Browsing by Subject "Autoimmunity"

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  • Tyster, Mikko (Helsingin yliopisto, 2020)
    Aplastisen anemian autoimmuunimuodossa (IAA) elimistön oma immuunipuolustus tuhoaa verta muodostavia luuydinsoluja, mistä seuraa usean solulinjan kattava pansytopenia. Tämän sairauden tarkkaa patologista mekanismia ei tunneta, mutta aiemmat kliiniset ja kokeelliset tutkimukset osoittavat kyseessä olevan pääosin lymfosyyttien välittämä autoimmuunireaktio. Tässä tutkimuksessa löysimme uuden autovasta-aineen IAA-potilaiden plasmasta käyttäen laajaa proteiinimikrosirupaneelia. Suuressa kansainvälisessä IAA-potilasaineistossa tämän uuden autovasta-aineen prevalenssi oli 36 %, ja autovasta-ainepositiivisilla potilailla todettiin matalammat verihiutaleiden määrät diagnoosihetkellä. Autovasta-ainepositiiviset potilaat olivat myös selvästi vanhempia verrattuna negatiivisiin. Erityisesti tämä autovasta-aine oli yhteydessä luokan II HLA (human leukocyte antigen) alleeliin; 86 % autovasta-ainepositiivisista potilaista kantoi HLA-DRB1*15-alleelia, negatiivisista vain 31 %. Lisäksi tämän uuden autovasta-aineen suhteen positiivisilla potilailla todettiin useammin merkittäviä PNH-klooneja (paroxysmal nocturnal hemoglobinuria) verrattuna autovasta-ainenegatiivisiin. Single-cell RNA-sekvenointianalyysillä todettiin luuytimen soluista hematopoieettisten kantasolujen ilmentävän tämän autovasta-aineen kohdeproteiinia koodaavaa geeniä. IAA-potilailla tämän geenin ilmentyminen oli selvästi suurempaa verrattuna terveisiin kontrolleihin sekä myelodysplastista syndroomaa sairastaviin potilaisiin. Nämä löydökset viittaavat siihen, että tämä uusi autovasta-aine voisi osallistua IAA:n patologiseen mekanismiin Lisäksi sitä voitaisiin hyödyntää differentiaalidiagnostisena työkaluna aplastisen anemian erilaisten ilmentymien kliinisessä hoidossa.
  • Sarkkinen, Joona (Helsingin yliopisto, 2018)
    Pahanlaatuisten veritautien ja luuytimen syöpien hoidossa käytetään allogeenista eli toiselta yksilöltä peräisin olevaa verta muodostavien kantasolujen siirrettä. Elintärkeän siirteen sivuvaikutuksena potilaalle voi kehittyä käänteishyljintäreaktio, jossa luovuttajan puolustusjärjestelmän solut vaurioittavat potilaan kudosrakenteita. Vaurioita kehittyy myös kateenkorvaan, elimeen, jossa immuunijärjestelmälle tärkeät T-solut kehittyvät ja ”kouluttautuvat”. Käänteishyljintäreaktion edetessä kateenkorva vaurioituu, minkä seurauksena elimistöön voi vapautua myös omia rakenteita vaurioittavia eli autoreaktiivisia T-soluja. Tiedetään, että T-solujen koulutus on häiriintynyt autoimmuunipolyendokrinopatia-kandidiaasi-ektodermidystrofiassa eli APECED:ssa (toiselta nimeltään APS1-oireyhtymä) sekä kateenkorvan epiteelisolujen kasvaimissa eli tymoomissa. APECED on autosomaalisesti peittyvästi periytyvä yhden geenin mutaation aiheuttama autoimmuunisairaus, jossa autoreaktiiviset T-solut aiheuttavat kudosvaurioita. Näissä sairauksissa potilailla on myös omia puolustusjärjestelmän sytokiineja estäviä vasta-aineita, niin kutsuttuja antisytokiini