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Paolo Ventura Herbert L. Bonkovsky Laurent Gouya Paula Aguilera-Peir D. Montgomery Bissell Penelope E. Stein Manisha Balwani D. Karl E. Anderson Charles Parker David J. Kuter Susana Monroy Jeeyoung Oh Bruce Ritchie John J. Ko Zhaowei Hua Marianne T. Sweetser Eliane Sardh 《Liver international》2022,42(1):i-i
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Abolhassani Hassan Landegren Nils Bastard Paul Materna Marie Modaresi Mohammadreza Du Likun Aranda-Guillén Maribel Sardh Fabian Zuo Fanglei Zhang Peng Marcotte Harold Marr Nico Khan Taushif Ata Manar Al-Ali Fatima Pescarmona Remi Belot Alexandre Béziat Vivien Zhang Qian Casanova Jean-Laurent Kämpe Olle Zhang Shen-Ying Hammarström Lennart Pan-Hammarström Qiang 《Journal of clinical immunology》2022,42(3):471-483
Journal of Clinical Immunology - Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the... 相似文献
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Abolhassani Hassan Vosughimotlagh Ahmad Asano Takaki Landegren Nils Boisson Bertrand Delavari Samaneh Bastard Paul Aranda-Guillén Maribel Wang Yating Zuo Fanglei Sardh Fabian Marcotte Harold Du Likun Zhang Shen-Ying Zhang Qian Rezaei Nima Kämpe Olle Casanova Jean-Laurent Hammarström Lennart Pan-Hammarström Qiang 《Journal of clinical immunology》2022,42(1):1-9
Journal of Clinical Immunology - Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the... 相似文献
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Nils Landegren Norito Ishii Maribel Aranda-Guilln Hrur Ingi Gunnarsson Fabian Sardh sa Hallgren Mona Sthle Eva Hagforsen Maria Bradley Per-Henrik D. Edqvist Fredrik Pontn Outi Mkitie Liv Eidsmo Lars Norln Adnane Achour Ingrid Dahlbom Ilma Korponay-Szab Daniel Agardh Mohammad Alimohammadi Daniel Eriksson Takashi Hashimoto Olle Kmpe 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(51)
Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.The identification of immune targets is crucial to the understanding of autoimmune disease mechanisms and can spur developments in clinical diagnostics and treatment. Autoantibodies in tissue-specific autoimmune disorders typically target proteins that are specifically expressed in the affected tissue and oftentimes also possess key functions. Autoimmune diseases may therefore present as phenocopies of monogenic disorders affecting the same proteins, as exemplified by the familial and acquired forms of epidermolysis bullosa caused either by mutations in the collagen VII type 1 alpha chain gene (COL7A1) or by autoantibodies targeting the corresponding protein (1, 2). Thus far targets of autoimmune attack have typically been identified by screening for immunoreactivity in individual disorders. Given the abundant and growing information about gene expression patterns across tissues, we reasoned that a reverse approach, starting with a candidate autoantigen, might serve to reveal a corresponding disease. To explore this possibility, we turned to the nine-member transglutaminase protein family, among which five clinically significant autoantigens have been identified (3) and is widely used for diagnostics. Gluten sensitivity frequently involves skin manifestations and, in rare cases, also symptoms from the nervous system. Dermatitis herpetiformis is associated with autoantibodies targeting epidermal transglutaminase 3 (TGM3) (4), while gluten-related cerebellar ataxia and peripheral neuropathy is linked with autoantibodies against transglutaminase 6 (TGM6) (5). Extending beyond gluten sensitivity, acquired factor XIII-deficient hemophilia is caused by autoantibodies targeting the catalytic alpha-subunit of coagulation factor FXIII (6), and the prostate-specific TGM4 is a major autoantigen in male patients with autoimmune polyendocrine syndrome type 1 (APS1) (7, 8). Given this range of autoantigens in the transglutaminase gene family, we were interested to learn whether some of the remaining members also might represent targets in as yet unexplained autoimmune disorders. We focused our attention on transglutaminase 1 (TGM1), which is predominantly expressed in squamous epithelia, having an integral function in the assembly of the cornified cell envelope (9, 10). Individuals with autosomal recessive congenital ichthyosis due to TGM1 gene mutations (Mendelian Inheritance in Man number 242300) suffer from lifelong severe scaling of the skin (11), suggesting a crucial role for skin barrier integrity. On this basis, we wanted to determine whether TGM1 constituted an autoantigen in acquired skin disease.Table 1.The transglutaminase protein family
Open in a separate windowMIM#, Mendelian Inheritance in Man number. 相似文献
Gene | Main functions | Main sites of expression/activity | Monogenic disorders (MIM#) | Autoimmune disorders |
TGM1 | Epithelial barrier integrity; cornified envelope | Stratified squamous epithelia | Ichthyosis, congenital, autosomal recessive 1 (242300) | — |
TGM2 | Apoptosis signaling; extracellular matrix stabilization | Widespread | — | Celiac disease |
