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SYSTEMIC LUPUS ERYTHEMATOSUS AND SJÖGREN'S SYNDROME: Edited by Mariana J. Kaplan

Update on the immunobiology of Sjögren's syndrome

Ambrosi, Aurélie; Wahren-Herlenius, Marie

Author Information
Current Opinion in Rheumatology: September 2015 - Volume 27 - Issue 5 - p 468-475
doi: 10.1097/BOR.0000000000000195
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Abstract

INTRODUCTION

Primary Sjögren's syndrome (pSS) is a chronic autoimmune rheumatic disease characterized by mononuclear cell infiltration of salivary and lacrimal glands, progressive glandular atrophy, and loss of function. The most common symptoms are dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca); however, extraglandular manifestations such as dryness of the body mucous membranes, arthritis, fatigue, skin vasculitis, or peripheral neuropathy may also be present. The most severe complication of pSS is non-Hodgkin's lymphoma, which develops in 5–10% of the patients. The estimated prevalence of pSS ranges from 0.9 to 6 per 1000 individuals depending on the population studied and the classification criteria used. The incidence rate was recently estimated to be 3.1 per 100 000 person-years in a Swedish population-based cohort study [1▪▪], with an estimated female-to-male ratio of about 14 : 1 and a mean age at diagnosis of 55 years.

The two main hallmarks that were first recognized for pSS are a progressive focal infiltration of mononuclear cells – mainly T and B cells – in exocrine glands and the presence of hypergammaglobulinemia and autoantibodies. Although these features clearly underline the importance of an aberrant adaptive immune response in the pathophysiology of pSS, the etiology and several aspects of disease pathogenesis remain elusive. Over the past decade, advances have been made with the recognition of the involvement of innate immune responses, and especially of the type I interferon (IFN) system, in pSS. Recent studies also indicate that other components of the innate immune system, such as natural killer (NK) cells and glandular epithelial cells, may contribute to disease pathogenesis.

In this review, we will discuss recent findings of relevance to pSS pathogenesis in three main areas: first, type I IFN and viral triggers; second, ectopic lymphoid structures and local immune responses in the target organ; third, contribution of B, T, and NK cells to disease.

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TYPE I IFN AND VIRAL TRIGGERS IN PRIMARY SJÖGREN'S SYNDROME PATHOGENESIS

Study of the early events leading to chronic inflammatory immune responses and tissue destruction in the exocrine glands in pSS is particularly difficult as clinical symptoms and subsequent diagnosis often occur once irreversible organ damage has already taken place. The realization that the type I IFN system is an important contributor to disease pathogenesis has, however, led to advances in understanding the role played by the innate immune system in pSS. Investigations on the potential role of viral infections are also generating new clues to understanding [11▪] pSS etiopathogenesis.

Type I IFN in primary Sjögren's syndrome

Following the initial demonstration of the presence of elevated levels of IFN-inducible genes (the IFN signature) in the salivary glands of patients with pSS [2], the involvement of the type I IFN system in disease pathogenesis has become well established. The presence of an IFN signature has been confirmed in the peripheral blood of about 55% of pSS patients and has been associated with higher disease activity, presence of autoantibodies, notably anti-Ro/SSA and anti-La/SSB antibodies, and hypergammaglobulinemia [3▪]. The existence of a crosstalk between type I IFN and adaptive immune responses leading to a ‘vicious circle’ of immune activation is also now well established, with autoantibodies promoting IFNα production via immune complex-mediated stimulation of plasmacytoid dendritic cells (pDCs) [4], and type I IFN promoting adaptive immune responses through activation of immune cells and induction of cytokine production [5–7] (Fig. 1). Recent identification of the IRF5 locus in a genome-wide association study [8▪▪] performed in pSS further highlights the involvement of type I IFN pathways in disease pathogenesis, as IRF5 encodes interferon regulatory factor 5, a transcription factor mediating type I IFN responses in various immune cells. Interestingly, presence of an IFN signature even before the appearance of autoantibodies and disease onset has recently been reported in type 1 diabetes [9]. Whether the same is true for pSS remains to be determined, but it is an interesting possibility that further raises the question of what triggers the type I IFN response in early pSS.

