A role for auto-immunity in chronic rhinosinusitis? Lessons learned from sub-epidermal bullous disorders of the skin
© The Author(s) 2016
Received: 8 June 2016
Accepted: 13 July 2016
Published: 5 August 2016
Chronic rhinosinusitis (CRS) is a frequent chronic condition, which has origins in complex interactions between genetic, immunological and microbial factors. The role of auto-immunity in CRS remains unclear, although recent studies have started to emerge in CRS patient refractory to maximal medical management. We discuss the possible auto-immunity link between CRS and other skin diseases, in particular acquired bullous dermatoses, and review the current evidence. We raise additional considerations for auto-immunity from both research and clinical standpoints.
Chronic rhinosinusitis (CRS) is a common condition affecting ~13 % of the US adult population, a prevalence higher than that of diabetes . The productivity loss accounting from CRS amounts to $13 billion USD , with total disease burden estimated around ~$60 billion USD . Of particular interest are patients with refractory CRS, for whom maximal medical therapy provides at most marginal benefits. Refractory CRS patients are currently managed with multiple sinus surgeries, yet they still experience recurrent exacerbations requiring antibiotics.
Auto-immunity in CRS
Conspicuously absent from these descriptions is the possibility of a role for auto-immunity in CRS pathogenesis. This is somewhat surprising as auto-immunity is a ubiquitous culprit in pathologies affecting every other organ, thus it is likely that a similar phenomenon also occurs in CRS. Here we explore the auto-immune avenue, with a focus on comparison with chronic auto-immune conditions compromising the skin epidermal barrier.
Evidence from immune complex disorders
The deposition of auto-immune complexes in the sinus mucosa disrupting the sinus mucosal surface is already demonstrated in vasculitides . Vasculitides which can present with sinusitis symptoms include granulomatosis with polyangiitis (GPA; formerly known as Wegener’s granulomatosis)  and eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss Syndrome) . Immune complexes formed by anti-neutrophil cytoplasmic auto-IgG antibodies (ANCA IgG) promote granuloma formation in the epithelium, effectively causing a chronically-inflamed permeable barrier [20, 21]. Although this constitutes an interesting autoimmune hypothesis for CRS, the severity of disease seen in these patients and the low prevalence of these disorders are not sufficient to account for the frequency of CRS. As an additional consideration, these two disorders differ markedly in their immunologic profile: GPA predominantly displays a TH1 response while immunity in EGPA is shifted towards TH2 cytokines, with both disorders showing TH17 profiles .
Given the pathophysiological differences between GPA and CRS, we postulate that other manifestations of auto-immunity are likely present in CRS. Since sinus mucosa represents an ectodermal barrier between internal microenvironments and external aggressors, CRS may share features with other barrier disorders, such as the skin.
Auto-immunity and blistering skin disorders
Auto-immune sub-epidermal blistering diseases of the skin epithelium include various acquired bullous disorders such as bullous pemphigoid, cicatricial pemphigoid, pemphigoid gestationis and epidermolysis bullosa acquisita . Auto-antibodies are classically directed against components of the hemidesmosome-anchoring filament complexes or anchoring fibrils, which link the basement membrane to the basal keratinocyte layer via cytoskeletal elements . These targeted proteins at the dermal–epidermal junction include laminins, collagens, integrins and other cell adhesion molecules .
Cicatricial, or mucous membrane, pemphigoid is a chronic auto-immune blistering disease that preferentially affects the oral and ocular mucosae, but can also affect the nasal mucosa and the genitalia . Cicatricial pemphigoid shows the highest heterogeneity among auto-immune bullous conditions, with the identification of auto IgA and/or IgG targeting the α6 integrin subunit, β4 integrin subunit, laminin 5 and/or BP180/collagen XVII α1 . Pemphigoid, or herpes gestationis is a bullous eruption of the third trimester and immediate post-partum that extends from the umbilicus in a centrifugal direction . In pemphigoid gestationis, a linear C3 deposition at the dermo-epidermal junctional is nearly always found, but auto IgG against BP180/collagen XVII and, less commonly, BP230 can be detected in a third of affected pregnancies [24, 26]. Similarly to other dermatoses of pregnancy, pemphigoid gestationis displays an immune imbalance towards a stronger TH2 response with concomitant depressed TH1 function . Epidermolysis bullosa acquisita is characterized by recurring blisters on skin and mucosae arising from IgG auto-immunity against collagen VII [28, 29].
