Preferences help
enabled [disable] Abstract
Number of results
2018 | 65 | 3 | 471-478
Article title

Immune response against HtrA proteases in children with cutaneous mastocytosis

Title variants
Languages of publication
Mast cells play an important role in both, the innate and adaptive immunity, however, clonal proliferation of abnormal mast cells in various organs leads to mastocytosis. A skin variant of the disease, cutaneous mastocytosis (CM) is the most frequent form of mastocytosis in children. HtrA proteases are modulators of important cellular processes, including cell signaling and apoptosis, and are related to development of several pathologies. The above and the observation that mast cells constitutively release the HtrA1 protein, prompted us to investigate a possible involvement of the HtrA proteins in pediatric CM. Levels of the serum autoantibodies (IgG) against the recombinant HtrA proteins (HtrA1-4) in children with CM (n=36) and in healthy controls (n=62) were assayed. Anti-HtrA IgGs were detected using enzyme linked immunosorbent assay (ELISA) and Western-blotting. In the CM sera, levels of the anti-HtrA1 and anti-HtrA3 autoantibodies were significantly increased when compared to the control group, while the HtrA protein levels were comparable. No significant differences in the anti-HtrA2 IgG level were found; for the anti-HtrA4 IgGs lower levels in CM group were revealed. In healthy children, the IgG levels against the HtrA1, -3 and -4 increased significantly with the age of children; no significant changes were observed for the anti-HtrA2 IgG. Our results suggest involvement of the HtrA1 and HtrA3 proteins in pediatric CM; involvement of the HtrA4 protein is possible but needs to be investigated further. In healthy children, the autoantibody levels against HtrA1, -3 and -4, but not against HtrA2, increase with age.
Physical description
  • Department of General and Medical Biochemistry, University of Gdańsk, Gdańsk, Poland
  • Department of General and Medical Biochemistry, University of Gdańsk, Gdańsk, Poland
  • Department of Dermatology, Venerology and Allergology Medical University of Gdańsk, Gdańsk, Poland
  • Department of Dermatology, Venerology and Allergology Medical University of Gdańsk, Gdańsk, Poland
  • Faculty of Health Sciences with Subfaculty of Nursing, Medical University of Gdańsk, Gdańsk, Poland
  • Department of Pediatrics, Gastroenterology, Hepatology and Nutrition, Medical University of Gdańsk, Gdańsk, Poland
  • Department of Occupational, Metabolic and Internal Diseases, Medical University of Gdańsk, Gdynia, Poland
  • Department of Geriatrics, Qilu Hospital, Shandong University Jinan, Shandong, China
  • Department of Geriatrics, Qilu Hospital, Shandong University Jinan, Shandong, China
  • Department of Geriatrics, Qilu Hospital, Shandong University Jinan, Shandong, China
  • Department of Geriatrics, Qilu Hospital, Shandong University Jinan, Shandong, China
  • Belford D, Rattan R, Chien J, Shridhar V (2010) High temperature requirement A3 (HtrA3) promotes etoposide- and cisplatin-induced cytotoxicity in lungcancer cell lines. J Biol Chem 285: 12011-12027. doi: 10.1074/jbc.M109.097790.
  • Chaganti, LK, Singh N, Bose K (2015) Cathepsins and HtrAs and multitasking proteases in programmed cell death In Proteases Apoptosis Pathw Protoc Transl Adv, Bose K ed, pp 95-141. Springer Internetional Publishing.
  • Chen YY, Chuang PY, Chen CP, Chiu YH, Lo HF, Cheong ML, Huang JY, Kuo PL, Chen H (2014) Functional antagonism between high temperature requirement protein A (HtrA) family members regulates trophoblast invasion. J Biol Chem 289: 22958-22968. doi: 10.1074/jbc.M114.576744.
  • Chien J, Campioni M, Shridhar V, Baldi A (2009) HtrA serine proteases as potential therapeutic targets in cancer. Curr Cancer Drug Targets 9: 451-468.
  • Clausen T, Kaiser M, Huber R, Ehrmann M (2011) HTRA proteases: regulated proteolysis in protein quality control. Nat Rev Mol Cell Biol 12: 152-162. doi: 10.1038/nrm3065.
  • Da Silva E, Jamur M, Oliver C (2014) Mast cell function: a new vision of an old cell. J Histochem Cytochem 62: 698-738. doi: 10.1369/0022155414545334.
  • Fernando J, Faber TW, Pullen NA, Falanga NA, Kolawole EM, Oskeritzian CA, Barnstein BO, Bandara G, Schwartz LB, Spiegel S, Straus DB, Conrad DH, Bunting KD, Ryan JJ (2013) Genotype-dependent effects of TGF-β1 on mast cell function: targeting the Stat5 pathway. J Immunol 191: 4505-4513. doi: 10.4049/jimmunol.1202723.
  • Gilicze A, Kohalmi B, Pocza P, Keszei M, Jaeger J, Gorbe E, Papp Z, Toth S, Falus A, Wiener Z (2007) HtrA1 is a novel mast cell serine protease of mice and men. Mol Immunol 44: 2961-2968. doi: 10.1016/j.molimm.2007.01.004.
  • Hansen G, Hilgenfeld R (2013) Architecture and regulation of HtrA family proteins involved in protein quality control and stress response. Cell Mol Life Sci 70: 761-775. doi: 10.1007/s00018-012-1076-4.
  • Harlow E, Lane D (1988) Antibodies. A laboratory manual, CSH, Cold Spring Harbor, New York.