TGM3 | Epithelial barrier integrity; cornified envelope; hair shaft stabilization | Stratified squamous epithelia | Uncombable hair syndrome 2 (617251) | Dermatitis herpetiformis |
TGM4 | Sperm capacitation; semen coagulation | Prostate epithelium/semen | — | Autoimmune polyendocrine syndrome type 1 |
TGM5 | Epithelial barrier integrity; cornified envelope | Stratified squamous epithelia | Peeling skin syndrome 2 (609796) | — |
TGM6 | Unknown | Not well-defined | Spinocerebellar ataxia 35 (613908) | Gluten associated neuropathy and ataxia |
TGM7 | Unknown | Not well-defined | — | — |
F13A1 | Blood clotting; wound healing | Blood plasma; widespread | Factor XIIIA deficiency (613225) | Autoimmune FXIII deficient hemophilia |
EPB42 | Erythrocyte cell membrane integrity | Erythrocytes | Spherocytosis, type 5 (612690) | — |
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Kölbeck KG Sardh E Gyllenhammar H Palmberg L Larsson K K Palmblad J 《Inflammation》2002,26(6):291-296
Short-time exposure to swine dust causes an intense airways inflammation and symptoms of systemic inflammation in healthy volunteers. Here, we sought to study whether this response involved signs of endothelial cell activation. Peripheral blood cell counts and plasma levels of sE-selectin, sP-selectin, sICAM-1, interleukin-8, nitrite and nitrate were measured in blood samples from 17 healthy subjects before and after a 3-hr exposure to swine dust in a swine confinement building. Dust exposure induced a 3-fold increase of blood neutrophil p = 0.0009) and 1.5-fold increase of monocyte counts (p = 0.0047). IL-8 was detected in 15 individuals after exposure (p = 0.001). Endothelial cell markers such as sICAM and nitrate increased by 10 and 34% resp. (p = 0.011 and 0.017), whereas sE-selectin remained unchanged and sP-selectin was reduced by 15% (p = 0.031). Thus, short time exposure to swine dust induced a systemic inflammatory response with evidence of endothelial and inflammatory cell activation. 相似文献
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BACKGROUND AND OBJECTIVE: Acute intermittent porphyria is an autosomal dominant disorder caused by deficient activity of the third enzyme in the haem biosynthetic pathway, porphobilinogen deaminase. It is characterised by acute, potentially life-threatening neurological attacks that are precipitated by various drugs, reproductive hormones and other factors. During acute attacks, the porphyrin precursors 5-aminolevulinic acid and porphobilinogen accumulate and are excreted at high concentrations in the urine. Current treatment is based on glucose loading and parenteral haem replenishment, which reduce the accumulation of 5-aminolevulinic acid and porphobilinogen. Recently, a new form of treatment based on porphobilinogen deaminase enzyme replacement therapy has been shown to be effective in an acute intermittent porphyria mouse model which, during phenobarbital (phenobarbitone) induction of haem biosynthesis, mimics the biochemical pattern of acute porphyric attacks. The objective of the present study was to investigate the safety, pharmacokinetics and pharmacodynamics of recombinant human porphobilinogen deaminase (P 9808), administered to healthy subjects and asymptomatic porphobilinogen deaminase-deficient subjects with high concentrations of porphobilinogen, the substrate of porphobilinogen deaminase. STUDY DESIGN: Forty individuals participated in this two-part study: 20 asymptomatic porphobilinogen deaminase-deficient subjects (both male and female) with > or =4 times the upper reference urinary porphobilinogen level, and 20 healthy male subjects. Four different doses of recombinant human porphobilinogen deaminase were studied (0.5, 1, 2 and 4 mg/kg bodyweight). Part A included 12 asymptomatic porphobilinogen deaminase-deficient subjects, and the enzyme was administered in an open-label, single-dose design. Part B included 20 asymptomatic porphobilinogen deaminase-deficient subjects and 20 healthy subjects. The same enzyme dosages were administered as divided doses every 12 hours for 4 consecutive days in a randomised, double-blinded, placebo-controlled design. The washout period between Parts A and B was 2 weeks. METHODS: The concentrations of recombinant human porphobilinogen deaminase and titres of antibodies against recombinant human porphobilinogen deaminase were analysed by ELISA. Plasma porphobilinogen and 5-aminolevulinic acid concentrations were analysed using a novel liquid chromatography-tandem mass spectrometry method. Urinary porphobilinogen, 5-aminolevulinic acid and porphyrin concentrations, as well as plasma porphyrin concentrations, were analysed using standard methods. The pharmacodynamic effect of the enzyme was studied through changes in plasma porphobilinogen concentrations. RESULTS: No serious adverse events were observed. Seven subjects (four healthy men and three asymptomatic porphobilinogen deaminase-deficient subjects) developed antibodies against recombinant human porphobilinogen deaminase but did not experience allergic manifestations. The