FIGURE 1
FIGURE 1:
Schematic representation of the immune processes hypothesized to underlie pSS pathogenesis. First, viral infections may initiate inflammation in the glandular tissue, in particular by activating pDCs to produce IFNα, which further promotes adaptive immune responses. Glandular epithelial cells may also contribute to the recruitment and activation of B and T cells by secreting cytokines and chemokines upon stimulation by IFNα or viral exposure. Second, activated T cells induce tissue damage via secretion of IFNγ and support B cell activation. BAFF and other cytokines produced by dendritic cells and epithelial cells further promote B cell activation and differentiation into autoantibody-producing plasma cells. Third, immune complexes containing RNA- or DNA-associated autoantigens released by dying epithelial cells activate pDCs to produce IFNα, leading to the establishment of a vicious circle of immune activation in genetically susceptible individuals, with uncontrolled type I IFN production, chronic B cell activation, and autoantibody production. pDCs, plasmacytoid dendritic cells; pSS, primary Sjögren's syndrome.

Viral triggers in primary Sjögren's syndrome etiopathogenesis

It has long been hypothesized that microbial stimuli, and in particular viral infections, might be involved in pSS etiopathogenesis by not only activating IFN pathways, but also promoting the formation of ectopic lymphoid structures and contributing to breach of tolerance [10▪]. No one specific virus has, however, been established as a causative agent in pSS so far. Rather, it seems likely that various kinds of microbial triggers might lead to overactive immune responses, and eventually to autoimmunity, in genetically susceptible individuals (Fig. 1).

Although the exact contribution of viral infections to pSS etiopathogenesis is difficult to assess in humans, mouse models offer interesting clues as to early events leading to disease. Bombardieri et al.[11▪] thus showed that C57BL/6 mice develop typical signs of pSS following delivery of a replication-deficient adenovirus to the submandibular gland, with lymphocytic infiltration of the glands, formation of ectopic lymphoid structures, production of autoantibodies, and decrease in salivary flow. Recently, Jin et al.[12▪] found that administration of the double-stranded RNA analog poly I:C leads to expression of IL-7, a cytokine involved in the regulation of mature T cells and in the formation of ectopic lymphoid structures, in the salivary glands of C57BL/6 mice in a mostly type I IFN-dependent manner and accelerates the development of pSS-like exocrinopathy in a mouse model of pSS. Interestingly, both studies link an initial virally induced innate immune response to the subsequent establishment of an adaptive immune response and formation of ectopic lymphoid structures within the salivary glands.

A recent study conducted in patients with pSS seems to further suggest a particular connection between viral infection and the presence of ectopic lymphoid structures in pSS: Croia et al. found that Epstein–Barr virus (EBV) was selectively present in the salivary glands of pSS patients that contained ectopic lymphoid structures, in contrast to pSS glandular tissue lacking such structures. In addition, a significant proportion of salivary gland EBV-infected plasma cells had a disease-specific autoreactive profile, especially displaying reactivity to the SS-associated autoantigen Ro52 [13▪]. An intriguing possibility is that a persistent latent EBV infection may contribute to the establishment of autoimmunity by providing antiapoptotic signals to autoreactive B cell clones within the target organs. In turn, differentiation of these cells into autoantibody-producing plasma cells may lead to EBV reactivation. Croia et al. indeed observed that a subset of salivary gland perifollicular plasma cells showed signs of EBV reactivation. It is, however, currently unclear whether EBV reactivation in the salivary glands of pSS patients is only a secondary event because of autoreactive B cell activation, or whether it plays a role in the formation and maintenance of ectopic lymphoid structures.

ECTOPIC LYMPHOID STRUCTURES AND PROPAGATION OF THE AUTOIMMUNE INFLAMMATION IN THE SALIVARY GLANDS IN PRIMARY SJÖGREN'S SYNDROME

The exocrine gland tropism and the formation of ectopic lymphoid structures promoting local autoimmune responses in target tissues are striking features of pSS; however, both remain unexplained.

