An Overview of Primary Sjögren's Syndrome (pSS)
Primary Sjögren's Syndrome (pSS) is a systemic autoimmune disease characterized by exocrinopathy[1] that often leads to chronic inflammatory infiltration and dysfunction of exocrine glands.[2] Oral and eye dryness are the most common clinical symptoms of pSS.[3] However, patients with pSS can also develop severe complications, such as vasculitis, pulmonary arterial hypertension, lymphoma, and encephalitis.[4,5] Previous studies revealed the crucial role of the innate immune system during the early stage of pSS.[6,7] Studies also found a strong association between T cell activation and pSS onset.[8] Recently, a considerable number of studies have investigated the role of B cell activation in pSS.[9] Studies have also identified alternations in patients with pSS at the genome, transcriptome, or proteome levels.[10-12] However, due to the lack of integration of the mechanisms involved, much uncertainty still exists about the pathogenesis of pSS.
The treatment for pSS is organ-based. For pSS patients with mild and chronic symptoms, local treatments aim to ameliorate discomfort by stimulating secretion or surrogate moistures. Glucocorticoid and immunosuppressant drugs are used for systemic treatment of severe and acute conditions.[13,14] There is considerable interest in target-synthesized disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs. The use of these drugs was recommended by the European League Against Rheumatism and American College of Rheumatology guidelines in 2013 and 2017, respectively. They have proved to be a promising treatment, with better efficacy for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).[15-20] However, compared with RA and SLE, for which DMARDs use is rapidly developing, the role of target-synthesized and biologic DMARDs therapies in pSS still remains controversial.[14] To improve the efficacy and safety of new treatments for pSS, more studies are needed to fully understand the pathogenesis of the disease.
An Overview of JAK-STAT Signaling Pathway
Janus kinases (JAKs) are non-receptor tyrosine kinases conserved between mammals and other classes of animals. So far, four JAK family members, JAK1, JAK2, JAK3, and TYK2, have been identified in mammals. A typical JAK gene has seven JAK homology (JH) domains, from the carboxyl terminus to the amino terminus JH1–7.[21] JH1 is a kinase that shares high homology with receptor tyrosine kinases.[22] JH2 is a pseudokinase with a vital regulatory function; mutation results in abrogate JAK production.[22] JH3–4 is a Src-homology 2 (SH2)-like domain, and JH5–7 is a FERM homology domain; both domains participate in single receptor-binding.[23]
Signal transducer and activator of transcription (STAT) proteins are a family of deoxyribonucleic acid (DNA)-binding dimer proteins first discovered in interferon (IFN)-α and IFN-γ pathways in the 1990s.[24] Human STAT family includes seven proteins that share similar core structures, STAT1-4, STAT5A, STAT5B, and STAT6. All structural elements of STAT proteins are required for their transcription factor functions. The extreme N and C termini of STATs are responsible for STATs tyrosine phosphorylation by an upstream kinase. The C terminus also acts as a transactivation domain. The coiled-coil domain and interactions between the DNA-binding domain and SH2 domain are crucial for STATs protein DNA-binding functions.[25,26]
Regardless of various JAK and STAT family members, JAK-STAT pathways share a similar mechanism. Cytokines, including interleukin (IL, especially members of IL-2 and IL-6 families), colony stimulating factor (CSF, granulocyte-macrophage CSF and granulocyte CSF), IFN (α, β, and γ), and growth factor, are the most important direct upstream signals in JAK-STAT pathways.[27,28] Upstream signals binding to pathway receptors results in conformational changes of receptors and activation of JAK. Activated JAK subsequently phosphorylates tyrosine residues on its receptors, in preparation for the recruitment of STATs.[26,29] Unphosphorylated STATs, which function in the cytoplasm as dimers in the canonical JAK-STAT pathway or in the nucleus for maintaining heterochromatin stability in the non-canonical pathway, are then phosphorylated by JAK.[30] The phosphorylated STATs (pSTATs) translocate to the nucleus and regulate the expression of genes with at least one small palindromic sequence.[26,29] Different JAK and STAT family members can be activated in response to different kinds of cytokines, while one type of cytokine can have different effects on the cell, according to the JAK-STAT pathway and cell type.[29,31] JAK-STAT pathways can also be downregulated in the initiation, duration, or termination stages via suppressors of cytokine signaling (SOCSs), protein inhibitors of activated STAT (PIASs), protein tyrosine phosphatases (PTPs), and ubiquitin and ubiquitin-like proteins.[32]
