Serological Biomarkers and Their Detection in Autoimmune Bullous Skin Diseases

Citation: Heckler I, Hong M, Sinha A, Venkataraman I. Serological Biomarkers and Their Detection in Autoimmune Bullous Skin Diseases, Dermatol Pract Concept. 2022;12(2):e2022116. DOI: https://doi.org/10.5826/dpc.1202a116

Accepted: November 22, 2021; Published: April 2022

Copyright: ©2022 Heckler et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.

Funding: None.

Competing interests: None.

Authorship: All authors have contributed significantly to this publication

Corresponding author: Iswariya Venkataraman, Ph.D., EUROIMMUN US, 1 Bloomfield Ave, Mountain Lakes, New Jersey, United States. Email: iswariya.venkataraman@euroimmun.us

Abstract

Autoimmune bullous diseases (AIBDs) are a group of skin-related disorders that involve damage to structures maintaining cell-cell adhesion, such as desmosomes and hemidesmosomes. Key autoimmune bullous diseases include pemphigus related diseases, pemphigoid related conditions, acquired epidermolysis bullosa (EBA), and dermatitis herpetiformis (DH). Each group of conditions exhibits characteristic clinical lesion patterns and is associated with specific autoantibodies targeting epidermal and dermal structures involved in cell-cell adhesion and skin integrity. Pemphigus diseases primarily target desmoglein (Dsg) 3 and Dsg1 proteins but several non-desmoglein autoantibodies have also been linked to pemphigus.

Pemphigoid diseases typically target BP (bullous pemphigoid)180 and BP230; EBA is associated with antibodies directed against anti-type VII collagen; and DH by IgA autoantibodies against tissue transglutaminase and deaminated gliadin. Investigation into the serological biomarkers found in autoimmune bullous diseases have allowed the development of diagnostic assessments (ie. tissue antibody detection and serological testing) based on the unique autoantibody profiles of a particular disease group.  The methods for the detection and quantification of disease-associated autoantibodies continue to evolve and improve.