Ectopic lymphoid structures in primary Sjögren's syndrome

Germinal center-like structures are present in the salivary glands of 25–30% of pSS patients and play an important role in local chronic B cell activation and autoantibody production, supporting B cell clonal expansion, somatic hypermutation, and Ig-class switching [14]. It is, however, still unclear why they form in a subset of pSS patients.

Importantly, a strong association between pSS and polymorphisms in the CXCR5 locus was recently detected in a genome-wide association study [8▪▪]. CXCR5 is the receptor for CXCL13 and is particularly important for the migration of B cells and IL-21-producing T follicular helper (Tfh) cells into the B cell zone of secondary lymphoid organs. Tfh cells have indeed been detected in the salivary glands of patients with pSS within germinal center-like structures [15,16] and have also previously been found to be more frequent in the peripheral blood of pSS patients compared with healthy controls [17]. Lymphotoxin-α (LTα), a cytokine critical to the formation of secondary lymphoid organs, has also recently been linked to pSS through an association between pSS and genetic variations in the LTα/LTβ/TNF locus [18]. A candidate gene study [19▪] recently detected an association between genetic variations in CCL11, a gene encoding the eosinophil-associated chemokine eotaxin, and the presence of germinal center-like structures in salivary glands of pSS patients. The same study reported suggestive associations with other genes involved in B cell activation and/or germinal center formation, such as AICDA, BANK1, and BCL2. Altogether, these recent findings from genetic association studies suggest that genetic variation may explain why only a subset of patients with pSS develops germinal center-like structures. Given that these patients have an increased risk of developing B cell lymphoma compared with patients without ectopic lymphoid structures in glandular tissue [20▪], one may speculate that they represent a distinct disease phenotype, with perhaps different mechanisms underlying chronic B cell activation and autoimmunity (Fig. 2).

FIGURE 2
FIGURE 2:
Ectopic lymphoid structures and B cell activation in pSS. Germinal center-like structures develop in the salivary gland tissue of about a third of pSS patients. fDC and IL-21-producing Tfh cells, together with BAFF, support local chronic B cell activation, proliferation, and differentiation into autoantibody-producing plasma cells. Genetic studies have identified associations between pSS and several genes related to B cell activation/survival and lymphoid structure formation. fDC, follicular dendritic cells; pSS, primary Sjögren's syndrome; Tfh, T follicular helper.

Salivary gland epithelial cells: not just victims

Intriguingly, pSS shares many features with SLE, but the specific mucosal tropism of pSS – targeting mostly salivary and lacrimal glands – remains unexplained. In recent years, evidence has started to suggest that epithelial cells from target tissue might be more than just the innocent victims of an immune response gone awry (Fig. 1).

Salivary gland epithelial cells have been shown to express cytokines such as BAFF, IL-7, IL-22, IL-6, CXCL10, CXCL12, and CXCL13 in response to viral triggers or type I IFN stimulation in vitro, or in tissue biopsies from pSS patients [12▪,21–27], thereby likely contributing to the local initiation and/or maintenance of both innate and adaptive immune responses and to the formation of ectopic lymphoid structures. Interestingly, specific downregulation of BAFF expression in salivary epithelial cells by interfering with BAFF mRNA splicing was recently reported to decrease lymphocytic infiltrates and the number of B cells and plasma cells in salivary glands of treated mice, as well as improve salivary flow, in a mouse model of pSS [28].

Epithelial cells also likely contribute to the maintenance of both autoreactive B cell responses and type I IFN production in the target tissue by locally providing autoantigens for the activation of autoreactive B cells and the formation of pDC-activating immune complexes. Recently, Aqrawi et al.[29] showed that the expression of the pSS autoantigen Ro52 was increased in the ductal epithelium of patients compared with nonpSS controls and correlated with the degree of inflammation in the salivary gland.

ADAPTIVE IMMUNE CONTRIBUTION TO PRIMARY SJÖGREN'S SYNDROME

Several cardinal features of Sjögren's syndrome point to a chronic activation of B cells being a major contributor to disease pathogenesis. The mechanisms underlying B cell chronic activation in pSS are, however, still not fully understood.

