Browsing by Subject "autoimmunity"

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  • Uzonyi, B; Szabo, Z; Trojnar, E; Hyvarinen, S; Uray, K; Nielsen, HH; Erdei, A; Jokiranta, TS; Prohaszka, Z; Illes, Z; Jozsi, M (2021)
    Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS), characterized by pathogenic, complement-activating autoantibodies against the main water channel in the CNS, aquaporin 4 (AQP4). NMOSD is frequently associated with additional autoantibodies and antibody-mediated diseases. Because the alternative pathway amplifies complement activation, our aim was to evaluate the presence of autoantibodies against the alternative pathway C3 convertase, its components C3b and factor B, and the complement regulator factor H (FH) in NMOSD. Four out of 45 AQP4-seropositive NMOSD patients (similar to 9%) had FH autoantibodies in serum and none had antibodies to C3b, factor B and C3bBb. The FH autoantibody titers were low in three and high in one of the patients, and the avidity indexes were low. FH-IgG complexes were detected in the purified IgG fractions by Western blot. The autoantibodies bound to FH domains 19-20, and also recognized the homologous FH-related protein 1 (FHR-1), similar to FH autoantibodies associated with atypical hemolytic uremic syndrome (aHUS). However, in contrast to the majority of autoantibody-positive aHUS patients, these four NMOSD patients did not lack FHR-1. Analysis of autoantibody binding to FH19-20 mutants and linear synthetic peptides of the C-terminal FH and FHR-1 domains, as well as reduced FH, revealed differences in the exact binding sites of the autoantibodies. Importantly, all four autoantibodies inhibited C3b binding to FH. In conclusion, our results demonstrate that FH autoantibodies are not uncommon in NMOSD and suggest that generation of antibodies against complement regulating factors among other autoantibodies may contribute to the complement-mediated damage in NMOSD.
  • Luo, Guo; Ambati, Aditya; Lin, Ling; Bonvalet, Melodie; Partinen, Markku; Ji, Xuhuai; Maecker, Holden Terry; Mignot, Emmanuel Jean-Marie (2018)
    Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide-specific CD4(+) T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA(273-287) (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17-31 and C-amidated but not native version of HCRT54-66 and HCRT86-97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3 beta TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA(273-287)-tetramers, suggesting molecular mimicry. This public CDR3 beta uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-alpha/beta CDR3 motifs of HCRT54-66-NH2 and HCRT86-97-NH2 tetramers were extensively shared: notably public CDR3 alpha, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-alpha/beta CDR3 sequences found in pHA(273-287), NP17-31, and HCRTNH2 tetramer-positive CD4(+) cells were also retrieved in single INF-gamma-secreting CD4(+) sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
  • Davis-Richardson, Austin G.; Ardissone, Alexandria N.; Dias, Raquel; Simell, Ville; Leonard, Michael T.; Kemppainen, Kaisa M.; Drew, Jennifer C.; Schatz, Desmond; Atkinson, Mark A.; Kolaczkowski, Bryan; Ilonen, Jorma; Knip, Mikael; Toppari, Jorma; Nurminen, Noora; Hyoty, Heikki; Veijola, Riitta; Simell, Tuula; Mykkanen, Juha; Simell, Olli; Triplett, Eric W. (2014)
  • Lamichhane, Santosh; Ahonen, Linda; Dyrlund, Thomas Sparholt; Dickens, Alex M.; Siljander, Heli; Hyöty, Heikki; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Hyötyläinen, Tuulia; Knip, Mikael; Oresic, Matej (2019)
    Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.
  • Saari, Viivi; Laakso, Saila; Tiitinen, Aila; Mäkitie, Outi; Holopainen, Elina (2021)
    ObjectiveIn autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) defects in the autoimmune regulator gene lead to impaired immunotolerance. We explored the effects of immunodeficiency and endocrinopathies on gynecologic health in patients with APECED. DesignCross-sectional cohort study combined with longitudinal follow-up data. MethodsWe carried out a gynecologic evaluation, pelvic ultrasound, and laboratory and microbiologic assessment in 19 women with APECED. Retrospective data were collected from previous study visits and hospital records. ResultsThe study subjects' median age was 42.6 years (range, 16.7-65.5). Sixteen patients (84%) had premature ovarian insufficiency, diagnosed at the median age of 16.5 years; 75% of them used currently either combined contraception or hormonal replacement therapy. In 76% of women, the morphology and size of the uterus were determined normal for age, menopausal status, and current hormonal therapy. Fifteen patients (79%) had primary adrenal insufficiency; three of them used dehydroepiandrosterone substitution. All androgen concentrations were under the detection limit in 11 patients (58%). Genital infections were detected in nine patients (47%); most of them were asymptomatic. Gynecologic C. albicans infection was detected in four patients (21%); one of the strains was resistant to azoles. Five patients (26%) had human papillomavirus infection, three of which were high-risk subtypes. Cervical cell atypia was detected in one patient. No correlation between genital infections and anti-cytokine autoantibodies was found. ConclusionsOvarian and adrenal insufficiencies manifested with very low androgen levels in over half of the patients. Asymptomatic genital infections, but not cervical cell atypia, were common in female patients with APECED.
