Browsing by Subject "Autoantibodies"
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Item Open Access Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases(BioMed Central, 2009) Chabchoub, G.; Uz, E.; Maalej, A.; Mustafa, C. A.; Rebai, A.; Mnif, M.; Bahloul, Z.; Farid, N. R.; Ozcelik, T.; Ayadi, H.Introduction The majority of autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) are characterized by a striking female predominance superimposed on a predisposing genetic background. The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of several autoimmune diseases.Item Open Access Evaluation of X chromosome inactivation with respect to HLA genetic susceptibility in rheumatoid arthritis and systemic sclerosis(Public Library of Science, 2016) Kanaan, S. B.; Onat, O. E.; Balandraud, N.; Martin, G. V.; Nelson, J. L.; Azzouz, D. F.; Auger, I.; Arnoux, F.; Martin, M.; Roudier, J.; Ozcelik, T.; Lambert, N. C.Background: Autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc) are characterized by a strong genetic susceptibility from the Human Leucocyte Antigen (HLA) locus. Additionally, disorders of epigenetic processes, in particular non-random X chromosome inactivation (XCI), have been reported in many female-predominant autoimmune diseases. Here we test the hypothesis that women with RA or SSc who are strongly genetically predisposed are less susceptible to XCI bias. Methods: Using methylation sensitive genotyping of the androgen receptor (AR) gene, XCI profiles were performed in peripheral blood mononuclear cells from 161 women with RA, 96 women with SSc and 100 healthy women. HLA-DRB1 and DQB1 were genotyped. Presence of specific autoantibodies was documented for patients. XCI skewing was defined as having a ratio ≥ 80:20 of cells inactivating the same X chromosome. Results: 110 women with RA, 68 women with SSc, and 69 controls were informative for the AR polymorphism. Among them 40.9% of RA patients and 36.8% of SSc patients had skewed XCI compared to 17.4% of healthy women (P = 0.002 and 0.018, respectively). Presence of RA-susceptibility alleles coding for the "shared epitope" correlated with higher skewing among RA patients (P = 0.002) and such correlation was not observed in other women, healthy or with SSc. Presence of SSc-susceptibility alleles did not correlate with XCI patterns among SSc patients. Conclusion: Data demonstrate XCI skewing in both RA and SSc compared to healthy women. Unexpectedly, skewed XCI occurs more often in women with RA carrying the shared epitope, which usually reflects severe disease. This reinforces the view that loss of mosaicism in peripheral blood may be a consequence of chronic autoimmunity. © 2016 Kanaan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Item Open Access Human genetic and immunological determinants of critical COVID-19 pneumonia(Springer Nature, 2022-03-24) Zhang, Qian; Bastard, Paul; Karbuz, Adem; Gervais, Adrian; Tayoun, Ahmad Abou; Aiuti, Alessandro; Belot, Alexandre; Bolze, Alexandre; Gaudet, Alexandre; Bondarenko, Anastasiia; Liu, Zhiyong; Spaan, András N.; Guennoun, Andrea; Arias, Andres Augusto; Planas, Anna M.; Sediva, Anna; Shcherbina, Anna; Neehus, Anna-Lena; Puel, Anne; Froidure, Antoine; Novelli, Antonio; Parlakay, Aslınur Özkaya; Pujol, Aurora; Yahşi, Aysun; Gülhan, Belgin; Bigio, Benedetta; Boisson, Bertrand; Drolet, Beth A.; Franco, Carlos Andres Arango; Flores, Carlos; Rodríguez-Gallego, Carlos; Prando, Carolina; Biggs, Catherine M.; Luyt, Charles-Edouard; Dalgard, Clifton L.; O’Farrelly, Cliona; Matuozzo, Daniela; Dalmau, David; Perlin, David