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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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Identification of a Novel Serological Marker in Seronegative Rheumatoid Arthritis Using the Peptide Library Approach.
Bason, C, Barbieri, A, Martinelli, N, Olivieri, B, Argentino, G, Bartoloni, E, Beri, R, Jadav, G, Puccetti, A, Tinazzi, E, et al
Frontiers in immunology. 2021;:753400
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation mainly affecting the joints leading to cartilage and bone destruction. The definition of seropositive or seronegative RA is based on the presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). Other autoantibodies have been identified in the last decade such as antibodies directed against carbamylated antigens, peptidyl-arginine deiminase type 4 and v-Raf murine sarcoma viral oncogene homologue B. In order to identify relevant autoantigens, we screened a random peptide library (RPL) with pooled IgGs obtained from 50 patients with seronegative RA. Patients' sera were then used in an ELISA test to identify the most frequently recognized peptide among those obtained by screening the RPL. Sera from age- and sex-matched healthy subjects were used as controls. We identified a specific peptide (RA-peptide) recognized by RA patients' sera, but not by healthy subjects or by patients with other immune-mediated diseases. The majority of sera from seronegative and seropositive RA patients (73.8% and 63.6% respectively) contained IgG antibodies directed against the RA-peptide. Interestingly, this peptide shares homology with some self-antigens, such as Protein-tyrosine kinase 2 beta, B cell scaffold protein, Liprin-alfa1 and Cytotoxic T lymphocyte protein 4. Affinity purified anti-RA-peptide antibodies were able to cross react with these autoantigens. In conclusion, we identified a peptide that is recognized by seropositive and, most importantly, by seronegative RA patients' sera, but not by healthy subjects, conferring to this epitope a high degree of specificity. This peptide shares also homology with other autoantigens which can be recognized by autoantibodies present in seronegative RA sera. These newly identified autoantibodies, although present also in a percentage of seropositive RA patients, may be considered as novel serum biomarkers for seronegative RA, which lacks the presence of RF and/or ACPAs.
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Activating Antibodies to The Calcium-sensing Receptor in Immunotherapy-induced Hypoparathyroidism.
Lupi, I, Brancatella, A, Cetani, F, Latrofa, F, Kemp, EH, Marcocci, C
The Journal of clinical endocrinology and metabolism. 2020;(5)
Abstract
CONTEXT Immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. OBJECTIVES The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. METHODS Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, immunoglobulin (Ig) subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. RESULTS The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalized with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a 9-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. CONCLUSION The finding confirms that ICI therapy can trigger, among other endocrinopathies, hypoparathyroidism, which can be caused by pathogenic autoantibodies.
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Glycation and Oxidative Stress Increase Autoantibodies in the Elderly.
Khan, MWA, Al Otaibi, A, Sherwani, S, Khan, WA, Alshammari, EM, Al-Zahrani, SA, Saleem, M, Khan, SN, Alouffi, S
Molecules (Basel, Switzerland). 2020;(16)
Abstract
Aging causes gradual changes in free radicals, antioxidants, and immune-imbalance in the elderly. This study aims to understand links among aging, gluco-oxidative stress, and autoantibodies in asymptomatic individuals. In vitro glycation of human serum albumin (Gly-HSA) induces appreciable biochemical changes. Significant inhibition of advanced glycation end products (AGEs) formation was achieved using garlic extract (53.75%) and epigallocatechin-3-gallate from green tea (72.5%). Increased amounts of serum carbonyl content (2.42 ± 0.5) and pentosidine (0.0321 ± 0.0029) were detected in IV-S (S represent smokers) vs. IV group individuals. Direct binding ELISA results exhibited significantly high autoantibodies against Gly-HSA in group IV-S (0.55 ± 0.054; p < 0.001) and III-S (0.40 ± 0.044; p < 0.01) individuals as compared to the age matched subjects who were non-smokers (group IV and III). Moreover, high average percent inhibition (51.3 ± 4.1%) was obtained against Gly-HSA in IV-S group individuals. Apparent association constant was found to be high for serum immunoglobulin-G (IgG) from group IV-S (1.18 × 10-6 M) vs. serum IgG from IV group (3.32 × 10-7 M). Aging induced gluco-oxidative stress and AGEs formation may generate neo-epitopes on blood-proteins, contributing to production of autoantibodies in the elderly, especially smokers. Use of anti-glycation natural products may reduce age-related pathophysiological changes.
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Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura.
Roose, E, Schelpe, AS, Tellier, E, Sinkovits, G, Joly, BS, Dekimpe, C, Kaplanski, G, Le Besnerais, M, Mancini, I, Falter, T, et al
Blood. 2020;(3):353-361
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Abstract
Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.
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The Effects of a Gluten-Free Diet on Immune Markers and Kynurenic Acid Pathway Metabolites in Patients With Schizophrenia Positive for Antigliadin Antibodies Immunoglobulin G.
Friendshuh, CR, Pocivavsek, A, Demyonovich, H, Rodriguez, KM, Cihakova, D, Talor, MV, Richardson, CM, Vyas, G, Adams, HA, Baratta, AB, et al
Journal of clinical psychopharmacology. 2020;(3):317-319
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Can Supplementation with Vitamin D Modify Thyroid Autoantibodies (Anti-TPO Ab, Anti-Tg Ab) and Thyroid Profile (T3, T4, TSH) in Hashimoto's Thyroiditis? A Double Blind, Randomized Clinical Trial.
