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HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD

Yıl 2024, Cilt: 87 Sayı: 4, 291 - 298, 25.10.2024
https://doi.org/10.26650/IUITFD.1489141

Öz

Objective: Infantile giant cell hepatitis with autoimmune hae molytic anaemia (GCH-AHA) is a rare disease characterised by giant cell and autoimmune haemolysis. The pathogenic mecha nisms involve several factors, including genetic and immunolog ical components, particularly those related to the lectin pathway of the complement system. In this study, we aimed to identify possible germline variations in patients with GCH-AHA.
Material and Method: Whole-exome sequencing (WES) was performed on a 6-month-old boy who was diagnosed with GCH AHA. An in-house data analysis pipeline was applied to deter mine familial segregation using Sanger sequencing. ELISA was used for MASP2 protein detection.
Result: WES revealed a likely pathogenic heterozygous missense variant (p.(Cys618Tyr)) in the Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) gene. The MASP2 variant identified in the serine protease domain was predicted to disrupt disulphide bonds. In vitro assays showed decreased MASP2 levels in the patient and mother compared with controls, supporting the potential pathogenicity of the variant.
Conclusion: This study highlighted the association between a novel MASP2 variant and GCH-AHA, emphasising the role of the lectin pathway in the pathogenesis of this rare disorder. The variable expressivity and incomplete penetrance observed in MASP2 deficiency underscore the complexity of genotype-phe notype correlations. Further investigations into the lectin path way's detailed activation and its impact on GCH-AHA pathogen esis are warranted for a comprehensive understanding of the disease mechanisms.

