Marginal Zone B (MZB) Cells: Comparison of the Initial Identification of Immune Activity Leading to Dacryoadenitis and Sialadenitis in Experimental Sjögren's Syndrome.

Although multiple mouse strains have been advanced as models for Sjögren's syndrome (SS), which is a human systemic autoimmune disease characterized primarily as the loss of lacrimal and salivary gland functions, the C57BL/6.NOD-Aec1Aec2 recombinant inbred (RI) mouse derived from the NOD/ShiLtJ line is considered one of the more appropriate models exhibiting virtually all the characteristics of the human disease. This mouse model, as well as other mouse models of SS, have shown that B lymphocytes are essential for the onset and development of observed clinical manifestations. Recently, studies carried out in the C57BL/6.IL14α transgenic mouse have provided clear evidence that the marginal zone B (MZB) cell population is directly involved in the early pathological events initiating the development of the clinical SS disease, as well as late-stage lymphomagenesis resulting in B-cell lymphomas. Since MZB cells are difficult to study in vivo and in vitro, we carried out a series of ex vivo investigations that utilize temporal global RNA transcriptomic analyses to profile differentially expressed genes exhibiting temporal upregulation during the initial onset and subsequent development of pathophysiological events within the lacrimal and salivary gland tissues per se or associated with the leukocyte cell migrations into these glands. The initial transcriptomic analyses revealed that while the upregulated gene expression profiles obtained from lacrimal and salivary glands overlap, multiple genetic differences exist between the defined activated pathways. In the current study, we present a concept suggesting that the initial pathological events differ between the two glands, yet the subsequent upregulated TLR4/TLR3 signal transduction pathway that activates the type-1 interferon signature appears to be identical in the two glands and indicates an autoimmune response against dsRNA, possibly a virus. Here, we attempt to put these findings into perspective and determine how they can impact the design of future therapeutic protocols.

A Temporal Comparative RNA Transcriptome Profile of the Annexin Gene Family in the Salivary versus Lacrimal Glands of the Sjögren's Syndrome-Susceptible C57BL/6.NOD-Aec1Aec2 Mouse.

A generally accepted hypothesis for the initial activation of an immune or autoimmune response argues that alarmins are released from injured, dying and/or activated immune cells, and these products complex with receptors that activate signal transduction pathways and recruit immune cells to the site of injury where the recruited cells are stimulated to initiate immune and/or cellular repair responses. While there are multiple diverse families of alarmins such as interleukins (IL), heat-shock proteins (HSP), Toll-like receptors (TLR), plus individual molecular entities such as Galectin-3, Calreticulin, Thymosin, alpha-Defensin-1, RAGE, and Interferon-1, one phylogenetically conserved family are the Annexin proteins known to promote an extensive range of biomolecular and cellular products that can directly and indirectly regulate inflammation and immune activities. For the present report, we examined the temporal expression profiles of the 12 mammalian annexin genes (Anxa1-11 and Anxa13), applying our temporal genome-wide transcriptome analyses of ex vivo salivary and lacrimal glands from our C57BL/6.NOD-Aec1Aec2 mouse model of Sjögren's Syndrome (SS), a human autoimmune disease characterized primarily by severe dry mouth and dry eye symptoms. Results indicate that annexin genes Anax1-7 and -11 exhibited upregulated expressions and the initial timing for these upregulations occurred as early as 8 weeks of age and prior to any covert signs of a SS-like disease. While the profiles of the two glands were similar, they were not identical, suggesting the possibility that the SS-like disease may not be uniform in the two glands. Nevertheless, this early pre-clinical and concomitant upregulated expression of this specific set of alarmins within the immune-targeted organs represents a potential target for identifying the pre-clinical stage in human SS as well, a fact that would clearly impact future interventions and therapeutic strategies.

A MZB Cell Activation Profile Present in the Lacrimal Glands of Sjögren's Syndrome-Susceptible C57BL/6.NOD-Aec1Aec2 Mice Defined by Global RNA Transcriptomic Analyses.

