Browsing by Author "Arkwright, Peter D."
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Publication Challenges in investigating patients with isolated decreased serum IgM: The SIMcal study(Wiley, 2019-06-01) Janssen, Lisanne M. A.; van Hout, Roeland W. N. M.; de Vries, Esther; Pignata, Claudio; Cirillo, Emilia; Arkwright, Peter D.; Lougaris, Vassilos; Buckland, Matthew; Garcia-Prat, Marina; Soler-Palacin, Pere; Ouederni, Monia; Kralickova, Pavlina; Abolhassani, Hassan; Hammerstroem, Lennart; Aghamohammadi, Asghar; Santos-Perez, Juan L.; Sobh, Ali; ten Bosch, Jutte van de Werff; Henriet, Stefanie; Kılıç, Sara S.; Karalı, Yasin; Ignacio Gonzalez-Granado, Luis; Sediva, Anna; SIMcal Consortium; KILIÇ GÜLTEKİN, SARA ŞEBNEM; KARALI, YASİN; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk İmmunoloji Anabilim Dalı.; AAH-1658-2021; FFS-1974-2022The clinical consequences of isolated decreased serum immunoglobulin (Ig)M are not sufficiently known. Therefore, it is difficult to determine the clinical policy following such a finding. Only few reported IgM-deficient patients fulfil the European Society for Immunodeficiencies (ESID) diagnostic criteria for selective IgM deficiency (true sIgMdef), or their diagnosis is uncertain due to insufficient laboratory data (possible sIgMdef). Decreased serum IgM is often incidentally found in asymptomatic adults. The objective of our study was to further characterize true sIgMdef and to compare the European data collected through the ESID Registry community (tertiary centres) to our previously published Dutch cohort (secondary centre). Fifteen centres (12 countries) participated with 98 patients. Patients were excluded if serum IgM was only determined once (n = 14), had normalized (n = 8), or if they also had other immunological abnormalities (n = 15). Ten patients (5 adults) completely fulfilled the ESID criteria for true sIgMdef. Age-matched cut-off values varied widely between centres; when using the ESID diagnostic protocol reference values, only six patients (five adults) had true sIgMdef. Because of these small numbers, further analyses were performed in patients with true or possible sIgMdef (13 adults, 48 children). Respiratory infections were commonly reported at presentation (adults 54%, children 60%). Symptomatic adults had lower serum IgM levels (mean 0.27 g/L, 95% CI 0.22-0.31) than those without symptoms (mean 0.33 g/L, 95% CI 0.30-0.36; P = 0.02). To be able to explore the clinical consequences of true sIgMdef, we should fully analyse and accurately describe those patients in whom a decreased serum IgM is found.Item Differences in Ig replacement therapy dosing in patients with common variable immunodeficiency in europe: Results from the ESID database(Mosby-Elsevier, 2011-02) Gathmann, B.; Mahlaoui, Nizar; Warnatz, Klaus; Kuijpers, Taco W.; Thon, Vojtech; Arkwright, Peter D.; Kumararatne, Dinakantha; Exley, Andrew; Borte, Michael; Jones, Alison; Belohradsky, Bernd H.; Baumann, Ulrich; Kütükçüler, Necil; Witte, Torsten; Feighery, C.; Wagstrom, Per; Longhurst, Hilary; Linde, Richard; Ritterbusch, Henrike; Farmaki, E.; Sediva, Anna; Alataki, Efimia Papadopoulou; Panahloo, Zoya; Grimbacher, Bodo; Kılıç, Sara Şebnem; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.; AAH-1658-2021Item Functional STAT3 deficiency compromises the generation of human T follicular helper cells(The American Society of Hematology, 2012-04-26) Ma, Cindy S.; Avery, Danielle T.; Chan, Anna; Batten, Marcel; Bustamante, Jacinta; Boisson-Dupuis, Stephanie; Arkwright, Peter D.; Kreins, Alexandra Y.; Averbuch, Diana; Engelhard, Dan; Magdorf, Klaus; Minegishi, Yoshiyuki; Nonoyama, Shigeaki; French, Martyn A.; Choo, Sharon; Smart, Joanne M.; Peake, Jane; Wong, Melanie; Gray, Paul; Cook, Matthew C.; Fulcher, David A.; Casanova, Jean-Laurent; Deenick, Elissa K.; Tangye, Stuart G.; Kılıç, Sara Şebnem; Uludağ Üniversitesi/Tıp Fakültesi/Pediatri Anabilim Dalı.; 0000-0001-8571-2581; AAH-1658-2021; 34975059200T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12R beta 1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.Item Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome(Mosby-Elsevier, 2010-02) Woellner, Cristina; Gertz, Edward Michael; Schaffer, Alejandro A.; Lagos, Macarena; Perro, Mario; Glocker, Erik Oliver; Pietrogrande, Maria Cristina; Cossu, Fausto; Franko, Josè Luis; Matamoros, Núria; Pietrucha, Barbara Maria; Heropolitańska-Pliszka, Edyta; Yeganeh, Mehdi; Moin, Mostafa; Español, Theresa; Ehl, Stephan; Gennery, Andrew R.; Abinun, Mario A.; Brȩborowicz, Anna; Niehues, Tim; Junker, Anne K.; Turvey, Stuart E.; Plebani, Alessandro; Sánchez, Berta; Garty, Ben