Keywords : Pemphigus, Pemphigoid, diagnostics, antibodies

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

References

Yousef H, Alhajj M, Sharma S. Anatomy, Skin (Integument), Epidermis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021. 2. Schmidt A, Koch PJ. Desmosomes: just cell adhesion or is there more? Cell Adh Migr. 2007;1(1):28-32. DOI: 10.4161/cam.1.1.4204. Epub 2007 Jan 26. PMID: 19262094. PMCID: PMC2633677. 3. Delva E, Tucker DK, Kowalczyk AP. The desmosome. Cold Spring Harb Perspect Biol. 2009;1(2):a002543. DOI: 10.1101/cshperspect.a002543. PMID: 20066089. PMCID: PMC2742091. 4. Garrod D, Chidgey M. Desmosome structure, composition and function. Biochim Biophys Acta. 2008;1778(3):572-87. DOI: 10.1016/j.bbamem.2007.07.014. PMID: 17854763. 5. Borradori L, Sonnenberg A. Structure and Function of Hemidesmosomes: More Than Simple Adhesion Complexes. J Invest Dermatol. 1999;112(4):411-418. DOI: 10.1046/j.1523-1747.1999.00546.x. PMID: 10201522. 6. Harrison OJ, Brasch J, Lasso G, et al. Structural basis of adhesive binding by desmocollins and desmogleins. Proc Natl Acad Sci U S A. 2016;113(26):7160-7165. DOI: 10.1073/pnas.1606272113. PMID: 27298358. PMCID: PMC4932976. 7. Rose NR. Autoimmune Diseases. In: Quah SR, ed. International Encyclopedia of Public Health (Second Edition). Oxford: Academic Press; 2017:192-195. 8. Dinse G, Parks C, Weinberg C, et al. Increasing Prevalence of Antinuclear Antibodies in the United States. Arthritis Rheumatol. 2020;72(6):1026-1035. DOI: 10.1002/art.41214. PMID: 32266792. PMCID: PMC7255943. 9. Julian MK. Autoimmune disease: Cost-effective care. Nurs Manage. 2014;45(11):24-29; quiz 30. DOI: 10.1097/01.NUMA.0000455740.32485.9c. PMID: 25304753. 10. Egami S, Yamagami J, Amagai M. Autoimmune bullous skin diseases, pemphigus and pemphigoid. J Allergy Clin Immunol. 2020;145(4):1031-1047. DOI: 10.1016/j.jaci.2020.02.013. PMID: 32272980. 11. Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. Pemphigus. Nat Rev Dis Primers. 2017;3:17026. DOI: 10.1038/nrdp.2017.26. PMID: 28492232. PMCID: PMC5901732. 12. Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol. 1999;40(2 Pt 1):167-170. DOI: 10.1016/s0190-9622(99)70183-0. PMID: 10025740. 13. Amagai M, Koch PJ, Nishikawa T, Stanley JR. Pemphigus vulgaris antigen (desmoglein 3) is localized in the lower epidermis, the site of blister formation in patients. J Invest Dermatol. 1996;106(2):351-355. DOI: 10.1111/1523-1747.ep12343081. PMID: 8601740. 14. Mahoney MG, Wang Z, Rothenberger K, Koch PJ, Amagai M, Stanley JR. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest. 1999;103(4):461-468. DOI: 10.1172/JCI5252. PMID: 10021453. PMCID: PMC408100. 15. Sinha AA, Sajda T. The Evolving Story of Autoantibodies in Pemphigus Vulgaris: Development of the “Super Compensation Hypothesis”. Front Med (Lausanne). 2018;5:218. DOI: 10.3389/fmed.2018.00218. PMID: 30155465. PMCID: PMC6102394. 16. Ahmed AR, Carrozzo M, Caux F, et al. Monopathogenic vs multipathogenic explanations of pemphigus pathophysiology. Exp Dermatol. 2016;25(11):839-846. DOI: 10.1111/exd.13106. PMID: 27305362. 17. Saschenbrecker S, Karl I, Komorowski L, et al. Serological Diagnosis of Autoimmune Bullous Skin Diseases. Front Immunol. 2019;10:1974. DOI: 10.3389/fimmu.2019.01974. PMID: 31552014. PMCID: PMC6736620. 18. Amber KT, Valdebran M, Grando SA. Non-Desmoglein Antibodies in Patients With Pemphigus Vulgaris. Front Immunol. 2018;9:1190. DOI: 10.3389/fimmu.2018.01190. PMID: 29915578. PMCID: PMC5994403. 