Two receptors for tumor necrosis factor (TNF) with different molecular weight (75-Kd and 55-Kd) and binding affinity have been recently discovered. To investigate the distribution and the functional role of these receptors on leukemic B cells from hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia (B-CLL) patients, we evaluated: (1) the cytofluorimetric pattern of uncultured and cultured leukemic B cells incubated with utr-1 and htr-9 monoclonal antibodies (MoAbs), which specifically recognize the 75-Kd and 55-Kd TNF receptors (TNFR), respectively; (2) the effect of TNF-alpha and TNF-beta on leukemic B cells in an in vitro proliferation assay; (3) the role of anti-TNFR MoAbs on TNF-alpha and TNF-beta-driven B-cell growth; and (4) the proliferative effect of utr-1 and htr-9 MoAbs on in vitro cultured leukemic cells. Our study shows that the high affinity (75-Kd) but not the low affinity (55-Kd) TNFR molecules are expressed on freshly isolated leukemic B cells recovered from HCL and B-CLL patients. The expression of these receptors was neither upregulated nor downregulated by different stimuli, including TNF-alpha, TNF-beta, B-cell growth factor, and interleukin-2. TNF-alpha efficiently triggers the proliferation of HC and, to a lesser extent, the growth of B-CLL cells. TNF-beta was also able to transduce the proliferative signal in HCL, but not in B-CLL patients. TNF-alpha- and TNF-beta-driven B-cell proliferation was inhibited by the preincubation of leukemic B cells with utr-1 but not htr-9 MoAb. Moreover, anti-75-Kd, but not anti-55-Kd TNFR MoAb, was able to trigger the proliferation of leukemic B cells, and in particular of HC. These results show that leukemic B cells from patients with HCL and B-CLL are equipped with a fully functional high affinity TNFR.
Background Acute pericarditis (AP) usually resolves with first-line treatment, but it may recur. Recurrences are attributed to a deranged immunity, but it is unclear if they may also be related to inappropriate treatment. Purpose The aim of our study was to clarify the potential role of inappropriate treatment on relapse episodes in AP. Methods Consecutive patients prospectively followed-up over 20 years at Padua University Cardio-immunology outpatient clinic were included. Clinical and instrumental findings were recorded at diagnosis and at each follow-up. Spectrum, appropriateness, efficacy and side effects of therapies received by patients before and after referral to our centre were considered. The distribution of recurrence-free survival probability was estimated using Kaplan-Meier method; impact of the covariates of interest on the outcome was assessed using Cox univariate analysis models. Results The study included 144 patients (57% male, mean age 50 years, 143 Caucasian and 1 African). 139 patients had AP, which was recurrent in 63; 5 had constrictive pericarditis. Etiology was idiopathic/presumed-viral in 112 patients, bacterial in 1, secondary to pericardial injury in 26, to Dressler syndrome in 2, and to a systemic immune-mediated disease in 3. At diagnosis, 68% were in NYHA class I; 9% developed cardiac tamponade; 84% received non-steroidal-anti-inflammatory drugs (NSAIDs), 54% colchicine and 19% corticosteroids. Treatment was not in line with ESC guidelines in 31% of patients for NSAIDs, in 12% for steroids and in 28% for colchicine, requiring readjustment. All patients with constrictive pericarditis underwent uncomplicated pericardiectomy. No patient was dead at last follow-up. Estimated recurrence-free-survival probability was 86% at 1st year, 58% at 5th, 52% at 10th. Variables which tended to be associated with a higher risk of recurrence were: cardiac tamponade at diagnosis, left heart failure, concomitant immune-mediated diseases, history of recurrence, inappropriate treatment with colchicine, inappropriate treatment with NSAIDs, III or IV NYHA class at diagnosis. Treatment of acute/recurrent forms before referral did not appear in line with the international recommendations in terms of daily dosage or duration, or both, in 43 patients for NSAIDs, in 17 for corticosteroids and in 39 for colchicine, which was omitted despite the absence of contraindications (Table 1). Following treatment adjustment to international guidelines, 107 patients with relapsing pericarditis obtained complete remission; only 13 (9%) of our AP patients showed a truly treatment-refractory form that required a second-line therapy. Conclusion When treated according to international guidelines, pericarditis has usually a favorable course, even in its most adverse presentations. Treatment inaccuracies seems to account, at least in part, to disease recurrences. Funding Acknowledgement Type of funding sources: None.
Background Myocarditis is characterized by the presence of an inflammatory infiltrate in the myocardium with degenerative/necrotic changes of cardiomyocytes, not-related to ischemic damage. Its clinical presentation is extremely heterogenous1. Endomyocardial Biopsy (EMB) is the diagnostic gold standard and provides etiopathogenetic diagnosis. Biopsy-proven myocarditis may be infectious, mainly viral, toxic o non-infectious immune-mediated/autoimmune. A complex interplay between genetic factors, environmental triggers (i.e. viral infection) and the immune response of the host is postulated at the basis of different disease evolution2. Purpose To determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in cardiomyopathy-related genes in a well-characterized cohort of biopsy-proven myocarditis. Methods Sixty-six biopsy-proven myocarditis-affected patients (mean age 51±9, 41 males) underwent screening of 200 genes related to inherited cardiomyopathies. Definite/moderate gene association with Dilated Cardiomyopathy (DCM)3 and Arrhythmogenic Cardiomyopathy4 was based on the ClinGen framework. Variant prioritization was carried out using American College of Medical Genetics and Genomics rules5. Correlation with presence of virus on endomyocardial biopsy by polymerase chain reaction, family history and serum anti-heart autoantibodies (AHA) and/or aintiintercalated-disk autoantibodies (AIDA) was appraised. Results Nineteen of the 66 biopsy-proven myocarditis patients (28%) carried a P/LP variant in cardiac-related genes. Titin (TTN) was the most overrepresented gene accounting for 11% of cases (7/66), followed by Myosin Heavy Chain 7 (MYH7) and Myosin Binding Protein C3 (MYBPC3) each accounting for 3% of cases (2/66), respectively. Of note, 29 of the 66 of index cases (44%) referred family history for cardiomyopathy and/or sudden cardiac death. However only 13/29 patients with family history were genotype-positive (45%), indicating that other immunogenetic factors might contribute to triggering myocarditis. Circulating AHA and/or AIDA were detected in 31% of our genotype-positive cohort (6 of 19); a virus positive diagnosis was obtained in 15% of cases. Conclusion The prevalence of clinically actionable P/LP variants in cardiomyopathy-related genes is nearly one third of biopsy-proven viral or autoimmune myocarditis patients, most of them associated with DCM. On the other hand, positive family history (44%) in the absence of known cardiomyopathy-related genes indicates that additional immunogenetic factors might contribute to disease pathogenesis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministero della Salute - Italy - Ricerca Sanitaria Finalizzata
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