BAFF

BAFF, an IFN-inducible cytokine, is known to play an important role in B cell activation and survival, as well as in plasma cell longevity. Serum BAFF levels are elevated in pSS patients and have been shown to correlate with several disease parameters, prompting interest in evaluating the potential effectiveness of belimumab, a BAFF-blocking antibody, in the treatment of pSS. Results from the first phase II clinical trial involving 30 pSS patients indicate that targeting BAFF may be effective in a subset of patients [30▪▪,31]. Recently, BAFF levels were shown to be associated with B cell clonal expansion in salivary glands of pSS patients [32] and to be more specifically increased in pSS patients who had developed B cell lymphoma compared with patients with no history of lymphoma [32,33].

Factors driving chronic B cell activation

Although the molecular and cellular environment in target tissues of pSS patients is no doubt an important contributor to the maintenance of B cell activation, recent studies have also highlighted possible intrinsic factors contributing to B cell hyperactivation. In particular, genetic association studies have suggested the involvement of a number of genes related to B cell activation and/or survival, such as BLK[8▪▪,34], EBF1, TNFSF4[34], and genes involved in the regulation of NF-κB signaling, such as TNFAIP3, which encodes A20, a key regulator of NF-κB activation [35▪,36▪], and TNIP1, a gene encoding TNFAIP3-interacting protein 1 [8▪▪] (Fig. 2). Notably, germline and somatic mutations in TNFAIP3 have recently been proposed to contribute to progression toward lymphoma development in patients with pSS [36▪].

Although the local production of cytokines such as BAFF or IL-6 and the formation of ectopic lymphoid structures certainly promote the differentiation of B cells into antibody-producing plasma cells, the selective forces driving B cell proliferation and selection in pSS remain unclear. Given the presence of germinal center-like structures and the production of autoantibodies locally in salivary glands, one may suppose that clonal B cell expansion is at least in part antigen-driven. In a recent study [37], analysis of the heavy and light chains secreted by antibody-producing cells derived from the glandular tissue of a patient with pSS revealed the presence of extensive somatic hypermutations, suggesting that the expansion and differentiation of these cells is indeed antigen-driven. Another study [38] analyzing the IgG and IgA repertoire in the salivary glands of pSS patients before and after treatment with B cell depletion therapy, however, found little evidence of (auto)antigen-driven positive selection. In contrast, IgG sequences with N-glycosylation motifs acquired after somatic hypermutation were more frequent in the salivary glands of pSS patients than in those of healthy individuals, indicating that nonclassical antigen-independent interactions such as those between a glycosylated B cell receptor and lectins present in the glandular tissue environment may confer a selective advantage for B cell proliferation and survival.

B cell depletion as a therapeutic strategy in primary Sjögren's syndrome

Results of two clinical trials evaluating the effectiveness of B cell depletion therapy (Rituximab) in pSS seemed promising [39,40]; however, a recent double-blind randomized controlled trial failed to detect any significant improvement in symptoms or disease activity at 6 months after treatment [41▪▪]. These findings highlight the need to better understand other aspects of pSS besides B cell involvement in order to design effective therapeutic strategies.

T cells in primary Sjögren's syndrome pathogenesis

T cells are among the first cells to infiltrate the exocrine glands in pSS, and the strong association of pSS with the HLA locus [8▪▪] underscores the importance of antigen presentation to T cells in disease pathogenesis. T cells likely contribute both directly and indirectly to tissue damage and systemic manifestations through production of cytokines (Th1, Th17 cells) and maintenance of B cell-mediated responses (Tfh cells). Further highlighting the contribution of T cells to disease pathogenesis, a small open-label study [42▪▪] recently showed that treatment with Abatacept, a CTLA-4-IgFc fusion molecule that blocks T cell activation, reduced disease activity and was associated with decreased levels of RF and Ig in early pSS patients.

