Novel Serum Oxidative Stress Biomarkers in Pemphigus Vulgaris: Clinical Insights and Implications for Pathogenesis
Keywords:
Advanced glycation end products, Advanced oxidation protein products, Oxidative stress, Pemphigus, Reactive oxygen speciesAbstract
Introduction: Pemphigus vulgaris is an autoimmune disorder characterized by blistering of the skin and mucous membranes due to the loss of cohesion between keratinocytes. Oxidative stress, a condition caused by an excess of reactive oxygen species that overwhelms the body's antioxidant defenses, has been implicated in various autoimmune diseases, including pemphigus vulgaris.
Objectives: This study aimed to evaluate serum levels of advanced glycation end-products and advanced oxidation protein products as novel biomarkers of oxidative stress in pemphigus vulgaris patients and to correlate these levels with disease activity.
Methods: Sixty participants were included, divided into 3 equal groups: 20 patients with active mucocutaneous pemphigus vulgaris not on systemic treatment, 20 patients in remission on minimal therapy, and 20 healthy controls. Serum levels of advanced glycation end products and advanced oxidation protein products were measured using the enzyme-linked immunosorbent assay.
Results: Serum levels of advanced glycation end products, and advanced oxidation protein products were significantly higher in the active pemphigus vulgaris patients’ group compared to both the remission group and healthy controls (p<0.001). No significant correlation was found between the oxidative stress markers, desmoglein 3, and the Pemphigus Disease Activity Index.
Conclusions: The findings of the present study demonstrate that oxidative stress may not play a primary role in the pathogenesis or severity of pemphigus vulgaris but could instead be a secondary effect associated with tissue damage. Factors such as diet, and ethnicity could have influenced the results, indicating the need for larger scale, population-specific studies.
References
Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet 2019; 394 (10201): 882–894. DOI:10.1016/S0140-6736(19)31778-7. PMID: 31498102.
Amagai M, Stanley JR. Desmoglein as a Target in Skin Disease and Beyond. J Invest Dermatol. 2012; 132 (3): 776–784. DOI:10.1038/jid.2011.390. PMID: 22189787.
Li WC, Mo LJ, Shi X, et al. Antioxidant status of serum bilirubin, uric acid and albumin in pemphigus vulgaris. Clin Exp Dermatol. 2018; 43(2):158-63. DOI:10.1111/ced.13289. PMID: 29067729.
Perl A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol 2013; 9(11): 67486. DOI: 10.1038/nrrheum.2013.147. PMID: 24100461
Gabr SA, Al-Ghadir AH. Role of cellular oxidative stress and cytochrome c in the pathogenesis of psoriasis. Arch Dermatol Res 2012; 304 (6): 451–457. DOI 10.1007/s00403-012-1230-8. PMID: 22421888.
Isik A, Koca SS, Ustundag B, Selek S. Decreased total antioxidant response and increased oxidative stress in Behcet’s disease. Tohoku J Exp Med 2007; 212 (2): 133–41. DOI: 10.1620/tjem.212.133. PMID: 17548957.
Naziroğlu M, Kökçam I, ŞimşŞek Η, Karakılçık AZ. Lipid peroxidation and antioxidants in plasma and red blood cells from patients with pemphigus vulgaris. J Basic Clin Physiol Pharmacol 2003; 14 (1): 31–42. DOI:10.1515/JBCPP.2003.14.1.31. PMID: 12901444.
Huang Y, Jedličková H, Cai Y, et al. Oxidative stress-mediated YAP dysregulation contributes to the pathogenesis of pemphigus vulgaris. Front Immunol. 2021;12:649502. DOI: 10.3389/fimmu.2021.649502. PMID: 33968042
Najafizadeh SR, Amiri K, Moghaddassi M, et al. Advanced glycation end products, advanced oxidation protein products, and ferric reducing ability of plasma in patients with rheumatoid arthritis: a focus on activity scores. Clin Rheumatol. 2021; 40(10):4019-4026. DOI:10.1007/s10067-021-05771-y. PMID: 34050440.
Di Lorenzo G, Minciullo PL, Leto-Barone MS, et al. Differences in the behavior of advanced glycation end products and advanced oxidation protein products in patients with allergic rhinitis. J Investig Allergol Clin Immunol. 2013; 23(2):101-106. PMID: 23654076.
