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Journal of Immunology Research
Volume 2019, Article ID 8101503, 3 pages
https://doi.org/10.1155/2019/8101503
Editorial

Sjögren’s Syndrome: Animal Models, Etiology, Pathogenesis, Clinical Subtypes, and Diagnosis

1University at Buffalo, Buffalo, USA
2Peking University People’s Hospital, Beijing, China
3Scheie Eye Institute, University of Pennsylvania, Philadelphia, USA

Correspondence should be addressed to Long Shen; ude.olaffub@lnehs

Received 9 May 2019; Accepted 9 May 2019; Published 20 May 2019

Copyright © 2019 Long Shen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Sjögren’s syndrome (SS) is a chronic autoimmune disease that classically affects the lacrimal and salivary glands resulting in dry eyes and dry mouth and can affect almost any organ system in the body including the lungs, kidney, and central nervous system [1]. Many systemic aspects of SS are described, including B cell lymphoma in addition to pulmonary and renal pathoses [24]. Diagnosis often takes several years once symptoms manifest [5], and even after the diagnosis is rendered, there are currently no treatments available that address the underlying disease etiology.

While the pathogenesis of SS is not well understood, both innate and adaptive immune responses are implicated in disease initiation and progression. In the innate response, an antiviral response is mounted through the recognition of viral nucleic acids by Toll-like receptors (TLRs). This recognition leads to the upregulation of the type 1 interferon (IFN) pathway. However, the means by which immune activation is initiated and maintained remain incompletely understood. Activation of TLRs is critical for the progression of numerous autoimmune diseases [6], although there are relatively few studies regarding the role of these receptors in SS. Studies in mice and humans reveal that TLRs are potent mediators of inflammation in SS. TLRs are expressed and functional in salivary tissue, and TLRs in peripheral blood cells of SS patients are also upregulated and hyperresponsive to ligation. In addition, interferon signatures have been detected in the blood and in the labial salivary gland tissues of patients with pSS [7]. However, it is unclear whether TLRs are activated by microbial products or host-derived ligands in SS [8]. Both animal models and patient studies are instrumental in understanding causes of TLR dysfunction in SS [9]. Studies that identify specific TLRs and clinically relevant ligands will likely lead to the development of novel therapeutics that will diminish chronic inflammation that is a characteristic of SS.

Several viruses have been implicated as possible environmental triggers of SS including Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus type 8 (HHV-8), human T-lymphotropic virus type 1 (HTLV-1), hepatitis C virus, and enterovirus [10]. In addition, paramyxovirus, which causes mumps, may persist in salivary glands and could provide the necessary trigger to initiate autoimmunity pathogenesis of SS in certain genetically susceptible individuals [11]. Cytokines, B cell growth factor, and serum B cell-activating factor (BAFF) levels also play an important role in the pathogenesis of SS. They are altered in patients with SS and correlate with antibodies to Ro and La [12, 13]. Previous studies have shown that most IL-14α transgenic mice develop gastrointestinal B cell lymphomas [14].

Most often, SS presents with polymorphic clinical presentations including the involvement of various systemic organs, which can result in delays in diagnosis. While SS is typically not associated with significant mortality, patients who demonstrate renal involvement are at risk for life-threatening complications. Renal involvement in SS is relatively rare and is seen in approximately 5-10% of SS patients [1518]. Studies are needed to understand the mechanisms that govern kidney dysfunction in SS and to uncover the optimal diagnostic strategies for SS patients with renal complications. In addition, it is important to identify SS patients who are at high risk of renal disease in SS in order to manage these individuals appropriately.

Non-Hodgkin lymphoma is another serious systemic manifestation of SS [19, 20]. SS is characterized by B cell hyperactivity, and the lymphomas that arise in SS patients originate exclusively from B cells [21]. There are several clinical and serological findings that are associated with lymphoma development in SS patients, including anemia, neutropenia, and thrombocytopenia [22]. In addition, BAFF polymorphisms have been identified, and BAFF levels tend to be elevated in patients who develop lymphoma [12, 2325]. While the relationship between lymphoma development, BAFF levels, and autoantibodies is not well understood, further work is needed to identify autoantibodies that may be indicative or predictive of lymphoma development in SS [21].