autovasta-aineita. Ajatellaan, että autoreaktiiviset T-solut osallistuvat kyseisten autovasta-aineiden muodostumiseen. Koska käänteishyljintäreaktio muistuttaa kateenkorvavaurioiltaan hieman APECED:a ja tymoomaa, syventävän projektini hypoteesina oli, että myös kroonisen käänteishyljintäreaktion potilailta löytyisi samoja antisytokiini autovasta-aineita kuin APECED:ssa ja tymoomassa. Huomio kiinnitettiin IFN-α 2a autovasta-aineiseen, mikä on yleisimpiä antisytokiini autovasta-aineita näissä sairauksissa. Tutkimusaineisto koostui 20:stä allogeenisen kantasolusiirteen saaneiden potilaiden seerumista, joista 18 kärsi kroonisesta käänteishyljinnästä. IFN-α 2a autovasta-aineen havaitsemiseksi käytettiin entsyymivälitteistä immunosorbenttianalyysiä, eli niin kutsuttua ELISA-menetelmää. Tutkimustulos oli negatiivinen eli potilasnäytteet eivät sisältäneet IFN-α 2a autovasta-ainetta. Tutkimushypoteesi oli täten väärä eli krooniseen käänteishyljintäreaktioon liittyvä kateenkorvavaurio ei aiheuta samanlaisia immunologisia vaikutuksia kuin APECED tai tymooma. Kateenkorvavaurion etiologia ja vaikutukset käänteishyljintäreaktiossa jäävät vielä avoimeksi ja selvittämiseksi vaaditaan tarkempaa solutason tutkimusta. Voi myös olla, että antisytokiini autovasta-aineiden muodostumiseen vaikuttavat muut, toistaiseksi tuntemattomat tekijät.
  • Mantere, O.; Saarela, M.; Kieseppä, T.; Raij, T.; Mäntylä, T.; Lindgren, M.; Rikandi, E.; Stoecker, W.; Teegen, B.; Suvisaari, J. (2018)
    It may be challenging to distinguish autoimmune encephalitis associated with anti-neuronal autoantibodies from primary psychiatric disorders. Here, serum was drawn from patients with a first-episode psychosis (n = 70) or a clinical high-risk for psychosis (n = 6) and controls (n = 34). We investigated the serum prevalence of 24 antineuronal autoantibodies: IgG antibodies for anti-N-methyl-D-aspartate-type glutamate receptor (anti-NMDAR), glutamate and gamma-aminobutyric acid alpha and beta receptors (GABA-a, GABA-b), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), glycine receptor (GlyR), metabotropic glutamate receptor 1 and 5 (mGluR1, mGluR5), anti-Tr/Delta/notch-like epidermal growth factor-related receptor (DNER), contactin-associated protein-like 2 (CASPR2), myelin oligodendrocyte glycoprotein (MOG), glutamic acid decarboxylase-65 (GAD65), collapsin response mediator protein 5/crossveinless-2 (CV2), aquaporin-4 (AQP4), anti-dipeptidyl-peptidase-like protein-6 (DPPX), type 1 anti-neuronal nuclear antibody (ANNA-1, Hu), Ri, Yo, IgLON5, Ma2, zinc finger protein 4 (ZIC4), Rho GTPase-activating protein 26, amphiphysin, and recoverin, as well as IgA and IgM for dopamine-2-receptor (DRD2). Anti-NMDA IgG antibodies were positive with serum titer 1:320 in one patient with a clinical high risk for psychosis. He did not receive a diagnosis of encephalitis after comprehensive neurological evaluation. All other antineuronal autoantibodies were negative and there were no additional findings with immunohistochemistry of brain issues. (C) 2017 Elsevier B.V. All rights reserved.
