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Utility of lymphocyte phenotype profile to differentiate primary Sjögren syndrome from Sicca syndrome
Abstract
Background:
blood B cell profile has been proposed to have diagnostic utility in primary Sjögren syndrome (pSS), but the potential utility of advanced lymphocyte profiling to differentiate between pSS and Sicca syndrome has not been fully investigated.
Methods:
distribution of peripheral lymphocyte subpopulations was analysed by flow cytometry in 68 patients with pSS, 26 patients with Sicca syndrome and 23 healthy controls. The ability to discriminate between pSS and Sicca syndrome was analysed using the area under the curve (AUC) of the receiver operating characteristic curve of the different lymphocyte subsets.
Results:
the ratio between naïve/memory B cell proportions showed an AUC of 0.742 to differentiate pSS and Sicca syndrome, with a sensitivity of 76.6% and a specificity of 72% for a cut-off value of 3.4. The ratio of non-switched memory B cells to activated CD4+ T cells percentage (BNSM/CD4ACT) presented the highest AUC (0.840) with a sensitivity of 83.3% and specificity of 81.7% for a cut-off value < 4.1. To differentiate seronegative pSS patients from Sicca patients the BNSM/CD4ACT ratio exhibited an AUC of 0.742 (sensitivity 75%, specificity 66.7%, cut-off value < 4.4), and the number of naïve CD4 T cells had an AUC of 0.821 (sensitivity 76.9%, specificity 88.9%, cut-off value < 312/mm3).
Conclusion:
patients with pSS show a profound imbalance in the distribution of circulating T and B lymphocytes subsets. The ratio BNSM/CD4ACT is useful to discriminate between pSS and Sicca syndrome.
... T-cells are crucial in SjS pathogenesis 4 , and a recent study that assessed the utility of lymphocyte phenotype profile to differentiate SjS from sicca syndrome focused on these cells 22 . However, to our knowledge, no study has been made regarding their use as a biomarker in SjS classification criteria. ...
Sjögren's Syndrome (SjS) is a chronic systemic immune-mediated inflammatory disease characterized by lymphocytic infiltration and consequent lesion of exocrine glands. SjS diagnosis and classification remains a challenge, especially at SjS onset, when patients may have milder phenotypes of the disease or uncommon presentations. New biomarkers are needed for the classification of SjS, thus, we aimed to evaluate the added-value of lymphocyte subpopulations in discriminating SjS and non-Sjögren Sicca patients. Lymphocyte subsets from 62 SjS and 63 Sicca patients were characterized by flow cytometry. The 2002 AECG and the 2016 ACR/EULAR SjS classification criteria were compared with clinical diagnosis. The added discriminative ability of joining lymphocytic populations to classification criteria was assessed by the area under the Receiver-Operating-Characteristic Curve (AUC). Considering clinical diagnosis as the gold-standard, we obtained an AUC = 0.952 (95% CI: 0.916–0.989) for AECG and an AUC = 0.921 (95% CI: 0.875–0.966) for ACR/EULAR criteria. Adding Tfh and Bm1 subsets to AECG criteria, performance increased, attaining an AUC = 0.985 (95% CI: 0.968–1.000) (p = 0.021). Th1/Breg-like CD24hiCD27⁺ and switched-memory B-cells maximized the AUC of ACR/EULAR criteria to 0.953 (95% CI: 0.916–0.990) (p = 0.043). Our exploratory study supports the potential use of lymphocyte subpopulations, such as unswitched memory B cells, to improve the performance of classification criteria, since their discriminative ability increases when specific subsets are added to the criteria.
... Loureiro-Amigo et al. used advanced lymphocyte profiling confirming a profound imbalance in the distribution of circulating T-and B-cells, with a decrease in CD4 + T-cells (mainly naïve and central memory CD4 subsets), diminished CD4/8 ratio and memory cells and an increase in activated T cells and naive B-cells in pSS. Moreover, they showed a good accuracy of the ratio between non-switched memory B-cells to activated CD4 + T-cells in discriminating between pSS and sicca syndrome also in seronegative patients (30 (35) showed that the combination of upregulated salivary TRIM29 levels and anti-SSA positivity allowed to differentiate pSS patients from non-pSS patients with a sensitivity around 99%. ...
Primary Sjögren's syndrome (pSS) is a complex disabling systemic autoimmune disorder. The hallmark of pSS is the T-cell-mediated hyperactivation of B-cells, evolving from asymptomatic conditions to systemic complications and lymphoma development. On tissue level, the typical feature is the lymphocytic infiltration of the salivary gland by B-, T- and antigen presenting cells, as mirrored by the diagnostic cornerstone role of minor salivary gland (MSG) biopsy. B-cells show multiple possible roles in disease pathogenesis, from autoantibody production, to antigen presentation, and cytokine production. B-cells hyperactivation is supported by genetic risk factors, T-cell dependent and independent mechanisms, and the presence of different pathogenic B-cell subsets must be reminded.Many aspects have been investigated in the last year regarding genetic and epigenetics, B- and T-cell role in pSS pathogenesis, their interaction with salivary gland epithelial cells (SGECs) and in their direct or indirect use as biomarkers and predictors of disease development, activity, and lymphomagenesis.In this review, following the others of this series, we will summarise the most recent literature on pSS pathogenesis and clinical features focusing in particular on new insights into pSS molecular stratification and therapeutic advances in the era of precision medicine.
... SjS patients share a series of symptoms with patients affected by Sicca syndrome, a SG disease characterised by dryness in absence of the hallmark antibody profile and aberrant B cell activation typical of SjS. Importantly, whilst often presenting a diffuse T cell infiltrate in the SG, patients with Sicca syndrome do not form TLS 41 . We used single cell analysis applied to 6 Sicca syndrome SG and ...
The key role of tertiary lymphoid structures in autoimmune and non-autoimmune conditions has been recently appreciated. While many of the molecular mechanisms involved in tertiary lymphoid structure (TLS) formation have been identified, their cellular sources and their temporal and spatial relationship to each other during the development of TLS remain unknown. Here we have constructed a cellular and functional map of key components involved in the formation of TLS in the minor salivary glands (SG) in humans. We have confirmed the presence of an immunofibroblast cell state and identified an undescribed immunopericyte cell state with potential immunological functions within TLS. The identification of TLS cellular and functional properties and their relevant modulators provided by this analysis provides key therapeutic cues for TLS associated conditions in autoimmunity and cancer.
... Sudzius et al. found no signi cant difference in the levels of IFNγ + Th1, IL-4 + Th2, and IL-17A + Th17 cells in the peripheral blood of patients with pSS [37] , while Kohriyama et al. found that the levels of IFN-γ + Th1 cells decreased and that those of IL-4 + Th2 cells were not signi cantly different [38] . A recent study reported that the levels of Th1 cells increased, those of Th2 cells decreased, while those of Th17 cells and Tregs were not signi cantly different [39] . Yao and Sudzius showed that the number of Th17 cells increased and that of Tregs decreased [26,40] . ...
Background: Primary Sjögren's syndrome (pSS) is an autoimmune disease that leads to the destruction of exocrine glands and formation of multisystem lesions. Abnormal proliferation, apoptosis, and differentiation of CD4 ⁺ T cells are key factors in the pathogenesis of pSS, seriously affecting the appearance, progression, and outcome of the disease. Human umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-Exos) may effectively simulate the immunoregulatory and tissue repair functions of MSCs while avoiding the risks associated with MSCs treatment. Hence, UCMSC-Exos treatment is expected to become a new treatment for pSS. However, if UCMSC-Exos can regulate the abnormal proliferation, apoptosis, and differentiation of CD4 ⁺ T cells in pSS and the specific underlying mechanisms remain to be elucidated. Methods: UCMSC-Exos were isolated and identified. Peripheral blood CD4 ⁺ T-cells were sorted using immunomagnetic beads. The proliferation, apoptosis, differentiation, and inflammatory factors of CD4 ⁺ T cells were determined using flow cytometry. Autophagosomes of CD4 ⁺ T cells were detected using transmission electron microscopy, autophagy-related proteins were detected using western blotting, and autophagy-related genes were detected using RT-PCR. Results: UCMSC-Exos inhibited excessive proliferation of peripheral blood CD4 ⁺ T cells in pSS patients, blocked the G0/G1 phase transition, inhibited S phase cells, suppressed excessive apoptosis of CD4 ⁺ T cells, reduced the Th17 cell ratio, elevated the regulatory T cell (Treg) ratio, restored the Th1/Th2 and Th17/Treg balance, inhibited the CD4 ⁺ T cell-associated pro-inflammatory factors IFN-γ, TNF-α, IL-6, IL-17A, and IL-17F secretion, and promoted anti-inflammatory factor IL-10 and TGF-β secretion. UCMSC-Exos reduced the elevated autophagy levels in the peripheral blood CD4 ⁺ T cells of patients with pSS. Furthermore, UCMSC-Exos regulated CD4 ⁺ T cell proliferation and early apoptosis in pSS patients through the autophagy pathway, inhibited Th17 cell differentiation, promoted Treg cell differentiation, and restored the Th17/Treg balance. Conclusions: UCMSC-Exos regulate CD4 ⁺ T cell proliferation, apoptosis, and differentiation in patients with pSS through the autophagy pathway and exhibit immunoregulatory effects. These results provide an important theoretical and experimental foundation for exploring UCMSC-Exos as a new treatment for pSS and its application in clinical transformation.