The diagnosis of SS can be very challenging due to the absence of specific clinical manifestations in the early stages of the disease and the lack of noninvasive diagnostic methods with high specificity and sensitivity. This can lead to significant delays in treatment and worse clinical outcomes. Therefore, novel biomarkers and imaging methods to help recognize the disease at an early stage are needed. For example, antibodies to salivary gland protein 1 (SP1), carbonic anhydrase 6 (CA6), and parotid secretory protein autoantibodies (PSP) were first described in a mouse model for SS and have also been found in SS patients together and without anti-SSA/Ro, as well as in patients with idiopathic dry mouth and dry eye disease [26]. However, despite the discovery of new biomarkers such as these, there are continued diagnostic delays due to the limited understanding of the sequence of events that trigger the activation of the autoimmunity against specific antigenic targets. It is important to study and elucidate the pathways leading to the activation of the antigenic targets as it may lead to more precise disease diagnosis and to the development of specific targeted therapies.

The ocular manifestations of SS often cause substantial morbidity as patients experience significant decreases in quality of life and visual functioning as a result of the disease [27]. Approximately 10% of dry eye patients have underlying SS, but because dry eye is a highly prevalent condition in the general population [27], it is not possible to work-up all dry eye patients for SS. Therefore, better tests that distinguish SS from other causes of dry eye are needed. In addition, further work is required to understand the inciting events that lead to the development of the ocular manifestations of SS. While immune dysfunction is thought to underlie the ocular dysfunction observed, [28] the contribution of environmental insults and genetics to the disease remain incompletely understood [29]. Thus, further work to understand the mechanisms that govern ocular dysfunction and to develop tests for dry eye that identify patients with SS will have a significant impact.

The goal of this special issue is to highlight recent advances in the understanding of the etiopathogenesis, varying clinical presentations, and diagnosis of SS. For example, Z. Mackiewicz et al. in their article entitled “Sjögren’s Syndrome: Concerted Triggering of Sicca Conditions” evaluate the role of the paramyxovirus in SS. J. Kramer and J. Kiripolsky in their paper “Current and Emerging Evidence for Toll-Like Receptor Activation in Sjögren’s Syndrome” explore the role of TLRs in the pathogenesis of SS based on findings in the various mouse models. They discuss the role and significance of putative damage-associated molecular patterns in SS. J. Luo et al. discuss renal involvement of SS, its diverse clinical presentation, and the role of renal biomarkers in kidney damage assessment in their article “High-Risk Indicators of Renal Involvement in Primary Sjogren’s Syndrome: A Clinical Study of 1002 Cases.” Z. Xian and colleagues, in their study entitled “Association between B Cell Growth Factors and Primary Sjögren’s Syndrome-Related Autoantibodies in Patients with Non-Hodgkin’s Lymphoma,” describe the relation between the cytokines BAFF and IL-14 with various traditional autoantibodies (anti-SSA/Ro) and newer tissue-specific autoantibodies. They also describe the role of cytokines and autoantibodies for the stratification of SS patients with gastrointestinal lymphomas. Finally, S. Karakus and colleagues conducted a cross-sectional study of dry eye patients to investigate the clinical significance of anti-salivary gland protein 1 (SP1), anti-carbonic anhydrase 6 (CA6), and anti-parotid secretory protein (PSP) autoantibodies. In their manuscript “Clinical Correlations of Novel Autoantibodies in Patients with Dry Eye,” they demonstrate that disease severity stratification may be feasible using new biomarkers and conclude that anti-CA6 is seen in patients with severe aqueous-deficient dry eye. Taken together, it appears that a new era is on the horizon for a better understanding of the clinical manifestations, diagnosis, etiology, and pathogenesis of SS.

Conflicts of Interest

Drs. Long Shen, Vatinee Bunya, Jing He, and Jill M. Kramer declare that they have no conflicts of interest related to this work. Dr. Bunya receives grant funding from Bausch & Lomb/Immco Diagnostics.