  • Ekman, Ilse; Ihantola, Emmi-Leena; Viisanen, Tyyne; Rao, Deepak A.; Näntö-Salonen, Kirsti; Knip, Mikael; Veijola, Riitta; Toppari, Jorma; Ilonen, Jorma; Kinnunen, Tuure (2019)
    Aims/hypothesis Type 1 diabetes is preceded by a period of asymptomatic autoimmunity characterised by positivity for islet autoantibodies. Therefore, T helper cell responses that induce B cell activation are likely to play a critical role in the disease process. Here, we aimed to evaluate the role of a recently described subset, C-X-C motif chemokine receptor type 5-negative, programmed cell death protein 1-positive (CXCR5(-)PD-1(hi)) peripheral T helper (Tph) cells, in human type 1 diabetes. Methods The phenotype of blood CXCR5(-)PD-1(hi) CD4(+) T cells was analysed by multicolour flow cytometry. The frequencies of circulating CXCR5(-)PD-1(hi) T cells were analysed in a cohort of 44 children with newly diagnosed type 1 diabetes, 40 autoantibody-positive (AAb(+)) at-risk children and 84 autoantibody-negative healthy control children, and the findings were replicated in a separate cohort of 15 children with newly diagnosed type 1 diabetes and 15 healthy control children. Results Circulating CXCR5(-)PD-1(hi) Tph cells share several features associated with B cell helper function with circulating CXCR5(+)PD-1(hi) follicular T helper (Tfh) cells. Moreover, the frequency of circulating Tph cells was increased in children with newly diagnosed type 1 diabetes, especially in those who are positive for multiple autoantibodies. Importantly, circulating Tph cells were also increased in autoantibody-positive at-risk children who later progressed to type 1 diabetes. Conclusions/interpretation Our results demonstrate that circulating CXCR5(-)PD-1(hi) Tph cells are associated with progression to clinical type 1 diabetes. Consequently, Tph cells could have potential both as a biomarker of disease progression and as a target for immunotherapy in type 1 diabetes.
  • Sandström, John (Helsingin yliopisto, 2019)
    Finland har världens högsta incidens för typ 1 diabetes (T1D). Incidensen har ökat mångfalt under de senaste årtiondena i Finland och i andra utvecklade länder. Bl.a. detta och sjukdomens säsongberoende natur har riktat blickarna mot säsongberoende miljö-faktorer som utlösare av sjukdomsprocessen. Denna studies syfte var att undersöka om detta säsongberoende kan påvisas också i Finland och hur den förhåller sig till kön och ålder. Studiepopulationen bestod av 0–14 åriga finländska barn som hade diagnosticerats med T1D under åren 2002–2015. Säsonganalyser gällande diagnostidpunkten gjordes med hjälp av Poissons regressionsanalys, som säsongmodifierades. Vi observerade inci-densmönstret i förhållande till debutmånad samt säsongberoendets förhållande till kön och ålder. Diabetikerbarnen jämfördes med den teoretiska populationsenliga riskgrup-pen bestående av totalt antal levande 0–14 åringar i Finland per månad. Vår studie utvisade ett starkt säsongberoende. Säsongberoendet påverkades inte av kön men verkade bli kraftigare med stigande diagnosålder. Incidensen för pojkar var högre än hos flickor. Den årliga incidenstrenden var sjunkande fr.o.m. år 2006. Intressant var också att den yngsta åldersgruppen uppvisade den klart mest sjunkande incidenstrenden bland grupperna vilket väcker frågor om rotavirusvaccinets roll gällande incidensföränd-ringen. Rotavirusvaccinet infogades i det nationella vaccinationsprogrammet år 2009. Resultaten kan generera nya insikter angående sjukdomens patogenes och etiologi.