Background
Primary Sjögren's syndrome (pSS) is an autoimmune disease that leads to the destruction of exocrine glands and multisystem lesions. Abnormal proliferation, apoptosis, and differentiation of CD4⁺ T cells are key factors in the pathogenesis of pSS. Autophagy is one of the important mechanisms to maintain immune homeostasis and function of CD4⁺ T cells. Human umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-Exos) may simulate the immunoregulation of MSCs while avoiding the risks of MSCs treatment. However, whether UCMSC-Exos can regulate the functions of CD4⁺ T cells in pSS, and whether the effects via the autophagy pathway remains unclear.
Methods
The study analyzed retrospectively the peripheral blood lymphocyte subsets in pSS patients, and explored the relationship between lymphocyte subsets and disease activity. Next, peripheral blood CD4⁺ T cells were sorted using immunomagnetic beads. The proliferation, apoptosis, differentiation, and inflammatory factors of CD4⁺ T cells were determined using flow cytometry. Autophagosomes of CD4⁺ T cells were detected using transmission electron microscopy, autophagy-related proteins and genes were detected using western blotting or RT-qPCR.
Results
The study demonstrated that the peripheral blood CD4⁺ T cells decreased in pSS patients, and negatively correlated with disease activity. UCMSC-Exos inhibited excessive proliferation and apoptosis of CD4⁺ T cells in pSS patients, blocked them in the G0/G1 phase, inhibited them from entering the S phase, reduced the Th17 cell ratio, elevated the Treg ratio, inhibited IFN-γ, TNF-α, IL-6, IL-17A, and IL-17F secretion, and promoted IL-10 and TGF-β secretion. UCMSC-Exos reduced the elevated autophagy levels in the peripheral blood CD4⁺ T cells of patients with pSS. Furthermore, UCMSC-Exos regulated CD4⁺ T cell proliferation and early apoptosis, inhibited Th17 cell differentiation, promoted Treg cell differentiation, and restored the Th17/Treg balance in pSS patients through the autophagy pathway.
Conclusions
The study indicated that UCMSC-Exos exerts an immunomodulatory effect on the CD4⁺ T cells, and maybe as a new treatment for pSS.
Objective
Sjögren’s disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjD Ro+ ) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised.
Methods
Whole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjD Ro− ); n=27 Ro/SSA positive (SjD Ro+ ) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log 2 fold change ≥2 or ≤0.5; p adj <0.05) were used to predict lncRNA function. LINC01871 was characterised by RNA-seq analyses of HSB-2 cells with CRISPR-targeted LINC01871 deletion ( LINC01871 −/ ⁻ ) and in vitro stimulation assays.
Results
Whole blood RNA-seq revealed autoantibody-specific transcription profiles and disproportionate downregulation of DE transcripts in SjD cases relative to HCs. Sixteen DE lncRNAs exhibited correlated expression with the interferon (IFN)-regulated gene, RSAD2 , in SjD Ro+ (r≥0.65 or ≤−0.6); four antisense lncRNAs exhibited IFN-regulated expression in immune cell lines. LINC01871 was upregulated in all SjD cases. RNA-seq and pathway analyses of LINC01871 −/ ⁻ cells implicated roles in cytotoxic function, differentiation and IFNγ induction. LINC01871 was induced by IFNγ in a myeloid cell line and regulated by calcineurin/NFAT pathway and T cell receptor (TCR) signalling in primary human T cells.
Conclusion
LINC01871 influences expression of many immune cell genes and growth factors, is IFNγ inducible, and regulated by calcineurin signalling and TCR ligand engagement. Altered LINC01871 expression may influence the dysregulated T cell inflammatory pathways implicated in SjD.
Background
Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease of the exocrine glands characterized by specific pathological features. Previous studies have pointed out that salivary glands from pSS patients express a unique profile of cytokines, adhesion molecules, and chemokines compared to those from healthy controls. However, there is limited evidence supporting the utility of individual markers for different stages of pSS. This study aimed to explore potential biomarkers associated with pSS disease progression and analyze the associations between key genes and immune cells.
Methods
We combined our own RNA sequencing data with pSS datasets from the NCBI Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) via bioinformatics analysis. Salivary gland biopsies were collected from 14 pSS patients, 6 non-pSS patients, and 6 controls. Histochemical staining and transmission electron micrographs (TEM) were performed to macroscopically and microscopically characterize morphological features of labial salivary glands in different disease stages. Then, we performed quantitative PCR to validate hub genes. Finally, we analyzed correlations between selected hub genes and immune cells using the CIBERSORT algorithm.
Results
We identified twenty-eight DEGs that were upregulated in pSS patients compared to healthy controls. These were mainly involved in immune-related pathways and infection-related pathways. According to the morphological features of minor salivary glands, severe interlobular and periductal lymphocytic infiltrates, acinar atrophy and collagen in the interstitium, nuclear shrinkage, and microscopic organelle swelling were observed with pSS disease progression. Hub genes based on above twenty-eight DEGs, including MS4A1, CD19, TCL1A, CCL19, CXCL9, CD3G, and CD3D, were selected as potential biomarkers and verified by RT-PCR. Expression of these genes was correlated with T follicular helper cells, memory B cells and M1 macrophages.
Conclusion
Using transcriptome sequencing and bioinformatics analysis combined with our clinical data, we identified seven key genes that have potential value for evaluating pSS severity.
Systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and primary Sjögrens syndrome (pSS) are clinically distinct systemic autoimmune diseases (SADs) that share molecular pathways. We quantified the frequency of circulating immune‐cells in 169 patients with these SADs and 44 healty controls (HC) using mass‐cytometry and assessed the diagnostic value of these results. Alterations in the frequency of immune‐cell subsets were present in all SADs compared to HC. Most alterations, including a decrease of CD56hi NK‐cells in SSc and IgM+ Bcells in pSS, were disease specific; only a reduced frequency of plasmacytoid dendritic cells was common between all SADs Strikingly, hierarchical clustering of SSc patients identified 4 clusters associated with different clinical phenotypes, and9 of the 12 cell subset‐alterations in SSc were also present during the preclinical‐phase of the disease. Additionally, we found a strong association between the use of prednisone and alterations in Bcell subsets. Although differences in immune‐cell frequencies between these SADs are apparent, the discriminative value thereof is too low for diagnostic purposes. Within each disease, mass cytometry analyses revealed distinct patterns between endophenotypes. Given the lack of tools enabling early diagnosis of SSc, our results justify further research into the value of cellular phenotyping as a diagnostic aid. This article is protected by copyright. All rights reserved
B-cells play a pivotal role in primary Sjögren’s syndrome (pSS) pathogenesis. We aim to (1) evaluate the distribution of B-lymphocyte subpopulations in pSS and Sicca patients, (2) establish cut-off points that discriminate pSS from controls, (3) evaluate the association between memory B-cells and phenotypic features in pSS. We included 57 pSS patients, 68 Sicca and 24 healthy controls. Circulating B-cells were characterized by flow cytometry as naïve and memory subsets and classified from Bm1 to Bm5. Compared to controls, pSS patients had lower percentages (29.5 vs 44.4%) and absolute numbers (47 vs 106 cells/µl) of memory B-cells. Through ROC curves, a cut-off of ≤ 58 total memory B-cells/µl yielded a specificity of 0.88 and a sensitivity of 0.60 for pSS, and was met by 59.6% of pSS patients, 38.8% of Sicca and 12.5% of controls. A cut-off of < 23.5 Switched-memory B-cells/µl yielded a specificity of 0.88 and a sensitivity of 0.54 and was met by 54.4% of pSS patients, 37.3% of Sicca and 12.5% of controls. In pSS, lower total memory B-cells count was associated with longer disease duration (14.3 vs 8.1 years, p = 0.006) and more active disease profile, as evaluated by the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) (3.1 vs 1.4, p = 0.043). Decreased numbers of memory B-cells clearly discriminated pSS from controls and can also have prognostic value. It remains to be clarified whether Sicca patients with decreased memory B-cells represent pSS and if B-cell profiling could help in the diagnosis of pSS.
Objective:
To develop and validate an international set of classification criteria for primary Sjögren's syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS.
Methods:
We assigned preliminary importance weights to a consensus list of candidate criteria items, using multi-criteria decision analysis. We tested and adapted the resulting draft criteria using existing cohort data on primary SS cases and non-SS controls, with case/non-case status derived from expert clinical judgment. We then validated the performance of the classification criteria in a separate cohort of patients.
Results:
The final classification criteria are based on the weighted sum of 5 items: anti-SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm(2) , each scoring 3; an abnormal ocular staining score of ≥5 (or van Bijsterveld score of ≥4), a Schirmer's test result of ≤5 mm/5 minutes, and an unstimulated salivary flow rate of ≤0.1 ml/minute, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS. Sensitivity and specificity against clinician-expert-derived case/non-case status in the final validation cohort were high, i.e., 96% (95% confidence interval [95% CI] 92-98%) and 95% (95% CI 92-97%), respectively.