Kaynakça

  • Perez-Atayde AR, Sirlin SM, Jonas M. Coombs-positive autoimmune hemolytic anemia and post infantile giant cell hepatitis in children. Pediatr Pathol 1994;14(1):69-77. [CrossRef] google scholar
  • Bakula A, Socha P, Klaudel-Dreszler M, Karolczyk G, Wozniak M, Rutynowska-Pronicka O, et al. Giant cell hepatitis with autoimmune hemolytic anemia in children: proposal for therapeutic approach. J Pediatr Gastroenterol Nutr 2014;58(5):669-73. [CrossRef] google scholar
  • Maggiore G, Sciveres M, Fabre M, Gori L, Pacifico L, Resti M, et al. Giant cell hepatitis with autoimmune hemolytic anemia in early childhood: long-term outcome in 16 children. J Pediatr 2011;159(1):127-32. [CrossRef] google scholar
  • Torbenson M, Hart J, Westerhoff M, Azzam RK, Elgendi A, Mziray-Andrew HC, et al. Neonatal giant cell hepatitis: histological and etiological findings. Am J Surg Pathol 2010;34(10):1498-503. [CrossRef] google scholar
  • Nastasio S, Matarazzo L, Sciveres M, Maggiore G. Giant cell hepatitis associated with autoimmune hemolytic anemia: an update. Transl Gastroenterol Hepatol 2021;6:25. [CrossRef] google scholar
  • Whitington PF, Vos MB, Bass LM, Melin-Aldana H, Romero R, Roy CC, et al. Humoral immune mechanism of liver injury in giant cell hepatitis with autoimmune hemolytic anemia. J Pediatr Gastroenterol Nutr 2014;58(1):74-80. [CrossRef] google scholar
  • Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res 2010;20(1):34-50. [CrossRef] google scholar
  • Vorup-Jensen T, Petersen SV, Hansen AG, Poulsen K, Schwaeble W, Sim RB, et al. Distinct pathways of mannan-binding lectin (MBL)- and C1-complex autoactivation revealed by reconstitution of MBL with recombinant MBL-associated serine protease-2. J Immunol 2000;165(4):2093-100. [CrossRef] google scholar
  • Dobo J, Kocsis A, Gal P. Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases. Front Immunol 2018;9:1851. [CrossRef] google scholar
  • Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022;42(7):1473-507. [CrossRef] google scholar
  • Stengaard-Pedersen K, Thiel S, Gadjeva M, Moller-Kristensen M, Sorensen R, Jensen LT, et al. Inherited deficiency of mannan-binding lectin-associated serine protease 2. N Engl J Med 2003;349(6):554-60. [CrossRef] google scholar
  • Hejazi R, Hasosah M. Tuberculosis, onychomycosis and immune deficiency in complicated Crohn’s disease. BMJ Case Rep 2019;12(8):e228986. [CrossRef] google scholar
  • Thiel S, Steffensen R, Christensen IJ, Ip WK, Lau YL, Reason IJ, et al. Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms. Genes Immun 2007;8(2):154-63. [CrossRef] google scholar
  • Boldt AB, Luz PR, Messias-Reason IJ. MASP2 haplotypes are associated with high risk of cardiomyopathy in chronic Chagas disease. Clin Immunol 2011;140(1):63-70. [CrossRef] google scholar
  • de Rooij BJ, van Hoek B, ten Hove WR, Roos A, Bouwman LH, Schaapherder AF, et al. Lectin complement pathway gene profile of donor and recipient determine the risk of bacterial infections after orthotopic liver transplantation. Hepatology 2010;52(3):1100-10. [CrossRef] google scholar
  • Mistegaard CE, Jensen L, Christiansen M, Bjerre M, Jensen JMB, Thiel S. Low levels of the innate immune system proteins MASP-2 and MAp44 in patients with common variable immunodeficiency. Scand J Immunol 2022;96(3):e13196. [CrossRef] google scholar
  • Xu WD, Liu XY, Su LC, Huang AF. Association of MASP2 levels and MASP2 gene polymorphisms with systemic lupus erythematosus. J Cell Mol Med 2020;24(18):10432-43. [CrossRef] google scholar
  • Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;25(14):1754-60. [CrossRef] google scholar
  • Besci O, Baser D, Ogulur I, Berberoglu AC, Kiykim A, Besci T, et al. Reference values for T and B lymphocyte subpopulations in Turkish children and adults. Turk J Med Sci 2021;51(4):1814-24. [CrossRef] google scholar
  • Poddighe D, Madiyeva A, Talipova D, Umirbekova B. Infantile giant cell hepatitis with autoimmune hemolytic anemia. World J Hepatol 2021;13(4):411-20. [CrossRef] google scholar
  • Unal S, Kuskonmaz B, Balamtekin N, Baysoy G, Aytac Elmas S, Orhan D, et al. Autoimmune hemolytic anemia and giant cell hepatitis: Report of three infants. Turk J Haematol 2010;27(4):308-13. [CrossRef] google scholar
  • Dubruc E, Nadaud B, Ruchelli E, Heissat S, Baruteau J, Broue P, et al. Relevance of C5b9 immunostaining in the diagnosis of neonatal hemochromatosis. Pediatr Res 2017;81(5):712-21. [CrossRef] google scholar
  • Ambrus G, Gal P, Kojima M, Szilagyi K, Balczer J, Antal J, et al. Natural substrates and inhibitors of mannan-binding lectin-associated serine protease-1 and -2: a study on recombinant catalytic fragments. J Immunol 2003;170(3):1374-82. [CrossRef] google scholar
  • Garcia-Laorden MI, Hernandez-Brito E, Munoz-Almagro C, Pavlovic-Nesic S, Rua-Figueroa I, Briones ML, et al. Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway. J Clin Immunol 2020;40(1):203-10. [CrossRef] google scholar
  • Ytting H, Christensen IJ, Thiel S, Jensenius JC, Svendsen MN, Nielsen L, et al. Biological variation in circulating levels of mannan-binding lectin (MBL) and MBL-associated serine protease-2 and the influence of age, gender and physical exercise. Scand J Immunol 2007;66(4):458-64. [CrossRef] google scholar