The C57BL/6.NOD-Aec1Aec2 mouse has been extensively studied to define the underlying cellular and molecular basis for the onset and development of Sjögren's syndrome (SS), a human systemic autoimmune disease characterized clinically as the loss of normal lacrimal and salivary gland functions leading respectively to dry eye and dry mouth pathologies. While an overwhelming majority of SS studies in both humans and rodent models have long focused primarily on pathophysiological events and the potential role of T lymphocytes in these events, recent studies in our murine models have indicated that marginal zone B (MZB) lymphocytes are critical for both development and onset of SS disease. Although migration and function of MZB cells are difficult to study in vivo and in vitro, we have carried out ex vivo investigations that use temporal global RNA transcriptomic analyses to track early cellular and molecular events in these exocrine glands of C57BL/6.NOD-Aec1Aec2 mice. In the present report, genome-wide transcriptome analyses of lacrimal glands indicate that genes and gene-sets temporally upregulated during early onset of disease define the Notch2/NF-kß14 and Type1 interferon signal transduction pathways, as well as identify chemokines, especially Cxcl13, and Rho-GTPases, including DOCK molecules, in the cellular migration of immune cells to the lacrimal glands. We discuss how the current results compare with our recently published salivary gland data obtained from similar studies carried out in our C57BL/6.NOD-Aec1Aec2 mice, pointing out both similarities and differences in the etiopathogeneses underlying the autoimmune response within the two glands. Overall, this study uses the power of transcriptomic analyses to identify temporal molecular bioprocesses activated during the preclinical covert pathogenic stage(s) of SS disease and how these findings may impact future intervention therapies as the disease within the two exocrine glands may not be identical.

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

Upregulated Chemokine and Rho-GTPase Genes Define Immune Cell Emigration into Salivary Glands of Sjögren's Syndrome-Susceptible C57BL/6.NOD-Aec1Aec2 Mice.

The C57BL/6.NOD-Aec1Aec2 mouse is considered a highly appropriate model of Sjögren's Syndrome (SS), a human systemic autoimmune disease characterized primarily as the loss of lacrimal and salivary gland functions. This mouse model, as well as other mouse models of SS, have shown that B lymphocytes are essential for the development and onset of observed clinical manifestations. More recently, studies carried out in the C57BL/6.IL14α transgenic mouse have indicated that the marginal zone B (MZB) cell population is responsible for development of SS disease, reflecting recent observations that MZB cells are present in the salivary glands of SS patients and most likely initiate the subsequent loss of exocrine functions. Although MZB cells are difficult to study in vivo and in vitro, we have carried out an ex vivo investigation that uses temporal global RNA transcriptomic analyses to profile differentially expressed genes known to be associated with cell migration. Results indicate a temporal upregulation of specific chemokine, chemokine receptor, and Rho-GTPase genes in the salivary glands of C57BL/6.NOD-Aec1Aec2 mice that correlate with the early appearance of periductal lymphocyte infiltrations. Using the power of transcriptomic analyses to better define the genetic profile of lymphocytic emigration into the salivary glands of SS mice, new insights into the underlying mechanisms of SS disease development and onset begin to come into focus, thereby establishing a foundation for further in-depth and novel investigations of the covert and early overt phases of SS disease at the cellular level.

Carnitine Palmitoyl Transferase Deficiency in a University Immunology Practice.

PURPOSE: This report describes the clinical manifestations of 35 patients sent to a University Immunology clinic with a diagnosis of fatigue and exercise intolerance who were identified to have low carnitine palmitoyl transferase activity on muscle biopsies. RECENT FINDINGS: All of the patients presented with fatigue and exercise intolerance and many had been diagnosed with fibromyalgia. Their symptoms responded to treatment of the metabolic disease. Associated symptoms included bloating, diarrhea, constipation, gastrointestinal reflux symptoms, recurrent infections, arthritis, dyspnea, dry eye, visual loss, and hearing loss. Associated medical conditions included Hashimoto thyroiditis, Sjogren's syndrome, seronegative arthritis, food hypersensitivities, asthma, sleep apnea, and vasculitis. This study identifies clinical features that should alert physicians to the possibility of an underlying metabolic disease. Treatment of the metabolic disease leads to symptomatic improvement.