Conclusion:
Using methodology consistent with other recent ACR/EULAR-approved classification criteria, we developed a single set of data-driven consensus classification criteria for primary SS, which performed well in validation analyses and are well-suited as criteria for enrollment in clinical trials.
Objective
. Th17 cells have been demonstrated to play an important role in the onset and development of primary Sjögren’s syndrome (pSS). In this study, we evaluated the expansion and clinical significance of circulating CD4+CD161+ T cell and its “effector” (CD4+CD25−CD161+ T cell) and “regulatory” (CD4+CD25+CD161+ T cell) subpopulations.
Methods
. Fifty-eight pSS patients and 16 healthy controls (HCs) were recruited in our study. The cell populations and intracellular IL-17 expression were analyzed by flow cytometry. The disease activity was evaluated by the EULAR-SS Disease Activity Index (ESSDAI). Autoantibodies were measured by ELISA or indirect immunofluorescence assay.
Results
. The CD161+ T cell fractions showed higher proportions of IL-17-producing cells. The frequencies of the overall CD4+CD161+ T cell population and its effector subset were positively correlated with disease activity parameters and more severe disease manifestations. A significant elevation of the CD4+CD25+CD161+ T cell subpopulation was observed in the peripheral blood of pSS patients compared to HCs and this subset showed decreased regulatory functions compared with the CD4+CD25+CD161− population.
Conclusion
. Circulating CD4+CD161+ T cell populations associated with pSS disease activity and severity. These cells might be involved in the development of pSS and could be potential therapeutic targets in the treatment of pSS.
Follicular T helper (TFH) cells have a crucial role in regulating immune responses within secondary lymphoid follicles by directing B cell differentiation toward memory B cells and plasma cells. Since abnormal humoral responses are key features in both primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE), the aim of this study was to profile the pathological connection between peripheral TFH cells and B cells in the two diseases. Twenty-five pSS patients, 25 SLE patients and 21 healthy controls were enrolled in the study. We determined the ratio of circulating TFH-like cells, their IL-21 production, and different B cell subsets by flow cytometry. We observed higher percentages of naive B cells in both diseases, while non-switched and switched memory B cells showed decreased frequencies. The proportions of double-negative B cells and plasmablasts were elevated in SLE and decreased in pSS. The percentages of transitional B cells and mature-naive B cells were higher in SLE. Patients with more severe disease course had elevated ratio of TFH-like cells and increased IL-21 production. Moreover, expansion of TFH-like cells correlated positively with parameters related to antibody secretion, including serum IgG, ICs and autoantibodies. Correlation analysis between TFH-like cells and certain B cell subsets revealed possible defects during B cell selection. In conclusion, our observations on the profound expansion of circulating TFH-like cells and their IL-21 production along with the characteristic aberrant peripheral B cell distribution in both pSS and SLE indicate the prominent role of TFH cell in the regulation of B cell selection. This article is protected by copyright. All rights reserved.
Purpose of this study was to evaluate the lymphocyte populations’ distribution changes in peripheral blood of patients with primary Sjögren’s syndrome (pSS). Lymphocyte populations’ distribution changes in peripheral blood of pSS patients were investigated in 52 patients with pSS and in 28 healthy controls by flow cytometry. We found decreased absolute count of CD3+ T cell population in pSS patients. Analysis of CD4+ T cell population showed significant proportion and absolute count differences in pSS patient’s blood with SSA/SSB antibodies (Abs) in comparison to controls. No significant differences were observed analyzing CD4+ and CD8+ Treg subpopulation. Proportion and absolute counts of Th17 cells were significantly lower in pSS patient’s blood. Absolute counts of CD8+ T cells were significantly lower in pSS patients in comparison to controls and also impaired proportion and absolute counts of CD8+ subpopulations according to CD27+ and CD57+ were observed. Absolute counts of NKT and NK cells were decreased in pSS with Abs. B cells proportion was increased only in blood of pSS with Abs. Lymphocyte distribution impairment can be due to genetically determined lymphopenia or lymphocyte migration from periphery to inflammatory sites or/and increased susceptibility to apoptosis.
Historically, primary Sjögren’s syndrome (pSS) was thought to be a T helper (h) 1 driven disease due to the predominance of CD4+T lymphocytes and their products in target organs and peripheral blood of patients. In the last decades, the identification of a number of T cell subsets, including Th17, T regulatory (Treg), and follicular helper T cells, challenged this long-standing paradigm and prompted to identify their role in pSS pathogenesis. In addition the impact of abnormal proinflammatory cytokine production, such as IL-6, IL-17, IL-22, and IL-23, has also attracted considerable attention. However, although several studies have been carried out in experimental models and patients with pSS, many aspects concerning the role of Treg cells and IL-17/Th17 cell system in pSS pathogenesis are not fully elucidated. In particular, the role played by different IL-17-producing T cell subsets as well as the effects of pharmacological therapies on Treg/Th17 cell balance represents an intriguing issue. The aim of this review article is to provide an overview of current knowledge on Treg cells and IL-17-producing T cells in pSS pathogenesis. We believe that these insights into pSS pathogenesis may provide the basis for successful therapeutic intervention in this disease.
Sjögren's syndrome (SS) is an autoimmune disease characterised by breach of self-tolerance towards nuclear antigens resulting in high affinity circulating autoantibodies. Although peripheral B cell disturbances have been described in SS, with predominance of naïve and reduction of memory B cells, the stage at which errors in B cell tolerance checkpoints accumulate in SS is unknown. Here we determined the frequency of self- and poly-reactive B cells in the circulating naïve and memory compartment of SS patients. Single CD27-IgD+ naïve, CD27+IgD+ memory unswitched and CD27+IgD- memory switched B cells were sorted by FACS from the peripheral blood of 7 SS patients. To detect the frequency of polyreactive and autoreactive clones, paired Ig VH and VL genes were amplified, cloned and expressed as recombinant monoclonal antibodies (rmAbs) displaying identical specificity of the original B cells. IgVH and VL gene usage and immunoreactivity of SS rmAbs were compared with those obtained from healthy donors (HD). From a total of 353 VH and 293 VL individual sequences, we obtained 114 rmAbs from circulating naïve (n = 66) and memory (n = 48) B cells of SS patients. Analysis of the Ig V gene repertoire did not show significant differences in SS vs. HD B cells. In SS patients, circulating naïve B cells (with germline VH and VL genes) displayed a significant accumulation of clones autoreactive against Hep-2 cells compared to HD (43.1% vs. 25%). Moreover, we demonstrated a progressive increase in the frequency of circulating anti-nuclear naïve (9.3%), memory unswitched (22.2%) and memory switched (27.3%) B cells in SS patients. Overall, these data provide novel evidence supporting the existence of both early and late defects in B cell tolerance checkpoints in patients with SS resulting in the accumulation of autoreactive naïve and memory B cells.
The aims of this study were to evaluate the diagnostic accuracy of blood B-cell subset profiling and immune-system activation marker assays in primary Sjogren's syndrome (pSS) and to assess whether adding these tools to the current laboratory item would improve the American-European Consensus Group (AECG) criteria.
In a single-center cohort of patients with suspected pSS, we tested the diagnostic performance of anti-SSA, antinuclear antibody (ANA), rheumatoid factor (RF), gammaglobulins, IgG titers, and B-cell ratio defined as (Bm2 + Bm2[prime])/(eBm5 + Bm5), determined using flow cytometry. The reference standard was a clinical diagnosis of pSS established by a panel of experts.
Of 181 patients included in the study, 77 had pSS. By logistic regression analysis, only ANA >=1:640 (sensitivity, 70.4%; specificity 83.2%) and B-cell ratio >=5 (sensitivity, 52.1%; specificity, 83.2%) showed independent associations with pSS, of similar strength. In anti-SSA-negative patients, presence of either of these two criteria had 71.0% sensitivity but only 67.3% specificity for pSS; whereas combining both criteria had 96.2% specificity but only 12.9% sensitivity. Adding either of these two criteria to the AECG criteria set increased sensitivity from 83.1% to 90.9% but decreased specificity from 97.1% to 85.6%, whereas adding both criteria in combination did not substantially modify the diagnostic performance of the criteria set. The adjunction of RF + ANA >= 1:320, as proposed in the new American College of Rheumatology (ACR) criteria, did not improve the diagnostic value of anti-SSA.
Blood B-cell subset profiling is a simple test that has good diagnostic properties for pSS. However, adding this test, with or without ANA positivity, does not improve current classification criteria.
The heterogeneity in the healthy human immune system, and the immunological changes that portend various diseases, have been only partially described. Their comprehensive elucidation has been termed the 'Human Immunology Project'. The accurate measurement of variations in the human immune system requires precise and standardized assays to distinguish true biological changes from technical artefacts. Thus, to be successful, the Human Immunology Project will require standardized assays for immunophenotyping humans in health and disease. A major tool in this effort is flow cytometry, which remains highly variable with regard to sample handling, reagents, instrument setup and data analysis. In this Review, we outline the current state of standardization of flow cytometry assays and summarize the steps that are required to enable the Human Immunology Project.
Objective:
To develop a disease activity index for patients with primary Sjögren's syndrome (SS): the European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI).
Methods:
Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific 'domains' contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0-10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain.
Results:
All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.001). Compared with 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true.