Zion; Pignata, Claudio; Cancrini, Caterina; Litzman, Jiří; Sanal, Özden; Baumann, Ulrich; Bacchetta, Rosa; Hsu, Amy P.; Davis, Joie N.; Hammarström, Lennart L.G.; Davis, Edward Graham; Eren, Efrem; Arkwright, Peter D.; Moilanen, Jukka S.; Viemann, Dorothee; Khan, Sujoy; Máródi, László D.R.; Cant, Andrew James; Freeman, Alexandra F.; Puck, Jennifer M.; Holland, Steven M.; Grimbacher, Bodo; Kılıç, Sara Şebnem; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.; 0000-0001-8571-2581; AAH-1658-2021; 34975059200Background: The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT-3) and severe reductions of T(H)17 cells. Objective: To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients. Methods: We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE > 1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation. Results: In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT-3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells. Conclusion: We propose the folio-wing diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.Item Mutations in the signal transducer and activator of transcription 3 (STAT3) and diagnostic guidelines for the Hyper-IgE Syndrome(Wiley, 2010-04) Woellner, Cristina; Gertz, M. E.; Schaffer, Alejandro; Lagos, Macarena; Perro, Mario; Glocker, Erik-Oliver; Pietrogrande, Maria Cristina; Cossu, Fausto; Marin Franco, Jose Luis; Matamoros, N.; Pietrucha, Bernard; Heropolitanska-Pliszka, Edyta; Yeganch, M.; Rezaei, Nima; Espanol, Teresa; Ehl, Stephan; Gennery, Andrew R.; Abinun, Mario; Breborowicz, Anna; Niehues, Tim; Junker, Anne K.; Turvey, Stuart E.; Plebani, Alessandro; Sanchez, Berta Erika Luis; Garty, Ben Zion; Pignata, Claudio; Cancrini, Caterina; Litzman, Jiří; Sanal, Özden; Batimann, U.; Bacchetta, Rosa; Hsu, Amy P.; Davis, Joie N.; Hammarström, Lennart L.G.; Davis, Edward Graham; Eren, Efrem; Arkwright, Peter D.; Moilanen, Jukka S.; Viemann, Dorothee; Khan, Sujoy; Máródi, László D.R.; Cant, Andrew James; Freeman, Alexandra F.; Puck, Jennifer M.; Holland, Steven M.; Grimbacher, Bodo; Kılıç, Sara Şebnem; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.; AAH-1658-2021Publication Simple measurement of iga predicts immunity and mortality in ataxia-telangiectasia(Springer/plenum Publishers, 2021-09-03) Zielen, Stefan; Duecker, Ruth Pia; Woelke, Sandra; Donath, Helena; Bakhtiar, Sharhzad; Buecker, Aileen; Kreyenberg, Hermann; Huenecke, Sabine; Bader, Peter; Mahlaoui, Nizar; Ehl, Stephan; El-Helou, Sabine M.; Pietrucha, Barbara; Plebani, Alessandro; van der Flier, Michiel; van Aerde, Koen; Reda, Shereen M.; Kostyuchenko, Larysa; McDermott, Elizabeth; Galal, Nermeen; Pignata, Claudio; Perez, Juan Luis Santos; Laws, Hans-Juergen; Niehues, Tim; Kutukculer, Necil; Seidel, Markus G.; Marques, Laura; Ciznar, Peter; Edgar, John David M.; Soler-Palacin, Pere; von Bernuth, Horst; Krueger, Renate; Meyts, Isabelle; Baumann, Ulrich; Kanariou, Maria; Grimbacher, Bodo; Hauck, Fabian; Graf, Dagmar; Granado, Luis Ignacio Gonzalez; Prader, Seraina; Reisli, Ismail; Slatter, Mary; Rodriguez-Gallego, Carlos; Arkwright, Peter D.; Bethune, Claire; Deripapa, Elena; Sharapova, Svetlana O.; Lehmberg, Kai; Davies, E. Graham; Schuetz, Catharina; Kindle, Gerhard; Schubert, Ralf; Kilic, Sara S.; KILIÇ GÜLTEKİN, SARA ŞEBNEM; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naive CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ss repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)Item Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4(+) T cells into distinct effector subsets(Rockefeller University Press, 2016-07-25) Ma, Cindy S.; Wong, Natalie; Rao, Geetha; Nguyen, Akira; Avery, Danielle T.; Payne, Kathryn; Torpy, James; O'Young, Patrick; Deenick, Elissa; Bustamante, Jacinta; Puel, Anne; Okada, Satoshi; Kobayashi, Masao; Martinez-Barricarte, Ruben; Elliott, Michael; El Baghdadi, Jamila; Minegishi, Yoshiyuki; Bousfiha, Aziz; Robertson, Nic; Hambleton, Sophie; Arkwright, Peter D.; French, Martyn; Blincoe, Annaliesse K.; Hsu, Peter; Campbell, Dianne E.; Stormon, Michael O.; Wong, Melanie; Adelstein, Stephen; Fulcher, David A.; Cook, Matthew C.; Stepensky, Polina; Boztuğ, Kaan; Beier, Rita; İkincioğulları, Aydan; Ziegler, John B.; Gray, Paul; Picard, Capucine; Boisson-Dupuis, Stephanie; Tri Giang, Phan; Grimbacher, Bodo; Warnatz, Klaus; Holland, Steven M.; Uzel, Gülbü; Casanova, Jean-Laurent; Tangye, Stuart G.; Kılıç, Sara Şebnem; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.; AAH-1658-2021; 34975059200Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12R beta 1/TYK2 and IFN-gamma R/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12R beta 1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.