Analysis of novel Sjogren's syndrome autoantibodies in patients with dry eyes.

BACKGROUND: Dry eye is a common problem in Ophthalmology and may occur for many reasons including Sjogren's syndrome (SS). Recent studies have identified autoantibodies, anti-salivary gland protein 1 (SP1), anti-carbonic anhydrase 6 (CA6) and anti-parotid secretory protein (PSP), which occur early in the course of SS. The current studies were designed to evaluate how many patients with idiopathic dry eye and no evidence of systemic diseases from a dry eye practice have these autoantibodies. METHODS: Patients from a dry eye clinic and normal controls were assessed by Schirmer's test for tear flow. Sera were assessed for autoantibodies using ELISA assays. Statistics was performed with Prism 7 software and student's unpaired t test. RESULTS: In this study 60% of the dry eye patients expressed one of these autoantibodies. Only 30% expressed one of the autoantibodies associated with long-standing SS, which are included in the diagnostic criteria for SS, anti-Ro and anti-La. Patients with disease for less than 2 years and mild dry eyes did not express anti-Ro or anti-La, while 25% expressed anti-SP1. Similar observations, with smaller numbers, were made when patients had not only dry eye but also dry mouth. CONCLUSIONS: Antibodies to SP1, CA6 and PSP occur in some patients with idiopathic dry eyes. Further studies will be needed to determine how many of these patients go on to develop systemic manifestations of SS. Testing for these autoantibodies may allow early recognition of patients with SS. This will lead to improved management of the patients and the development of new strategies to maintain normal lacrimal and salivary gland function in patients with SS.

Central role for marginal zone B cells in an animal model of Sjogren's syndrome.

Patients with Sjogren's syndrome (SS) have been shown to have abnormal B cell function and increased numbers of marginal zone B cells (MZB and MZB precursors. The current studies utilized the Interleukin 14 alpha transgenic mouse model (IL14aTG) for SS to investigate the roles of marginal zone B cells (MZB) of the innate immune system in the pathophysiology of the disease. Eliminating MZB from IL14aTG mice by B cell specific deletion of RBP-J resulted in complete elimination of all disease manifestations of SS. Mice had normal salivary gland secretions, negative autoantibodies and normal histology of the salivary and lacrimal glands compared to IL14aTG mice at the same time points. In contrast, eliminating B1 cells by deleting btk did not ameliorate the disease. Therefore, MZB are critical for the development of SS.

Relationship between Inflammation and Aspirin and Clopidogrel Antiplatelet Responses in Acute Ischemic Stroke.

OBJECTIVE: We measured serum levels of proinflammatory/prothrombotic markers P-selectin, CD40L, matrix metalloproteinase 9 (MMP-9), intracellular adhesion molecule 1 (ICAM-1), and interleukin (IL)-6 in ischemic stroke patients, correlating their levels with the results of aspirin (ASA) and clopidogrel antiplatelet responses, using 3 "point of care" platelet function instruments, thromboelastograph (TEG), Accumetrics (ACU), and impedance aggregometer (IMP). METHODS: Patients on chronic ASA regimen at the time of stroke were switched to 300 mg clopidogrel loading dose and 75 mg clopidogrel maintenance dose. Serum levels of the aforementioned inflammatory mediators were measured in 51 patients at baseline (on ASA regimen), and at 26 ± 5 hours and 64 ± 18 hours postclopidogrel administration by enzyme-linked immunosorbent assay. RESULTS: P-selectin, CD40L, and MMP-9 serum levels were reduced; ICAM-1 and IL-6 serum levels showed no difference postclopidogrel administration relative to baseline. Patients' stratification based on ASA dose showed more significant reductions in P-selectin, CD40L, and MMP-9 serum levels postclopidogrel administration in patients who were on baseline 81 mg ASA, as compared to patients on 325 mg ASA. Measurement with TEG was sensitive for correlating ASA antiplatelet responses to serum levels of inflammatory markers, whereas measurements with ACU and IMP were sensitive for correlating clopidogrel antiplatelet responses to serum levels of inflammatory markers. CONCLUSION: Clopidogrel exerts both platelet-dependent and platelet-independent anti-inflammatory effects. The association between platelet function and inflammation depends on the platelet function analyzer, the type of antiplatelet agent, the nature of the inflammatory marker, and the time of measurement relative to the time of drug administration.