Conclusions:
The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials.
To evaluate the relevance of the blood B-cell subset profile for the diagnosis of Sjögren syndrome.
The distribution of mature blood B cells from Bm1 through Bm5 was determined in 161 patients, of whom 25 fulfilled the American-European Consensus Group criteria for primary SS (pSS), and 136 served as disease controls.
The percentage of Bm2 and Bm2' cells was increased in the patients with pSS compared with 54 patients with rheumatoid arthritis (RA) and 18 with systemic lupus erythematosus (SLE) (p<0.001 for the two comparisons). In contrast, those of early Bm5 (eBm5) and Bm5 were decreased in patients with pSS, compared with patients with RA and with SLE (p<0.001 for the two comparisons). The receiver operating characteristic curves allowed for an optimising cut-off value of Bm2+Bm2' cells at 71.1% for 88.0% sensitivity and 83.1% specificity, that of eBm5+Bm5 cells at < or =13.5% for 84.0% sensitivity and 83.1% specificity, and, consequently, that of Bm2+Bm2'/eBm5+Bm5 at > or =5 for 88.0% sensitivity and 84.6% specificity.
Given its presentation as a signature for pSS, relative to RA and SLE, such a distribution of B-cell subsets might provide a useful diagnostic tool.
Analyses of B cells in the bone marrow and secondary lymphoid tissues have revealed a broad range of cell surface markers defining B cell subpopulations, but only a few of these have been used to analyze B cell subpopulations in peripheral blood (PB). We report here the delineation of circulating PB B cell subpopulations by staining for CD19, CD38, and IgD in combination with CD10, CD44, CD77, CD95, CD23, IgM, and the B cell memory marker CD27. The utility of this approach is shown by the demonstration of disturbances of circulating B cell subpopulations in patients with autoimmune disease. Five mature B cell (Bm) subpopulations were identified in normal PB that were comparable with the tonsillar Bm1, Bm2, early Bm5, Bm5 subpopulations and, surprisingly, to the germinal center (GC) founder cell subpopulation (Bm2' and Bm3delta-4delta), suggesting that some GC founder cells are circulating. No PB B cells resembled the Bm3 and Bm4 GC cells. Remarkably, some cells with the CD38-IgD+ phenotype, previously known as naive Bm1 cells, expressed CD27. The CD38-IgD+ subpopulation therefore includes both naive Bm1 cells and IgD+ memory B cells. This new classification of B cell developmental stages reveals disturbances in the proportions of B cell subpopulations in primary Sjögren's syndrome (pSS) patients compared with healthy donors and rheumatoid arthritis patients. Patients with pSS contained a significantly higher percentage of B cells in two activated stages, which might reflect a disturbance in B cell trafficking and/or alteration in B cell differentiation. These findings could be of diagnostic significance for pSS.
Genetic risk factors associated with primary Sjögren syndrome (pSS) can promote B cell activation, as can epigenetic changes, which can sometimes affect the same disease-associated genes.
BAFF (also known as TNF ligand superfamily member 13B) is central to the crosstalk between early activation of the innate immune system and the stimulation of autoreactive B cells.
CD27⁺ memory B cells, marginal zone B cells, plasmablasts and plasma cells are the key subsets of B cells involved in the pathogenesis of pSS.
Target organs (salivary and lachrymal glands) are involved in B cell activation, notably via the formation of germinal centre-like structures within the epithelium and plasma cell niches.
Continuous stimulation of autoreactive B cells by immune complexes is the first step towards lymphomagenesis associated with pSS.
Continuously activated autoreactive B cells need to be tightly controlled by genetic factors and by the tissue microenvironment as subtle defects in these controls might promote clonal escape and lymphomagenesis.
An accurate dissection of peripheral blood enumeration is lacking in primary Sjögren's syndrome. The purpose of this study was to quantify different leukocyte populations in peripheral blood of patients with pSS. Numbers of specific leukocyte subsets were determined in 86 pSS patients and 74 healthy donors quantifying 21 distinct subtypes by flow cytometry. Subgroups of pSS patients were stratified based on presence of extraglandular manifestations (EGM) and SSA/SSB autoantibodies. Overall, pSS patients manifested decreased lymphocyte subpopulations compared to healthy donors. Such decreases were more pronounced in SSA/SSB positive patients and patients with EGM. Granulocyte and monocyte subpopulations were increased in pSS patients compared to healthy donors, with the greatest increases in SSA/SSB positive patients. Unsupervised hierarchal clustering based on cell quantities was used to further subgroup the pSS patients into four clusters. One of the clusters characterized by higher concentrations of NKT cells, CD56hi NK cells, CD20+CD38- B cells and CD8+CD38- T cells was associated with weaker clinical symptoms than the other clusters, possibly marking a milder disease phenotype. In conclusion, our analyses indicate significant alterations in the cellular profiles of peripheral blood leukocytes in patients with pSS and may help to stratify the patients according to disease severity.
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease, characterized by B cell hyperactivity and pathogenic autoantibodies formation. The objective of this study is to evaluate the distribution of B cell subsets in patients with SLE. We included patients with SLE followed in First Affiliated Hospital of Xi’an JiaoTong University, Xi’an, China. Flow cytometry was used to measure frequencies of B cell subsets, including memory B cells, switched memory B cells, non-switched memory B cells, double-negative memory B cells, and naïve B cells in 130 patients with SLE and 55 healthy controls. The different distributions of B cell subsets were further evaluated by their associations with disease activity and clinical manifestation. SLE patients showed significant alteration of B cell subsets, including lower frequency of non-switched memory B cells and higher double-negative memory B cells. The frequencies of B cell subsets also varied between new-onset SLE patients and chronic SLE patients. Frequencies of total memory B cells, switched memory B cells, and non-switched memory B cells were lower in new-onset SLE patients and frequency of naïve B cells was higher compared with healthy controls. Chronic SLE patients showed increased switched memory B cells and double-negative memory B cells. In addition, switched memory B cells and double-negative B cells were higher in patients with lupus nephritis (LN) regardless of disease activity. Our findings suggested that abnormalities of the B cell subsets homeostasis might contribute to the pathogenesis of SLE.
Sjögren's syndrome (SS) is a chronic autoimmune disease with broad clinical spectrum, extending from benign exocrinopathy to severe systemic disease and lymphoma development. The glandular and extraglandular dysfunction of SS is associated with lymphocytic infiltrates that invade the epithelial structures of affected organs. The in-depth study of autoimmune lesions in the minor salivary glands (MSG), which are the major target-organ of SS responses, revealed that the lymphocytic infiltrates vary in severity and composition among SS-patients, are full-blown at diagnosis and remain unchanged thereafter. Although the pathogenetic pathways underlying SS have not yet elucidated, it is well-established that glandular epithelial cells are central regulators of local autoimmune responses. Moreover, chronic inflammation affects epithelial function and phenotype, which strengthens or weakens their immunoregulatory/secretory function, leading to deterioration of autoimmune phenomena. Herein, the current findings regarding the autoimmune lesions, the role of epithelial cells and their interaction with infiltrating lymphocytic cells are discussed.
Background:
Mass cytometry has recently emerged as a promising tool for clinical research. However, few studies have demonstrated its benefit for patient stratification and biomarker identification. Primary Sjögren's syndrome (pSS) is a prototype of chronic autoimmune disease, the pathogenesis of which remains unclear and for which treatment does not exist.
Objective:
This observational case-control study was designed to discover new cellular biomarkers and therapeutic targets in patients with pSS.
Methods:
Forty-nine patients with pSS and 45 control subjects were enrolled for clinical evaluation and mass cytometry quantification of 34 protein markers in blood. For a third of these subjects, matched labial salivary gland biopsy specimens were also analyzed by mass cytometry and immunohistochemistry.
Results:
In salivary gland biopsy specimens from patients with pSS, we identified a high number of activated CD8(+) T cells, terminally differentiated plasma cells, and activated epithelial cells, pointing to new pathogenic mechanisms for future clinical intervention. In blood, we identified a 6-cell disease signature defined by decreased numbers of CD4 and memory B lymphocytes, decreased plasmacytoid dendritic cell numbers, and increased representation of activated CD4 and CD8 T cells and plasmablasts. These blood cellular components correlated with clinical parameters and, when taken together, clustered patients into subsets with distinct disease activity and glandular inflammation.
Conclusion:
This first application of mass cytometry to a well-stratified clinical cohort and small biopsy tissues establishes the benefits of such an approach for the discovery of new biomarkers and therapeutic targets. Similar high-dimensional immunophenotyping strategies could be implemented in longitudinal and interventional clinical settings in this and other disease areas.
Objective To develop and validate ClinESSDAI (Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index), ie, ESSDAI without the biological domain.
Patients and methods The 702 fictive vignettes derived from 96 real cases of primary Sjögren's syndrome of the ESSDAI development study were used. As for ESSDAI development, the physician assessment of disease activity (0–10 scale) was used as the ‘gold standard’ in a multivariate model for weighting domains, after removing the biological domain. The reliability, assessed by intraclass correlation coefficient (ICC) between ClinESSDAI and ESSDAI, explored if ClinESSDAI was equivalent to ESSDAI. Its psychometric (ie, measurement) properties were compared with that of ESSDAI in an independent cohort. Also, its use was evaluated on data of two clinical trials.