OTOİMMÜN HEMOLİTİK ANEMİLİ İNFANTİL DEV HÜCRELİ HEPATİTLİ BİR ÇOCUKTA HASTALIKLA İLİŞKİLİ HETEROZİGOT PATOJENİK MASP2 VARYANTI

Yıl 2024, Cilt: 87 Sayı: 4, 291 - 298, 25.10.2024
https://doi.org/10.26650/IUITFD.1489141

Öz

Amaç: Otoimmün hemolitik anemili infantil dev hücreli hepatit (GCH-AHA), dev hücre ve otoimmün hemoliz ile karakterize nadir bir hastalıktır. Patojenik mekanizmalar, genetik ve immünolojik bileşenler, özellikle de kompleman sisteminin lektin yolağı ile ilgili olanlar dahil olmak üzere çeşitli faktörleri içerir. Bu çalışmada GCH-AHA'daki olası germ hattı varyasyonlarını analiz etmeyi amaçladık.
Gereç ve Yöntem: GCH-AHA tanısı konan 6 aylık bir çocukta tüm ekzom dizileme (TED) yapıldı. In house veri analizi algoritması uygulandı ve Sanger sekanslama ile ailesel segregasyon belirlendi. MASP2 protein tespiti için ELISA kullanıldı.
Bulgular: TED, mannoz bağlayıcı lektin (MBL) ile ilişkili serin proteaz-2 (MASP-2) geninde muhtemel bir patojenik heterozigot yanlış anlamlı varyantı (p.(Cys618Tyr)) ortaya çıkardı. Tahmin araçları bulgularına göre, serin proteaz domainde bulunan MASP2 varyantının disülfit bağlarını bozduğu tahmin edilmiştir. In vitro testler, hastada ve etkilenen annede MASP2 seviyelerinin kontrollere kıyasla azaldığını göstererek varyantın potansiyel patojenitesini desteklemiştir.
Sonuç: Bu çalışma, yeni bir MASP2 varyantı ile GCH-AHA arasındaki ilişkiyi vurgulayarak, bu nadir bozukluğun patogenezinde lektin yolunun rolünü vurgulamaktadır. MASP2 eksikliğinde gözlemlenen değişken ifade ve eksik penetrasyon, genotip-fenotip korelasyonlarının karmaşıklığının altını çizmektedir. Lektin yolunun ayrıntılı aktivasyonu ve bunun GCH-AHA patogenezi üzerindeki etkisine ilişkin daha fazla araştırma, hastalık mekanizmalarının kapsamlı bir şekilde anlaşılması için önem arz etmektedir.