Studies over the past two decades have provided important information about the physiological and pathological roles of JAK-STAT pathways. JAK-STAT pathway is an evolutionarily conserved pathway involved in cell proliferation, survival, and differentiation. It has been noted that the pathway is crucial for normal homeostasis of liver, pancreas, muscle, hematopoietic system, and central nervous system.[33,34] Prior research found that JAK-STAT pathway dysregulation contributes to the pathogenesis of obesity and diabetes,[34,35] cancer development and metastatic progression,[36,37] and regeneration dysfunction in muscle,[38,39] bone,[38,39] the nervous system,[40] skin,[41] and intestine.[42]
Recently, increasing studies on its association with the immune system have led to renewed interest in JAK-STAT pathway. In macrophages and T cells, STATs can promote deposition of epigenetic marks[43,44]; STAT-driven epigenetic modifications have not been discovered in other immune cells.[45] It has been shown that STATs co-localize and synergize in multi-factorial networks with other transcriptional factors, such as NF-κB,[46] IFN regulatory factor,[47] and IL[45,48] in macrophages and T cells. Results suggest that these tandem-spaced sites contribute to transcription, though the mechanisms remain unclear.[45] Members of STAT family compete for common DNA-binding sites, which can lead to T cell differentiation.[49] Early studies have demonstrated strong associations between activated JAK-STAT pathways and inflammatory and autoimmune diseases, including RA,[50,51] SLE,[52-55] inflammatory bowel diseases,[56] and inflammatory skin diseases.[57-59] As the roles of JAK-STAT signaling pathway in pathogenesis are identified, JAK-STAT pathway inhibitors become promising small-molecule drugs for the treatment of these diseases. To date, several JAK-STAT pathway inhibitors have been approved for clinical use, such as tofacitinib for RA and psoriatic arthritis, and baricitinib for RA.[60] Other JAK-STAT pathway inhibitors, such as filgotinib, ABT-494, peficitinib, ruxolitinib, decernotinib, solcitinib, itacitinib, and upadacitinib, are under investigation in clinical trials as treatments for autoimmune diseases and inflammatory bowel and skin diseases.[61,62]
Role of JAK-STAT Signaling Pathway in Pathogenesis of pSS
Up to now, a number of studies have revealed the correlation between JAK-STAT signaling pathway and pSS [Figure 1]. Most of these studies have found that overexpression of JAK and STAT family members is associated with the pathogenesis of pSS. In particular, STAT1, STAT3, and STAT5 have been identified as contributors, respectively or synergically, to disease development. Several studies have also assumed that cytokines and non-coding ribonucleic acid (RNA) result in pSS via JAK-STAT pathway, though the mechanisms are not completely understood [Table 1].
;)
Figure 1: JAK-STAT signaling pathway in pathogenesis and treatment of pSS. JAK-STAT pathway consists of six types of modulators, cytokines, cytokine receptors, JAK, STAT, target DNAs, and negative regulatory proteins. Cytokines bind to transmembrane receptors, and the conformation change of cytokine receptors initiates activation and phosphorylation of JAK. Unphosphorylated STATs in the cytoplasm (the canonical JAK-STAT pathway) or in the nucleus (the non-canonical pathway) are then phosphorylated by JAK. pSTATs translocate to the nucleus and lead to epigenetic and expression changes of target genes. Several negative regulatory proteins, such as SOCSs, PIASs, and PTPs, downregulate JAK-STAT pathway by blocking signal transduction, phosphorylation, and function. Family members of TNF, NF-κB, TLR, IFN, and IL initiate inflammatory response and pathological changes via JAK-STAT pathway and network, and therefore contribute to the pathogenesis of pSS. IFN, Interferon; IL, Interleukin; JAK, Janus kinases; PIAS, Protein inhibitors of activated STAT; pSS, Primary Sjögren's syndrome; pSTAT, Phosphorylated STAT; PTP, Protein tyrosine phosphatases; SOCS, Suppressors of cytokine signaling; STAT, Signal transducer and activator of transcription; TLR, Toll-like receptor; TNF, Tumor necrosis factor.