Long Shen
Jing He
Jill M. Kramer
Vatinee Y. Bunya

References

  1. R. I. Fox, “Sjögren’s syndrome,” The Lancet, vol. 366, no. 9482, pp. 321–331, 2005. View at Publisher · View at Google Scholar
  2. M. Ramos-Casals, P. Brito-Zerón, R. Seror et al., “Characterization of systemic disease in primary Sjögren's syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements,” Rheumatology, vol. 54, no. 12, pp. 2230–2238, 2015. View at Publisher · View at Google Scholar
  3. A. S. Malladi, K. E. Sack, S. C. Shiboski et al., “Primary Sjögren's syndrome as a systemic disease: A study of participants enrolled in an International Sjögren's syndrome registry,” Arthritis Care & Research, vol. 64, no. 6, pp. 911–918, 2012. View at Publisher · View at Google Scholar
  4. F. Vivino, V. Y. Bunya, G. Massaro-Giordano et al., “Sjogren’s syndrome: an update on disease pathogenesis, clinical manifestations and treatment,” Clinical Immunology, vol. 203, pp. 81–121, 2019, Epub 2019/04/26. View at Publisher · View at Google Scholar
  5. Sjogren’s Syndrome Foundation – Diagnosis, “Sjogren’s Syndrome Foundation, Inc.,” 2018, https://www.sjogrens.org/home/about-sjogrens/diagnosis.
  6. J. Q. Chen, P. Szodoray, and M. Zeher, “Toll-like receptor pathways in autoimmune diseases,” Clinical Reviews in Allergy and Immunology, vol. 50, no. 1, pp. 1–17, 2016. View at Publisher · View at Google Scholar
  7. J. C. Hall, A. N. Baer, A. A. Shah et al., “Molecular subsetting of interferon pathways in Sjögren’s syndrome,” Arthritis & Rheumatology, vol. 67, no. 9, pp. 2437–2446, 2015. View at Publisher · View at Google Scholar
  8. J. Kiripolsky, L. G. McCabe, and J. M. Kramer, “Innate immunity in Sjögren's syndrome,” Clinical Immunology, vol. 182, pp. 4–13, 2017. View at Publisher · View at Google Scholar
  9. A. B. Peck and C. Q. Nguyen, “What can Sjögren's syndrome-like disease in mice contribute to human Sjögren's syndrome?” Clinical Immunology, vol. 182, pp. 14–23, 2017. View at Publisher · View at Google Scholar
  10. P. Sandhya, B. Kurien, D. Danda, and R. Scofield, “Update on pathogenesis of Sjogren’s syndrome,” Current Rheumatology Reviews, vol. 13, no. 1, pp. 5–22, 2017. View at Publisher · View at Google Scholar
  11. N. Holdgate and E. W. S. Clair, “Recent advances in primary Sjogren’s syndrome,” F1000Research, vol. 5, 2016. View at Publisher · View at Google Scholar
  12. X. Mariette, S. Roux, J. Zhang et al., “The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren’s syndrome,” Annals of the Rheumatic Diseases, vol. 62, no. 2, pp. 168–171, 2003. View at Publisher · View at Google Scholar
  13. L. Shen and L. Suresh, “Autoantibodies, detection methods and panels for diagnosis of Sjögren’s syndrome,” Clinical Immunology, vol. 182, pp. 24–29, 2017. View at Publisher · View at Google Scholar
  14. L. Shen, C. Zhang, T. Wang et al., “Development of Autoimmunity in IL-14α-Transgenic Mice,” The Journal of Immunology, vol. 177, no. 8, pp. 5676–5686, 2006. View at Publisher · View at Google Scholar
  15. R. Evans, A. Zdebik, C. Ciurtin, and S. B. Walsh, “Renal involvement in primary Sjögren’s syndrome,” Rheumatology, vol. 54, no. 9, pp. 1541–1548, 2015. View at Publisher · View at Google Scholar