Th1 cells and type II IFN

Increased levels of Th1 cell cytokines such as IFNγ and TNFα are thought to contribute directly to tissue damage in exocrine glands in pSS. Recently, the contribution of the Th1 cell subtype to pSS pathogenesis has attracted renewed attention as polymorphisms in STAT4 and IL12A have been found to be associated with pSS [8▪▪,34,35▪]. Interestingly, another study [43] also suggests that some of the signals classically attributed to a type I IFN signature in the salivary glands of pSS patients could also be linked to IFNγ activity.

Th17 cells and IL-17-related pathways

The cytokine IL-17, as well as Th17 cells and IL-17-producing CD4CD8 double negative T cells, have been implicated in pSS pathogenesis in humans [44–47]. In addition, IL-17 has recently been shown to be required for the development of pSS-like features in a mouse model of pSS based on immunization with salivary gland proteins [48]. A recent study [49] seeking to assess the involvement of RORγt, a transcription factor typically expressed in IL-17-producing cells, in pSS pathogenesis, however, found that IL-17 was not required for RORγt-transgenic mice to develop sialadenitis. Instead, the findings suggested that development of sialadenitis might be due, at least in part, to a decreased regulatory T cell population in the RORγt-transgenic mice.

NATURAL KILLER CELLS IN PRIMARY SJÖGREN'S SYNDROME

Although the mechanisms underlying aberrant adaptive immune responses and type I IFN system dysregulation in pSS pathogenesis are the focus of much attention, recent studies have also shed light on the potential contribution of other cell types, such as NK cells, to initiation and/or maintenance of immune responses. NK cells might play a role in pSS pathogenesis, not only directly via production of IFNγ, but also indirectly by promoting IL-12 secretion by dendritic cells, leading to subsequent Th1 cell differentiation. Recently, a subset of NK cells producing high levels of IL-22 was also found in the salivary glands of pSS patients [23]. Findings from a recent genetic association study further support a role for NK cells in pSS pathogenesis: Rusakiewicz et al.[50▪▪] found that a polymorphism in the promoter region of NCR3, which encodes the NK-specific activating receptor NKp30, was associated with susceptibility to pSS, with the major allele found in pSS patients associated with higher expression of NKp30 on peripheral blood NK cells. The study further showed that levels of NCR3/NKp30 were increased in pSS patients compared with controls and correlated with increased secretion of IFNγ by NK cells following NCR3/NKp30 stimulation.

CONCLUSION

Over the past decade, significant advances have been made in understanding pSS pathogenesis. Recent large genetic studies have allowed the identification of many genes associated with pSS, confirming the involvement of important immune pathways such as the type I IFN system and aberrant B cell responses in disease pathogenesis. Crucially, as our understanding of the immune mechanisms underlying pSS pathogenesis improves, novel relevant therapeutic targets have been, and continue to be, discovered. Considering the broad immune activation involving both innate and adaptive pathways, combination therapy may prove the optimal strategy for satisfactory treatment of pSS.

Acknowledgements

The authors acknowledge research support from the Swedish Research Council, the Heart-Lung Foundation, the Stockholm County Council, the Karolinska Institute, the Swedish Rheumatism Association, King Gustaf the Vth 80-year Foundation, the Freemason Children Foundation Stockholm, and the Torsten and Ragnar Söderberg Foundation.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

REFERENCES

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This is the first prospective, population-based study looking at the incidence rate of pSS. The authors reported an incidence rate of 3.1 cases per 100 000 person-years. Interestingly, the prevalence of autoantibodies in this cohort of incident cases is lower than previously reported, and severe extraglandular manifestations are less frequent than in prevalent pSS.

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Important study supporting a role for viral infections in pSS pathogenesis. The authors demonstrated that administration of adenovirus to the salivary glands of mice led to features of pSS, including formation of ectopic lymphoid structures in the glands, production of autoantibodies, and reduced salivary flow.

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Study linking an initial virally induced innate immune response to the development of adaptive immune responses and disease acceleration in a mouse model of pSS.

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This study shows that there may be a particular connection between persistent viral infections (such as EBV) and the presence of ectopic lymphoid structures and autoantibody production in pSS patients.

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This study identifies genetic variations that are selectively associated with the presence of ectopic lymphoid structures in the salivary glands of pSS patients, supporting the idea that individuals with such histopathologic characteristics may represent a distinct disease phenotype.