  • Niinisto, Sari; Takkinen, Hanna-Mari; Erlund, Iris; Ahonen, Suvi; Toppari, Jorma; Ilonen, Jorma; Veijola, Riitta; Knip, Mikael; Vaarala, Outi; Virtanen, Suvi M. (2017)
    Aims/hypothesis We investigated the association of early serum fatty acid composition with the risk of type 1 diabetes-associated autoimmunity. Our hypothesis was that fatty acid status during infancy is related to type 1 diabetes-associated autoimmunity and that long-chain n-3 fatty acids, in particular, are associated with decreased risk. Methods We performed a nested case-control analysis within the Finnish Type 1 Diabetes Prediction and Prevention Study birth cohort, carrying HLA-conferred susceptibility to type 1 diabetes (n = 7782). Serum total fatty acid composition was analysed by gas chromatography in 240 infants with islet autoimmunity and 480 control infants at the age of 3 and 6 months. Islet autoimmunity was defined as repeated positivity for islet cell autoantibodies in combination with at least one of three selected autoantibodies. In addition, a subset of 43 infants with primary insulin autoimmunity (i.e. those with insulin autoantibodies as the first autoantibody with no concomitant other autoantibodies) and a control group (n = 86) were analysed. A third endpoint was primary GAD autoimmunity defined as GAD autoantibody appearing as the first antibody without other concomitant autoantibodies (22 infants with GAD autoimmunity; 42 infants in control group). Conditional logistic regression was applied, considering multiple comparisons by false discovery rate <0.05. Results Serum fatty acid composition differed between breastfed and non-breastfed infants, reflecting differences in the fatty acid composition of the milk. Fatty acids were associated with islet autoimmunity (higher serum pentadecanoic, palmitic, palmitoleic and docosahexaenoic acids decreased risk; higher arachidonic: docosahexaenoic and n-6: n-3 acid ratios increased risk). Furthermore, fatty acids were associated with primary insulin autoimmunity, these associations being stronger (higher palmitoleic acid, cis-vaccenic, arachidonic, docosapentaenoic and docosahexaenoic acids decreased risk; higher a-linoleic acid and arachidonic: docosahexaenoic and n-6: n-3 acid ratios increased risk). Moreover, the quantity of breast milk consumed per day was inversely associated with primary insulin autoimmunity, while the quantity of cow's milk consumed per day was directly associated. Conclusions/interpretation Fatty acid status may play a role in the development of type 1 diabetes-associated autoimmunity. Fish-derived fatty acids may be protective, particularly during infancy. Furthermore, fatty acids consumed during breastfeeding may provide protection against type 1 diabetes-associated autoimmunity. Further studies are warranted to clarify the independent role of fatty acids in the development of type 1 diabetes.
  • Heikkilä, Nelli; Sormunen, Silja; Mattila, Joonatan; Härkönen, Taina; Knip, Mikael; Ihantola, Emmi-Leena; Kinnunen, Tuure; Mattila, Ilkka P.; Sarama, Jari; Arstila, T. Petteri (2021)
    The T-cell receptor (TCR) repertoire is generated in a semistochastic process of gene recombination and pairing of TCR? to TCR? chains with the estimated total TCR diversity of >108. Despite this high diversity, similar or identical TCR chains are found to recur in immune responses. Here, we analyzed the thymic generation of TCR sequences previously associated with recognition of self- and nonself-antigens, represented by sequences associated with autoimmune diabetes and HIV, respectively. Unexpectedly, in the CD4+ compartment TCR? chains associated with the recognition of self-antigens were generated in significantly higher numbers than TCR? chains associated with the recognition of nonself-antigens. The analysis of the circulating repertoire further showed that these chains are not lost in negative selection nor predominantly converted to the regulatory T-cell lineage. The high abundance of self-reactive TCR? chains in multiple individuals suggests that the human thymus has a predilection to generate self-reactive TCR? chains independently of the HLA-type and that the individual risk of autoimmunity may be modulated by the TCR? repertoire associated with these chains.
