Autoantibody-Mediated Dysfunction of Salivary Glands Leads to Xerostomia in SKG Mice
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초록
Sjögren's syndrome (SS) is a chronic heterogeneous disease that mainly affects exocrine glands, leading to sicca syndromes such as xerostomia. Despite the second highest prevalence rate among systemic autoimmune diseases, its pathophysiology remains largely unknown. Here we report that SKG mice, a cardinal model of Th17 cell-mediated arthritis, also develop a secondary form of SS-like disorder upon systemic exposure to purified curdlan, a type of β-glucan. The reduced production of saliva was not caused by focal immune cell infiltrates but was associated with IgG deposits in salivary glands. Sera from curdlan-injected SKG mice contained elevated titers of IgG (predominantly IgG1), autoantibody to the muscarinic type 3 receptor (M3R) and inhibited carbachol-induced Ca2+ signaling in salivary acinar cells. These results suggest that the Th17 cells that are elicited in SKG mice promote the production of salivary gland-specific autoantibodies including anti-M3R IgG; the antibodies are then deposited on acinar cells and inhibit M3R-mediated signaling required for salivation, finally leading to hypofunction of the salivary glands. This type II hypersensitivity reaction may explain the origin of secondary SS occurring without focal leukocyte infiltrates.
Abstract
Sjögren's syndrome (SS) is a chronic heterogeneous disease that mainly affects exocrine glands, leading to sicca syndromes such as xerostomia. Despite the second highest prevalence rate among systemic autoimmune diseases, its pathophysiology remains largely unknown. Here we report that SKG mice, a cardinal model of Th17 cell-mediated arthritis, also develop a secondary form of SS-like disorder upon systemic exposure to purified curdlan, a type of β-glucan. The reduced production of saliva was not caused by focal immune cell infiltrates but was associated with IgG deposits in salivary glands. Sera from curdlan-injected SKG mice contained elevated titers of IgG (predominantly IgG1), autoantibody to the muscarinic type 3 receptor (M3R) and inhibited carbachol-induced Ca2+ signaling in salivary acinar cells. These results suggest that the Th17 cells that are elicited in SKG mice promote the production of salivary gland-specific autoantibodies including anti-M3R IgG; the antibodies are then deposited on acinar cells and inhibit M3R-mediated signaling required for salivation, finally leading to hypofunction of the salivary glands. This type II hypersensitivity reaction may explain the origin of secondary SS occurring without focal leukocyte infiltrates.
참고문헌 (29)
- Sandhya P, "Update on pathogenesis of Sjögren's syndrome", Curr Rheumatol Rev, 13, pp.5~22 (2017)
- Maślińska M, "Sjögren's syndrome: still not fully understood disease", Rheumatol Int, 35, pp.233~241 (2015)
- 김지원, "Circulating CCR7loPD-1hi Follicular Helper T Cells Indicate Disease Activity and Glandular Inflammation in Patients with Primary Sjögren's Syndrome", Immune Network, 19(4), pp.1~13 (2019), 대한면역학회
- Sharma R, "Sjögren syndrome without focal lymphocytic infiltration of the salivary glands", J Rheumatol (2019)
- Ramos-Casals M, "The overlap of Sjögren's syndrome with other systemic autoimmune diseases", Semin Arthritis Rheum, 36, pp.246~255 (2007)
- Gilboe IM, "Sicca symptoms and secondary Sjögren's syndrome in systemic lupus erythematosus: comparison with rheumatoid arthritis and correlation with disease variables", Ann Rheum Dis, 60, pp.1103~1109 (2001)
- Uhlig T, "Sicca symptoms, saliva and tear production, and disease variables in 636 patients with rheumatoid arthritis", Ann Rheum Dis, 58, pp.415~422 (1999)
- Yadlapati S, "Autoimmune", inflammatory arthritis associated lymphomas: who is at risk?, 2016, pp.2016, 8631061~
- Theofilopoulos AN, "The multiple pathways to autoimmunity", Nat Immunol, 18, pp.716~724 (2017)
- Verstappen GM, "Th17 cells in primary Sjögren's syndrome: pathogenicity and plasticity", J Autoimmun, 87, pp.16~25 (2018)
- Youinou P, "Disturbance of cytokine networks in Sjögren's syndrome", Arthritis Res Ther, 13, pp.227~ (2011)
- Mitsdoerffer M, "Proinflammatory T helper type 17 cells are effective B-cell helpers", Proc Natl Acad Sci U S A, 107, pp.14292~14297 (2010)
- Pfeifle R, "Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease", Nat Immunol, 18, pp.104~113 (2017)
- Hsu HC, "Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice", Nat Immunol, 9, pp.166~175 (2008)
- Sakaguchi N, "Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice", Nature, 426, pp.454~460 (2003)
- Hirota K, "T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis", J Exp Med, 204, pp.41~47 (2007)
- Hashimoto M, "Complement drives Th17 cell differentiation and triggers autoimmune arthritis", J Exp Med, 207, pp.1135~1143 (2010)
- Ruutu M, "β-glucan triggers spondylarthritis and Crohn's disease-like ileitis in SKG mice", Arthritis Rheum, 64, pp.2211~2222 (2012)
- 최석산, "Aged Sanroque Mice Spontaneously Develop Sjögren's Syndrome-like Disease", Immune Network, 19(1), pp.1~11 (2019), 대한면역학회[DOI]
- Shirasuna K, "A neoplastic epithelial duct cell line established from an irradiated human salivary gland", Cancer, 48, pp.745~752 (1981)
- Kim YH, "Membrane-delimited coupling of TRPV1 and mGluR5 on presynaptic terminals of nociceptive neurons", J Neurosci, 29, pp.10000~10009 (2009)
- Miozza V, "Enhancement of carbachol-induced amylase secretion in parotid glands from rats with experimental periodontitis", Arch Oral Biol, 56, pp.1514~1520 (2011)
- Nakamura T, "muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice", J Physiol, 558, pp.561~575 (2004)
- Ambudkar IS, "Calcium signalling in salivary gland physiology and dysfunction", J Physiol, 594, pp.2813~2824 (2016)
- 김진만, "Calcium Signaling in Salivary Secretion", Journal of Korean Dental Science, 10(2), pp.45~52 (2017), 대한치의학회[DOI]
- Jin M, "Autoantibodies in primary Sjögren's syndrome patients induce internalization of muscarinic type 3 receptors", Biochim Biophys Acta, 1822, pp.161~167 (2012)
- Dawson LJ, "Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells", Arthritis Rheum, 54, pp.1165~1173 (2006)
- Lilienthal GM, "Potential of murine IgG1 and human IgG4 to inhibit the classical complement and Fcγ receptor activation pathways", Front Immunol, 9, pp.958~ (2018)
- Appel SH, "The role of acetylcholine receptor antibodies in myasthenia gravis", Fed Proc, 38, pp.2381~2385 (1979)