19. Powell JG, Grover RK, Plunkett RW, Seiffert-Sinha K, Sinha AA. Evaluation of a Newly Available ELISA for Envoplakin Autoantibodies for the Diagnosis of Paraneoplastic Pemphigus. J Drugs Dermatol. 2015;14(10):1103-1106. PMID: 26461820. 20. Anhalt GJ. Paraneoplastic pemphigus. J Investig Dermatol Symp Proc. 2004;9(1):29-33. DOI: 10.1111/j.1087-0024.2004.00832.x. PMID: 14870982. 21. Poot AM, Diercks GF, Kramer D, et al. Laboratory diagnosis of paraneoplastic pemphigus. Br J Dermatol. 2013;169(5):1016-1024. DOI: 10.1111/bjd.12479. PMID: 23796242. 22. Hashimoto T, Teye K, Hashimoto K, et al. Clinical and Immunological Study of 30 Cases With Both IgG and IgA Anti-Keratinocyte Cell Surface Autoantibodies Toward the Definition of Intercellular IgG/IgA Dermatosis. Front Immunol. 2018;9:994. DOI: 10.3389/fimmu.2018.00994. PMID: 29867971. PMCID: PMC5950707. 23. Kridin K. Pemphigus group: overview, epidemiology, mortality, and comorbidities. Immunol Res. 2018;66(2):255-270. DOI: 10.1007/s12026-018-8986-7. PMID: 29479654. 24. Miyamoto D, Santi CG, Aoki V, Maruta CW. Bullous pemphigoid. An Bras Dermatol. 2019;94(2):133-146. DOI: 10.1590/abd1806-4841.20199007. PMID: 31090818. PMCID: PMC6486083. 25. Kridin K, Ludwig RJ. The Growing Incidence of Bullous Pemphigoid: Overview and Potential Explanations. Front Med (Lausanne). 2018;5:220. DOI: 10.3389/fmed.2018.00220. PMID: 30177969. PMCID: PMC6109638. 26. Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pemphigus and bullous pemphigoid. Autoimmun Rev. 2014;13(4-5):477-481. DOI: 10.1016/j.autrev.2014.01.011. PMID: 24424192. 27. Ishiura N, Fujimoto M, Watanabe R, et al. Serum levels of IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid. J Dermatol Sci. 2008;49(2):153-161. DOI: 10.1016/j.jdermsci.2007.08.008. PMID: 17920818. 28. Yoshida M, Hamada T, Amagai M, et al. Enzyme-linked immunosorbent assay using bacterial recombinant proteins of human BP230 as a diagnostic tool for bullous pemphigoid. J Dermatol Sci. 2006;41(1):21-30. DOI: 10.1016/j.jdermsci.2005.11.002. PMID: 16364599. 29. Shimanovich I, Skrobek C, Rose C, et al. Pemphigoid gestationis with predominant involvement of oral mucous membranes and IgA autoantibodies targeting the C-terminus of BP180. J Am Acad Dermatol. 2002;47(5):780-784. DOI: 10.1067/mjd.2002.113677. PMID: 12399776. 30. Schumann H, Baetge J, Tasanen K, et al. The shed ectodomain of collagen XVII/BP180 is targeted by autoantibodies in different blistering skin diseases. Am J Pathol. 2000;156(2):685-695. DOI: 10.1016/S0002-9440(10)64772-4. PMID: 10666397. PMCID: PMC1850053. 31. Chiorean R, Danescu S, Virtic O, et al. Molecular diagnosis of anti-laminin 332 (epiligrin) mucous membrane pemphigoid. Orphanet J Rare Dis. 2018;13(1):111. DOI: 10.1186/s13023-018-0855-x. PMID: 29980216. PMCID: PMC6035451. 32. Kamaguchi M, Iwata H. The Diagnosis and Blistering Mechanisms of Mucous Membrane Pemphigoid. Front Immunol. 2019;10:34. DOI: 10.3389/fimmu.2019.00034. PMID: 30740099. PMCID: PMC6357922. 33. Egan CA, Lazarova Z, Darling TN, Yee C, Coté T, Yancey KB. Anti-epiligrin cicatricial pemphigoid and relative risk for cancer. Lancet. 2001;357(9271):1850-1851. DOI: 10.1016/S0140-6736(00)04971-0. PMID: 11410196. 34. Mehren CR, Gniadecki R. Epidermolysis bullosa acquisita: current diagnosis and therapy. Dermatol Reports. 2011;3(3):e38. DOI: 10.4081/dr.2011.e38. PMID: 25386290. PMCID: PMC4211502. 35. Kridin K, Kneiber D, Kowalski EH, Valdebran M, Amber KT. Epidermolysis bullosa acquisita: A comprehensive review. Autoimmunity Reviews. 2019;18(8):786-795. DOI: 10.1016/j.autrev.2019.06.007. PMID: 31181325. 36. Antiga E, Caproni M. The diagnosis and treatment of dermatitis herpetiformis. Clin Cosmet Investig Dermatol. 