Results In multivariate modelling, all 11 domains remained significantly associated with disease activity, with slight modifications of some domain weights. Reliability between clinESSDAI and ESSDAI was excellent (ICC=0.98 and 0.99). Psychometric properties of clinESSDAI, disease activity levels and minimal clinically important improvement thresholds and its ability to detect change over time in clinical trials were very close to that of ESSDAI.
Conclusions ClinESSDAI appears valid and very close to the original ESSDAI. This score provides an accurate evaluation of disease activity independent of B-cell biomarkers. It could be used in various circumstances: (i) in biological/clinical studies to avoid data collinearity, (ii) in clinical trials, as secondary endpoint, to detect change independent of biological effect of the drug, (iii) in clinical practice to assess disease activity for visits where immunological tests have not been done.
To score systemic activity at diagnosis and correlate baseline activity with survival in a large cohort of patients with primary Sjögren syndrome (SS).
We include 1045 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of activity (EULAR-SS Disease Activity Index (ESSDAI) scores) were assessed at diagnosis as predictors of death using Cox proportional hazards regression analysis adjusted for age at diagnosis. The risk of death was calculated at diagnosis according to four different predictive models.
After a mean follow-up of 117 months, 115 (11%) patients died. The adjusted standardised mortality ratio for the total cohort was 4.66 (95% CI 3.85 to 5.60), and survival rates at 5, 10, 20 and 30 years were 96%, 90%, 81% and 60%, respectively. The main baseline factors associated with overall mortality in the multivariate analysis were male gender, cryoglobulins and low C4 levels. Baseline activity in the constitutional, pulmonary and biological domains was associated with a higher risk of death. High activity in at least one ESSDAI domain (HR 2.14), a baseline ESSDAI score ≥14 (HR 1.85) and more than one laboratory predictive marker (lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4 and/or cryoglobulins) (HR 2.82) were associated with overall mortality; these HRs increased threefold to 10-fold when the analysis was restricted to mortality associated with systemic disease.
Patients with primary SS, who present at diagnosis with high systemic activity (ESSDAI ≥14) and/or predictive immunological markers (especially those with more than one), are at higher risk of death.
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Primary Sjögren Syndrome (pSS) is an autoimmune disease associated with an increased risk of lymphoma. Lymphomas complicating pSS are mostly low-grade B cell non-Hodgkin lymphomas, predominantly of marginal zone histological type. Mucosal localization is predominant, notably mucosa-associated lymphoid tissue lymphomas. Lymphomas often develop in organs where pSS is active, such as salivary glands. Germinal centre (GC)-like structures, high TNFSF13B (BAFF) and Flt3-ligand (FLT3LG) levels and genetic impairment of TNFAIP3 are new predictors of lymphoma development. These new findings allow a better understanding of the pathogenic mechanisms leading to lymphoma. We propose the following scenario: auto-immune B cells with rheumatoid factor (RF) activity are continuously stimulated by immune complexes containing antibodies against more specific auto-antigens, such as SSA/Ro, SSB/La or others. Germline abnormality of TNFAIP3 leads to a decreased control of the NF-kB pathway and thus promotes survival of B cells and oncogenic mutations especially in GC structure. Moreover, B cells are stimulated by a positive loop of activation induced by BAFF secretion. Thus, lymphomagenesis associated with pSS exemplifies the development of antigen-driven B-cell lymphoma. The control of disease activity by a well-targeted immunosuppressor is the primary objective of the management of the patient in order to repress chronic B cell stimulation.
Objective:
Epidemiological studies of primary Sjögren's syndrome (pSS) are crucial for describing the burden to society and the public medical system and for shedding light on aetiology. Previous reports of the epidemiology of pSS show variable outcomes. We conducted a systematic review of the epidemiology of pSS to assess the prevalence rates (PRs) and incidence rates (IRs), and to investigate possible geographic variations in pSS.
Methods:
A systematic literature search of PubMed and Embase (updated to 22 October 2013) was performed to identify all published reports on the epidemiology of pSS. The incidence and prevalence rates of pSS were summarised with IRs or PRs and 95% CIs.
Results:
The literature search yielded 1880 related citations. Only 21 fulfilled the inclusion criteria. According to a random-effects model, the pooled IR for pSS was 6.92 (95% CI 4.98 to 8.86) per 100 000 person-years. The overall PR was 60.82 (95% CI 43.69 to 77.94) cases per 100 000 inhabitants with a slightly lower estimate of Baodong Qin is BDQ, Jiaqi Wang is JQW, Zaixing Yang is ZXY, Renqian Zhong is RQZ. 43.03 (25.74 to 60.31) cases per 100 000 inhabitants when only considering population-based studies. The female/male ratio in incidence data was 9.15 (95% CI 3.35 to 13.18). The female/male ratio in prevalence data was 10.72 (95% CI 7.35 to 15.62). The overall age of pSS patients was 56.16 years (95% CI 52.54 to 59.78).
Conclusions:
Incidence and prevalence rates of pSS vary widely around the world. The results help us better understand the global epidemiology of pSS. Large population-based studies combining meticulous case-finding and case-ascertainment strategies are needed.
Objective:
The significance of distinct B cell abnormalities in primary Sjögren's syndrome (SS) remains to be established. We undertook this study to analyze the phenotype and messenger RNA (mRNA) transcript profiles of B cell subsets in patients with primary SS and to compare them with those in sicca syndrome patients and healthy controls.
Methods:
CD19+ B cells from 26 patients with primary SS, 27 sicca syndrome patients, and 22 healthy controls were analyzed by flow cytometry. Gene expression profiles of purified B cell subsets (from 3-5 subjects per group per test) were analyzed using Affymetrix gene arrays.
Results:
Patients with primary SS had lower frequencies of CD27+IgD- switched memory B cells and CD27+IgD+ unswitched memory B cells compared with healthy controls. Unswitched memory B cell frequencies were also lower in sicca syndrome patients and correlated inversely with serologic hyperactivity in both disease states. Further, unswitched memory B cells in primary SS had lower expression of CD1c and CD21. Gene expression analysis of CD27+ memory B cells separated patients with primary SS from healthy controls and identified a subgroup of sicca syndrome patients with a primary SS-like transcript profile. Moreover, unswitched memory B cell gene expression analysis identified 187 genes differentially expressed between patients with primary SS and healthy controls.
Conclusion:
A decrease in unswitched memory B cells with serologic hyperactivity is characteristic of both established primary SS and a subgroup of sicca syndrome, which suggests the value of these B cells both as biomarkers of future disease progression and for understanding disease pathogenesis. Overall, the mRNA transcript analysis of unswitched memory B cells suggests that their activation in primary SS takes place through innate immune pathways in the context of attenuated antigen-mediated adaptive signaling. Thus, our findings provide important insight into the mechanisms and potential consequences of decreased unswitched memory B cells in primary SS.
Objective:
To evaluate systemic involvement in primary SS in a large cohort of Spanish patients using the EULAR-SS disease activity index (ESSDAI) definitions.
Methods:
Systemic involvement was characterized using ESSDAI definitions for the 10 clinical domains (constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, peripheral nervous system, central nervous system and muscular). ESSDAI scores at diagnosis, during follow-up and cumulated at the last visit were calculated.
Results:
The cohort consisted of 921 patients. After a mean follow-up of 75 months, 77 (8%) patients still had an ESSDAI score of zero at the last visit. Organ by organ, the percentage of patients who developed activity during the follow-up (ESSDAI score ≥ 1 at any time) ranged between 1.4% and 56%, with articular, pulmonary and peripheral neurological involvement being the most common. Logistic multivariate regression analysis showed the following features at diagnosis and had the closest association with systemic activity (statistically significant independent variables in at least two domains): cryoglobulinaemia in five domains; anaemia, lymphopenia and low C3 levels in three domains each and age <35 years in two domains. Sicca features, ANA and RF at diagnosis were not associated with a higher cumulated activity score in any clinical domain.
Conclusion:
Primary SS is undeniably a systemic disease, with the joints, lungs, skin and peripheral nerves being the most frequently involved organs. Cytopenias, hypocomplementaemia and cryoglobulinaemia at diagnosis strongly correlated with higher cumulated ESSDAI scores in the clinical domains. Clinically the ESSDAI provides a reliable picture of systemic involvement in primary SS.
To study the clinical and laboratory profile evolution, as well as morbidity and mortality impact, of primary Sjögren's syndrome (pSS), in a large cohort of patients followed-up longitudinally.
We studied the evolution of the clinical picture and laboratory profile of pSS, the incidence and predictors for systemic sequelae, and the impact of pSS on overall survival in a prospective cohort study of 261 patients with pSS. Analyses included calculation of incidence rates, Cox proportional hazards predictive models, and estimation of standardized mortality ratios (SMRs) compared with the general Greek population, adjusting for age and sex.