Kaynakça

  • Perez-Atayde AR, Sirlin SM, Jonas M. Coombs-positive autoimmune hemolytic anemia and post infantile giant cell hepatitis in children. Pediatr Pathol 1994;14(1):69-77. [CrossRef] google scholar
  • Bakula A, Socha P, Klaudel-Dreszler M, Karolczyk G, Wozniak M, Rutynowska-Pronicka O, et al. Giant cell hepatitis with autoimmune hemolytic anemia in children: proposal for therapeutic approach. J Pediatr Gastroenterol Nutr 2014;58(5):669-73. [CrossRef] google scholar
  • Maggiore G, Sciveres M, Fabre M, Gori L, Pacifico L, Resti M, et al. Giant cell hepatitis with autoimmune hemolytic anemia in early childhood: long-term outcome in 16 children. J Pediatr 2011;159(1):127-32. [CrossRef] google scholar
  • Torbenson M, Hart J, Westerhoff M, Azzam RK, Elgendi A, Mziray-Andrew HC, et al. Neonatal giant cell hepatitis: histological and etiological findings. Am J Surg Pathol 2010;34(10):1498-503. [CrossRef] google scholar
  • Nastasio S, Matarazzo L, Sciveres M, Maggiore G. Giant cell hepatitis associated with autoimmune hemolytic anemia: an update. Transl Gastroenterol Hepatol 2021;6:25. [CrossRef] google scholar
  • Whitington PF, Vos MB, Bass LM, Melin-Aldana H, Romero R, Roy CC, et al. Humoral immune mechanism of liver injury in giant cell hepatitis with autoimmune hemolytic anemia. J Pediatr Gastroenterol Nutr 2014;58(1):74-80. [CrossRef] google scholar
  • Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res 2010;20(1):34-50. [CrossRef] google scholar
  • Vorup-Jensen T, Petersen SV, Hansen AG, Poulsen K, Schwaeble W, Sim RB, et al. Distinct pathways of mannan-binding lectin (MBL)- and C1-complex autoactivation revealed by reconstitution of MBL with recombinant MBL-associated serine protease-2. J Immunol 2000;165(4):2093-100. [CrossRef] google scholar
  • Dobo J, Kocsis A, Gal P. Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases. Front Immunol 2018;9:1851. [CrossRef] google scholar
  • Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022;42(7):1473-507. [CrossRef] google scholar
  • Stengaard-Pedersen K, Thiel S, Gadjeva M, Moller-Kristensen M, Sorensen R, Jensen LT, et al. Inherited deficiency of mannan-binding lectin-associated serine protease 2. N Engl J Med 2003;349(6):554-60. [CrossRef] google scholar
  • Hejazi R, Hasosah M. Tuberculosis, onychomycosis and immune deficiency in complicated Crohn’s disease. BMJ Case Rep 2019;12(8):e228986. [CrossRef] google scholar
  • Thiel S, Steffensen R, Christensen IJ, Ip WK, Lau YL, Reason IJ, et al. Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms. Genes Immun 2007;8(2):154-63. [CrossRef] google scholar
  • Boldt AB, Luz PR, Messias-Reason IJ. MASP2 haplotypes are associated with high risk of cardiomyopathy in chronic Chagas disease. Clin Immunol 2011;140(1):63-70. [CrossRef] google scholar
  • de Rooij BJ, van Hoek B, ten Hove WR, Roos A, Bouwman LH, Schaapherder AF, et al. Lectin complement pathway gene profile of donor and recipient determine the risk of bacterial infections after orthotopic liver transplantation. Hepatology 2010;52(3):1100-10. [CrossRef] google scholar
  • Mistegaard CE, Jensen L, Christiansen M, Bjerre M, Jensen JMB, Thiel S. Low levels of the innate immune system proteins MASP-2 and MAp44 in patients with common variable immunodeficiency. Scand J Immunol 2022;96(3):e13196. [CrossRef] google scholar
  • Xu WD, Liu XY, Su LC, Huang AF. Association of MASP2 levels and MASP2 gene polymorphisms with systemic lupus erythematosus. J Cell Mol Med 2020;24(18):10432-43. [CrossRef] google scholar
  • Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;25(14):1754-60. [CrossRef] google scholar
  • Besci O, Baser D, Ogulur I, Berberoglu AC, Kiykim A, Besci T, et al. Reference values for T and B lymphocyte subpopulations in Turkish children and adults. Turk J Med Sci 2021;51(4):1814-24. [CrossRef] google scholar
  • Poddighe D, Madiyeva A, Talipova D, Umirbekova B. Infantile giant cell hepatitis with autoimmune hemolytic anemia. World J Hepatol 2021;13(4):411-20. [CrossRef] google scholar
  • Unal S, Kuskonmaz B, Balamtekin N, Baysoy G, Aytac Elmas S, Orhan D, et al. Autoimmune hemolytic anemia and giant cell hepatitis: Report of three infants. Turk J Haematol 2010;27(4):308-13. [CrossRef] google scholar
  • Dubruc E, Nadaud B, Ruchelli E, Heissat S, Baruteau J, Broue P, et al. Relevance of C5b9 immunostaining in the diagnosis of neonatal hemochromatosis. Pediatr Res 2017;81(5):712-21. [CrossRef] google scholar
  • Ambrus G, Gal P, Kojima M, Szilagyi K, Balczer J, Antal J, et al. Natural substrates and inhibitors of mannan-binding lectin-associated serine protease-1 and -2: a study on recombinant catalytic fragments. J Immunol 2003;170(3):1374-82. [CrossRef] google scholar
  • Garcia-Laorden MI, Hernandez-Brito E, Munoz-Almagro C, Pavlovic-Nesic S, Rua-Figueroa I, Briones ML, et al. Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway. J Clin Immunol 2020;40(1):203-10. [CrossRef] google scholar
  • Ytting H, Christensen IJ, Thiel S, Jensenius JC, Svendsen MN, Nielsen L, et al. Biological variation in circulating levels of mannan-binding lectin (MBL) and MBL-associated serine protease-2 and the influence of age, gender and physical exercise. Scand J Immunol 2007;66(4):458-64. [CrossRef] google scholar
Toplam 25 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Hizmetleri ve Sistemleri (Diğer)
Bölüm ARAŞTIRMA
Yazarlar

