur with rather non-specific symptoms and overlap with alternative conditions, including recurrent angioedema. No specific biomarkers for MRS exist and clinical diagnosis is often of exclusion. The finding of complement or immune alterations, as in our patient, may be further confounding and justify the need for skin or mucosal biopsy to establish a correct diagnosis and prescribe targeted therapy