  • He X, Khurana A, Maguire JL, Chien J, Shridhar V (2012) HtrA1 sensitizes ovarian cancer cells to cisplatin-induced cytotoxicity by targeting XIAP for degradation. Int J Cancer 130: 1029-1035. doi: 10.1002/ijc.26044.
  • Heinze A, Kuemmet T, Chiu Y, Galbraith S (2017) Longitudinal study of pediatric urticarial pigmentosa. Pediatr Dermatol 34: 144-149. doi: 10.1111/pde.13066.
  • Horie-Inoue K, Inoue S (2014) Genomic aspects of age-related macular degeneration. Biochem Biophys Res Commun 452: 263-275. doi: 10.1016/j.bbrc.2014.08.013.
  • Hou Y, Lin H, Zhu L, Liu Z, Hu F, Shi J, Yang T, Shi X, Zhu M, Godley BF, Wang Q, Li Z, Zhao Y (2013) Lipopolysaccharide increases the incidence of collagen-induced arthritis in mice through induction of protease HTRA-1 expression. Arthritis Rheum 65: 2835-2846. doi: 10.1002/art.38124.
  • Iannaccone A, Giorgianni F, New D, Hollingsworth TJ, Umfress A, Alhatem AH, Neeli I, Lenchik NI, Jennings BJ, Calzada JI, Satterfield S, Mathews D, Diaz RI, Harris T, Johnson KC, Charles S, Kritchevsky SB, Gerling IC, Beranova-Giorgianni S, Radic MZ (2015) Health ABC study. Circulating autoantibodies in age-related macular degeneration recognize human macular tissue antigens implicated in autophagy, immunomodulation, and protection from oxidative stress and apoptosis. PLoS One 10: e0145323. doi: 10.1371/journal.pone.0145323.
  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680-685.
  • Lange M, Niedoszytko M, Renke J, Gleń J, Nedoszytko B (2013) Clinical aspects of paediatric mastocytosis: a review of 101 cases. JEADV 27: 97-102. doi: 10.1111/j.1468-3083.2011.04365.x.
  • Latar I, Koufany M, Hablot J, Loeuille D, Netter P, Jouzeau JY, Chary-Valckenaere I, Moulin D (2016) Association between rheumatoid arthritis and systemic mastocytosis: a case report and literature review. Clin Rheumatol 35: 2619-2623. doi: 10.1007/s10067-016-3368-9.
  • Lipinska B, Zylicz M, Georgopoulos C (1990) The HtrA (DegP) protein, essential for Escherichia coli survival at high temperatures, is an endopeptidase. J Bacteriol 172: 1791-1797.
  • Melcalfe D, Mecori Y (2017) Pathogenesis and pathology of mastocytosis. Annu Rev Pathol 12: 487-514. doi: 10.1146/annurev-pathol-052016-100312.
  • Narkiewicz J, Klasa-Mazurkiewicz D, Zurawa-Janicka D, Skorko-Glonek J, Emerich J, Lipinska B (2008) Changes in mRNA and protein levels of human HtrA1, HtrA2 and HtrA3 in ovarian cancer. Clin Biochem 41: 561-569. doi: 10.1016/j.clinbiochem.2008.01.004.
  • Pullen NA, Falanga YT, Morales JK, Ryan JJ (2012) The Fyn-STAT5 Pathway: A New Frontier in IgE- and IgG-Mediated Mast Cell Signaling. Front Immunol 3: 117. doi: 10.3389/fimmu.2012.00117.
  • Ryan JJ, Kashyap M, Bailey D, Kennedy S, Speiran K, Brenzovich J, Barnstein B, Oskeritzian C, Gomez G (2007) Mast cell homeostasis: a fundamental aspect of allergic disease. Crit Rev Immunol 27: 15-32.
  • Singh N, Kuppili R, Bose K (2011) The structural basis of mode of activation and functional diversity: a case study with HtrA family serine proteases. Arch Biochem Biophys 516: 85-96. doi: 10.1016/
  • Skorko-Glonek J, Zurawa-Janicka D, Koper T, Figaj D, Glaza P, Lipinska B (2013) HtrA protease family as therapeutic targets. Curr Pharm Des 19: 977-1009.
  • Tiaden A, Richards P (2013) The emerging roles of HtrA1 in musculoskeletal disease. Am J Pathol 182: 1482-1488. doi: 10.1016/j.ajpath.2013.02.003.
  • Tosi G, Caldi E, Neri G, Nuti E, Marigliani D, Baiocchi S, Traversi C, Cevenini G, Tarantello A, Fusco F, Nardi F, Orlandini M, Galvagni F (2017) HtrA1 and TGF-β1 concentrations in the aqueous humor of patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 58: 162-167. doi: 10.1167/iovs.16-20922.
  • Wenta T, Glaza P, Jarząb M, Zarzecka U, Zurawa-Janicka D, Lesner A, Skorko-Glonek J, Lipinska B (2017) The role of the LB structural loop and its interactions with the PDZ domain of the human HtrA3 protease. Biochim Biophys Acta Proteins Proteom 1865: 1141-1151. doi: 10.1016/j.bbapap.2017.06.013.
  • Zhao J, Zhang X, Zhang M, Feng J Qu (2016) High temperature requirement A3 (HtrA3) expression predicts postoperative recurrence and survival in patients with non-small-cell lung cancer. Oncotarget 7: 40725-40734. doi: 10.18632/oncotarget.9173.
  • Zurawa-Janicka D, Wenta T, Jarzab M, Skorko-Glonek J, Glaza P, Gieldon A, Ciarkowski J, Lipinska B (2017) Structural insights into the activation mechanisms of human HtrA serine proteases. Arch Biochem Biophys 621: 6-23. doi: 10.1016/
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.