Sajda T, Sinha AA. Autoantibody signaling in pemphigus vulgaris: development of an integrated model. Front Immunol. 2018; 9: 692. DOI: 10.3389/fimmu.2018.00692 PMID: 29755451.
Chen CY, Zhang JQ, Li L, et al. Advanced glycation end products in the skin: Molecular mechanisms, methods of measurement, and inhibitory pathways. Front Med. 2022 11;9:837222. DOI: 10.3389/fmed.2022.837222. PMID: 35646963
Kalousova M, Skrha J, Zima T. Advanced glycation end-products and advanced oxidation protein products in patients with diabetes mellitus. Physio Res. 2002; 51(6):597-604. PMID: 12511184.
Witko-Sarsat V, Friedlander M, Khoa TN, et al. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure1, 2. J Immunol. 1998;161(5):2524-2532. PMID: 9725252.
Hegab Z, Gibbons S, Neyses L, Mamas MA. Role of advanced glycation end products in cardiovascular disease. World J Cardiol. 2012; 4(4): 90. DOI: 10.4330/wjc.v4.i4.90. PMID: 22558488
Murrell DF, Dick S, Ahmed AR, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol. 2008;58(6):1043-1046. DOI: 10.1016/j.jaad.2008.01.012. PMID: 18339444
Rosenbach M, Murrell DF, Bystryn JC, et al. Reliability and convergent validity of two outcome instruments for pemphigus. J Invest Dermatol. 2009;129(10):2404-2410. DOI:10.1038/jid.2009.72. PMID: 19357707
Boulard C, Duvert Lehembre S, Picard‐Dahan C, et al. Calculation of cut‐off values based on the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Pemphigus Disease Area Index (PDAI) pemphigus scoring systems for defining moderate, significant and extensive types of pemphigus. Br J Dermatol. 2016;175(1):142-149. DOI: 10.1111/bjd.14405. PMID: 26800395.
Kwon EJ, Yamagami J, Nishikawa T, Amagai M. Anti‐desmoglein IgG autoantibodies in patients with pemphigus in remission. J Euro Acad Dermatol Venereol. 2008; 22(9):1070-1075. DOI: 10.1111/j.1468-3083.2008.02715.x. PMID: 18410336.
Sardana K, Garg VK, Agarwal P. Is there an emergent need to modify the desmoglein compensation theory in pemphigus on the basis of Dsg ELISA data and alternative pathogenic mechanisms? Br J Dermatol. 2013; 168(3):669-74. DOI: 10.1111/bjd.12012. PMID: 22913529.
Moro F, Sinagra JL, Salemme A, et al. Pemphigus: trigger and predisposing factors. Front Med. 2023;10:1326359. DOI: 10.3389/fmed.2023.1326359. PMID: 38213911.
Marchenko S, Chernyavsky AI, Arredondo J, et al. Antimitochondrial Autoantibodies in Pemphigus Vulgaris: A missing link in disease pathophysiology. J Biol Chem. 2010 ; 285(6):3695-3704. DOI: 10.1074/jbc.M109.081570. PMID: 20007702.
Kalantari-Dehaghi M, Chen Y, Deng W, et al. Mechanisms of mitochondrial damage in keratinocytes by pemphigus vulgaris antibodies. J Biol Chem. 2013;288(23):16916-16925. DOI: 10.1074/jbc.M113.472100. PMID: 23599429.
Abida O, Ben Mansour R, Gargouri B, et al. Catalase and lipid peroxidation values in serum of Tunisian patients with pemphigus vulgaris and foliaceus. Biol Trace Elem Res. 2012;150 (1-3):74-80. DOI: 10.1007/s12011-012-9497-3. PMID: 22907559.
Yesilova Y, Ucmak D, Selek S, et al. Oxidative stress index may play a key role in patients with pemphigus vulgaris. J Euro Acad Dermatol Venereol. 2013 ;27(4):465-467. DOI: 10.1111/j.1468-3083.2012.04463.x. PMID: 22324759.
