Browsing by Subject "Immunology"

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  • Joenperä, Jasmin (Helsingfors universitet, 2015)
    Borrelia burgdorferi ja Anaplasma phagocytophilum ovat puutiaisvälitteisiä bakteereja. B. burgdorferi aiheuttaa ihmisille borrelioosia, mutta sen merkitystä hevosten taudinaiheuttajana ei täysin tunneta. A. phagocytophilum puolestaan aiheuttaa granulosyyttistä anaplasmoosia ihmisillä, koiralla ja hevosella sekä laidunkuumetta märehtijöillä. Tämän tutkimuksen tarkoituksena oli tutkia Borrelia- ja Anaplasma-vasta-aineiden yleisyyttä suomalaisilla hevosilla. Eri Euroopan maissa tehdyissä tutkimuksissa on todettu Borrelia-vasta-aineita noin 3-29 %:lla ja Anaplasma-vasta-aineita noin 9-73 %:lla hevosista. Suomessa aihetta ei ole aiemmin tutkittu tässä mittakaavassa. Hypoteesina oli, että hevosista löydetään vasta-aineita molempia taudinaiheuttajia vastaan erityisesti etelässä ja rannikkoalueilla sekä iäkkäillä ja Suomeen tuoduilla hevosilla. Tutkimuksessa kerättiin 281 varsojen ja 319 aikuisten hevosten verinäytettä Manner-Suomesta ja Ahvenanmaalta. Hevosenomistajilta pyydettiin lisäksi tietoja hevosesta kysymyslomakkeella. Näytteet tutkittiin koirien vektorivälitteisten tartuntojen diagnostiikkaan kehitettyä SNAP 4DX Plus –pikatestiä. Tulosten tilastollinen analyysi suoritettiin SPSS-ohjelmalla käyttäen yhden muuttujan logistista regressioanalyysiä ja ristiintaulukointia. Borrelia-vasta-aineita todettiin 60/319 (18,8 %) aikuisella ja 11/281 (3,9 %) varsalla ja Anaplasma-vasta-aineita 20/319 (6,3 %) aikuisella ja 4/281 varsalla (1,4 %). Seroprevalenssit olivat korkeimmat Ahvenanmaalla (aikuisilla Borrelia 89,5 % ja Anaplasma 47,4 %), Etelä-Suomessa (25,5 % ja 4.9 %) sekä Itä-Suomessa (17,0 % ja 4,9 %). Borrelia-seropositiivisuuden kannalta tilastollisesti merkitseviä tekijöitä olivat hevosessa havaitut puutiaiset, alue, hevosen alkuperämaa, ikä, käyttötarkoitus, roturyhmä sekä Anaplasma-seropositiivisuus yhden muuttujan mallissa. Anaplasma-seropositiivisuuden kannalta mahdollisesti merkitseviä tekijöitä olivat puutiaiset, alue, hevosen alkuperämaa, ikä sekä Borrelia-seropositiivisuus. Tulosten perusteella Borrelia burgdorferi- ja Anaplasma phagocytophilum -tartuntoja esiintyy yleisesti suomalaisilla hevosilla. Tartuntapaine oli korkein Ahvenanmaalla sekä Etelä- ja Itä-Suomessa. Käytännössä bakteeria kantavan puutiaisen purema on ainoa syy tartuntaan, mutta taustatekijät kuten asuminen puutiaisen levinneisyysalueella tai ulkoileminen maastossa tai laitumella ja voivat altistaa hevosen puutiaisille ja siten Borrelia- tai Anaplasma-tartunnalle. Riskitekijöiden selvittäminen vaatii laajempaa tilastollista analyysiä ja esimerkiksi Borrelia-tartunnan mahdollista yhteyttä kliinisiin oireisiin pitäisi selvittää lisätutkimuksin.