mean elimination half-lives of the highest doses of recombinant human porphobilinogen deaminase ranged between 1.7 and 2.5 hours for both healthy men and asymptomatic porphobilinogen deaminase-deficient subjects. The area under the plasma concentration-time curve was proportional to the respective dose. In asymptomatic porphobilinogen deaminase-deficient subjects, plasma porphobilinogen concentrations decreased below measurable levels almost instantaneously after administration of any dose of the enzyme. The effect lasted for approximately 2 hours, after which the plasma porphobilinogen concentration slowly increased, reaching about 70% of the initial values 12 hours after administration. There was no effect on plasma 5-aminolevulinic acid concentrations, and there was a transitory increment in porphyrin concentrations. The corresponding concentrations of metabolites in the urine reflected the pattern observed in the plasma. CONCLUSIONS: The recombinant human porphobilinogen deaminase enzyme preparation was found to be safe to administer and effective for removal of the accumulated metabolite porphobilinogen from plasma and urine. The pharmacokinetic profile of recombinant human porphobilinogen deaminase showed dose proportionality, and the elimination half-life was about 2.0 hours for the two highest doses. Thus, clinical grounds were established for investigation of the therapeutic efficacy of the enzyme during periods of overt disease in patients with acute intermittent porphyria. 相似文献
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Paolo Ventura Herbert L. Bonkovsky Laurent Gouya Paula Aguilera-Peir D. Montgomery Bissell Penelope E. Stein Manisha Balwani D. Karl E. Anderson Charles Parker David J. Kuter Susana Monroy Jeeyoung Oh Bruce Ritchie John J. Ko Zhaowei Hua Marianne T. Sweetser Eliane Sardh 《Liver international》2022,42(1):161-172
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Eliane Sardh Staffan Wahlin Mikael Björnstedt Pauline Harper Dan E. H. Andersson 《Journal of inherited metabolic disease》2013,36(6):1063-1071
Background/aims
Previous studies have indicated a high risk of hepatocellular carcinoma in acute hepatic porphyrias. In this retrospective study we present the incidence of primary liver cancer and clinical characteristics in a cohort of 179 acute porphyria patients above the age of 50 years.Methods
Twenty-three cases with primary liver cancer were found either by a surveillance program or due to clinical suspicion. Standardized rate ratio was used to estimate the relative risk of primary liver cancer after indirect standardization. Survival data were calculated using the Kaplan-Meier method.Results
The mean age at diagnosis was 69 years. Hepatocellular carcinoma was found in 19 patients while four patients had cholangiocarcinoma or a combination of the two. Four patients had underlying cirrhosis. Mean tumour size was 4.3 cm in the surveillance group and 10.3 cm in the non-surveillance group (p?=?0.01). The overall relative risk of primary liver cancer was 86 above the age of 50: 150 for women and 37 for men. Mean survival time was 5.7 years.Conclusion
Acute hepatic porphyria carries a high risk of primary liver cancer above the age of 50 which warrants ultrasound surveillance. Sex distribution and frequency of cirrhosis differs from more common aetiologies of primary liver cancer. 相似文献10.
Floderus Y Sardh E Möller C Andersson C Rejkjaer L Andersson DE Harper P 《Clinical chemistry》2006,52(4):701-707
BACKGROUND: The heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) accumulate during overt crises of acute intermittent porphyria (AIP), and high excretion of these metabolites often continues in the asymptomatic phase. METHODS: We measured concentrations of PBG and ALA and investigated the correlation between these metabolites in plasma and urine in 10 asymptomatic AIP carriers with high excretion and in 5 healthy individuals. We quantified plasma concentrations with an HPLC-mass spectrometric method and urine concentrations with ion-exchange chromatography. RESULTS: The mean (SD) plasma concentrations of PBG and ALA in the AIP carriers were 3.1 (1.0) and 1.7 (0.7) micromol/L, respectively. The mean 8-h urinary excretion amounts of PBG and ALA in the AIP carriers were 102 (25) and 56 (18) micromol, respectively, whereas the corresponding values for healthy individuals were 2.9 (0.7) and 9.3 (1.2) micromol. The correlations between PBG and ALA values in plasma and urine of the AIP carriers were 0.678 and 0.856, respectively. The mean PBG/ALA ratio was approximately 2.0 in both plasma and urine for the AIP carriers and 0.3 in urine for the healthy individuals. The renal clearance rates for PBG and ALA were 71 (15) and 70 (13) mL/min, respectively. CONCLUSIONS: The described HPLC-mass spectrometric method enabled characterization of variations in plasma PBG and ALA in AIP carriers during an 8-h period. The renal clearances were similar for both metabolites. This method could be used to monitor AIP patients during treatment. 相似文献