Abida O, Gargouri B, Ben Mansour R, et al. Biomarkers of oxidative stress in epidermis of Tunisian pemphigus foliaceus patients. J Euro Acad Dermatol Venereol. 2013;27(3):e271-275. DOI: 10.1111/j.1468-3083.2012.04626.x. PMID: 22738420.
Shah AA, Dey-Rao R, Seiffert-Sinha K, Sinha AA. Increased oxidative stress in pemphigus vulgaris is related to disease activity and HLA-association. Autoimmunity. 2016;49(4):248-257. DOI: 10.3109/08916934.2016.1145675. PMID: 26911801.
Javanbakht MH, Djalali M, Daneshpazhooh M, et al. Evaluation of antioxidant enzyme activity and antioxidant capacity in patients with newly diagnosed pemphigus vulgaris. Clin Exp Dermatol. 2015;40(3):313-317. DOI: 10.1111/ced.12489. PMID: 25683954.
Mohammadi H, Djalali M, Daneshpazhooh M, et al. Effects of L-carnitine supplementation on biomarkers of oxidative stress, antioxidant capacity and lipid profile, in patients with pemphigus vulgaris: a randomized, double-blind, placebo-controlled trial. Eur J Clin Nutr. 2018;72(1):99-104. DOI: 10.1038/ejcn.2017.131. PMID: 28832573.
Rasheed Z, Ahmad R, Sheikh N, Ali R. Enhanced recognition of reactive oxygen species damaged human serum albumin by circulating systemic lupus erythematosus autoantibodies. Autoimmunity 2007; 40 (4): 512–520. DOI: 10.1080/08916930701574331. PMID: 17966041.
Inumaru J, Nagano O, Takahashi E, et al. Molecular mechanisms regulating dissociation of cell-cell junction of epithelial cells by oxidative stress. Genes Cells.2009; 14(6):703–716. DOI: 10.1111/j.1365-2443.2009.01303.x. PMID: 19422420.
Van WS, Van Buul JD, Quik S, et al. Reactive oxygen species mediate Rac-induced loss of cell-cell adhesion in primary human endothelial cells. J Cell Sci. 2002; 115 :1837–1846 DOI: 10.1242/jcs.115.9.1837. PMID: 11956315.
Egu DT, Schmitt T, Waschke J. Mechanisms causing acantholysis in pemphigus-lessons from human skin. Front Immunol. 2022;13:884067. DOI: 10.3389/fimmu.2022.884067. PMID: 35720332.
Jolly PS, Berkowitz P, Bektas M, et al. p38MAPK signaling and desmoglein-3 internalization are linked events in pemphigus acantholysis. J Biol Chem. 2010;285(12):8936-8941. DOI: 10.1074/jbc.M109.087999. PMID: 20093368.
Stahley SN, Warren MF, Feldman RJ, Swerlick RA, Mattheyses AL, Kowalczyk AP. Super Resolution Microscopy Reveals Altered Desmosomal Protein Organization in Tissue from Patients with Pemphigus Vulgaris. J Cell Sci. 2016;136(1):59-66 DOI: 10.1038/JID.2015.353. PMID: 26763424.
Berkowitz P, Hu P, Liu Z, et al. Desmosome signaling. Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization. J Biol Chem. 2005;280(25):23778-23784. DOI: 10.1074/jbc.M501365200. PMID: 15840580.
Spindler V, Rotzer V, Dehner C, et al. Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering. J Clin Invest. 2013;123(2):800-811 DOI: 10.1172/JCI60139. PMID: 23298835.
Vielmuth F, Wanuske MT, Radeva MY, et al. Keratins Regulate the Adhesive Properties of Desmosomal Cadherins through Signaling. J Invest Dermatol. 2018b;138(1):121-31 DOI: 10.1016/j.jid.2017.08.033. PMID: 28899688.
Mao X, Sano Y, Park JM, Payne AS. p38 MAPK activation is downstream of the loss of intercellular adhesion in pemphigus vulgaris. J Biol Chem. 2011;286(2):1283-1291. DOI: 10.1074/jbc.M110.172874. PMID: 21078676.
Yue Q, Song Y, Liu Z, Zhang L, Yang L, Li J. Receptor for advanced glycation end products (RAGE): a pivotal hub in immune diseases. Molecules. 2022;27(15):4922. DOI: 10.3390/molecules27154922. PMID: 35956875.
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