  • Hetemäki, Iivo; Jian, Ching; Laakso, Saila Marita; Mäkitie, Outi; Pajari, Anne-Maria; Vos de, Willem Meindert; Arstila, Petteri; Salonen, Anne (2021)
    Backgrounds and Aims: APECED is a rare autoimmune disease caused by mutations in the Autoimmune Regulator gene. A significant proportion of patients also have gastrointestinal symptoms, including malabsorption, chronic diarrhea, and obstipation. The pathological background of the gastrointestinal symptoms remains incompletely understood and involves multiple factors, with autoimmunity being the most common underlying cause. Patients with APECED have increased immune responses against gut commensals. Our objective was to evaluate whether the intestinal microbiota composition, predicted functions or fungal abundance differ between Finnish patients with APECED and healthy controls, and whether these associate to the patients’ clinical phenotype and gastrointestinal symptoms. Methods: DNA was isolated from fecal samples from 15 patients with APECED (median age 46.4 years) together with 15 samples from body mass index matched healthy controls. DNA samples were subjected to analysis of the gut microbiota using 16S rRNA gene amplicon sequencing, imputed metagenomics using the PICRUSt2 algorithm, and quantitative PCR for fungi. Extensive correlations of the microbiota with patient characteristics were determined. Results: Analysis of gut microbiota indicated that both alpha- and beta-diversity were altered in patients with APECED compared to healthy controls. The fraction of Faecalibacterium was reduced in patients with APECED while that of Atopobium spp. and several gram-negative genera previously implicated in biofilm formation, e.g. Veillonella, Prevotella, Megasphaera and Heamophilus, were increased in parallel to lipopolysaccharide (LPS) synthesis in imputed metagenomics. The differences in gut microbiota were linked to patient characteristics, especially the presence of anti-Saccharomyces cerevisiae antibodies (ASCA) and severity of gastrointestinal symptoms. Conclusions: Gut microbiota of patients with APECED is altered and enriched with predominantly gram-negative bacterial taxa that may promote biofilm formation and lead to increased exposure to LPS in the patients. The most pronounced alterations in the microbiota were associated with more severe gastrointestinal symptoms.
  • Viisanen, Tyyne; Gazali, Ahmad M.; Ihantola, Emmi-Leena; Ekman, Ilse; Näntö-Salonen, Kirsti; Veijola, Riitta; Toppari, Jorma; Knip, Mikael; Ilonen, Jorma; Kinnunen, Tuure (2019)
    The dysfunction of FOXP3-positive regulatory T cells (Tregs) plays a key role in the pathogenesis of autoimmune diseases, including type 1 diabetes (T1D). However, previous studies analyzing the peripheral blood Treg compartment in patients with T1D have yielded partially conflicting results. Moreover, the phenotypic complexity of peripheral blood Tregs during the development of human T1D has not been comprehensively analyzed. Here, we used multi-color flow cytometry to analyze the frequency of distinct Treg subsets in blood samples from a large cohort comprising of 74 children with newly diagnosed T1D, 76 autoantibody-positive children at-risk for T1D and 180 age- and HLA-matched control children. The frequency of CD4+CD25+CD127lowFOXP3+ Tregs was higher in children with T1D compared to control children, and this change was attributable to a higher proportion of naive Tregs in these subjects. Further longitudinal analyses demonstrated that the increase in Treg frequency correlated with disease onset. The frequencies of the minor subsets of CD25+FOXP3low memory Tregs as well as CD25lowCD127lowFOXP3+ Tregs were also increased in children with T1D. Moreover, the ratio of CCR6-CXCR3+ and CCR6+CXCR3- memory Tregs was altered and the frequency of proliferating Ki67-positive and IFN-gamma producing memory Tregs was decreased in children with T1D. The frequency of CXCR5+FOXP3+ circulating follicular T regulatory cells was not altered in children with T1D. Importantly, none of the alterations observed in children with T1D were observed in autoantibody-positive at-risk children. In conclusion, our study reveals multiple alterations in the peripheral blood Treg compartment at the diagnosis of T1D that appear not to be features of early islet autoimmunity.