Table 1 -
A summary of JAK-STAT pathways and their effects in the pathogenesis of pSS.
| Species |
Upstream signal(s) |
Target cell(s) |
STAT(s) |
Effect(s) |
Reference(s) |
| STAT1 |
| Human |
TLR 7/8 |
moDCs |
STAT1↓ |
T cell activation |
[69,70]
|
| Human |
IFNα, IFNγ
IL-6 |
Lymphocytes and monocytes |
pSTAT1↑ |
Upregulating CXCL10 |
[65]
|
Human &
Mouse |
- |
Epithelial cells |
STAT1↑ |
Caspase11-caspase 1 activation and upregulating apoptosis |
[66,67]
|
| Human |
IFNγ |
Salivary gland ductal cells |
STAT1↑ |
Upregulating CXCL10
Chemotaxis of Jurkat T cells |
[71]
|
| Human |
IFNα |
Naive CD4+ T cells |
STAT1↑ |
Tfh cell polarization
BCL6 expression |
[73]
|
| Human |
IFNα, IFNγ
IL1-β
TNF-α |
Ductal cells |
STAT1↑ |
Upregulating CXCL10 |
[72]
|
| Human |
TNF-α |
Acinar cells |
STAT1↑ |
Upregulating CXCL10 |
[72]
|
| STAT3 |
| Human |
IL-18, IL-22 |
Minor salivary glands and non-Hodgkin lymphoma |
STAT3↑ |
- |
[74]
|
| Human |
IFNα, IFNγ
H2O2
|
Salivary gland cells |
STAT3↑ |
Global DNA hydroxymethylation and lymphocytic infiltration |
[75-77,81]
|
| Human |
IL-6 |
Salivary duct epithelial cells |
STAT3↑ |
Upregulating REG Iα, a gene related to inflammatory diseases |
[86]
|
| Human |
TLR 7 and 9 |
Peripheral blood mononuclear cells |
STAT3↑ |
Overactivity of B cells |
[82]
|
Human &
Mouse |
IFNγ
IL-1β, IL-6
NF-κB
TLR |
Salivary duct epithelial cells |
STAT3↑ |
Downregulating apoptosis |
[83,84]
|
| STAT5 |
| Human |
- |
T cells, B cells, and monocytes |
STAT5↑ |
- |
[92]
|
| JAK-STAT networks |
Human &
Mouse |
IFNα, IFNγ |
SGECs |
pSTAT-1↑
STAT-3↑
pSTAT-3↑ |
- |
[93]
|
| Human |
IFNα |
B cells |
pSTAT1↑ |
Upregulating type I IFN-inducible gene expression and higher levels of autoantibodies |
[94]
|
| Human |
IFN |
Blood monocytes |
STAT1↑
STAT3↑
STAT5↑
STAT6↑ |
Augmented plasmin generation in exocrine gland damage |
[97]
|
BCL6, B cell lymphoma 6; CXCL: cxc-chemokine motif ligand; IFN, Interferon; IL, Interleukin; JAK, Janus kinases; moDC, Monocyte-derived dendritic cell; pSS, Primary Sjögren's syndrome; pSTAT, Phosphorylated STAT; SGECs, Salivary gland epithelial cells; STAT, Signal transducer and activator of transcription; Tfh, Follicular helper T; TLR, Toll-like receptor; TNF, Tumor necrosis factor.
In summary, JAK-STAT pathways are associated with abnormalities in activation, chemotaxis, and infiltration of B cells and T cells. In cells in involved exocrine organs, aberrant epigenetic regulation and apoptosis are remarkable changes that result from activated JAK-STAT pathways.