Glandular manifestations of the syndrome were typically present at the time of diagnosis. Systemic manifestations such as arthritis, Raynaud's phenomenon, purpura, interstitial nephritis, and liver involvement, as well as the serological profile, also did not change substantially during subsequent follow-up. Incidence rates for peripheral neuropathy, glomerulonephritis, and lymphoproliferative disorders were 3.3, 6.6, and 12.2 per 1,000 person-years, respectively. Glomerulonephritis and lymphoma tended to co-exist in the same patients (relative risk, 34.0; P < .0001). The development of lymphoproliferative disorders was associated with low levels of C4 complement (relative risk, 7.5; P = .0016), the presence of mixed monoclonal cryoglobulins (relative risk, 7.9; P = .0012), and purpura (relative risk, 3.9; P = .037). Low levels of C4 was the strongest predictor for mortality after adjusting for age (relative risk, 6.5; P =.0041). Patients with pSS had an SMR of 2.07 (95% CI, 1.03 to 3.71). However, when patients with adverse predictors were excluded, the mortality rate was identical to that of the general population (SMR 1.02).
The initial presentation of pSS determines subsequent outcome. Purpura, decreased C4 complement levels, and mixed monoclonal cryoglobulinemia are adverse prognostic factors. The overall mortality of patients with pSS compared with the general population is increased only in patients with adverse predictors.
Sjogren's syndrome (SS) is characterized by infiltration of exocrine glands with T and B lymphocytes, leading to glandular dysfunction and frequently accompanied by hypergammaglobulinemia and autoantibodies. The role of T cells, which predominate in the lesions, has attracted much interest. CD4 T cells seem to be responding to autoantigens on apoptotic cells, such as the Ro and La antigens, or to the cytoskeletal antigen α-fodrin. Physical injury to ocular surfaces may also lead to T cell mediated responses to self antigens and perpetuate disease. Within the salivary glands, T cell responsiveness is further promoted by the special capacity of salivary epithelial tissue to provide costimulation and enhanced antigen presentation. Cytokines are key mediators of the T cell contribution to pathology, with roles attributed both to Th1 and Th2 cells. Recently, striking data implicate Th17 cells in the stimulation of B cells, and a role for the related cytokine IL-21 produced by follicular T helper cells is now appreciated. Dysfunction of T regulatory cells has been shown to have a role in the exuberant production of cytokines by Th17 cells. Beyond their role in provoking B cell hyperactivity and immunoglobulin secretion, T cells are directly involved in destruction of glands through Fas and perforin-mediated cytotoxicity. Animal models of SS have confirmed the role of T cell derived cytokines in disease and support a role for effector-memory cells in pathogenesis. Further elucidation of the role of T cells will open avenues for better treatment of SS, whose current management is still mainly supportive.
Objectives:To study the clinical and laboratory profile evolution, as well as morbidity and mortality impact, of primary Sjögren's syndrome (pSS), in a large cohort of patients followed-up longitudinally.Methods:We studied the evolution of the clinical picture and laboratory profile of pSS, the incidence and predictors for systemic sequelae, and the impact of pSS on overall survival in a prospective cohort study of 261 patients with pSS. Analyses included calculation of incidence rates, Cox proportional hazards predictive models, and estimation of standardized mortality ratios (SMRs) compared with the general Greek population, adjusting for age and sex.Results:Glandular manifestations of the syndrome were typically present at the time of diagnosis. Systemic manifestations such as arthritis, Raynaud's phenomenon, purpura, interstitial nephritis, and liver involvement, as well as the serological profile, also did not change substantially during subsequent follow-up. Incidence rates for peripheral neuropathy, glomerulonephritis, and lymphoproliferative disorders were 3.3, 6.6, and 12.2 per 1,000 person-years, respectively. Glomerulonephritis and lymphoma tended to co-exist in the same patients (relative risk, 34.0; P < .0001). The development of lymphoproliferative disorders was associated with low levels of C4 complement (relative risk, 7.5; P = .0016), the presence of mixed monoclonal cryoglobulins (relative risk, 7.9; P = .0012), and purpura (relative risk, 3.9; P = .037). Low levels of C4 was the strongest predictor for mortality after adjusting for age (relative risk, 6.5; P = .0041). Patients with pSS had an SMR of 2.07 (95% Cl, 1.03 to 3.71). However, when patients with adverse predictors were excluded, the mortality rate was identical to that of the general population (SMR 1.02).Conclusions:The initial presentation of pSS determines subsequent outcome.Purpura, decreased C4 complement levels, and mixed monoclonal cryoglobulinemia are adverse prognostic factors. The overall mortality of patients with pSS compared with the general population is increased only in patients with adverse predictors.
Sjögren's syndrome (SS) is a chronic autoimmune exocrinopathy associated with variable degree of lymphocytic infiltration of the affected organs (primarily salivary and lacrimal glands) and broad clinical manifestations. Minor salivary gland (MSG) lesions mainly consist of T and B cells, while antigen-presenting cells have been reported in heavy infiltrates. Evidence suggests that the infiltrate composition differs according to lesion severity; however, these differences are not well-defined. To investigate the differential distribution of the major infiltrating mononuclear cell (MNC) types in SS-lesions of variable severity, total-T, CD4+-T, CD8+-T, Treg, and B cell, macrophage (MΦ), interdigitating (iDC) and follicular dendritic cell (fDC), and natural-killer (NK)-cell incidence (%-total infiltrating MNC) was analyzed in MSG biopsies with mild (n = 11), intermediate (n = 13) or severe (n = 15) lesions. T cells, CD4+-T cells and Tregs, B lymphocytes, MΦs and iDCs were significantly different among MSG tissues with mild, intermediate or severe inflammatory lesions, while CD8+-T cell, fDC and NK cell incidence was not correlated with lesion severity. T cell, CD4+-T cell, T/B cell ratio and iDC incidence was negatively, whereas B cell and MΦ incidence was positively correlated with infiltration grade and biopsy focus score. Tregs predominated in intermediate lesions. Multivariate analysis revealed several associations between the incidence of each infiltrating MNC-type and disease manifestations, implying an involvement of local immune responses in systemic disease features. Our findings support that the distribution of infiltrating MNCs at the SS-lesions varies according to lesion severity and correlates with disease manifestations. The significance of this differential distribution and the underlying aetiopathogenic factors need to be elucidated.
Sjögren's syndrome (SS) or autoimmune epithelitis is a prototype autoimmune disorder with unique features: a broad clinical spectrum that extends from local exocrinopathy to systemic disease and lymphoma development, and an easy access to the inflamed tissues (minor salivary glands; MSG), which enables the investigators to study the autoimmune processes. The autoimmune lesion consists of lymphocytic infiltrates that develop around the ducts and vary in severity and composition. T cells (mainly CD4(+)) are the dominant lymphocytes in mild MSG lesions, whereas B cells in severe ones. Th1 cytokines predominate in SS infiltrates, albeit Th2 and Th17 responses have been also reported. Notably, increased infiltration by IL-18(+) cells has been associated with parotid gland enlargement and C4-hypocomplementemia, which are adverse prognostic factors for lymphoma development. Even though SS pathogenesis has not been fully revealed, several aspects have been delineated. Among them, the key role of MSG epithelia in the initiation and perpetuation of local autoimmune responses is well-established and involves the capacity of epithelial cells to mediate the recruitment, homing, activation, proliferation and differentiation of immunocytes. In addition, genetic features, including certain HLA phenotypes and polymorphisms in genes encoding cytokines or factors implicated in cytokine signaling, environmental (such as viruses) and hormonal factors are thought to participate in disease pathogenesis. Herein, the known aspects of SS pathogenesis, as well as unmet issues are discussed.
To assess the risk and predictors of lymphoma development in a large cohort of patients with primary Sjögren's syndrome (pSS).
Cox-regression analyses were used to study the predictive value of clinical and laboratory findings at pSS diagnosis, and Kaplan-Meier survival curves to compare survival probability between patients who developed lymphoma and the total cohort. Expected risk for lymphoma was calculated by comparison with the background population.
Eleven (4.5%) from 244 patients developed a non-Hodgkin lymphoma (NHL). Diffuse large B-cell and mucosa-associated lymphoid tissue lymphomas occurred at a similar frequency. Three (27.3%) patients died: 2 due to transformation from mucosa-associated lymphoid tissue to diffuse large B-cell. Purpura (HR 8.04, 95% confidence interval [CI] 2.33-27.67), parotidomegaly (HR 6.75, 95%CI 1.89-23.99), anemia (HR 3.43, 95%CI 1.04-11.35), leukopenia (HR 8.70, 95%CI 2.38-31.82), lymphocytopenia (HR 16.47, 95%CI 3.45-78.67), hypergammaglobulinemia (HR 4.06, 95%CI 1.06-15.58), low C3 (HR 36.65, 95%CI 10.65-126.18), and low C4 (HR 39.70, 95%CI 8.85-126.18) levels at pSS diagnosis were significant predictors of NHL development, but only hypocomplementemia and lymphocytopenia were independent risk factors. Hypocomplementemia was related to earlier development of NHL and higher mortality. The cumulative risk of developing lymphoma ranged from 3.4% in the first 5 years to 9.8% at 15 years. Standardized incidence ratio (95%CI) for NHL development was 15.6 (95%CI 8.7-28.2).
Patients with pSS have a 16-fold increased risk of developing lymphoma. This risk increases with time. Hypocomplementemia and lymphocytopenia at pSS diagnosis are the strongest predictors. Survival is clearly reduced in patients with hypocomplementemia. Indolent lymphomas tend to evolve over time toward a more aggressive histologic type.