S.; Mansouri, Davood; van de Beek, Diederik; Vinh, Donald C.; Dominguez-Garrido, Elena; Hsieh, Elena W. Y.; Erdeniz, Emine Hafize; Jouanguy, Emmanuelle; Şevketoglu, Esra; Talouarn, Estelle; Quiros-Roldan, Eugenia; Andreakos, Evangelos; Husebye, Eystein; Alsohime, Fahad; Haerynck, Filomeen; Casari, Giorgio; Novelli, Giuseppe; Aytekin, Gökhan; Morelle, Guillaume; Alkan, Gulsum; Bayhan, Gulsum Iclal; Feldman, Hagit Baris; Su, Helen C.; von Bernuth, Horst; Resnick, Igor; Bustos, Ingrid; Meyts, Isabelle; Migeotte, Isabelle; Tancevski, Ivan; Bustamante, Jacinta; Fellay, Jacques; El Baghdadi, Jamila; Martinez-Picado, Javier; Casanova, Jean-Laurent; Rosain, Jeremie; Manry, Jeremy; Chen, Jie; Christodoulou, John; Bohlen, Jonathan; Franco, José Luis; Li, Juan; Anaya, Juan Manuel; Rojas, Julian; Ye, Junqiang; Uddin, K. M. Furkan; Yasar, Kadriye Kart; Kisand, Kai; Okamoto, Keisuke; Chaïbi, Khalil; Mironska, Kristina; Maródi, László; Abel, Laurent; Renia, Laurent; Lorenzo, Lazaro; Hammarström, Lennart; Ng, Lisa F. P.; Quintana-Murci, Lluis; Erazo, Lucia Victoria; Notarangelo, Luigi D.; Reyes, Luis Felipe; Allende, Luis M.; Imberti, Luisa; Renkilaraj, Majistor Raj Luxman Maglorius; Moncada-Velez, Marcela; Materna, Marie; Anderson, Mark S.; Gut, Marta; Chbihi, Marwa; Ogishi, Masato; Emiroglu, Melike; Seppänen, Mikko R. J.; Uddin, Mohammed J.; Shahrooei, Mohammed; Alexander, Natalie; Hatipoglu, Nevin; Marr, Nico; Akçay, Nihal; Boyarchuk, Oksana; Slaby, Ondrej; Akcan, Ozge Metin; Zhang, Peng; Soler-Palacín, Pere; Gregersen, Peter K.; Brodin, Petter; Garçon, Pierre; Morange, Pierre-Emmanuel; Pan-Hammarström, Qiang; Zhou, Qinhua; Philippot, Quentin; Halwani, Rabih; de Diego, Rebeca Perez; Levy, Romain; Yang, Rui; Öz, Şadiye Kübra Tüter; Muhsen, Saleh Al; Kanık-Yüksek, Saliha; Espinosa-Padilla, Sara; Ramaswamy, Sathishkumar; Okada, Satoshi; Bozdemir, Sefika Elmas; Aytekin, Selma Erol; Karabela, Şemsi Nur; Keles, Sevgi; Senoglu, Sevtap; Zhang, Shen-Ying; Duvlis, Sotirija; Constantinescu, Stefan N.; Boisson-Dupuis, Stephanie; Turvey, Stuart E.; Tangye, Stuart G.; Asano, Takaki; Özcelik, Tayfun; Le Voyer, Tom; Maniatis, Tom; Morio, Tomohiro; Mogensen, Trine H.; Sancho-Shimizu, Vanessa; Beziat, Vivien; Solanich, Xavier; Bryceson, Yenan; Lau, Yu-Lung; Itan, Yuval; Cobat, Aurélie; Casanova, Jean-LaurentSARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1–5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 15–20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation. © 2022, Springer Nature Limited.Item Open Access The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies(National Academy of Sciences, 2022-05-16) Manry, J.; Bastard, P.; Gervais, A.; Le Voyer, T.; Rosain, J.; Philippot, Q.; Michailidis, E.; Hoffmann, H.; Eto, S.; Garcia-Prat, M.; Bizien, L.; Parra-Martínez, A.; Yang, R.; Haljasmägi, L.; Migaud, M.; Särekannu, K.; Maslovskaja, J.; de Prost, N.; Tandjaoui-Lambiotte, Y.; Luyt, C.; Amador-Borrero, B.; Gaudet, A.; Poissy, J.; Morel, P.; Richard, P.; Cognasse, F.; Troya, J.; Trouillet-Assant, S.; Belot, A.; Saker, K.; Garçpn, P.; Rivière, J. G.; Lagier, J.; Gentile, S.; Rosen, L. B.; Shaw, E.; Morio, T.; Tanaka, J.; Dalmau, D.; Tharaux, P.; Sene, D.; Stepanian, A.; Mégarbane, B.; Triantafyllia, V.; Fekkar, A.; Heath, J. R.; Franco, J. L.; Anaya, J.; Solé-Violán, J.; Imberti, L.; Biondi, A.; Bonfanti, P.; Castagnoli, R.; Delmonte, O. M.; Zhang, Y.; Snow, A. L.; Holland, S. M.; Biggs, C. M.; Moncada-Vélez, M.; Arias, A. A.; Lorenzo, L.; Boucherit, S.; Anglicheau, D.; Planas, A. M.; Haerynck, F.; Duvlis, S.; Ozcelik, Tayfun; Keles, S.; Bousfiha, A. A.; El