Different stages of primary Sjogren's syndrome involving lymphotoxin and type 1 IFN.

Primary Sjögren's syndrome (pSS) is a complex autoimmune disease starting in the salivary and lacrimal glands and continuing to involve the lungs and kidneys with the eventual development of lymphoma. Many studies have emphasized the role of type 1 IFN (IFN-α) and lymphotoxin α (LTα) in the pathogenesis of the disease. The present studies were designed to delineate the role of IFN-α in pSS using an animal model, the IL-14α (IL14αTG) transgenic mouse. IL14αTG mice lacking the type 1 IFNR (IL14αTG.IFNR(-/-)) had the same submandibular gland and lacrimal gland injury as did the IL14αTG mice, but they lacked the later parotid gland and lung injury. Development of lymphoma was delayed in IL14αTG.IFNR(-/-) mice. The switch from IgM to IgG autoantibodies as well as the increase in serum IgG2a seen is IL14αTG mice was inhibited in IL14αTG.IFNR(-/-) mice. Production of LTα was identified in both IL14αTG mice and IL14αTG.IFNR(-/-) mice at the time that salivary gland injury was occurring. These and previous studies suggest a model for pSS that separates the disease into several stages: 1) initial injury to the submandibular and lacrimal glands via an environmental insult and LTα; 2) amplification of local injury via the production of type 1 IFN; injury to the parotid glands, lungs, and kidneys is seen; 3) progression of systemic inflammation with the eventual development of large B cell lymphoma. Understanding these different stages will help to develop strategies for treatment of patients with pSS based on the status of their disease.

Investigation of novel autoantibodies in Sjogren's syndrome utilizing Sera from the Sjogren's international collaborative clinical alliance cohort.

BACKGROUND: Sjogren's syndrome (SS) is a chronic autoimmune disease mainly affecting salivary and lacrimal glands. Current diagnostic criteria for SS utilize anti-Ro and anti-La as serological markers. Animal models for SS have identified novel autoantibodies, anti-salivary gland protein 1 (SP1), anti-carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP). These novel antibodies are seen in the animals at an earlier stage of SS than anti-Ro and anti-La. The current studies were designed to evaluate these novel autoantibodies in the sera of well-characterized patients with dry eyes and dry mouth and lip biopsies from the Sjogren's International Collaborative Clinical Alliance (SICCA) to determine if they indeed identify SS with less severe disease than patients expressing anti-Ro and anti-La. METHODS: Sera were obtained from SICCA registry in patients for whom lymphocytic foci per 4 mm(2) on the lip biopsies was either 0 (F = 0), <1 (F <1) or > 3 (F >3). ELISA assays were utilized to evaluate these sera for anti-Ro, anti-La, anti-SP1, anti-CA6, and anti-PSP. RESULTS: In patients with dry eyes and dry mouth but F = 0, increased expression of anti- CA6 was noted compared to the F <1 group (p = .032) or the F > 3 group (p = .006). Neither anti-PSP nor anti-SP1 reached statistical significance because of the small numbers in the F0 group, although there was a trend for their expression to be higher in the F0 group. On the other hand, the expression of anti-Ro was significantly reduced in the F0 group compared to the F <1 (p = .0021) and F > 3 (p = .0003) groups. The reduced expression of anti-La in the F0 group compared to the F <1 and F > 3 groups did not quite reach statistical significance. CONCLUSIONS: Anti-Ro and anti-La identify patients with SS and more severe disease than anti-SP1, anti-CA6, and anti-PSP. More studies are needed to identify the timing in the course of SS when these different autoantibodies are expressed and/or whether they are expressed in patients with different clinical manifestations.