  • Karvonen, Eira; Krohn, Kai J. E.; Ranki, Annamari; Hau, Annika (2022)
    APECED (Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal-Dystrophy) is a severe and incurable multiorgan autoimmune disease caused by mutations in the AIRE (autoimmune regulator) gene. Without functional AIRE, the development of central and peripheral immune tolerance is severely impaired allowing the accumulation of autoreactive immune cells in the periphery. This leads to multiple endocrine and non-endocrine autoimmune disorders and mucocutaneous candidiasis in APECED patients. Recent studies have suggested that AIRE also has novel functions in stem cells and contributes to the regulatory network of pluripotency. In preparation of therapeutic gene correction, we generated and assessed patient blood cell-derived iPSCs, potentially suitable for cell therapy in APECED. Here, we describe APECED-patient derived iPSCs's properties, expression of AIRE as well as classical stem cell markers by qPCR and immunocytochemistry. We further generated self-aggregated EBs of the iPSCs. We show that APECED patient-derived iPSCs and EBs do not have any major proliferative or apoptotic defects and that they express all the classical pluripotency markers similarly to healthy person iPSCs. The results suggest that the common AIRE R257X truncation mutation does not affect stem cell properties and that APECED iPSCs can be propagated in vitro and used for subsequent gene-correction. This first study on APECED patient-derived iPSCs validates their pluripotency and confirms their ability for differentiation and potential therapeutic use.
  • Gadina, Massimo; Le, Mimi T.; Schwartz, Daniella M.; Silvennoinen, Olli; Nakayamada, Shingo; Yamaoka, Kunihiro; O'Shea, John J. (2019)
    Cytokines are critical mediators of diverse immune and inflammatory diseases. Targeting cytokines and cytokine receptors with biologics has revolutionized the treatment of many of these diseases, but targeting intracellular signalling with Janus kinase (JAK) inhibitors (jakinibs) now represents a major new therapeutic advance. We are still in the first decade since these drugs were approved and there is still much to be learned about the mechanisms of action of these drugs and the practical use of these agents. Herein we will review cytokines that do, and just as importantly, do not signal by JAKs, as well as explain how this relates to both efficacy and side effects in various diseases. We will review new, next-generation selective jakinibs, as well as the prospects and challenges ahead in targeting JAKs.
  • 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
  • Laakso, Saila; Holopainen, Elina; Betterle, Corrado; Saari, Viivi; Vogt, Elinor; Schmitt, Monica M.; Winer, Karen K.; Kareva, Maria; Sabbadin, Chiara; Husebye, Eystein S.; Orlova, Elizaveta; Lionakis, Michail S.; Mäkitie, Outi (2022)
    Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also known as autoimmune polyendocrine syndrome type 1) has a severe, unpredictable course. Autoimmunity and disease components may affect fertility and predispose to maternal and fetal complications, but pregnancy outcomes remain unknown. Objective: To assess fetal and maternal outcomes and course of clinical APECED manifestations during pregnancy in women with APECED. Design and Setting: A multicenter registry-based study including 5 national patient cohorts. Patients: 321 females with APECED. Main Outcome Measure: Number of pregnancies, miscarriages, and deliveries. Results: Forty-three patients had altogether 83 pregnancies at median age of 27 years (range, 17-39). Sixty (72%) pregnancies led to a delivery, including 2 stillbirths (2.4%) and 5 (6.0%) preterm livebirths. Miscarriages, induced abortions, and ectopic pregnancies were observed in 14 (17%), 8 (10%), and 1 (1.2%) pregnancies, respectively. Ovum donation resulted in 5 (6.0%) pregnancies. High maternal age, premature ovarian insufficiency, primary adrenal insufficiency, or hypoparathyroidism did not associate with miscarriages. Women with livebirth had, on average, 4 APECED manifestations (range 0-10); 78% had hypoparathyroidism, and 36% had primary adrenal insufficiency. APECED manifestations remained mostly stable during pregnancy, but in 1 case, development of primary adrenal insufficiency led to adrenal crisis and stillbirth. Birth weights were normal in >80% and apart from 1 neonatal death of a preterm baby, no serious perinatal complications occurred. Conclusions. Outcome of pregnancy in women with APECED was generally favorable. However, APECED warrants careful maternal multidisciplinary follow-up from preconceptual care until puerperium.