Bakkouri, J.; Ramirez-Santana, C.; Paul, S.; Pan-Hammarström, Q.; Hammarström, L.; Dupont, A.; Kurolap, A.; Metz, C. N.; Aiuti, A.; Casari, G.; Lampasona, V.; Ciceri, F.; Barreiros, L. A.; Dominguez-Garrido, E.; Vidigal, M.; Zatz, M.; van de Beek, D.; Sahanic, S.; Tancevski, I.; Stepanovskyy, Y.; Boyarchuk, O.; Nukui, Y.; Tsumura, M.; Vidaur, L.; Tangye, S. G.; Burrel, S.; Duffy, D.; Quintana-Murci, L.; Klocperk, A.; Kann, N. Y.; Shcherbina, A.; Lau, Y.; Leung, D.; Coulongeat, M.; Marlet, J.; Koning, R.; Reyes, L. F.; Chauvineau-Grenier, A.; Venet, F.; Monneret, G.; Nussenzweig, M. C.; Arrestier, R.; Boudhabhay, I.; Baris-Feldman, H.; Hagin, D.; Wauters, J.; Meyts, I.; Dyer, A. H.; Kennelly, S. P.; Bourke, N. M.; Halwani, R.; Sharif-Askari, F. S.; Dorgham, K.; Sallette, J.; Sedkaoui, S. M.; AlKhater, S.; Rigo-Bonnin, R.; Morandeira, F.; Roussel, L.; Vinh, D. C.; Erikstrup, C.; Condino-Neto, A.; Prando, C.; Bondarenko, A.; Spaan, A. N.; Gilardin, L.; Fellay, J.; Lyonnet, S.; Bilguvar, K.; Lifton, R. P.; Mane, S.; Anderson, M. S.; Boisson, B.; Béziat, V.; Zhang, S.; Andreakos, E.; Hermine, O.; Pujol, A.; Peterson, P.; Mogensen, T. H.; Rowen, L.; Mond, J.; Debette, S.; de Lamballerie, X.; Burdet, C.; Bouadma, L.; Zins, M.; Soler-Palacin, P.; Colobran, R.; Gorochov, G.; Solanich, X.; Susen, S.; Martinez-Picado, J.; Raoult, D.; Vasse, M.; Gregersen, P. K.; Piemonti, L.; Rodríguez-Gallego, C.; Notarangelo, L. D.; Su, H. C.; Kisand, K.; Okada, S.; Puel, A.; Jouanguy, E.; Rice, C. M.; Tiberghien, P.; Zhang, Q.; Casanova, J.; Abel, L.; Cobat, A.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged [removed]4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.Item Open Access SOX1 antibodies are markers of paraneoplastic Lambert-Eaton myasthenic syndrome(Lippincott Williams & Wilkins, 2008) Sabater, L.; Titulaer, M.; Saiz, A.; Verschuuren, J.; Güre, A. O.; Graus, F.BACKGROUND/OBJECTIVE: We reported that 43% of patients with Lambert-Eaton myasthenic syndrome (LEMS) and small cell lung cancer (SCLC) had an antibody called anti-glial nuclear antibody (AGNA), defined by the immunoreaction with the nuclei of the Bergmann glia of the cerebellum. This study was undertaken to identify the antigen recognized by AGNA and to confirm the association with paraneoplastic LEMS in a larger series. METHODS: We probed a fetal brain cDNA library with AGNA-positive sera. The presence of antibodies against the isolated antigen was detected by immunoblot of phage plaques from two positive clones. We studied 105 patients with LEMS (55 with SCLC), 50 with paraneoplastic neurologic syndromes, SCLC, and Hu antibodies, and 50 with only SCLC. RESULTS: Probing of the fetal brain expression library with AGNA sera resulted in the isolation of SOX1, a highly immunogenic tumor antigen in SCLC. IgG eluted from SOX1 clones produced the same cerebellar immunoreactivity as of AGNA sera. SOX1 antibodies were present in 64% of patients with LEMS and SCLC but in none of the 50 with idiopathic LEMS (p < 0.0001). Compared with paraneoplastic LEMS, the frequency of SOX1 antibodies was significantly lower in patients with Hu antibodies (32%, p = 0.002) and in those with only SCLC (22%). CONCLUSIONS: SOX1 is the antigen recognized by anti-glial nuclear antibody-positive sera. The detection of SOX1 antibodies in patients with Lambert-Eaton myasthenic syndrome (LEMS) predicts the presence of small cell lung cancer and may be used to follow more closely those LEMS patients with no evidence of cancer at the initial workup.