Abstract
Phototoxic reaction is a known feature of EPP at least in part triggered by the oxidative status, complement system activation, and mast cell response. The aim of this study was to verify some aspects involved in phototoxic reaction during a season. The complement system was evaluated by C3 assay, alternative pathway by factor-B, and classical pathway by C1q; oxidative status was tested with malondialdehyde (MDA) and mast cell by IL-10 assay. The serum samples were collected in winter and summer from 19 EPP patients and 13 controls. The reaction to sun exposure within each group was monitored without any invasive treatment. In summer, C3 and factor B were higher in patients than in controls (p = 0.002 and < 0.0001 respectively), while no change was detected for C1q. The oxidative stress was increased in summer in comparison with the control group (p = 0.04), and IL-10 an assay was normal in both seasons. The correlation between the C3 and factor-B in summer was significant. This study shows that the phototoxic reaction is not limited to the dermis but can also exert a systemic response, which could affect the general health of a patient. The knowledge of the pathophysiology of phototoxic reaction is essential for identifying new disease markers useful for improving clinical studies of known and future drugs.
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References
Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017;377:862–72.
Balwani M, Naik H, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, et al. Clinical, biochemical, and genetic characterization of North American patients with erythropoietic protoporphyria and X-linked Protoporphyria. JAMA Dermatol. 2017;153:789–96.
Sachar M, Ma X. Role of ABCG2 in liver injury associated with erythropoietic protoporphyria. Hepatology. 2016;64:305.
Brancaleoni V, Balwani M, Granata F, Graziadei G, Missineo P, Fiorentino V, et al. X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria. Clin Genet. 2016;89:20–6.
de Bataille S, Dutartre H, Puy H, Deybach JC, Gouya L, Raffray E, et al. Influence of meteorological data on sun tolerance in patients with erythropoietic protoporphyria in France. Br J Dermatol. 2016;175:768–75.
Dawe R. An overview of the cutaneous porphyrias. F1000Res 2017; 6:1906.
Naik H, Shenbagam S, Go AM, Balwani M. Psychosocial issues in erythropoietic protoporphyria - the perspective of parents, children, and young adults: a qualitative study. Mol Genet Metab. 2019.
Brun A, Western A, Malik Z, Sandberg S. Erythropoietic protoporphyria: photodynamic transfer of protoporphyrin from intact erythrocytes to other cells. Photochem Photobiol. 1990;51:573–7.
Thunell S, Harper P, Brock A, Petersen NE. Porphyrins, porphyrin metabolism and porphyrias. II. Diagnosis and monitoring in the acute porphyrias. Scand J Clin Lab Invest. 2000;60:541–59.
Lim HW, Poh-Fitzpatrick MB, Gigli I. Activation of the complement system in patients with porphyrias after irradiation in vivo. J Clin Invest. 1984;74:1961–5.
Poh-Fitzpatrick MB. Molecular and cellular mechanisms of porphyrin photosensitization. Photodermatol. 1986;3:148–57.
Gigli I, Schothorst AA, Soter NA, Pathak MA. Erythropoietic protoporphyria. Photoactivation of the complement system. J Clin Invest. 1980;66:517–22.
Giang J, Seelen MAJ, van Doorn MBA, Rissmann R, Prens EP, Damman J. Complement activation in inflammatory skin diseases. Front Immunol. 2018;9:639.
Goldstein BD, Harber LC. Erythropoietic protoporphyria: lipid peroxidation and red cell membrane damage associated with photohemolysis. J Clin Invest. 1972;51:892–902.
Tsikas D. Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges. Anal Biochem. 2017;524:13–30.
Rinnerthaler M, Bischof J, Streubel MK, Trost A, Richter K. Oxidative stress in aging human skin. Biomolecules. 2015;5:545–89.
Grimbaldeston MA, Nakae S, Kalesnikoff J, Tsai M, Galli SJ. Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat Immunol. 2007;8:1095–104.
Harrison RA. The properdin pathway: an “alternative activation pathway” or a “critical amplification loop” for C3 and C5 activation? Semin Immunopathol. 2018;40:15–35.
Chen JY, Cortes C, Ferreira VP. Properdin: a multifaceted molecule involved in inflammation and diseases. Mol Immunol. 2018;102:58–72.
Smith-Jackson K, Marchbank KJ. Targeting properdin in the treatment of atypical haemolytic uraemic syndrome: better than eculizumab? Ann Transl Med. 2018;6:S62.
Gialeli C, Gungor B, Blom AM. Novel potential inhibitors of complement system and their roles in complement regulation and beyond. Mol Immunol. 2018;102:73–83.
Frimat M, Tabarin F, Dimitrov JD, Poitou C, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood. 2013;122:282–92.
Khan A, Bai H, Shu M, Chen M, Bai Z. Antioxidative and antiphotoaging activities of neferine upon UV-A irradiation in human dermal fibroblasts. Biosci Rep. 2018;38.
Bjørklund G, Chirumbolo S. Role of oxidative stress and antioxidants in daily nutrition and human health. Nutrition. 2017;33:311–21.
Kadiiska MB, Peddada S, Herbert RA, Basu S, Hensley K, Jones DP, et al. Biomarkers of oxidative stress study VI. Endogenous plasma antioxidants fail as useful biomarkers of endotoxin-induced oxidative stress. Free Radic Biol Med. 2015;81:100–6.
Heerfordt IM, Wulf HC. Protoporphyrin IX in the skin measured noninvasively predicts photosensitivity in patients with erythropoietic protoporphyria. Br J Dermatol. 2016;175:1284–9.
Wiersema-van Gog H, de Wilde-Verburg MW, Suurmond D. Determination of protoporphyrin in plasma and suction-blister fluid from light-irradiated and non-irradiated skin in protoporphyria patients. Dermatologica. 1975;151:9–15.
Minder EI, Schneider-Yin X, Steurer J, Bachmann LM. A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria. Cell Mol Biol (Noisy-le-grand). 2009;55:84–97.
Liu Z, Ren Z, Zhang J, Chuang CC, Kandaswamy E, Zhou T, et al. Role of ROS and nutritional antioxidants in human diseases. Front Physiol. 2018;9:477.
Acknowledgments
We are indebted to all patients who participated in this research and made it possible and to the DH staff of UOC rare centre diseases at Fondazione IRCCS Ospedale Maggiore Policlinico, who assisted every day the EPP patients, especially during the summer season.
The author would like to acknowledge, with gratitude, Prof. MD Cappellini for her constant support. The RC–2018/ RC–2019 to MDC supported this work.
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Ministero della salute: RC-2019 to MDC supported this work.
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FG designed the study, performed statistical analysis, and wrote the manuscript. LD performed the ELISA experiments. GG recruited the patients. VB executed the genetic diagnosis of patients. PM determined the PPIX levels. SF critically revised the manuscript. EDP critically revised the results and manuscript.
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Granata, F., Duca, L., Graziadei, G. et al. Inflammatory involvement into phototoxic reaction in erythropoietic protoporphyria (EPP) patients. Immunol Res 67, 382–389 (2019). https://doi.org/10.1007/s12026-019-09097-5
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DOI: https://doi.org/10.1007/s12026-019-09097-5