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Important study showing that the presence of germinal center-like structures in salivary glands is a useful and highly predictive marker for lymphoma development in pSS patients.

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First phase II clinical trial investigating the efficacy and safety of belimumab, a BAFF-blocking antibody, in the treatment of pSS. The primary end-point was achieved in 60% of patients, indicating that targeting BAFF may be a promising therapeutic strategy in pSS that warrants larger randomized controlled trials.

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One of the first two GWAS performed in pSS. This study confirms in a Han Chinese population genetic associations previously reported in European populations in the HLA locus as well as in loci including STAT4 and TNFAIP3. It also identifies a new susceptibility locus, GTF2IRD1-GTF2I.

36▪. Nocturne G, Boudaoud S, Miceli-Richard C, et al. Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren's syndrome. Blood 2013; 122:4068–4076.

This study shows that mutations in TNFAIP3, which encodes a key regulator of NF-κB activation, are associated with progression toward lymphoma development in a substantial proportion of pSS patients, suggesting a possible mechanism for progression from autoimmunity to lymphomagenesis in the context of chronic B cell activation in pSS.

37. Maier-Moore JS, Koelsch KA, Smith K, et al. Antibody-secreting cell specificity in labial salivary glands reflects the clinical presentation and serology in patients with Sjogren's syndrome. Arthritis Rheumatol 2014; 66:3445–3456.
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41▪▪. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Treatment of primary Sjogren syndrome with rituximab: a randomized trial. Ann Intern Med 2014; 160:233–242.

Double-blind randomized controlled trial of B cell depletion therapy (Rituximab) in pSS. No significant improvement in symptoms or disease activity was found 6 months after treatment, highlighting the need to target additional pathways related to pSS pathogenesis in order to achieve satisfactory treatment of pSS.

42▪▪. Meiners PM, Vissink A, Kroese FG, et al. Abatacept treatment reduces disease activity in early primary Sjogren's syndrome (open-label proof of concept ASAP study). Ann Rheum Dis 2014; 73:1393–1396.

Small proof-of-concept clinical trial showing that blocking T cell costimulation (Abatacept) may be useful in the treatment of pSS. Disease activity as well as RF and IgG levels decreased during and after treatment, while fatigue and quality of life reported by patients improved.

43. Hall JC, Casciola-Rosen L, Berger AE, et al. Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proc Natl Acad Sci U S A 2012; 109:17609–17614.
44. Alunno A, Bistoni O, Bartoloni E, et al. IL-17-producing CD4-CD8- T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjogren's syndrome. Ann Rheum Dis 2013; 72:286–292.
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46. Fei Y, Zhang W, Lin D, et al. Clinical parameter and Th17 related to lymphocytes infiltrating degree of labial salivary gland in primary Sjogren's syndrome. Clin Rheumatol 2014; 33:523–529.
47. Katsifis GE, Rekka S, Moutsopoulos NM, et al. Systemic and local interleukin-17 and linked cytokines associated with Sjogren's syndrome immunopathogenesis. Am J Pathol 2009; 175:1167–1177.
48. Lin X, Rui K, Deng J, et al. Th17 cells play a critical role in the development of experimental Sjogren's syndrome. Ann Rheum Dis 2015; 74:1302–1310.
49. Iizuka M, Tsuboi H, Matsuo N, et al. A crucial role of RORgammat in the development of spontaneous Sialadenitis-like Sjogren's syndrome. J Immunol 2015; 194:56–67.
50▪▪. Rusakiewicz S, Nocturne G, Lazure T, et al. NCR3/NKp30 contributes to pathogenesis in primary Sjogren's syndrome. Sci Transl Med 2013; 5:196.

This study identifies an association between a polymorphism in the NCR3 locus and susceptibility to pSS, and shows that elevated levels of the NCR3-encoded NK cell-activating receptor in pSS patients correlate with enhanced secretion of IFNγ by NK cells. These new findings support a role for NK cells in pSS that warrants further investigation.

Keywords:

B cell; genetic association; IFN; Sjögren's syndrome

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