2015;8:257-265. DOI: 10.2147/CCID.S69127. PMID: 25999753. PMCID: PMC4435051. 37. Salmi TT. Dermatitis herpetiformis. Clin Exp Dermatol. 2019;44(7):728-731. DOI: 10.1111/ced.13992. PMID: 31093998. 38. Witte M, Zillikens D, Schmidt E. Diagnosis of Autoimmune Blistering Diseases. Front Med (Lausanne). 2018;5:296. DOI: 10.3389/fmed.2018.00296. PMID: 30450358. PMCID: PMC6224342. 39. Murrell DF, Peña S, Joly P, et al. Diagnosis and management of pemphigus: Recommendations of an international panel of experts. J Am Acad Dermatol. 2020;82(3):575-585.e1. DOI: 10.1016/j.jaad.2018.02.021. PMID: 29438767. PMCID: PMC7313440. 40. Shetty VM, Subramaniam K, Rao R. Utility of immunofluorescence in dermatology. Indian Dermatol Online J. 2017;8(1):1-8. DOI: 10.4103/2229-5178.198774. PMID: 28217464. PMCID: PMC5297263. 41. Feibelman C, Stolzner G, Provost TT. Pemphigus Vulgaris: Superior Sensitivity of Monkey Esophagus in the Determination of Pemphigus Antibody. Arch Dermatol. 1981;117(9):561-562. DOI: 10.1001/archderm.117.9.561. PMID: 7027966. 42. Ghohestani RF, Nicolas JF, Rousselle P, Claudy AL. Diagnostic value of indirect immunofluorescence on sodium chloride-split skin in differential diagnosis of subepidermal autoimmune bullous dermatoses. Arch Dermatol. 1997;133(9):1102-1107. PMID: 9301587. 43. Liu AY, Valenzuela R, Helm TN, Camisa C, Melton AL, Bergfeld WF. Indirect immunofluorescence on rat bladder transitional epithelium: a test with high specificity for paraneoplastic pemphigus. J Am Acad Dermatol. 1993;28(5 Pt 1):696-699. DOI: 10.1016/0190-9622(93)70095-b. PMID: 7684408. 44. Wolf J, Jahnke A, Fechner K, et al. Primate liver tissue as an alternative substrate for endomysium antibody immunofluorescence testing in diagnostics of paediatric coeliac disease. Clin Chim Acta. 2016;460:72-77. DOI: 10.1016/j.cca.2016.06.023. PMID: 27346479. 45. Chanprapaph K, Ounsakul V, Pruettivorawongse D, Thadanipon K. Anti-BP180 and anti-BP230 enzyme-linked immunosorbent assays for diagnosis and disease activity tracking of bullous pemphigoid: A prospective cohort study. Asian Pac J Allergy Immunol. 2019; 39(4):272-278. DOI: 10.12932/AP-231118-0446. PMID: 31175713. 46. Delavarian Z, Layegh P, Pakfetrat A, Zarghi N, Khorashadizadeh M, Ghazi A. Evaluation of desmoglein 1 and 3 autoantibodies in pemphigus vulgaris: correlation with disease severity. J Clin Exp Dent. 2020;12(5):e440-e445. DOI: 10.4317/jced.56289. PMID: 32509225. PMCID: PMC7263783. 47. Koga H, Teye K, Yamashita K, Ishii N, Tsuruta D, Nakama T. Detection of anti-type VII collagen IgE antibodies in epidermolysis bullosa acquisita. Br J Dermatol. 2019;180(5):1107-1113. DOI: 10.1111/bjd.17310. PMID: 30311191. 48. Kim JH, Kim YH, Kim S, et al. Serum levels of anti-type VII collagen antibodies detected by enzyme-linked immunosorbent assay in patients with epidermolysis bullosa acquisita are correlated with the severity of skin lesions. J Eur Acad Dermatol Venereol. 2013;27(2):e224-e230. DOI: 10.1111/j.1468-3083.2012.04617.x. PMID: 22731917. 49. Mutasim DF. Therapy of autoimmune bullous diseases. Ther Clin Risk Manag. 2007;3(1):29-40. DOI: 10.2147/tcrm.2007.3.1.29. PMID: 18360613. PMCID: PMC1936286. 50. Alaeen H, Toosi R, Mahmoudi H, et al. Short-term clinical and serological follow-up with conventional and conformational anti-desmoglein antibodies in treatment-naïve and previously treated patients with pemphigus vulgaris after receiving rituximab. Int J Womens Dermatol. 2019;5(5):372-377. DOI: 10.1016/j.ijwd.2019.05.008. PMID: 31909160. PMCID: PMC6938821.