  • Uunila, Oona (Helsingfors universitet, 2017)
    Hevosen kesäihottuma (engl. insect bite hypersensitivity, IBH) on tyypin I yliherkkyysreaktio Culicoides spp. -lajin hyönteisille. Yliherkkyysreaktiota tavataan kaikilla mantereilla kaikilla alueilla, joissa hyönteislajia esiintyy, lukuun ottamatta pieniä maantieteellisesti eristettyjä alueita. Suomessa lajista esiintyy Culicoiden nubeculos:ta ja C. obsoletus:ta. Yliherkkyyden esiintyvyys vaihtelee 3 %:sta 60 %:iin ja se koetaan omistajien keskuudessa haastavaksi ja vaikeaksi taudiksi. Hevosen kesäihottumassa hevosen immuunivasteen T-auttajasolupopulaatio (Th) kääntyy normaalin terveen hevosen Th1- soluvasteesta Th2-soluvasteen puolelle aiheuttaen allergeenille spesifisen vasta-aineen immunoglobuliini E:n (IgE) ylituotannon immunoglobuliini G:n ja A:n sijasta. Immunologisen vasteen muutokseen vaikuttaa major histocombatibility II (MHCII)- allergeeniesittelijämolekyylin geenin monimuotoisuus sekä vallitseva sytokiiniprofiili. Akuuteissa ja kroonisissa taudeissa on havaittu Th-soluvasteen ja sytokiinien eroavaisuuksia ja siten hankaloittaa taudin kulun ja hoitovaihtoehtojen tutkimista. Kesäihottuman diagnosointi perustuu esitietoihin, kliiniseen tutkimukseen ja taudin kausiluontoisuuteen. Allergeenipaneeleja on kehitetty luomaan uusi diagnosointimenetelmä. Myös ihmisillä ja koirilla on tyypin I yliherkkyyttä, atooppista dermatiittiä eli atopiaa. Ihmisen ja koiran yliherkkyyksistä on runsaammin tutkimuksia kuin hevosten ja taudeissa on huomattavia yhtäläisyyksiä, joita voidaan käyttää apuna kesäihottuman tutkimuksessa. Koiran ja ihmisten atopia noudattavat sytokiiniprofiililtaan hevosen kesäihottumaa kroonisissa ja akuuteissa taudinkuvissa. Kutinan syntymekanismia on tutkittu hiiri- ja koiramallein ja kutinasytokiineja ovat mm. histamiini ja interleukiini 31 (IL-31). Histamiinia vapautuu syöttösolujen pinnalle kiinnittyneen allergeenispesifisen IgE:n kohdatessa allergeenin. IL-31 on Th2-solujen tuottama soluvälittäjäaine, joka aiheuttaa kutinaa. Hevosilla IL-31 -välitteistä kutinaa ei ole raportoitu. Myös serotoniini, asetyylikoliini, substanssi P, eri leukotrieenit ja bradykiniinit, proteaasit ja lysofostidiinihappo aiheuttavat kutinaa eri signaalireittien kautta. Yhtenä yhdistävänä, epäspesifisenä signaalireittinä pidetään Transient Receptor Potential Vallinoid 1:stä (TRPV1), joka aktivoituu toissijaisesti hermosolun depolarisoituessa muiden kutinaa aiheuttavien sytokiinien läsnäollessa. Vastaavia tutkimuksia hevosilla ei ole tehty. Kesäihottuman lääkkeelliset hoitovaihtoehdot ovat kutinan hillitseminen kortisonilla, mutta ei sovellu pirkäaikaiskäyttöön. Teoriassa on mahdollista käyttää koiran atopiassa käytettävää oklasitinibiä kutinan hillitsemiseksi myös kesäihottumassa, mikäli hevosen kutinamekanismi on yhteneväinen koiran kutinan signaalireittien kanssa. Siklosporiinia käytetään koirien ja ihmisten atopiaan, mutta se toimii parhaiten Th1-soluvasteen torjumiseen. Antihistamiinien teho hevosella on huono. Nykyinen markkinoilla oleva siedätyshoito koetaan kalliiksi ja hoitovasteeltaan huonoksi. Uudet tutkimukset apuaineen kanssa injektoidusta allergeenistä ovat lupaavia, mutta vaativat lisätutkimuksia. Muut hoitovaihtoehdot ovat tieteellisiltä perusteiltaan heikkoja, näyttö puuttuu täysin tai tutkimukset ovat olleet heikkolaatuisia. Hevosen kesäihottuman diagnostiikka on toistaiseksi haastavaa ja hoitovaihtoehdot heikohkot tieteelliseltä näytöltään.