Insights from bullous pemphigoid
Studies from bullous pemphigoid (BP), a more common blistering disease of the elderly, have shed insights into the link between a dysbiotic flora and auto-immunity . Auto IgG, and to a much lesser extent, auto IgA, against BP180/collagen XVII and BP230, a transmembrane protein of the hemidesmosal plaque, have been implicated in the pathogenesis of BP for many years [31, 32]. Recently, auto IgE antibodies have been consistently isolated from a subset of patients with BP, both at their dermal-epidermal junction [33, 34] and in their sera [35, 36]. This led to the successful use of omalizumab, a humanized monoclonal that binds and inactivates free and membrane-bound IgE, to manage patients with standard treatment-refractory BP and elevated IgE titers [37, 38].
BP180 auto-antibodies in CRS
The discovery of autoantibodies in CRS patients is emerging. Anti-nuclear IgG and IgA autoantibody titers are elevated in CRS patients with nasal polyposis . Recently, the discovery of elevated circulating levels of auto IgG against BP180/collagen XVII in CRS patients vs. healthy patients bring the link with bullous pemphigoid back into the spotlight . However, deposition of these autoantibodies at the dermal-epidermal junction has been absent from the nasal mucosa of CRS patients, in stark contrast with BP in which it is pathogenic . Nevertheless, auto-immunity appears to play an important role in CRS, and similarities to BP and other acquired skin bullous dermatoses are numerous.
Genetics, CRS and skin bullous conditions
Other links to epithelial blistering disorders are suggested by genome-wide association studies (GWAS) of refractory CRS, in which several of the most common gene polymorphisms in CRS patients code for basement membrane and extra-cellular matrix proteins, including the laminins [6, 49]. Other polymorphisms associated with CRS are found in collagen- and keratin-interacting genes ; the complete absence of these genes and related genes as well as aberrant gene expression can lead to some of the rare hereditary epidermolysis bullosa genodermatoses . Taken together, these findings suggest that interference with epithelial structure leading to epithelial blistering disorders in skin may mimic changes seen in CRS.
CRS similarities to other skin conditions
In addition to skin bullous diseases, other skin conditions may yield insight into the pathophysiology of CRS. In chronic urticaria, dysregulated cellular function and autoantibodies targeting directly IgE or their receptor on mast cells lead to the degranulation of mast cells and subsequent release of pre-formed pro-inflammatory cytokines . In CRS with nasal polyposis, mast cells in the epithelium and glandular structures are increased in number and are producing abnormally-high quantities of proteases, thus contributing to the chronic inflammation and lack of complete repair . Circulating auto-IgE antibodies have also been detected in chronic urticaria patients .
CRS likely arises from the interaction of genetic, immunological and microbial factors. This concept may evolve to incorporate a contribution from auto immune disorders. While experience with autoimmunity in CRS is still very limited, insights may be drawn from experience with skin epidermal disorders. Notably, in skin, auto-immunity in epidermis-basement membrane unit renders the epidermis dysfunctional and more permeable to surface pathogens, which may penetrate into the dermis, enabling the colonization by a dysbiotic flora that maintains a chronic inflammation state. This contributes to the secondary mucosal changes seen in skin disorders. These concepts resonate well with the disease process observed in CRS. The role of auto-immunity in CRS, especially in refractory cases, appears compelling. Given the aforementioned similarities between sub-epidermal bullous dermatoses, focusing on the basal keratinocyte–hemidesmosome–cytoskeleton–basal membrane interface might reveal additional mechanistic information. Additionally, it is important to recognize that not all autoimmune actors are IgG auto-antibodies, and that IgA and IgE auto-antibodies may be more common than expected. Assessment for these should also be performed. As previously mentioned in the case of anti-BP180 in CRS , it is important to distinguish circulating auto-antibodies from those bound to the epithelium as these are probably significant for the maintenance of the disease. Nevertheless, dosing circulating auto-antibodies may serve as a proxy for detecting auto-immunity. As in BP and chronic urticaria, refractory CRS might also feature auto-IgE antibodies.
Suggestions for further studies include (1) verifying the presence of other circulating auto-antibodies targeting the dermal–epidermal junction and the hemidesmosome plaque in CRS patients, and (2) determining the presence of auto-antibodies on sinus biopsies/tissues and nasal polyps from CRS patients using dermato-histopathological techniques.
On the clinical side, implications of these findings are twofold. First, investigation of CRS should include the possibility of auto-immunity. Second, clinicians may have to consider biological and targeted therapies aimed at decreasing auto-immunity in refractory CRS patients. Experience with those treatment regimens from diseases involving other body systems should come in handy for CRS. However, therapeutic agents used in other disorders will require prospective assessment prior to clinical deployment.