  16. H. X. Yang, J. Wang, Y. B. Wen et al., “Renal involvement in primary Sjögren's syndrome: A retrospective study of 103 biopsy-proven cases from a single center in China,” International Journal of Rheumatic Diseases, vol. 21, no. 1, pp. 223–229, 2018. View at Publisher · View at Google Scholar
  17. M. Jasiek, A. Karras, V. Le Guern et al., “A multicentre study of 95 biopsy-proven cases of renal disease in primary Sjögren’s syndrome,” Rheumatology, vol. 56, no. 3, pp. 362–370, 2017. View at Publisher · View at Google Scholar
  18. A. V. Goules, I. P. Tatouli, H. M. Moutsopoulos, and A. G. Tzioufas, “Clinically Significant Renal Involvement in Primary Sjögren's Syndrome: Clinical Presentation and Outcome,” Arthritis and Rheumatism, vol. 65, no. 11, pp. 2945–2953, 2013. View at Publisher · View at Google Scholar
  19. C. P. Mavragani and H. M. Moutsopoulos, “Sjӧgren’s syndrome,” Annual Review of Pathology: Mechanisms of Disease, vol. 9, no. 1, pp. 273–285, 2014. View at Publisher · View at Google Scholar
  20. A. Alunno, M. C. Leone, R. Giacomelli, R. Gerli, and F. Carubbi, “Lymphoma and Lymphomagenesis in Primary Sjögren’s Syndrome,” Frontiers in Medicine, vol. 5, p. 102, 2018. View at Publisher · View at Google Scholar
  21. A. V. Goules and A. G. Tzioufas, “Lymphomagenesis in Sjögren's syndrome: Predictive biomarkers towards precision medicine,” Autoimmunity Reviews, vol. 18, no. 2, pp. 137–143, 2019. View at Publisher · View at Google Scholar
  22. A. Papageorgiou, D. C. Ziogas, C. P. Mavragani et al., “Predicting the outcome of Sjogren’s syndrome-associated non-Hodgkin’s lymphoma patients,” PLoS One, vol. 10, no. 2, article e0116189, 2015. View at Publisher · View at Google Scholar
  23. M. V. Jonsson, P. Szodoray, S. Jellestad, R. Jonsson, and K. Skarstein, “Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjögren’s syndrome,” Journal of Clinical Immunology, vol. 25, no. 3, pp. 189–201, 2005. View at Publisher · View at Google Scholar
  24. A. J. Novak, S. L. Slager, Z. S. Fredericksen et al., “Genetic variation in B-cell-activating factor is associated with an increased risk of developing B-cell non-Hodgkin lymphoma,” Cancer Research, vol. 69, no. 10, pp. 4217–4224, 2009. View at Publisher · View at Google Scholar
  25. A. Nezos, A. Papageorgiou, G. Fragoulis et al., “B-Cell activating factor genetic variants in lymphomagenesis associated with primary Sjogren’s syndrome,” Journal of Autoimmunity, vol. 51, pp. 89–98, 2014. View at Publisher · View at Google Scholar
  26. S. Karakus, A. N. Baer, D. Agrawal, M. Gurakar, R. W. Massof, and E. K. Akpek, “Utility of novel autoantibodies in the diagnosis of Sjögren’s syndrome among patients with dry eye,” Cornea, vol. 37, no. 4, pp. 405–411, 2018. View at Publisher · View at Google Scholar
  27. E. K. Akpek, V. Y. Bunya, and I. J. Saldanha, “Sjögren’s Syndrome,” Cornea, vol. 38, no. 5, pp. 658–661, 2019. View at Publisher · View at Google Scholar
  28. J. L. Reyes, D. T. Vannan, B. Eksteen et al., “Innate and adaptive cell populations driving inflammation in dry eye disease,” Mediators of Inflammation, vol. 2018, Article ID 2532314, 12 pages, 2018. View at Publisher · View at Google Scholar
  29. G. Galperin, M. Berra, M. I. Marquez, M. Mandaradoni, J. Tau, and A. Berra, “Impact of environmental pollution on the ocular surface of Sjögren’s syndrome patients,” Arquivos Brasileiros de Oftalmologia, vol. 81, no. 6, pp. 481–489, 2018. View at Publisher · View at Google Scholar