STAT1
In labial salivary glands from pSS patients, two forms of STAT1 messenger RNA (mRNA), STAT1α mRNA and its naturally occurring non-functional splicing variant STAT1β mRNA, are both highly transcribed. However, only STAT1α protein is highly translated. pSTAT1α abundantly localizes according to their various phosphorylated sites in infiltrating lymphocytes or ductal epithelia of labial salivary glands from pSS patients. Three STAT1-inducible genes, IFNγ-inducible 10-kd protein, IFN regulatory factor-1, and Fas gene, are exclusively highly expressed in cells with Ser727 pSTAT1α in labial salivary glands from pSS patients. Given the functions of these genes, this study indicated that STAT1α induces apoptosis of epithelial cells in labial salivary glands and subsequent pathogenesis of pSS regulated by IFNγ, but not IFNα; STAT1β might function as an agonist to resist apoptosis.[63,64] Pertovaara et al[65] confirmed that a higher level of downstream gene expression is due to increasing pSTAT1 rather than increasing cytokines activating JAK-STAT pathway. However, they found that in addition to IFNγ, IFNα, and IL-6 can function as upstream cytokines in peripheral blood lymphocytes and monocytes. Killedar's and Bulosan's research groups offered an explanatory theory for the association between increasing STAT1, apoptosis, and pSS in NOD mice and humans.[66,67] Using microarray analysis, they found that NF-κB and STAT1 can bind to promotors of proinflammatory stimuli, which can subsequently induce caspase1/11 activation and secretion of IL-1β/18. The resulting initiation of apoptosis up-regulation in epithelial cells leads to chronic inflammatory conditions in salivary glands of pSS patients.[66,67]
Under conditions of inflammation, monocytes can differentiate into a type of antigen-presenting cell, the monocyte-derived dendritic cell (moDC).[68] The moDC is a component of the infiltrating lymphocytes in the salivary glands of pSS patients. Vogelsang et al[69] discovered that in moDCs from patients with pSS, activation of toll-like receptors (TLRs) 7/8 significantly decreases expression of an NF-κB suppressor, STAT1, resulting in high-level expressions of two cytokines, IL-12p40 and MIP-1α. It was proved that IL-12p40 can attenuate regulatory T cells and therefore prevent peripheral tolerance.[70] This change can then lead to typical systemic autoimmune manifestations, including T cell activation.
Jurkat T cells are stimulated in response to IFN in salivary gland ductal cells. This change is consistent with the histology results (i.e., changes in levels of T cell infiltration) in salivary glands from patients with pSS. Preventing phosphorylation of JAK2 and STAT1 can decrease production of cxc-chemokine motif ligand 10 (CXCL10) and thus inhibit chemotaxis of Jurkat T cells.[71] Further research also identified the role of CXCL10 regulation in the pathogenesis of pSS. Upstream cytokines, including IFNγ, IFNα, tumor necrosis factor (TNF) α, and IL1β in ductal cells, and TNFα in acinar cells, initiate JAK-STAT signaling pathway. IFNγ plays the most important role in inducing CXCL10 and leading to pSS via JAK-STAT1 and NF-κB pathways.[72] Follicular helper T (Tfh) cells are a crucial subgroup of T cells in the pathogenesis of pSS. It is suggested that IFN-α induced JAK-STAT1 signaling activation facilitates Tfh cell differentiation via overexpression of thymocyte selection-associated high mobility group box protein.[73]
Pertovaara et al[65] cultured peripheral blood monocellular cells from 16 pSS patients and 15 healthy controls. They then treated the cells with IFNγ and with or without lipopolysaccharide (LPS). The presence of LPS downregulated IFNγ-induced JAK-STAT pathway in both pSS patients and healthy controls. But, the inhibitory effects of LPS in pSS patients were more prominent. They also found that SOCS1/3 mRNA expression increased in patients with pSS. This finding provides a plausible explanation: the inhibitory effect is prominent in patients with pSS due to activation of JAK-STAT pathway. However, the authors failed to specify whether the lack of SOCS or the excessive activation of JAK-STAT pathway, or both, contribute to the pathogenesis of pSS.
STAT3
Many small-molecule chemicals can initiate JAK-STAT3 pathway as upstream signals. Overexpression of IL-18 and IL-22 in local tissues and peripheral blood is a signature characteristic of pSS patients. IL-22 receptor 1 binding with IL-22 can upregulate STAT3, IL-17, and IL-22. IL-18 has an important role in the regulation of IL-22 binding to IL-22 receptor 1 via two distinct ways. IL-18 downregulates an antagonist of IL-22, IL-22 binding protein, by inhibiting its expression in cells with IL-18. IL-18 also upregulates the level of IL-22 receptor 1, which is an important alteration in the minor salivary glands and in non-Hodgkin lymphoma patients with pSS.[74] This study provided a new understanding that the interaction between IL-18 axis and IL-22 axis can result in pSS and pSS-related lymphoma via JAK-STAT3 pathway.
