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Severe muscle damage with myofiber necrosis and macrophage infiltrates characterize anti-Mi2 positive dermatomyositis.
Fornaro, M, Girolamo, F, Cavagna, L, Franceschini, F, Giannini, M, Amati, A, Lia, A, Tampoia, M, D'Abbicco, D, Maggi, L, et al
Rheumatology (Oxford, England). 2021;(6):2916-2926
Abstract
OBJECTIVE The aim of our study was to investigate clinical and histopathological findings in adult DM patients positive for anti-Mi2 (anti-Mi2+) antibodies compared with DM patients negative for anti-Mi2 (anti-Mi2-). METHODS Clinical data of adult DM patients, who fulfilled EULAR/ACR 2017 classification criteria, were gathered from electronic medical records of three tertiary Rheumatology Units. Histopathological study was carried out on 12 anti-Mi2+ and 14 anti-Mi2- muscle biopsies performed for diagnostic purpose. Nine biopsies from immune mediated necrotizing myopathy (IMNM) patients were used as control group. RESULTS Twenty-two anti-Mi2+ DM [90.9% female, mean age 56.5 (15.7) years] were compared with 69 anti-Mi2- DM patients [71% female, mean age 52.4 (17) years]. Anti-Mi2+ patients presented higher levels of serum muscle enzymes than anti-Mi2- patients [median (IQR) creatine-kinase fold increment: 16 (7-37)vs 3.5 (1-9.9), P <0.001] before treatment initiation. Moreover, a trend towards less pulmonary involvement was detected in anti-Mi2+ DM (9.1% vs 30.4%, P =0.05), without any case of rapidly progressive interstitial lung disease. At muscle histology, anti-Mi2+ patients showed more necrotic/degenerative fibres than anti-Mi2- patients [mean 5.3% (5) vs 0.8% (1), P <0.01], but similar to IMNM [5.9% (6), P >0.05]. In addition, the endomysial macrophage score was similar between anti-Mi2+ and IMNM patients [mean 1.2 (0.9) vs 1.3 (0.5), P >0.05], whereas lower macrophage infiltration was found in anti-Mi2- DM [mean 0.4 (0.5), <0.01]. CONCLUSIONS Anti-Mi2+ patients represent a specific DM subset with high muscle damage. Histological hallmarks were a higher prevalence of myofiber necrosis, endomysial involvement and macrophage infiltrates at muscle biopsy.
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Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes.
Piemonti, L, Everly, MJ, Maffi, P, Scavini, M, Poli, F, Nano, R, Cardillo, M, Melzi, R, Mercalli, A, Sordi, V, et al
Diabetes. 2013;(5):1656-64
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Abstract
Long-term clinical outcome of islet transplantation is hampered by the rejection and recurrence of autoimmunity. Accurate monitoring may allow for early detection and treatment of these potentially compromising immune events. Islet transplant outcome was analyzed in 59 consecutive pancreatic islet recipients in whom baseline and de novo posttransplant autoantibodies (GAD antibody, insulinoma-associated protein 2 antigen, zinc transporter type 8 antigen) and donor-specific alloantibodies (DSA) were quantified. Thirty-nine recipients (66%) showed DSA or autoantibody increases (de novo expression or titer increase) after islet transplantation. Recipients who had a posttransplant antibody increase showed similar initial performance but significantly lower graft survival than patients without an increase (islet autoantibodies P < 0.001, DSA P < 0.001). Posttransplant DSA or autoantibody increases were associated with HLA-DR mismatches (P = 0.008), induction with antithymocyte globulin (P = 0.0001), and pretransplant panel reactive alloantibody >15% in either class I or class II (P = 0.024) as independent risk factors and with rapamycin as protective (P = 0.006) against antibody increases. DSA or autoantibody increases after islet transplantation are important prognostic markers, and their identification could potentially lead to improved islet cell transplant outcomes.
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Targeting receptor antibodies in immune cardiomyopathy.
Jahns, R, Schlipp, A, Boivin, V, Lohse, MJ
Seminars in thrombosis and hemostasis. 2010;(2):212-8
Abstract
Although autoimmunity represents a well-established pathogenetic principle in several endocrine (Graves' disease), rheumatic (systemic lupus erythematosus), and neurological disorders (myasthenia gravis, multiple sclerosis), this mechanism has only recently gained more attention in cardiac diseases. Depending on individual genetic predisposition, heart-directed autoimmune reactions are supposed to emerge as a consequence of cardiomyocyte injury induced by inflammation, ischemia, or exposure to cardiotoxic substances. Myocyte apoptosis or necrosis and subsequent liberation of a "critical amount" of cardiac autoantigens may then induce a self-directed immune response, which in the worst case results in perpetuation of autoantibody-mediated cardiac damage. In particular, functionally active autoantibodies (aabs) directed against the cardiac beta1-adrenergic receptor (beta1-aabs) have been assigned a pivotal role in the pathogenesis of immune cardiomyopathy. Conformational beta1-aabs allosterically activate the sympathetic transmembrane signaling cascade, thereby increasing sarcoplasmatic cyclic adenosine monophosphate (cAMP) and calcium concentrations. Chronic cAMP production and calcium overload are cardiotoxic, leading to myocyte apoptosis, fibrotic repair, subsequent heart muscle dysfunction, and, finally, a dilative cardiomyopathic phenotype. Elimination by (extracorporeal) immunoadsorption or direct neutralization of the harmful receptor autoantibodies in the circulating blood represent promising strategies to protect the heart from beta1-(auto)antibody-induced damage.
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Circulating antibodies recognising oxidatively-modified low-density lipoproteins in patients with IgA nephropathy, membranous glomerulonephritis and focal glomerulosclerosis.
Fornasieri, A, Perugini, C, Seccia, M, Napodano, P, D'Amico, G, Bellomo, G
Journal of nephrology. 2002;(4):349-57
Abstract
BACKGROUND Oxidation of low-density lipoproteins (LDL) generates molecular epitopes that play a pathologic role in experimental glomerular diseases and can also elicit an immune response and the generation of anti-oxidatively-modified LDL antibodies. METHODS We investigated, for the first time in humans, the enhanced induction of LDL oxidation in chronic glomerulonephritis, the presence of circulating antibodies against oxidatively-modified LDL in patients with IgA glomerulonephritis (IgA GN) or with nephrotic syndrome associated with focal glomerulosclerosis (FGS) and primary membranous glomerulonephritis (MGN). The antibody levels were measured by enzyme-linked immunosorbent assay (ELISA) using native and copper-, peroxidase-, hypochlorite-, and peroxynitrite-oxidized LDL. RESULTS Compared to control subjects, the three groups of patients, particularly the IgA GN patients, had higher serum levels of antibodies recognising LDL oxidised with the four different modalities and higher concentrations of cholesterol in circulating immune complexes. None of these were significantly correlated with any demographic, histological or biochemical laboratory finding. In patients with IgAGN, we investigated the possible confounding effects of cardiovascular risk factors (hypercholesterolemia, hypertension, diabetes and overt atherosclerosis). Although the concentration of cholesterol in circulating immune complexes was significantly higher in patients with cardiovascular risk factors, no significant differences were observed in the level of anti-oxidised-LDL antibodies. This analysis, however, was impossible in FGS and MGN patients because of the high prevalence of hypercholesterolemia in these groups. CONCLUSIONS These results suggest that IgA GN, MGN and FGS are associated with an enhanced immune response to LDL oxidised with different stimuli mimicking the pro-oxidant environment occurring in vivo, mirrored by the increased levels of specific antibodies, very likely linked to enhanced in vivo LDL oxidation which might participate in glomerular damage and progression.