PL, HC, BC and MD wrote the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Adams PF, Hendershot GE, Marano MA, Centers for Disease Control, Prevention/ National Center for Health Statistics. Current estimates from the National Health Interview Survey, 1996. Vital Health Stat 10. 1996;1999(200):1–203.Google Scholar
- Rudmik L, Soler ZM, Smith TL, Mace JC, Schlosser RJ, DeConde AS. Effect of continued medical therapy on productivity costs for refractory chronic rhinosinusitis. JAMA Otolaryngol Head Neck Surg. 2015;141(11):969–73.View ArticlePubMedGoogle Scholar
- Caulley L, Thavorn K, Rudmik L, Cameron C, Kilty SJ. Direct costs of adult chronic rhinosinusitis by using 4 methods of estimation: results of the US Medical Expenditure Panel Survey. J Allergy Clin Immunol. 2015;136(6):1517–22.View ArticlePubMedGoogle Scholar
- Hsu J, Avila PC, Kern RC, Hayes MG, Schleimer RP, Pinto JM. Genetics of chronic rhinosinusitis: state of the field and directions forward. J Allergy Clin Immunol. 2013;131(4):977–93.View ArticlePubMedPubMed CentralGoogle Scholar
- Castano R, Bosse Y, Endam LM, Filali-Mouhim A, Desrosiers M. c-MET pathway involvement in chronic rhinosinusitis: a genetic association analysis. Otolaryngol Head Neck Surg. 2010;142(5):665–71.View ArticlePubMedGoogle Scholar
- Bosse Y, Bacot F, Montpetit A, Rung J, Qu HQ, Engert JC, Polychronakos C, Hudson TJ, Froguel P, Sladek R, et al. Identification of susceptibility genes for complex diseases using pooling-based genome-wide association scans. Hum Genet. 2009;125(3):305–18.View ArticlePubMedGoogle Scholar
- Tournas A, Mfuna L, Bosse Y, Filali-Mouhim A, Grenier JP, Desrosiers M. A pooling-based genome-wide association study implicates the p73 gene in chronic rhinosinusitis. J Otolaryngol Head Neck Surg. 2010;39(2):188–95.PubMedGoogle Scholar
- Shapiro GG, Virant FS, Furukawa CT, Pierson WE, Bierman CW. Immunologic defects in patients with refractory sinusitis. Pediatrics. 1991;87(3):311–6.PubMedGoogle Scholar
- Srinivasa BT, Alizadehfar R, Desrosiers M, Shuster J, Pai NP, Tsoukas CM. Adult primary immune deficiency: what are we missing? Am J Med. 2012;125(8):779–86.View ArticlePubMedGoogle Scholar
- Van Zele T, Claeys S, Gevaert P, Van Maele G, Holtappels G, Van Cauwenberge P, Bachert C. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy. 2006;61(11):1280–9.View ArticlePubMedGoogle Scholar
- Lane AP, Truong-Tran QA, Schleimer RP. Altered expression of genes associated with innate immunity and inflammation in recalcitrant rhinosinusitis with polyps. Am J Rhinol. 2006;20(2):138–44.PubMedPubMed CentralGoogle Scholar
- Van Crombruggen K, Zhang N, Gevaert P, Tomassen P, Bachert C. Pathogenesis of chronic rhinosinusitis: inflammation. J Allergy Clin Immunol. 2011;128(4):728–32.View ArticlePubMedGoogle Scholar
- Kramer MF, Heath MD. Probiotics in the treatment of chronic rhinoconjunctivitis and chronic rhinosinusitis. J Allergy. 2014;2014:983635.View ArticleGoogle Scholar
- Cope EK, Lynch SV. Novel microbiome-based therapeutics for chronic rhinosinusitis. Curr Allergy Asthma Rep. 2015;15(3):504.View ArticlePubMedGoogle Scholar
- Nayan S, Maby A, Endam LM, Desrosiers M. Dietary modifications for refractory chronic rhinosinusitis? Manipulating diet for the modulation of inflammation. Am J Rhinol Allergy. 2015;29(6):170–4.View ArticleGoogle Scholar
- Harvey RJ, Wallwork BD, Lund VJ. Anti-inflammatory effects of macrolides: applications in chronic rhinosinusitis. Immunol Allergy Clin North Am. 2009;29(4):689–703.View ArticlePubMedGoogle Scholar
- Montone KT. The molecular genetics of inflammatory, autoimmune, and infectious diseases of the sinonasal tract: a review. Arch Pathol Lab Med. 2014;138(6):745–53.View ArticlePubMedGoogle Scholar