To develop a score for assessment of patients' symptoms in primary Sjögren's syndrome (SS): the EULAR SS Patient Reported Index (ESSPRI).
Dryness, pain, somatic and mental fatigue were identified as the main symptoms of patients with primary SS, in studies developing the Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptoms Inventory (SSI). It was suspected that a single 0-10 numerical scale for each domain was sufficient to assess these symptoms. These four scales were gathered to form the ESSPRI. 230 patients, from 12 countries completed the ESSPRI, SSI and PROFAD questionnaires and a 0-10 patient global assessment (PGA). Correlations between each symptom and PGA were obtained. Multiple regression modelling, using PGA as 'gold standard' was used to select domains and estimate their weights.
PGA had good correlation with dryness, limb pain, fatigue and mental fatigue (r=0.49-0.59, all p<0.0001), but correlated less well with individual dryness features. In multivariate analysis, dryness, limb pain and fatigue, but not mental fatigue, were significantly associated with PGA; weights derived from the regression were identical for these three domains. Thus, ESSPRI was redefined as the mean of the three scales: dryness, limb pain and fatigue. Lastly, ESSPRI significantly correlated with PGA (r=0.70), PROFAD (r=0.73) and SSI (r=0.66).
ESSPRI is a very simple index designed to measure patients' symptoms in primary SS. It has good construct validity and is well correlated with SSI and PROFAD. ESSPRI should now be validated for use as an outcome measure in clinical trials.
To compare health-related quality of life (HR-QOL), employment and disability of primary and secondary SS (pSS and sSS, respectively) patients with the general Dutch population.
HR-QOL, employment and disability were assessed in SS patients regularly attending the University Medical Center Groningen (n = 235). HR-QOL, employment and disability were evaluated with the Short Form-36 questionnaire (SF-36) and an employment and disability questionnaire. Results were compared with Dutch population data (matched for sex and age). Demographical and clinical data associated with HR-QOL, employment and disability were assessed.
Response rate was 83%. SS patients scored lower on HR-QOL than the general Dutch population. sSS patients scored lower on physical functioning, bodily pain and general health than pSS patients. Predictors for reduced HR-QOL were fatigue, tendomyalgia, articular involvement, use of artificial saliva, use of anti-depressants, comorbidity, male sex and eligibility for disability compensation (DC). Employment was lower and DC rates were higher in SS patients compared with the Dutch population.
SS has a large impact on HR-QOL, employment and disability.
To clarify the pathological role of the apoptosis-related molecules expressed on peripheral blood (PB) lymphocyte subsets in primary Sjögren's syndrome (SS).
The levels of apoptosis-regulating proteins, Fas and bcl-2, were determined in the PB lymphocyte subsets from 21 patients with SS and 14 healthy controls by 2-color flow cytometry.
In the PB from SS patients, lymphocytopenia, especially CD4+ cell-lymphocytopenia, was prominent. As observed in previous studies, the percentages of CD4+ CD45RA+ cells were lower in the SS patients than in the controls, while activated (DR+) cells were increased in CD4+ cells from the patients. Fas+ cells were also increased in the patients' CD4+ cells and CD8+ cells, but not in their B cells or natural killer cells. Furthermore, we observed several positive correlations among the percentages of activated cells (DR+ cells or CD45RA-cells) and Fas+ cells recognized in the CD4+ and/or CD8+ cells from the patients. On the other hand, intra-cellular bcl-2 proteins measured as mean fluorescence intensity were significantly diminished in the CD4+ cells, CD8+ cells, CD19+ cells, CD45RO+ cells and Fas+ cells from 14 SS patients compared with 12 healthy controls. In addition, the numbers and/or percentages of CD4+ cells and Fas+ cells positively correlated with their expression of bcl-2 in SS patients.
The abnormal balance between Fas and bcl-2 expression detected in the PB lymphocyte subsets from SS patients relates, at least partially, to the lymphocytopenia observed in the patients.
Primary Sjögren's syndrome (1 degree SS) is an autoimmune disease, usually accompanied by manifest immune hyperactivity. In some cases the disease converts to malignant neoplasia. On the other hand, there are clinical similarities to HIV infection. Since the rare phenomenon of persistent depletion of CD4+ T-lymphocytes in peripheral blood without HIV infection was recently defined as idiopathic CD4+ T-lymphocytopenia (ICL), we have used the ICL criteria to investigate the prevalence of this phenomenon among 1 degree SS patients.
During the period 1988-94, 115 caucasian patients (10 males), mean age 57.8 (range 19-82) years, with 1 degree SS were prospectively studied. Lymphocyte subsets were investigated by means of monoclonal antibodies and flow cytometry. For the detection of HIV and HTLV antibodies, we used an enzyme immunoassay (for HIV-1 and HIV-2), Western blot techniques (HIV-1, HIV-2, HTLV-I and HTLV-II), and the polymerase chain reaction procedure (HIV-1, HTLV-I and HTLV-II). HIV antigens were tested for with the HIV-1 p-24 Ag test.
Six patients with 1 degree SS fulfilled the criteria for ICL. While the clinical condition of 5 of those six patients remained stable, one patient developed malignant lymphoma three years after her disease was classified as a case of ICL. The prevalence of ICL among our 115 patients with 1 degree SS was 5.2%, which is significantly higher than the rates reported for any other patient or population group. We have estimated the relative risk of ICL in 1 degree SS patients to vary from 3.4 to 6,000 (P values of 0.0001-0.025).
We suggest that subjects with ICL should be carefully examined for 1 degree SS and, if its presence is confirmed, that they should be followed with regard to the possible complications of this disease, including the development of malignant lymphoma.
To define whether Sjögren's syndrome (SS) patients have lymphocytopenia compared to healthy controls, and to assess which lymphocyte subset might be involved. The presence of any concurrent infection was recorded.
A cohort of ten consecutive patients with SS was studied, and the results were compared with ten sex- and age-matched controls (C).
In SS, a significant cytopenia of CD4+ (679 +/- 339 vs 1110 +/- 222 cells/mm3, p < 0.005) and an even more impressive decrease in the CD4+CD45 RA+ (242 +/- 154 vs 491 +/- 190 cells/mm3, p < 0.005) subset was observed. An absolute CD4 lymphocytopenia (CD4+ < 300 cells/mm3) was seen in two patients. In one patient an unusual finding was the expansion of a double positive population of CD4+CD8+ lymphocytes. No striking relationship with any particular infection was shown. A retrospective review of the absolute CD4+ cytopenia in 54 consecutive SS cases revealed a prevalence of 5.5%.
Some SS patients have T lymphocytopenia which mainly affects the CD4+CD45 RA+ subset. Occasional cases with absolute CD4 lymphocytopenia may also be observed. These patients show some evidence of mild recurrent or chronic, but never severe, opportunistic infections.
To investigate whether a change in the CD95-related apoptosis of T lymphocytes might have a share in the development of the disease in patients with primary Sjögren's syndrome (SS).
Two-color cytometric analysis was used to study the phenotype of freshly separated mononuclear cells, while Western blotting was used to detect CD95 ligand (CD95L) expression in total homogenates of isolated CD4+ T lymphocytes. The ability of various subpopulations of T cells to undergo apoptosis was investigated in 1-day cultures in medium alone or following various (anti-CD3, anti-CD95 monoclonal antibody, calcium ionophore) treatments. Apoptosis was detected using 7-aminoactinomycin D dye.
Compared with the findings in healthy controls, the number of CD4+ T lymphocytes was decreased, while their expression of CD95, HLA-DR, and CD45RO was significantly increased in patients with primary SS. A positive correlation was found between the activity of disease, the decrease in the CD4+ T cell number, and the increase in the expression of CD95, CD95L, HLA-DR, and CD45RO molecules within the CD4+ T cell subset. An increased rate of spontaneous, anti-CD3-, or anti-CD95-induced apoptosis was found in the T cells of SS patients, and this was more pronounced in the CD4+ T cell population, correlated with the decreased CD4+ T cell number, increased CD45RO expression, and activity of disease, and concerned mainly the CD95+ cells.
These observations indicate that the increased susceptibility to apoptosis of peripheral CD4+ T cells from SS patients correlates with disease activity. These findings support the hypothesis that the chronic activation of the immune system that occurs in this autoimmune disease is the primary mechanism responsible for this cell-deletion process.
The percentage of CD27(+) B cells in peripheral blood (PB) of patients with primary Sjögren's syndrome (pSS) is significantly decreased compared to normals. In contrast, serum levels of the soluble form of CD27 (sCD27) are significantly higher in pSS patients, with a strong positive correlation between sCD27 and serum IgG levels. In vitro experiments demonstrate that normal B cells cultured under conditions driving plasma cell differentiation result in the production of substantial amounts of sCD27. Analyses of V(H)-region genes from sorted CD27(+) and CD27(-) B cells from pSS patients confirm that the CD27(+) population corresponds to the somatically mutated memory compartment, as in healthy individuals. Together our data indicate that in pSS, there is an abnormal differentiation of B cells to plasma cells resulting in a depression of the circulating memory B-cell pool and the release of significant amounts of sCD27 and IgG.
Classification criteria for Sjögren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.
To delineate the mechanism of the abnormalities in B cell biology found in patients with primary Sjögren's syndrome (SS).