  • Nozal, Pilar; Bernabeu-Herrero, Maria E.; Uzonyi, Barbara; Szilagyi, Agnes; Hyvarinen, Satu; Prohaszka, Zoltan; Jokiranta, T. Sakari; Sanchez-Corral, Pilar; Lopez-Trascasa, Margarita; Jozsi, Mihaly (2016)
    Factor H (FH) autoantibodies are present in 6-10% of atypical hemolytic uremic syndrome (aHUS) patients, most of whom have homozygous deficiency of the FH-related protein FHR-1. Although the pathogenic role of the autoantibodies is established, little is known about their molecular characteristics and changes over time. Here, we describe the specificity and other immunological features of anti-FH autoantibodies in the Spanish and Hungarian aHUS cohorts. A total of 19 patients were included and serial samples of 14 of them were available. FH autoantibodies from FHR-1 deficient patients (n = 13) mainly recognized FH, its SCR19-20 fragment and FHR-1, but autoantibody specificity in patients who are homoor heterozygous for the CFHR1 gene (n = 6) was heterogeneous. No significant changes apart from total antibody titer were observed during follow-up in each patient. Fine epitope mapping with recombinant FH SCR19-20 containing single amino acid mutations showed significantly reduced binding in 6 out of 14 patients. In most cases, autoantibody binding to residues 1183-1189 and 1210-1215 was impaired, revealing a major common autoantibody epitope. Avidities showed variations between patients, but in most cases the avidity index did not change upon time. Most autoantibodies were IgG3, and all but three presented only with kappa or with lambda light chains. Although the pathogenic role of anti-FH autoantibodies in aHUS is well established, this study shows autoantibody heterogeneity among patients, but no significant variation in their characteristics over time in each patient. The presence of a single light chain in 16 out of 19 patients and the limited number of recognized epitopes suggest a restricted autoantibody response in most patients. (C) 2015 Elsevier Ltd. All rights reserved.
  • Gazali, Ahmad M.; Schroderus, Anna-Mari; Näntö-Salonen, Kirsti; Rintamäki, Reeta; Pihlajamäki, Jussi; Knip, Mikael; Veijola, Riitta; Toppari, Jorma; Ilonen, Jorma; Kinnunen, Tuure (2020)
    Aims/hypothesis Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognise derivatives of bacterial riboflavin metabolites presented by MHC-Ib-related protein 1 (MR1) molecules and are important effector cells for mucosal immunity. Their development can be influenced by the intestinal microbiome. Since the development of type 1 diabetes has been associated with changes in the gut microbiome, this can be hypothesised to lead to alterations in circulating MAIT cells. Accordingly, peripheral blood MAIT cell alterations have been reported previously in patients with type 1 diabetes. However, a comprehensive analysis of the frequency and phenotype of circulating MAIT cells at different stages of type 1 diabetes progression is currently lacking. Methods We analysed the frequency, phenotype and functionality of peripheral blood MAIT cells, as well as gamma delta T cells, invariant natural killer T (iNKT) cells and natural killer (NK) cells with flow cytometry in a cross-sectional paediatric cohort (aged 2-15) consisting of 51 children with newly diagnosed type 1 diabetes, 27 autoantibody-positive (AAb(+)) at-risk children, and 113 healthy control children of similar age and HLA class II background. The frequency of MAIT cells was also assessed in a separate cross-sectional adult cohort (aged 19-39) of 33 adults with established type 1 diabetes and 37 healthy individuals of similar age. Results Children with newly diagnosed type 1 diabetes displayed a proportional increase of CD8(-)CD27(-)MAIT cells compared with healthy control children (median 4.6% vs 3.1% of MAIT cells, respectively, p = 0.004), which was associated with reduced expression of C-C chemokine receptor (CCR)5 (median 90.0% vs 94.3% of MAIT cells, p = 0.02) and beta 7 integrin (median 73.5% vs 81.7% of MAIT cells, p = 0.004), as well as decreased production of IFN-gamma (median 57.1% vs 69.3% of MAIT cells, p = 0.04) by the MAIT cells. The frequency of MAIT cells was also decreased in AAb(+)children who later progressed to type 1 diabetes compared with healthy control children (median 0.44% vs 0.96% of CD3(+)T cells, p = 0.04), as well as in adult patients with a short duration of type 1 diabetes (less than 6 years after diagnosis) compared with control individuals (median 0.87% vs 2.19% of CD3(+)T cells, p = 0.007). No alterations in gamma delta T cell, iNKT cell or NK cell frequencies were observed in children with type 1 diabetes or in AAb(+) children, with the exception of an increased frequency of IL-17A(+)gamma delta T cells in children with newly diagnosed diabetes compared with healthy control children (median 1.58% vs 1.09% of gamma delta T cells, p = 0.002). Conclusions/interpretation Changes in the frequency and phenotype of circulating MAIT cells were detectable before, at the onset and after diagnosis of type 1 diabetes in cross-sectional cohorts. Our results suggest a possible temporal association between peripheral blood MAIT cell alterations and the clinical onset of type 1 diabetes.