- Tarabishy AB, Schulte M, Papaliodis GN, Hoffman GS. Wegener’s granulomatosis: clinical manifestations, differential diagnosis, and management of ocular and systemic disease. Surv Ophthalmol. 2010;55(5):429–44.View ArticlePubMedGoogle Scholar
- Bacciu A, Bacciu S, Mercante G, Ingegnoli F, Grasselli C, Vaglio A, Pasanisi E, Vincenti V, Garini G, Ronda N, et al. Ear, nose and throat manifestations of Churg-Strauss syndrome. Acta Otolaryngol. 2006;126(5):503–9.View ArticlePubMedGoogle Scholar
- van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, van der Giessen M, van der Hem GK, The TH. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet. 1985;1(8426):425–9.View ArticlePubMedGoogle Scholar
- Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med. 2004;117(1):39–50.View ArticlePubMedGoogle Scholar
- Fagin U, Csernok E, Muller A, Pitann S, Fazio J, Krause K, Bremer P, Wipfler-Freissmuth E, Moosig F, Gross WL, et al. Distinct proteinase 3-induced cytokine patterns in Wegener’s granulomatosis, Churg-Strauss syndrome, and healthy controls. Clin Exp Rheumatol. 2011;29(1 Suppl 64):S57–62.PubMedGoogle Scholar
- Olasz EB, Yancey KB. Bullous pemphigoid and related subepidermal autoimmune blistering diseases. Curr Dir Autoimmun. 2008;10:141–66.View ArticlePubMedGoogle Scholar
- Mihai S, Sitaru C. Immunopathology and molecular diagnosis of autoimmune bullous diseases. J Cell Mol Med. 2007;11(3):462–81.View ArticlePubMedPubMed CentralGoogle Scholar
- Rashid KA, Gurcan HM, Ahmed AR. Antigen specificity in subsets of mucous membrane pemphigoid. J Invest Dermatol. 2006;126(12):2631–6.View ArticlePubMedGoogle Scholar
- Shimanovich I, Brocker EB, Zillikens D. Pemphigoid gestationis: new insights into the pathogenesis lead to novel diagnostic tools. BJOG. 2002;109(9):970–6.View ArticlePubMedGoogle Scholar
- Fabbri P, Caproni M, Berti S, Bianchi B, Amato L, De Pita O, Frezzolini A. The role of T lymphocytes and cytokines in the pathogenesis of pemphigoid gestationis. Br J Dermatol. 2003;148(6):1141–8.View ArticlePubMedGoogle Scholar
- Woodley DT, Briggaman RA, O’Keefe EJ, Inman AO, Queen LL, Gammon WR. Identification of the skin basement-membrane autoantigen in epidermolysis bullosa acquisita. N Engl J Med. 1984;310(16):1007–13.View ArticlePubMedGoogle Scholar
- Woodley DT, Burgeson RE, Lunstrum G, Bruckner-Tuderman L, Reese MJ, Briggaman RA. Epidermolysis bullosa acquisita antigen is the globular carboxyl terminus of type VII procollagen. J Clin Investig. 1988;81(3):683–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Ujiie H. IgE autoantibodies in bullous pemphigoid: supporting role, or leading player? J Dermatol Sci. 2015;78(1):5–10.View ArticlePubMedGoogle Scholar
- Cozzani E, Drosera M, Parodi A, Carrozzo M, Gandolfo S, Rebora A. Frequency of IgA antibodies in pemphigus, bullous pemphigoid and mucous membrane pemphigoid. Acta Dermato-Venereologica. 2004;84(5):381–4.View ArticlePubMedGoogle Scholar
- Schmidt E, Zillikens D. Pemphigoid diseases. Lancet. 2013;381(9863):320–32.View ArticlePubMedGoogle Scholar
- Kamiya K, Aoyama Y, Noda K, Miyake T, Yamaguchi M, Hamada T, Tokura Y, Iwatsuki K. Possible correlation of IgE autoantibody to BP180 with disease activity in bullous pemphigoid. J Dermatol Sci. 2015;78(1):77–9.View ArticlePubMedGoogle Scholar
- Moriuchi R, Nishie W, Ujiie H, Natsuga K, Shimizu H. In vivo analysis of IgE autoantibodies in bullous pemphigoid: a study of 100 cases. J Dermatol Sci. 2015;78(1):21–5.View ArticlePubMedGoogle Scholar
- Delaporte E, Dubost-Brama A, Ghohestani R, Nicolas JF, Neyrinck JL, Bergoend H, Janin A, Capron M. IgE autoantibodies directed against the major bullous pemphigoid antigen in patients with a severe form of pemphigoid. J Immunol. 1996;157(8):3642–7.PubMedGoogle Scholar