In addition, JAK-STAT3 pathway has been found to be activated by IFN and reactive oxygen species, including IFNα, IFNγ, and H2O2. These upstream signals are respectively produced by plasmacytoid dendritic cells, CD4+ T cells, and natural killer cells in minor salivary glands of pSS patients.[75,76] Increased pSTAT3 induced by the signals subsequently upregulates expression of ten-eleven translocation methylcytosine dioxygenase, which can increase DNA hydroxymethylation.[77] In salivary glands of patients with pSS, the decrease in global DNA methylation and the increase in global DNA hydroxymethylation are two of the most significant changes in the genes of epithelial cells.[78-80] The balance between DNA methylation and hydroxymethylation is associated with lymphocytic infiltration.[81] Therefore, IFN and reactive oxygen species can initiate the pathogenesis of pSS via JAK-STAT3 pathway.
In an exploratory analysis of JAK-STAT signaling pathway, Davies et al[82] identified single-cell-based phosphorylation profiling as a promising indicator for the differentiation of patients with pSS from healthy controls and the evaluation of disease activity in patients with pSS. They also found that overactivity in B cells stimulated by TLRs 7 and 9 via pSTAT3 or NF-κB is correlated with type I IFN score, which represents the overall expression level of IFN-inducible genes. Therefore, this study found that TLRs 7 and 9 are important connections between type I IFN and JAK in the JAK-STAT3 pathway.
Using Aire–/– mice that exhibit exocrinopathy and excessive lymphocytic infiltration in exocrine glands similar to pSS, Chen et al[83] investigated the activation of several cytokines and signaling pathways previously reported as involved in inflammation and cell death (i.e., IFNγ, IL-1β, NF-κB, TLR, and IL-6 STAT3 pathway). Furthermore, immunostaining assays showed that excessive pSTAT3, an inhibitor of cell apoptosis, localizes in ductal cells but not acinar cells. These results indicated that STAT3 has an important role in ductal cell death evasion, which may contribute to the early development of pSS. Similar results were also found in patients with pSS.[84]
In the human genome, the Reg family comprises five isolated genes that are involved in inflammatory diseases.[85]In vitro experiments illustrated that in human salivary ductal cell lines, pSTAT3 stimulated by IL-6 binds to the -141 to -117 region of the REG Iα promotor and induces overexpression of REG Iα mRNA and protein. Therefore, increased REG Iα contributes to the pathogenesis and progression of pSS.[86]
IL-6 indirectly upregulates pSTAT3 via JAK-STAT3 pathway. pSTAT3 induces expression of SOCS3, which can in turn inhibit the catalytic activity of JAK and suppress production of pSTAT3 via a negative feedback loop.[87-90] SOCS3 expression increases both locally and systemically in pSS patients compared with healthy controls. However, intriguingly, the expression level of pSTAT3 also elevates. This result suggests that although there is an increase in expression, there is a reduction in SOCS3 function. This change may be due to the co-expression of SOCS3 and proinflammatory IL-17 in salivary glands and peripheral blood mononuclear cells, which was revealed using immunohistochemistry and flow cytometry assays.[91]
STAT5
The phosphorylation levels of STAT5 are higher in T cells, B cells, and monocytes in the peripheral blood of pSS patients compared with healthy controls.[92] However, the level of STAT5 mRNA is not significantly different between pSS patients and healthy controls. This result suggests changes in upstream cytokines of JAK-STAT5 pathway increase the ratio of pSTAT5/STAT5. Conversely, contrary to the previously discussed research, this study found no prominent differences in the activation of other STATs between the pSS groups and healthy controls.[92]
JAK-STAT Signaling Networks
It has been noted that several upstream signals contribute to the pathogenesis of pSS via more than one JAK-STAT pathway. Under this condition, various JAKs and STATs respond to one signal and synergize through JAK-STAT signaling networks. One study found that in patients with pSS, differentially expressed genes, such as IFN-related genes and B cell-activating factor (BAFF), which is a determinant of B cell survival, are highly expressed in salivary glands.[84] Knockdown of differentially expressed genes or reductions in BAFF levels downregulate IFNα- and IFNγ-inducible pSTAT1 and PIAS3 in human salivary gland epithelial cells (SGECs); pSTAT1, pSTAT3, and PIAS1 are also downregulated in NOD/ShiLtJ mice.[93] A study of another patient cohort found that IFNα-activated pSTAT1 in B cells is positively correlated with levels of type I IFN-inducible gene expression and autoantibodies; in T cells, pSTAT3 is negatively correlated with the level of type I IFN-inducible gene expression.[94] In addition, secretory leukocyte protease inhibitors can inhibit proteolytic activity and delay matrix accumulation via reduction of matrix metalloproteinases and suppression of plasmin activation.[95,96] A reduction in the level of secretory leukocyte protease inhibitor in the minor salivary glands of pSS patients indicates the possible role of plasmin activation in pSS pathology. In blood monocytes of pSS patients, IFNγ upregulates tissue-type plasminogen activator via various JAK-STAT pathways and promotes conversion from plasminogen to plasmin, which leads to permanent tissue damage.[97]