Merve Sarıtaş 0000-0003-4753-9372

Sinem Fırtına 0000-0002-3370-8545

Süheyla Ocak 0000-0001-7479-7444

Ayça Kıykım 0000-0001-5821-3963

Zeynep Ocak 0000-0001-9784-2228

Begüm Işıkgil 0000-0002-7541-4596

Müge Sayitoğlu 0000-0002-8648-213X

Yayımlanma Tarihi 25 Ekim 2024
Gönderilme Tarihi 24 Mayıs 2024
Kabul Tarihi 20 Ağustos 2024
Yayımlandığı Sayı Yıl 2024 Cilt: 87 Sayı: 4

Kaynak Göster

APA Sarıtaş, M., Fırtına, S., Ocak, S., Kıykım, A., vd. (2024). HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD. Journal of Istanbul Faculty of Medicine, 87(4), 291-298. https://doi.org/10.26650/IUITFD.1489141
AMA Sarıtaş M, Fırtına S, Ocak S, Kıykım A, Ocak Z, Işıkgil B, Sayitoğlu M. HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD. İst Tıp Fak Derg. Ekim 2024;87(4):291-298. doi:10.26650/IUITFD.1489141
Chicago Sarıtaş, Merve, Sinem Fırtına, Süheyla Ocak, Ayça Kıykım, Zeynep Ocak, Begüm Işıkgil, ve Müge Sayitoğlu. “HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD”. Journal of Istanbul Faculty of Medicine 87, sy. 4 (Ekim 2024): 291-98. https://doi.org/10.26650/IUITFD.1489141.
EndNote Sarıtaş M, Fırtına S, Ocak S, Kıykım A, Ocak Z, Işıkgil B, Sayitoğlu M (01 Ekim 2024) HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD. Journal of Istanbul Faculty of Medicine 87 4 291–298.
IEEE M. Sarıtaş, S. Fırtına, S. Ocak, A. Kıykım, Z. Ocak, B. Işıkgil, ve M. Sayitoğlu, “HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD”, İst Tıp Fak Derg, c. 87, sy. 4, ss. 291–298, 2024, doi: 10.26650/IUITFD.1489141.
ISNAD Sarıtaş, Merve vd. “HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD”. Journal of Istanbul Faculty of Medicine 87/4 (Ekim 2024), 291-298. https://doi.org/10.26650/IUITFD.1489141.
JAMA Sarıtaş M, Fırtına S, Ocak S, Kıykım A, Ocak Z, Işıkgil B, Sayitoğlu M. HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD. İst Tıp Fak Derg. 2024;87:291–298.
MLA Sarıtaş, Merve vd. “HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD”. Journal of Istanbul Faculty of Medicine, c. 87, sy. 4, 2024, ss. 291-8, doi:10.26650/IUITFD.1489141.
Vancouver Sarıtaş M, Fırtına S, Ocak S, Kıykım A, Ocak Z, Işıkgil B, Sayitoğlu M. HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD. İst Tıp Fak Derg. 2024;87(4):291-8.

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