The distribution of peripheral B cell subpopulations in 21 patients with primary SS was analyzed by immunofluorescence labeling and flow cytometry. Immunoglobulin rearrangements were analyzed in single B cells isolated from the peripheral blood and parotid glands by fluorescence-activated cell sorting.
A significant reduction in the number of peripheral CD27+ memory B cells was found in SS patients, including a significantly reduced number of CD27+/IgD+/IgM+/CD5+ memory B cells. Remarkably, SS patients with secondary lymphoma uniquely exhibited an increase in CD27-expressing peripheral B cells, including CD27(high) plasmablasts. Molecular analysis for mutated Ig gene rearrangements confirmed that CD27 expression distinguished naive and memory cells in SS. In contrast to the peripheral blood, the majority of parotid B cells from 1 patient examined exhibited both the mutational status and phenotype of memory B cells. Accordingly, the mutational frequencies of V(H) rearrangements were significantly greater in parotid B cells than in peripheral blood B cells, whereas the V(H) gene repertoire appeared to be very similar between the compartments.
These data indicate that there is an accumulation/retention of memory B cells in the inflamed salivary glands of SS patients. It is possible that preferential accumulation of CD27+ memory B cells in the inflamed parotid gland explains their reduction in the peripheral blood.
To examine the role of apoptosis in the pathogenesis of Sjögren syndrome (SS), a chronic autoimmune disease characterized by the infiltration of mononuclear cells in the salivary and lacrimal glands, leading to the destruction of the parenchymal tissue.
A detailed search via MEDLINE (PubMed) and Biosis, covering the period from January 1994 to July 2002, was accomplished, combining the key terms SS and apoptosis. A qualitative review of the articles was undertaken and the obtained information was summarized.
Apoptosis of the acinar and ductal epithelial cells of the salivary and lacrimal glands has been proposed as a possible mechanism responsible for the impairment of secretory function. Apoptotic cell death may be induced by either cytotoxic T cells through the release of proteases, such as perforin and granzyme B, or the interaction of Fas ligand (FasL/CD95L), expressed by T lymphocytes, with Fas (Apo-1/CD95) on epithelial cells. The increased rate of apoptosis of epithelial cells in SS may result from either the imbalance between the down-regulated apoptosis-inhibitor Bcl-2 and the up-regulated apoptosis-inducer Bax, or the autocrine and/or paracrine Fas/FasL interaction. Lymphocytes infiltrating the salivary glands are blocked in their ability to commit to apoptosis, despite the expression of the apoptosis-inducer Fas. The expression of Bcl-2 in these cells may explain their resistance to apoptosis, resulting in a prolonged production of proinflammatory cytokines and autoantibodies, as well as in their longer survival that may result in the late development of lymphoma in some SS patients. Studies of the SS-like sialoadenitis of nonobese diabetic (NOD) mice with severe combined immunodeficiency (NOD.scid) suggest that the primary defect responsible for the initiation of SS resides in the epithelial cells that undergo apoptosis mediated by the autocrine Fas/FasL interaction. This first not-immune-mediated phase of target cell destruction is followed by a lymphocyte-dependent autoimmune aggression, which leads to extensive tissue damage and subsequent loss of secretory function. Apoptosis of the salivary epithelial cells has been shown in other animal models of SS and in cell lines in vitro. Apoptosis may also play a role in the pathogenesis of some extraglandular manifestations of SS, such as interstitial nephritis and peripheral CD4(+) lymphocytopenia.
The possible role of apoptosis in SS is suggested from the literature review. A better understanding of the mechanisms responsible for the epithelial cell apoptosis may allow the discovery of new therapeutic strategies. By inhibiting programmed cell death, the glandular damage and the subsequent impairment of the secretory function should be reduced.
Case reports have described an association between idiopathic CD4+ T-lymphocytopenia (ICL) and non-Hodgkin's malignant lymphoma (NHML), and both entities have an increased prevalence in patients with primary Sjögren's syndrome (SS). We investigated lymphocyte subset counts in patients with primary SS to determine if presence of different autoantibodies is associated with ICL and hence may represent an increased risk for development of NHML.
A total of 80 patients with primary SS according to the American-European Consensus Classification Criteria (AECC) and 37 non-AECC sicca patients were studied for presence of different autoantibodies, and lymphocyte subsets were investigated by flow cytometry.
Absolute CD4+ T-lymphocyte counts were significantly lower among anti-SSA antibody seropositive SS patients compared to correlating seronegatives and non-AECC sicca patients (601/microl vs 956/microl and 1087/microl; p < 0.001 and p < 0.001, respectively). ICL was found in 16% of anti-SSA seropositive patients.
ICL, a proposed risk factor for development of NHML, occurs frequently and presumably exclusively in patients with primary SS who are anti-SSA antibody seropositive. These findings support that this group comprises patients at risk for development of NHML.
To delineate disturbances in peripheral B cell memory in primary Sjögren's syndrome (SS).
Isotype-specific immunoglobulin (Ig) heavy-chain transcripts were analyzed in single-sorted CD19+,CD27- naive and CD19+,CD27+ memory B cells from patients with primary SS and normal healthy control subjects.
A significantly higher frequency of B cells expressing mu-, alpha-, and/or gamma-chain transcripts were found in patients with primary SS compared with controls (58.0% versus 14.3%; P < 0.0001). Notably, 30.5% of individual B cells (for primary SS, 38.7%; for controls, 12.7% [P < 0.0001]) simultaneously expressed transcripts for different Ig heavy-chain isotypes using identical V(H)-D-J(H) rearrangements. However, these cells lacked surface expression of more than one of the respective Ig heavy-chain isotypes as well as messenger RNA (mRNA) transcripts for 2 germinal center markers, activation-induced cytidine deaminase, and Bcl-6. In contrast with the findings in normal healthy controls, peripheral B cell memory in patients with primary SS was characterized by 1) circulating CD27+ B cells expressing heavily mutated Ig V(H) transcripts (mutational frequency 8.6% versus 4.3%; P < 0.0001), 2) significantly enhanced mutational frequencies of C mu transcripts (9.6% versus 2.5%; P < 0.0001), 3) a high proportion (61.2%) of CD27+ B cells expressing transcripts for multiple Ig heavy-chain isotypes, and 4) a CD27- memory-type B cell subpopulation expressing mutated C mu transcripts.
Altogether, both B cell hyperactivity and striking abnormalities in peripheral B cell memory are indicated at the single-cell mRNA level in patients with primary SS. Detection of multiple Ig heavy-chain transcripts in peripheral CD19+,CD27+ memory B cells of patients with SS may represent the abnormal retention of pre-switch mRNA transcripts in circulating post-switch B cells.
To assess whether abnormal chemokine receptor expression and/or abnormal responsiveness to the cognate ligands might underlie some of the disturbances in B cell homeostasis characteristic of primary Sjögren's syndrome (SS).
Chemokine receptor expression by CD27- naive and CD27+ memory B cells from patients with primary SS and healthy control subjects was analyzed using flow cytometry, single-cell reverse transcriptase-polymerase chain reaction (RT-PCR), and migration assays.
In contrast to healthy subjects, significantly higher expression of both surface CXCR4 and CXCR4 messenger RNA (mRNA) was seen in peripheral blood B cells from patients with primary SS. These differences were most prominent in CD27- naive B cells (P < or = 0.0006). In addition, significantly higher frequencies of CD27- naive B cells from patients with primary SS expressed mRNA for the inhibitory regulator of G protein signaling 13 (P = 0.001). Expression of CXCR5 by peripheral CD27+ memory B cells was moderately diminished in patients with primary SS compared with healthy controls (P = 0.038). No significant differences were noted in the expression of CXCR3, CCR6, CCR7, and CCR9 between B cells from healthy controls and those from patients with primary SS. Transmigration assays of blood B cells from patients with primary SS and healthy controls showed comparable responses of CD27- naive B cells but significantly diminished responses of activated primary SS CD27+ memory B cells to the ligands of CXCR4 and CXCR5, CXCL12 (P = 0.032), and CXCL13 (B lymphocyte chemoattractant; B cell-attracting chemokine 1; P = 0.018), respectively, when compared with those from healthy controls. Finally, compared with controls, peripheral reduction but glandular accumulation of CXCR4+,CXCR5+,CD27+ memory B cells was identified in patients with primary SS.
In primary SS, overexpression of CXCR4 by circulating blood B cells does not translate into enhanced migratory response to the cognate ligand, CXCL12. This migratory response may be modulated by intracellular regulators. Retention of CXCR4+,CXCR5+, CD27+ memory B cells in the inflamed glands seems to contribute to diminished peripheral CD27+ memory B cells in primary SS.
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2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts
- CH Shiboski
- SC Shiboski
- R Seror
Cytometry by time of flight identifies distinct signatures in patients with systemic sclerosis, systemic lupus erythematosus and Sjögrens syndrome
- M van der Kroef
- LL van den Hoogen
- JS Mertens
Patients with primary Sjögren’s syndrome have alterations in absolute quantities of specific peripheral leucocyte populations
- R Davies
- D Hammenfors
- B Bergum
The risk of lymphoma development in autoimmune diseases: a meta-analysis
- Zintzaras