- Ishiura N, Fujimoto M, Watanabe R, Nakashima H, Kuwano Y, Yazawa N, Echigo T, Okochi H, Tamaki K. Serum levels of IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid. J Dermatol Sci. 2008;49(2):153–61.View ArticlePubMedGoogle Scholar
- London VA, Kim GH, Fairley JA, Woodley DT. Successful treatment of bullous pemphigoid with omalizumab. Arch Dermatol. 2012;148(11):1241–3.View ArticlePubMedGoogle Scholar
- Yu KK, Crew AB, Messingham KA, Fairley JA, Woodley DT. Omalizumab therapy for bullous pemphigoid. J Am Acad Dermatol. 2014;71(3):468–74.View ArticlePubMedGoogle Scholar
- Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8(3):205–17.View ArticlePubMedGoogle Scholar
- Holgate ST. Pathogenesis of asthma. Clin Exp Allergy. 2008;38(6):872–97.View ArticlePubMedGoogle Scholar
- Pearlman AN, Chandra RK, Chang D, Conley DB, Tripathi-Peters A, Grammer LC, Schleimer RT, Kern RC. Relationships between severity of chronic rhinosinusitis and nasal polyposis, asthma, and atopy. Am J Rhinol Allergy. 2009;23(2):145–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Chao PZ, Hsieh MS, Lee FP, Chen SY, Cheng CW, Chang HW, Lin YT, Ting LL, Lin YF, Chen CH. Serum level of interleukin-21 is elevated in chronic rhinosinusitis. Am J Rhinol Allergy. 2015;29(1):e1–6.View ArticlePubMedGoogle Scholar
- Penn R, Mikula S. The role of anti-IgE immunoglobulin therapy in nasal polyposis: a pilot study. Am J Rhinol. 2007;21(4):428–32.View ArticlePubMedGoogle Scholar
- Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, Hellings P, Brusselle G, De Bacquer D, van Cauwenberge P, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 2013;131(1):110–6.View ArticlePubMedGoogle Scholar
- Pinto JM, Mehta N, DiTineo M, Wang J, Baroody FM, Naclerio RM. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology. 2010;48(3):318–24.PubMedGoogle Scholar
- Henault J, Riggs JM, Karnell JL, Liarski VM, Li J, Shirinian L, Xu L, Casey KA, Smith MA, Khatry DB, et al. Self-reactive IgE exacerbates interferon responses associated with autoimmunity. Nat Immunol. 2016;17(2):196–203.View ArticlePubMedGoogle Scholar
- Tan BK, Li QZ, Suh L, Kato A, Conley DB, Chandra RK, Zhou J, Norton J, Carter R, Hinchcliff M, et al. Evidence for intranasal antinuclear autoantibodies in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2011;128(6):1198–206.View ArticlePubMedPubMed CentralGoogle Scholar
- Jeffe JS, Seshadri S, Hamill KJ, Huang JH, Carter R, Suh L, Hulse KE, Norton J, Conley DB, Chandra RK, et al. A role for anti-BP180 autoantibodies in chronic rhinosinusitis. Laryngoscope. 2013;123(9):2104–11.View ArticlePubMedPubMed CentralGoogle Scholar
- Mfuna-Endam L, Zhang Y, Desrosiers MY. Genetics of rhinosinusitis. Curr Allergy Asthma Rep. 2011;11(3):236–46.View ArticlePubMedGoogle Scholar
- Has C, Bruckner-Tuderman L. The genetics of skin fragility. Annu Rev Genomics Hum Genet. 2014;15:245–68.View ArticlePubMedGoogle Scholar
- Chan YC, Ramadani F, Santos AF, Pillai P, Ohm-Laursen L, Harper CE, Fang C, Dodev TS, Wu SY, Ying S, et al. “Auto-anti-IgE”: naturally occurring IgG anti-IgE antibodies may inhibit allergen-induced basophil activation. J Allergy Clin Immunol. 2014;134(6):1394–401.View ArticlePubMedPubMed CentralGoogle Scholar
- Takabayashi T, Kato A, Peters AT, Suh LA, Carter R, Norton J, Grammer LC, Tan BK, Chandra RK, Conley DB, Kern RC, et al. Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2012;130(2):410–20.View ArticlePubMedPubMed CentralGoogle Scholar
- Altrichter S, Peter HJ, Pisarevskaja D, Metz M, Martus P, Maurer M. IgE mediated autoallergy against thyroid peroxidase—a novel pathomechanism of chronic spontaneous urticaria? PLoS ONE. 2011;6(4):e14794.View ArticlePubMedPubMed CentralGoogle Scholar