Chahardoli, R, Saboor-Yaraghi, AA, Amouzegar, A, Khalili, D, Vakili, AZ, Azizi, F
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2019;(5):296-301
Abstract
Hashimoto's thyroiditis (HT) is the most prevalent autoimmune disorder characterized by the destruction of thyroid cells caused by leukocytes and antibody-mediated immune processes accompanied by hypothyroidism. In recent years, evidence has emerged pointing to various roles for vitamin D, including, proliferation and differentiation of normal and cancer cells, cardiovascular function, and immunomodulation. Vitamin D deficiency has been especially demonstrated in HT patients. The aim of this study was to investigate the effect of vitamin D on circulating thyroid autoantibodies and thyroid hormones profile (T4, T3, and TSH) in females with HT. Forty-two women with HT disease were enrolled in this randomized clinical trial study and divided into vitamin D and placebo groups. Patients in the vitamin D and placebo groups received 50 000 IU vitamin D and placebo pearls, weekly for 3 months, respectively. The serum levels of 25-hydroxy vitamin D [25(OH) D], Ca++ion, anti-thyroperoxidase antibody (anti-TPO Ab), anti-thyroglobulin antibody (anti-Tg Ab), T4, T3, and TSH were measured at the baseline and at the end of the study using enzyme-linked immunosorbent assays. The results of this study showed a significant reduction of anti-Tg Ab and TSH hormone in the Vitamin D group compared to the start of the study; however, there was a no significant reduction of anti-TPO Ab in the Vitamin D group compared to the placebo group (p=0.08). No significant changes were observed in the serum levels of T3 and T4 hormones. Therefore, vitamin D supplementation can be helpful for alleviation of the disease activity in HT patients; however, further well controlled, large, longitudinal studies are needed to determine whether it can be introduced in clinical practice.
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Novel autoantibodies in Sjögren's syndrome: A comprehensive review.
Martín-Nares, E, Hernández-Molina, G
Autoimmunity reviews. 2019;(2):192-198
Abstract
Sjögren's syndrome is a systemic autoimmune disease characterized by immune- mediated injury of exocrine glands, as well as a diverse array of extraglandular manifestations. B cell over-activation is a key feature of the disease, attested by the wide spectrum of autoantibodies detected in these patients. Up to date, anti- Ro/SSA and anti-La/SSB antibodies are traditional biomarkers for disease classification and diagnosis. On the other hand, the detection of novel autoantibodies in SS has increased in the last years, opening a window of opportunity to denote particular stages of the disease, to establish clinical phenotypes, and to predict long-term complications such as lymphoma. For instance, anti-SP-1, anti-CA6 and anti-PSP antibodies occur in an earlier stage than anti-Ro/La antibodies, and may identify a subset of primary Sjögren's syndrome patients with mild or incomplete disease, whereas anti-cofilin-1, anti- alpha-enolase and anti-RGI2 antibodies are potential biomarkers of MALT lymphoma. Antibody detection is also important to elucidate new aspects of SS pathophysiology, and in the future to permit a phenotype-specific patient approach. Herein we review the literature regarding new autoantibodies in SS and attempt to dissect their usefulness as diagnostic tools, pathogenic role, identification of clinical phenotypes and as predictors of an overlap syndrome.
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Recurrent aphthous stomatitis - Etiology, serum autoantibodies, anemia, hematinic deficiencies, and management.
Chiang, CP, Yu-Fong Chang, J, Wang, YP, Wu, YH, Wu, YC, Sun, A
Journal of the Formosan Medical Association = Taiwan yi zhi. 2019;(9):1279-1289
Abstract
Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases characterized by recurrent and painful ulcerations on the movable or nonkeratinized oral mucosae. Clinically, three types of RAS, namely minor, major, and herpetiform types, can be identified. RAS more commonly affects labial mucosa, buccal mucosa, and tongue. Previous studies indicate that RAS is a multifactorial T cell-mediated immune-dysregulated disease. Factors that modify the immunologic responses in RAS include genetic predisposition, viral and bacterial infections, food allergies, vitamin and microelement deficiencies, systemic diseases, hormonal imbalance, mechanical injuries, and stress. Our previous study found the presence of serum gastric parietal cell antibody, thyroglobulin antibody, and thyroid microsomal antibody in 13.0%, 19.4%, and 19.7% of 355 RAS patients, respectively. We also found anemia, serum iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia in 20.9%, 20.1%, 4.8%, 2.6%, and 7.7% of 273 RAS patients, respectively. Therefore, it is very important to examine the complete blood count, serum autoantibody, hematinic, and homocysteine levels in RAS patients before we start to offer treatments for RAS. Because RAS is an immunologically-mediated disease, topical and systemic corticosteroid therapies are the main treatments of choice for RAS.
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The structure, specificity and function of anti-citrullinated protein antibodies.
Ge, C, Holmdahl, R
Nature reviews. Rheumatology. 2019;(8):503-508
Abstract
In this Perspectives article, we outline a proposed model for understanding the specificity and function of anti-citrullinated protein antibodies (ACPAs). We suggest that ACPAs vary in specificity between two extremes: some are 'promiscuous' in that they are highly specific for the citrulline side chain, but cross-react with a range of citrullinated peptides, whereas others are 'private' in that their recognition of citrulline as well as proximal amino acid side chains enables protein-specific interactions. Promiscuous ACPAs tend to dominate in the sera both before and after the onset of rheumatoid arthritis, but their functional role has not been clarified. No firm evidence exists that these ACPAs are pathogenic. By contrast, private ACPAs encompass antibodies that specifically recognize citrullinated epitopes on joint proteins or that cross-react with joint proteins, thereby opening up the possibility that these private ACPAs are arthritogenic. These joint-reactive antibodies are more likely to target joints by binding to joint tissues and to promote the formation of local immune complexes leading to bone erosions, pain and arthritis.