Other proteins and RNAs are associated with the pathogenesis of pSS, but the relevant mechanisms remain unclear. It was noted that IL-21 expression increases both locally and systemically in pSS patients, and it might target SOCS via JAK-STAT, MAPK, and PI3K pathways.[98] In IFNγ-treated SGECs, increased myocardial infarction-associated transcript two upregulates miR-377 that is repressed by IFNγ; inhibition of the proinflammatory factors is thus abolished.[99] This study provided valuable insight into the role of non-coding RNA networks in pSS pathology. Furthermore, JAK-STAT pathway may also correlate with some complications of pSS, such as lymphoma.[100]
Role of JAK-STAT Signaling Pathway in Treatment of pSS
Rheumatological Janus kinase inhibitors (Jakinibs) are most commonly used for RA treatment. To date, five Jakinibs (tofacitinib, baricitinib, upadacitinib, peficitinib, and filgotinib) have been approved for treatment for moderate-to-severe RA with inadequate or intolerant response to methotrexate.[101] These Jakinibs have a positive treatment effect on RA, though drug-related adverse effects have been reported.[102-104] In SLE, no rheumatological Jakinibs have been approved for clinical treatment. But tofacitinib and solcitinib (GSK2586184) have been used in various phases of clinical trials.
The mainstream treatment for pSS is local symptomatic treatment and non-biologic (synthetic) DMARDs. However, in some individuals, symptoms do not improve or drug-related adverse events occur, or both.[105,106] Though a recent phase-2b clinical trial of ianalumab (VAY736) reported efficacy, clinical trials of other biologic DMARDs (eg, rituximab, belimumab, and abatacept) had conflicting clinical results in pSS patients.[107-115] Due to the important role of JAK-STAT pathway in the pathogenesis of pSS and the success of Jakinibs for the treatment of RA and SLE, Jakinibs seem to be promising therapies for pSS patients.[101,116] At the cell level, JAK1/2 inhibitors can suppress JAK-STAT pathway activated by IFNα/γ or H2O2. This suppression subsequently inhibits downstream effects, including the increase in aberrant DNA epigenetic reprograming,[77] high expression of tissue-type plasminogen activator,[97] and CXCL10 expression.[117] Lee et al[93] performed a series of experiments to determine the safety and efficacy of a JAK1 inhibitor, filgotinib, for pSS treatment, from the molecular to the pathologic levels. Primary SGECs from patients with pSS treated with various doses of filgotinib (0–10 μmol/L) for 24 h showed no significant difference in viability. This result indicated that filgotinib is not cytotoxic at a certain dose range. Primary SGECs stimulated by IFNα or IFNγ were treated with or without 4 μM filgotinib. Compared with cells in the control group, cells treated with filgotinib had decreased expression of various phosphorylated types of STAT1 and STAT3. But whether the expression of PIAS decreased was associated with the type of IFN. Therefore, filgotinib has a role in the suppression of JAK-STAT pathway activation. Due to its role in B cell activation, BAFF (downstream molecules of types I and II IFN) has been considered the core component in pSS pathogenesis.[118] IFIT and RSAD are two other IFN downstream gene families related to pSS.[119] High production of IFIT, RSAD, and BAFF mRNAs in primary SGECs and BAFF protein in salivary glands are suppressed by filgotinib in a dose-dependent manner. Thus, filgotinib additionally inhibits the expression of IFN-related genes and BAFF. Further investigation using hematoxylin and eosin staining of salivary glands revealed that by week 24, the area of lymphocyte infiltration in filgotinib-treated mice salivary glands significantly decreases, compared with a vehicle-treated group. Immunohistochemistry staining reveals lower expression of BAFF in filgotinib-treated mouse salivary glands. In conclusion, the results of this series of experiments suggested that filgotinib and other Jakinibs have potential for treatment of pSS. Recently, a pilot study that was also the first to evaluate the efficacy and safety of baricitinib in pSS found that baricitinib is both effective and well-tolerated in patients with moderate-to-high disease activity. Baricitinib contributes to improving disease activity, achieves minimal clinically important improvement, and ameliorates symptoms (e.g., weight loss, skin rash, arthritis, anemia, and cytopenia) in patients with pSS.[120] However, a randomized-controlled study of filgotinib in patients with pSS with moderate-to-high disease activity found no significant improvement in prespecified criteria based on C-reactive protein and SS-related symptoms at week 12. But the results of a subgroup analysis indicated the potential effectiveness of filgotinib in patients with severe disease activity and with no concomitant medications.[121] More clinical trials of the safety and efficacy of tofacitinib (NCT04496960) and baricitinib (NCT05016297) in patients with pSS are in progress in the US and China[122] [Table 2].