Evaluation of salivary gland protein 1 antibodies in patients with primary and secondary Sjogren's syndrome.

Sjogren's syndrome (SS) has been associated with the expression of anti-Ro and anti-La antibodies. Anti-salivary gland protein 1 (SP1) antibodies have recently been identified in patients with SS. The current work involved a cross sectional study to determine whether anti-SP1 antibodies were identified in particular subgroups of patients with SS. The results of this study revealed that anti-SP1 antibodies were present in the sera of 52% of SS patients while anti-Ro/anti-La was present in 63% of patients. 19% of patients had anti-SP1 without anti-Ro/anti-La. Patients with SS and lymphoma expressed anti-Ro, anti-La and anti-SP1 together. In SS associated with RA, 50% had antibodies anti-SP1 while 40% had anti-Ro/anti-La. In conclusion, anti-SP1 antibodies are commonly seen in both primary and secondary SS and rarely in normal controls. Future studies are needed to determine the roles and timing of expression of anti-SP1 antibodies in Sjogren's syndrome.

Association of Systemic Markers of Inflammation with Signs and Symptoms of Dry Eye Disease and Sjogren's Syndrome in the Dry Eye Assessment and Management (DREAM©) Study.

PURPOSE: To evaluate the possible role of systemic inflammation in dry eye disease (DED) via systemic inflammatory marker associations with DED signs and symptoms, and an analysis of a subgroup with Sjogren's Syndrome (SS). METHODS: Participant serums were analyzed using line immunoassays (LIAs) for the presence of antibodies against 34 systemic inflammatory markers. Using the 2012 American College of Rheumatology definition, the 481 participants were categorized into group 1 (SS; n = 52), group 2 (autoimmune disease not including SS; n = 66), or group 3 (control, i.e. no autoimmune disease; n = 363). RESULTS: 3 markers were positive in ≥10% of participants: Ro52 (19.3%), Scl-70 (15.0%), CN-1A (14.2%). 2 markers were positively associated with symptoms: PM-Scl100 (p = 0.02), Sm (p = 0.009). 5 markers were positively associated with signs: U2SnRNP A', Ro52, La, DNA, Ro60. SS participants showed significantly higher positivity for 4 markers compared to participants with no autoimmune disease: PL-7 (p = 0.02), Ro52 (p < 0.0001), La (p < 0.0001), Ro60 (p < 0.0001). SS participants showed significantly higher positivity for 3 markers compared to participants with another autoimmune disease: Ro52 (p < 0.0001), La (p = 0.002), Ro60 (p < 0.0001). CONCLUSIONS: This study did not show evidence of significant systemic inflammation in participants with moderate-to-severe DED, based on the markers tested. PM-Scl100 and Sm may be associated with more severe DED symptoms. U2SnRNP A', Ro52, La, DNA, and Ro60 may be associated with more severe ocular surface disease. Ro52 and PL-7 may be diagnostic markers for SS. Future research evaluating these relationships and their clinical significance is needed.

Temporal histological changes in lacrimal and major salivary glands in mouse models of Sjogren's syndrome.