  • Ilves, Marit (Helsingin yliopisto, 2018)
    Nanotechnology is exerting a huge impact on various sectors of everyday life as it has a tremendous potential for revolutionizing a long list of consumer products and industrial applications. The key to success in the nanotechnology field lies in the fact that materials at the nanoscale possess novel and enhanced properties such as greater strength and improved conductivity when compared with their bulk-sized equivalents. The most probable occupational and consumer routes of exposure to engineered nanomaterials (ENM) are via the respiratory tract and skin. Due to their small size, ENM are able to bypass physical and chemical barriers in the human body and come into contact with the immune system which is capable of recognizing foreign structures including ENM. However, the downscaling of the materials also increases their chemical reactivity, which in combination with the small size and other physicochemical properties, means that ENM could influence our immune system exerting possibly beneficial but also adverse effects on our health. The aim of this thesis was to investigate modulatory effects and physiological outcomes of ENM on a healthy and a compromised immune system in the lungs and skin. The main findings of the thesis were that rigid, rod-like but not long and tangled carbon nanotubes (CNT) were able to induce a condition similar to allergic airway inflammation via activation of innate immunity. Although nanofibrillated celluloses triggered acute pulmonary inflammation, their effects subsided within one month and regardless of the material’s biopersistence, their health outcomes differed significantly from the long-term pathologies of rigid, rod-like CNT. Uncoated and functionalized CuO nanomaterials demonstrated an ability to worsen allergic asthma by eliciting pulmonary neutrophilia, however it was found that surface PEGylation significantly suppressed the inflammatory potential of the pristine CuO ENM; this effect was especially evident at the transcriptional level. Topical exposure to nano-sized ZnO in a murine model of atopic dermatitis revealed that the particles were able to pass through mechanically injured allergic skin. This penetration of the material resulted in a local inhibition of pro-inflammatory and allergic reactions and a systemic exacerbation of IgE antibody production. This work provides knowledge of pulmonary and dermal effects of ENM. The results of this thesis demonstrate that ENM with different physicochemical characteristics possess an ability to modulate our immune system. These observations emphasize the diversity and complexity of the materials as well as highlighting their impacts on the immune system and the resulting consequences on health. These data contribute to the safety assessment of ENM as well as information that can be useful in nanomedicine.
  • Valkonen, Sami; Holopainen, Minna; Colas, Romain A.; Impola, Ulla; Dalli, Jesmond; Käkelä, Reijo; Siljander, Pia R.-M.; Laitinen, Saara (2019)
    Platelets are collected for transfusion to patients with different hematological disorders, and for logistical reasons, platelets are stored as concentrates. Despite the carefully controlled conditions, platelets become activated during storage, and platelet concentrates (PLCs) may cause adverse inflammatory reactions in the recipients. We studied by mass spectrometry the lipidomic changes during storage of the clinical PLCs, the platelets isolated from PLCs, and the extracellular vesicles (EVs) thereof. The release of EVs from platelets increased with the prolonged storage time. The molar percentages of arachidonic acid -containing species were increased during storage especially in the phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine classes of glycerophopholipids. The increase of these species in the membrane glycerophopholipid composition paralleled the production of both proinflammatory and proresolving lipid mediators (LMs) as the amount of the arachidonic acid-derived LMs such as thromboxane B2 and prostaglandin E2 also increased in time. Moreover, several monohydroxy pathway markers and functionally relevant proinflammatory and proresolving LMs were detected in the PLC and the EVs, and some of these clearly accumulated during storage. By Western blot, the key enzymes of these pathways were shown to be present in the platelets and in many cases also in the EVs. Since the EVs were enriched in the fatty acid precursors of LMs, harbored LM-producing enzymes, contained the related monohydroxy pathway markers, and also secreted the final LM products, the PLC-derived EVs appear to have the potential to regulate inflammation and healing, and may thereby aid the platelets in exerting their essential physiological functions.
  • Kaartinen, Miia; Karlsson, Linnea; Paavonen, E. Juulia; Polo-Kantola, Päivi; Pelto, Juho; Nousiainen, Niko; Scheinin, Noora M.; Maksimow, Mikael; Salmi, Marko; Karlsson, Hasse (2019)
    Objective: Sleep disturbances relate to altered levels of inflammatory mediators in general population, but not much is known about the associations between sleep disturbances and inflammatory mediators during pregnancy. The present exploratory study investigated whether insomnia, tiredness, general sleep quality, and insufficient sleep duration during pregnancy relate to the concentrations of maternal peripheral circulating cytokines. As sleep disturbances are frequently observed in mood disorders, the results were controlled for symptoms of depression and anxiety. Methods: 137 participants were randomly drawn from a representative FinnBrain Birth Cohort. Serum concentrations of selected cytokines were analyzed using Multiplex bead arrays from blood samples drawn at the gestational week 24. The sleep disturbances were evaluated using the Basic Nordic Sleep Questionnaire. Depressive and anxiety symptoms were measured with the Edinburgh Postnatal Depression Scale and the anxiety subscale of the self-rated Symptom Checklist 90, respectively. Results: Enhanced tiredness was associated with cytokine concentrations of IL-2, IL-10, IL-12, IL-13, and TNF-alpha. The observed associations resembled a reversed U-shaped curve rather than being linear. Having a good general sleep quality was associated with higher logarithmic cytokine concentrations of IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, and IFN-gamma. There was no evidence for associations between insomnia or sleep loss and cytokines. Conclusions: Maternal subjective tiredness and good general sleep quality were associated with altered levels of immunological markers during pregnancy. The association was independent from symptoms of depression and anxiety.