Table 2 -
A summary of studies on different JAK inhibitors in pSS.
| JAK inhibitor |
Subjects |
Effect(s)/clinical trials |
Reference(s) |
| Filgotinib (JAK1) |
Salivary gland and epithelial cells from pSS patients |
Molecular: pSTAT1↓, pSTAT3↓, BAFF↓
Pathological: lymphocyte infiltration↓ |
[93]
|
|
SS patients |
No significant improvement, but potentially effective in severe SS (NCT03100942) |
[121]
|
| Baricitinib (non-selective) |
Salivary gland ductal cells from pSS patients |
Inhibit aberrant high expression of tissue-type plasminogen activator |
[97]
|
|
pSS patients |
Effective and well-tolerated (NCT04916756) |
[120]
|
|
pSS patients |
NCT05016297 |
- |
| Tofacitinib (non-selective, mainly JAK3) |
pSS patients |
NCT04496960 |
- |
BAFF, B cell-activating factor; JAK, Janus kinases; pSS, Primary Sjögren's syndrome; pSTAT, Phosphorylated STAT; SS, Sjögren's syndrome; STAT, Signal transducer and activator of transcription.
Conclusion and Prospective
pSS is a systemic autoimmune disease with a high prevalence and possible poor prognosis. The disease is characterized by oral and ocular dryness, and can also involve multiple organs, including kidney and lung. B cell hyperactivity has been considered the core component of pSS pathogenesis. Recent studies have revealed the important role of JAK-STAT pathway in pSS, which may contribute to the pathogenesis by directly activating B cells or detouring B cells. These studies provide researchers with valuable insights into Jakinibs as promising novel treatments for pSS.
Most studies on the role of JAK-STAT pathway in pSS have revealed the increases in JAK and STAT molecules (i.e., JAK-STAT pathway activation), the aberrant expression of negative regulatory proteins, and downstream pathologic effects related to corresponding clinical symptoms in patients. However, there are some conflicting experimental findings among these studies. For instance, the changes in the expression levels of negative regulatory proteins vary in some cases. Furthermore, compared with that in RA and SLE, the role of JAK-STAT signaling pathway in the pathogenesis of pSS has been less adequately elucidated. Further studies should attempt to identify the possible roles of molecules in JAK-STAT pathway, rather than only focus on changes in expression levels. More studies are required to better understand the functions of upstream cytokines and other molecules, such as non-coding RNAs, in the JAK-STAT pathway. In addition, research is also needed to determine the relationships between JAK-STAT pathway and various pSS subtypes.
Due to the vital roles of the JAK-STAT pathway in several autoimmune diseases, Jakinibs are considered promising treatments for these refractory diseases. However, the numbers of studies on the applications of Jakinibs for the treatment of pSS are still limited. More preclinical work and further clinical trials are needed to determine the safety and efficacy of current Jakinibs for pSS treatment. The development of novel Jakinibs may also contribute to treatment of this disease.
In conclusion, this review discussed the role of JAK-STAT signaling pathway in the pathogenesis and treatment of pSS. As the development of basic medical research and research into JAK inhibitors continue, the quality of life of patients with pSS may fundamentally improve. Precision medicine is also expected to be included in the treatment for pSS to achieve better Jakinib efficacy.
Funding
This study was supported by grants from the Chinese National Key Technology R&D Program, Ministry of Science and Technology (No. 2017YFC0907601, 2017YFC0907605), and CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-005).
Conflicts of interest
None.
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