BACKGROUND: Evidence in imaging studies suggests that there may be differences in glandular involvement in Sjogren's syndrome (SS) depending on the stage of the disease. No detailed histological studies are available to show if there are any such difference in glandular involvement at various time periods and stages of SS. This cross sectional study examines the inflammatory changes in mouse models of SS at various ages. METHODS: The histological changes in major salivary and lacrimal glands were studied at ages of 3, 6, 9, 12, 15 and 18 months in both sexes in well characterized mouse models of SS, non-obese diabetes mouse and Interleukin-14 alpha-transgenic mice. RESULTS: Our results indicate that early inflammation concurrently occur in submandibular and lacrimal glands around the age of 6 weeks. Parotid glands are involved much later in the course of SS with less severe inflammation. Sublingual glands are rarely involved. CONCLUSIONS: Our conclusions are that SS may be an organ specific disease with early inflammation occurring in submandibular and lacrimal glands, followed by the parotid. Non organ specific events occur in later courses of the disease. The understanding of the disease progression is important in tailoring early local therapeutic interventions before complete destruction of salivary and lacrimal glands.

Metformin-induced activation of Ca2+ signaling prevents immune infiltration/pathology in Sjogren's syndrome-prone mouse models.

Immune cell infiltration and glandular dysfunction are the hallmarks of autoimmune diseases such as primary Sjogren's syndrome (pSS), however, the mechanism(s) is unknown. Our data show that metformin-treatment induces Ca2+ signaling that restores saliva secretion and prevents immune cell infiltration in the salivary glands of IL14α-transgenic mice (IL14α), which is a model for pSS. Mechanistically, we show that loss of Ca2+ signaling is a major contributing factor, which is restored by metformin treatment, in IL14α mice. Furthermore, the loss of Ca2+ signaling leads to ER stress in salivary glands. Finally, restoration of metformin-induced Ca2+ signaling inhibited the release of alarmins and prevented the activation of ER stress that was essential for immune cell infiltration. These results suggest that loss of metformin-mediated activation of Ca2+ signaling prevents ER stress, which inhibited the release of alarmins that induces immune cell infiltration leading to salivary gland dysfunction observed in pSS.

Targeting alarmin release reverses Sjogren's syndrome phenotype by revitalizing Ca2+ signalling.

BACKGROUND: Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS. METHODS: Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real-time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS. RESULTS: We provide evidence that loss of Ca2+ signaling precedes a decrease in saliva secretion and/or immune cell infiltration in IL14α, a mouse model for pSS. We also showed that Ca2+ homeostasis was mediated by transient receptor potential canonical-1 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration/release of pro-inflammatory cytokines. In addition, both IL14α and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14α restored Ca2+ homeostasis that inhibited alarmin release thereby reverting the pSS phenotype. CONCLUSIONS: These results indicate that loss of Ca2+ signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca2+ signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS.

Novel autoantibodies in Sjogren's syndrome.

Sjogren's syndrome (SS) is defined by autoantibodies to Ro and La. The current studies identified additional autoantibodies in SS to salivary gland protein 1 (SP-1), carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP). These autoantibodies were present in two animal models for SS and occurred earlier in the course of the disease than antibodies to Ro or La. Patients with SS also produced antibodies to SP-1, CA6 and PSP. These antibodies were found in 45% of patients meeting the criteria for SS who lacked antibodies to Ro or La. Furthermore, in patients with idiopathic xerostomia and xerophthalmia for less than 2 years, 76% had antibodies to SP-1 and/or CA6 while only 31% had antibodies to Ro or La. Antibodies to SP-1, CA6 and PSP may be useful markers for identifying patients with SS at early stages of the disease or those that lack antibodies to either Ro or La.

A role for lymphotoxin in primary Sjogren's disease.

The etiology of salivary gland injury in primary Sjögren's disease is not well understood. We have previously described a mouse model of Sjögren's disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sjögren's disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA(-/-) mice, the IL14αTG.LTA(-/-) mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA(-/-) mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA(-/-) mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjögren's disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sjögren's disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjögren's disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.