  • Hemminki, Otto; dos Santos, Joao Manuel; Hemminki, Akseli (2020)
    In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains. As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors. Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.
  • Hemminki, Otto; dos Santos, João M; Hemminki, Akseli (BioMed Central, 2020)
    Abstract In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains. As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors. Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.
  • Soderlund, Stina; Persson, Inger; Ilanderd, Mette; Guilhot, Joelle; Hjorth-Hansen, Henrik; Koskenvesa, Perttu; Richter, Johan; Saussele, Susanne; Mustjoki, Satu; Olsson-Strömberg, Ulla (2020)
    Several studies have now shown that chronic myeloid leukaemia (CML) patients in deep molecular remission may discontinue tyrosine kinase inhibitor (TKI) treatment with a treatment free remission (TFR) rate of approximately 40-60 %. Some factors influencing the possibility of TFR have been described but better tools are needed for individual prediction of long-term TFR. Herein, two multiplex panels were utilised to analyse a total of 162 different plasma proteins from 56 patients included in the TKI stopping trial EURO-SKI (Saussele a al., 2018). The purpose was to identify possible plasma protein markers for prediction of successful TKI discontinuation and to evaluate effects of TKI discontinuation on plasma protein profiles. No protein biomarkers sampled before TKI discontinuation could separate relapse cases from non-relapse cases but some plasma proteins differed between patients who relapsed and those who remained in TFR when followed over time after TKI cessation. In conclusion, the plasma protein markers in this study could not predict relapse after TKI discontinuation but may be of use to understand the mechanisms involved in maintenance of TFR.
  • Schatorje, Ellen; van der Flier, Michiel; Seppanen, Mikko; Browning, Michael; Morsheimer, Megan; Henriet, Stefanie; Neves, Joao Farela; Vinh, Donald Cuong; Alsina, Laia; Grumach, Anete; Soler-Palacin, Pere; Boyce, Thomas; Celmeli, Fatih; Goudouris, Ekaterini; Hayman, Grant; Herriot, Richard; Forster-Waldl, Elisabeth; Seidel, Markus; Simons, Annet; de Vries, Esther (2016)
    Background: Patients with syndromic features frequently suffer from recurrent respiratory infections, but little is known about the spectrum of immunological abnormalities associated with their underlying chromosomal aberrations outside the well-known examples of Down and DiGeorge syndromes. Therefore, we performed this retrospective, observational survey study. Methods: All members of the European Society for Immunodeficiencies (ESID) were invited to participate by reporting their patients with chromosomal aberration (excluding Down and DiGeorge syndromes) in combination with one or more identified immunological abnormalities potentially relating to primary immunodeficiency. An online questionnaire was used to collect the patient data. Results: Forty-six patients were included from 16 centers (24 males, 22 females; median age 10.4 years [range 1.0-69. 2 years]; 36 pediatric, 10 adult patients). A variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immune deficiency was reported. The most important clinical presentation prompting the immunological evaluation was 'recurrent ear-nose-throat (ENT) and airway infections'. Immunoglobulin isotype and/or IgG-subclass deficiencies were the most prevalent immunological abnormalities reported. Conclusions: Our survey yielded a wide variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immunodeficiency. Although respiratory tract infections can often also be ascribed to other causes (e.g. aspiration or structural abnormalities), we show that a significant proportion of patients also have an antibody deficiency requiring specific treatment (e.g. immunoglobulin replacement, antibiotic prophylaxis). Therefore, it is important to perform immunological investigations in patients with chromosomal aberrations and recurrent ENT or airway infections, to identify potential immunodeficiency that can be specifically treated.
  • Helve, Otto; Dikareva, Evgenia; Stefanovic, Vedran; Kolho, Kaija-Leena; Salonen, Anne; de Vos, Willem M.; Andersson, Sture (2021)
    Summary Infants born by cesarean section have an intestinal microbiota that differs from that of infants delivered vaginally. Here, we report a protocol for performing oral transplantation of maternal fecal microbiota to newborn infants born by elective cesarean section. The crucial step of this protocol is the health screening process. This protocol can only be applied to healthy mothers and infants. For complete details on the use and execution of this protocol, please refer to Korpela et al. (2020).