  • Saari, Viivi (Helsingin yliopisto, 2021)
    Autoimmuunipolyendokrinopatia-kandidiaasi-ektodermidystrofia (APECED) on harvinainen perinnöllinen suomalaiseen tautiperintöön kuuluva autoimmuunisairaus. Taudin tyypillisiä ilmentymiä ovat pitkäaikaiset kandidainfektiot, lisämunuaiskuoren vajaatoiminta ja lisäkilpirauhasten vajaatoiminta. Kolmanneksi yleisin hormonivaje naisilla on ennenaikainen munasarjojen vajaatoiminta, jonka seurauksia ovat kuukautisten puuttuminen, vaihdevuosioireet sekä estrogeenipuutoksen aiheuttamat pitkäaikaiset terveyshaitat. Tutkimuksen tavoitteena oli kuvata APECED-tautia sairastavien naispotilaiden murrosiän kehitys, kasvu murrosiän aikana ja ennenaikaisen munasarjojen vajaatoiminnan ilmaantuminen. Tutkimukseen kerättiin tietoja yhteensä 40 naispotilaasta suomalaisesta APECED-kohortista. Tutkimukseen otettiin mukaan yli 12-vuotiaat potilaat, joiden munasarjojen toiminnasta oli kerättävissä riittävästi tietoa sairaskertomuksista vuosilta 1968-2018. Ennenaikaisen munasarjojen vajaatoiminnan diagnoosi perustui vaihdevuosioireisiin, kuukautisten poisjäämiseen ja/tai FSH-arvoon ≥ 40 IU/L ennen 40 v ikää. Murrosikä alkoi spontaanisti 34 potilaalla, joista 29:llä kuukautiset alkoivat spontaanisti. Yhdellätoista potilaalla tarvittiin hormonikorvaushoitoa murrosiän kehitystä varten. Munasarjojen vajaatoiminta kehittyi yhteensä 28 potilaalle (70%) 16.0 vuoden mediaani-iässä. Munasarjojen vajaatoimintaa sairastavat potilaat olivat lyhyempiä menarken aikaan kuin muut APECED-potilaat, mutta aikuispituus ei eronnut ryhmien välillä. Munasarjojen vajaatoimintaa sairastavilla oli merkittävästi useammin lisämunuaiskuoren vajaatoiminta (93% vs. 58%, p = 0.017) ja munasarjavasta-aineita (81% vs. 30%, p = 0.003) kuin muilla APECED-potilailla (n = 12). Harvat potilaista olivat saaneet lapsia, mutta hedelmällisyydessä ei havaittu eroa munasarjojen vajaatoimintaa sairastavien ja muiden naispotilaiden välillä. Ennenaikainen munasarjojen vajaatoimina kehittyi suurimmalle osalle APECED-potilaista ja useimmiten pian menarken jälkeen. Hormonikorvaushoidon oikea-aikainen aloittaminen on tärkeää normaalin murrosiän kehityksen ja kasvun turvaamiseksi. Mahdollisuuksia hedelmällisyyden säilyttämiseen ennen munasarjojen vajaatoiminnan kehittymistä tulee pyrkiä kehittämään.
  • 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.
  • Lokki, A. Inkeri; Heikkinen-Eloranta, Jenni K.; Laivuori, Hannele (2018)
    Pregnancy is an immunological challenge to the mother. The fetal tissues including the placenta must be protected from activation of the maternal immune system. On the other hand, the placental tissue sheds into the maternal circulation and must be adequately identified and phagocytized by the maternal immune system. During a healthy pregnancy, numerous immunosuppressive processes take place that allow the allograft fetus to thrive under exposure to humoral and cellular components of the maternal immune system. Breakdown of immune tolerance may result in sterile inflammation and cause adverse pregnancy outcomes such as preeclampsia, a vascular disease of the pregnancy with unpredictable course and symptoms from several organs. Immunological incompatibility between mother and fetus is strongly indicated in preeclampsia. Recently, genetic factors linking immunological pathways to predisposition to preeclampsia have been identified. In this mini-review genetic variation in immunological factors are discussed in the context of preeclampsia. Specifically, we explore immunogenetic and immunomodulary mechanisms contributing to loss of tolerance, inflammation, and autoimmunity in preeclampsia.