  • Melén, Krister; Jalkanen, Pinja; Kukkonen, Jyrki P.; Partinen, Markku; Nohynek, Hanna; Vuorela, Arja; Vaarala, O.; Freitag, Tobias L.; Meri, Seppo; Julkunen, Ilkka (2020)
    Narcolepsy type 1, likely an immune-mediated disease, is characterized by excessive daytime sleepiness and cataplexy. The disease is strongly associated with human leukocyte antigen (HLA) DQB1∗06:02. A significant increase in the incidence of childhood and adolescent narcolepsy was observed after a vaccination campaign with AS03-adjuvanted Pandemrix influenza vaccine in Nordic and several other countries in 2010 and 2011. Previously, it has been suggested that a surface-exposed region of influenza A nucleoprotein, a structural component of the Pandemrix vaccine, shares amino acid residues with the first extracellular domain of the human OX2 orexin/hypocretin receptor eliciting the development of autoantibodies. Here, we analyzed, whether H1N1pdm09 infection or Pandemrix vaccination contributed to the development of autoantibodies to the orexin precursor protein or the OX1 or OX2 receptors. The analysis was based on the presence or absence of autoantibody responses against analyzed proteins. Entire OX1 and OX2 receptors or just their extracellular N-termini were transiently expressed in HuH7 cells to determine specific antibody responses in human sera. Based on our immunofluorescence analysis, none of the 56 Pandemrix-vaccinated narcoleptic patients, 28 patients who suffered from a laboratory-confirmed H1N1pdm09 infection or 19 Pandemrix-vaccinated controls showed specific autoantibody responses to prepro-orexin, orexin receptors or the isolated extracellular N-termini of orexin receptors. We also did not find any evidence for cell-mediated immunity against the N-terminal epitopes of OX2. Our findings do not support the hypothesis that the surface-exposed region of the influenza nucleoprotein A would elicit the development of an immune response against orexin receptors. © 2020 The Authors
  • Id, Johannes (Helsingfors universitet, 2015)
    Rasmussenin enkefaliitti (RE) on erittäin harvinainen toiseen aivopuoliskoon rajautuva etiologialtaan tuntematon inflammatorinen sairaus, joka puhkeaa useimmiten lapsuusiässä. Sairaudelle ovat tyypillisiä tiheät epileptiset kohtaukset sekä etenevä neurologinen puutosoireisto, joka sopii toispuoleiseen aivovaurioon. Tätä tutkimusta varten kerättiin tiedot Hyks Lastenlinnan epilepsiayksikössä vuosina 1990-2013 hoidettujen RE-potilaiden taudinkuvasta ja heidän saamistaan hoitomuodoista. Vaikka aineisto oli pieni, tutkimuksessa kävi selväksi että sairaus on hyvin heterogeeninen ja taudinkuva vaihtelee huomattavasti potilaiden välillä – kaikilla potilailla taudinkuva ei täysin noudattanut aiemmissa julkaisuissa kuvattua. Tutkimuksessa havaittiin lisäksi, että alle 6-vuotiaana alkaneessa RE:ssä näyttää olevan huonompi ennuste sekä motoriikan että kognition suhteen yli 6-vuotiaana sairastuneisiin nähden. Kuten aiemmissakin tutkimuksissa, omassa aineistossamme ainoa tehokas hoitomuoto epilepsiaan oli diskonnektiivinen eli sairaan aivopuoliskon yhteydet muuhun keskushermostoon katkaiseva leikkaus. Kaikki diskonnektion läpikäyneet potilaat saavuttivat seuranta-aikana kohtauksettomuuden viimeistään uusintaleikkausten jälkeen.