  • Nascimento, Gustavo G.; Baelum, Vibeke; Sorsa, Timo; Tervahartiala, Taina; Skottrup, Peter D.; Lopez, Rodrigo (2019)
    Aim: This study aimed to investigate the association between salivary levels of myeloperoxidase (MPO), neutrophil elastase (NE), soluble urokinase-type plasminogen activator receptor (suPAR), matrix metalloproteinase (MMP)-8 and tissue inhibitor of matrix metalloproteinases (TIMP)-1 and gingival inflammation development during an experimental gingivitis study. Methods: A three-week experimental gingivitis study was conducted. Clinical recordings of dental plaque biofilm (Modified Quigley Hein Plaque Index, TQHPI) and gingival inflammation (Modified Gingival Index, MGI) were made at specific time points for each of the 42 participants. Salivary levels of MPO, NE, suPAR, MMP-8 and TIMP-1 at the same time points were measured using distinct immunoassays. For data analysis growth curve modelling was employed to account for the time-varying outcome (MGI score) and the time-varying covariates (salivary marker levels, and TQHPI score). Analyses were stratified according to the MGI-score trajectory groups previously identified as 'fast', respectively 'slow' responders. Results: Overall, higher MGI scores were statistically significantly positively associated with higher levels of MPO, MMP-8 and TIMP-1. Stratified analysis according to inflammation development trajectory group revealed higher levels of salivary MPO, MMP-8 and MMP-8/TIMP-1 ratio among the 'fast' responders than among 'slow' responders. None of the investigated salivary protein markers was associated with a 'slow' inflammation development response. Conclusions: Salivary levels of MPO, MMP-8 and TIMP-1 were associated with the extent and severity of gingival inflammation. While the 'fast' gingival inflammation response was associated with increased levels of MPO, MMP-8 and MMP-8/TIMP-1 ratio, the 'slow' response was not associated with any of the salivary protein markers investigated in this study. Neutrophil activity seems to orchestrate a 'fast' gingival inflammatory response among participants previously primed to gingival inflammation.
  • Jayachandran, Rupesh Balaji (Helsingin yliopisto, 2022)
    COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has thus far claimed over six million lives. Vaccines against SARS-CoV-2 have successfully mitigated severe disease and eased the burden on healthcare systems. Neutralizing antibodies play crucial roles both in vaccine derived immunity, and as drugs widely utilized in monoclonal antibody therapy. Neutralizing antibodies primarily target the spike protein, where most of the neutralizing epitopes are located in the receptor binding domain (RBD). Elucidating the sites of vulnerability to neutralization on SARS-CoV-2 can facilitate the development of therapeutics. 7A12 is a newly-discovered IgG antigen-binding fragment (Fab) isolated from a COVID-19 patient in Finland that can neutralize SARS-CoV-2 by targeting the spike protein. In this thesis, a complex of the Fab 7A12 with SARS-CoV-2 spike ectodomain trimer was studied using cryogenic electron microscopy (cryo-EM) single-particle analysis to elucidate the epitope of 7A12 and to gain insight into the neutralization mechanism of 7A12. Cryo-EM data of the complex revealed that Fab 7A12 can bind to both “open” and “closed” conformations of RBD. Rigid-body fitting of the spike trimer and Fab 7A12 models into the cryo-EM density indicates that 7A12 recognizes an epitope in the RBD which is mainly located outside the ACE2 binding site. Together, these results suggest that the 7A12 epitope belongs to class III of SARS-CoV-2 neutralizing epitopes located in the RBD, indicating that 7A12 could neutralize by sterically hindering ACE2 and by preventing the adjacent RBD from changing to ”up” conformation. Furthermore, our results revealed an overlap of 7A12 epitope with the putative binding site of heparan sulfate, a host factor of SARS-CoV-2 infection, which might contribute to neutralization. 7A12-RBD interface mapping delineated the residues comprising the epitope, which do not include mutants found in Beta, Gamma, and Delta variants, while four mutants were found in Omicron within the epitope indicating that 7A12 is likely to neutralize Beta, Gamma, and Delta variants of concern.
  • Mannerström, Helga (Helsingfors universitet, 2013)
    Autoimmune polyendocrinopathy-candidasis-ectodermal dystrophy, APECED, is a rare monogenic autoimmune disease in humans, which is caused by loss-of-function mutation in Autoimmune Regulator gene, AIRE. Previous results have shown impairments in the circulating T cells of the APECED patients. In this study we wanted to look closer on the disturbance in the T cell receptor development of APECED patients. By studying the TCR-mediated responsiveness of CD3 stimulation and comparing the activation threshold between APECED patients and controls we here show a lower response on Zap-70 phosphorylation to TCR-mediated stimulation in naïve T cell population of APECED patients as well as an increased IFN-γ production in lymphocytes of APECED patients. The higher cytokine production and the insensitivity toward further activation could in part explain some of the pathogenesis behind disease manifestations seen in APECED.