  • Lundgren, Sofie Alexandra (Helsingin yliopisto, 2013)
    The role of somatic mutations in cancer development is undisputable, but our knowledge of the prevalence and function of somatic mutations in healthy cells is yet unresolved question. In immune-mediated bone-marrow failure (such as aplastic anemia and hypoplastic myelodysplastic syndromes) hematopoietic stem cells are destroyed by cytotoxic T cells, which have been shown to be oligoclonal and in some cases harbor STAT3 mutations. We addressed clonality of non-malignant T cells by investigating somatic mutations with a custom- made gene panel of 2533 genes. We sequenced CD4+ and CD8+ cells of 29 patients with immune-mediated bone marrow failure and compared the results to 20 healthy controls as well as previously published data on patients with aplastic anemia. Somatic variants in lymphocytes were common both in patients and healthy controls, but especially enriched in aplastic anemia patients and CD8+ T cells. CD8+ T cells of aplastic anemia patients accumulated most mutations on JAK-STAT and MAPK pathways. The number of somatic mutations was associated with CD8+ T cell clonality, assessed by T cell receptor beta sequencing. To further understand the role of mutations in T cells, we performed single-cell RNA sequencing from 6 longitudinal samples of 2 aplastic anemia patients with STAT3, KRAS, NFATC2 and PTPN22 mutations in CD8+ T cell clones. Mutated clones showed cytotoxic phenotype, which was altered by successful immunosuppressive treatment. Our results suggest that somatic mutations in T cells are common, associate with clonality and may alter T cell phenotype. The role of somatic mutations in the initiation and persistence of autoreactive clones needs to be further investigated.
  • El-Sayed, Zeinab A.; Abramova, Irina; Carlos Aldave, Juan; Al-Herz, Waleed; Bezrodnik, Liliana; Boukari, Rachida; Bousfiha, Ahmed Aziz; Cancrini, Caterina; Condino-Neto, Antonio; Dbaibo, Ghassan; Derfalvi, Beata; Dogu, Figen; Edgar, J. David M.; Eley, Brian; El-Owaidy, Rasha Hasan; Elva Espinosa-Padilla, Sara; Galal, Nermeen; Haerynck, Filomeen; Hanna-Wakim, Rima; Hossny, Elham; Ikinciogullari, Aydan; Kamal, Ebtihal; Kanegane, Hirokazu; Kechout, Nadia; Lau, Yu Lung; Morio, Tomohiro; Moschese, Viviana; Neves, Joao Farela; Ouederni, Monia; Paganelli, Roberto; Paris, Kenneth; Pignata, Claudio; Plebani, Alessandro; Qamar, Farah Naz; Qureshi, Sonia; Radhakrishnan, Nita; Rezaei, Nima; Rosario, Nelson; Routes, John; Sanchez, Berta; Sediva, Anna; Seppanen, Mikko R. J.; Serrano, Edith Gonzalez; Shcherbina, Anna; Singh, Surjit; Siniah, Sangeetha; Spadaro, Guiseppe; Tang, Mimi; Maria Vinet, Ana; Volokha, Alla; Sullivan, Kathleen E. (2019)
    Background: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. Methods: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. Results: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. Conclusions: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.