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1.  Correlation of Increased Blood Levels of GITR and GITRL with Disease Severity in Patients with Primary Sjögren's Syndrome 
Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a type I transmembrane protein belonging to the TNFR superfamily. After activated by its ligand GITRL, GITR could influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases included rheumatoid arthritis and autoimmune thyroid disease. We previously reported that serum GITRL levels are increased in systemic lupus erythematosus (SLE) patients compared with healthy controls (HC). Here, we tested serum soluble GITR (sGITR) and GITRL levels in 41 primary Sjögren's syndrome (pSS) patients and 29 HC by ELISA and correlated sGITR and GITRL levels with clinical and laboratory variables. GITR and GITRL expression in labial salivary glands was detected by immunohistochemistry. pSS patients had significantly increased serum levels of sGITR and GITRL compared with controls (GITR: 5.66 ± 3.56 ng/mL versus 0.50 ± 0.31 ng/mL; P < 0.0001; GITRL: 6.17 ± 7.10 ng/mL versus 0.36 ± 0.28 ng/mL; P < 0.0001). Serum sGITR and GITRL levels were positively correlated with IgG (GITRL: r = 0.6084, P < 0.0001; sGITR: r = 0.6820, P < 0.0001) and ESR (GITRL: r = 0.8315, P < 0.0001; sGITR: r = 0.7448, P < 0.0001). Moreover, GITR and GITRL are readily detected in the lymphocytic foci and periductal areas of the LSGs. In contrast, the LSGs of HC subjects did not express GITR or GITRL. Our findings indicate the possible involvement of GITR-GITRL pathway in the pathogenesis of pSS. Further studies may facilitate the development of targeting this molecule pathway for the treatment of pSS.
PMCID: PMC3722791  PMID: 23935647
2.  Microparticles as biomarkers in autoimmunity: from dust bin to center stage 
Microparticles are small membrane-bound vesicles released from activated and dying cells. As shown in a study of primary Sjogren's syndrome, systemic lupus erythematosus and rheumatoid arthritis, levels of microparticles in the blood, as measured by a solid-phase prothrombinase assay or flow cytometry, are increased with autoimmunity. Among patients with these conditions, however, particle numbers were inversely related to disease activity and levels of the enzyme secretory phospholipase A2 that can digest membrane lipids and perhaps cause particle loss. These findings suggest microparticles as novel biomarkers for autoimmunity, with levels reflecting events leading to their loss as well as production.
PMCID: PMC3003533  PMID: 19954508
3.  Polymerase chain reaction fails to incriminate exogenous retroviruses HTLV-I and HIV-1 in rheumatological diseases although a minority of sera cross react with retroviral antigens. 
Annals of the Rheumatic Diseases  1994;53(11):749-754.
OBJECTIVES--To investigate the presence of antibodies to HTLV and HIV retroviral antigens in the rheumatological diseases rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM), primary Sjögren's syndrome (pSS), and systemic lupus erythematosus (SLE), and to use polymerase chain reaction (PCR) to seek these exogenous retroviruses in proviral form in cellular DNA from these patients. METHODS--Thirty patients with active RA, 13 with PM, 14 with pSS and five with SLE were recruited and their sera tested for antibodies to HTLV-I in enzyme linked immunosorbent assay (ELISA) and Western blot analysis. Seropositivity to HIV-1 was also sought. DNA was extracted from peripheral blood lymphocytes, synovial tissue and muscle biopsies and tested by polymerase chain reaction using consensus primers for HTLV-I and HIV-1. RESULTS--In HTLV-I ELISA, nine rheumatological sera (4/30 RA, 3/13 PM/DM and 2/5 SLE patients) were considered positive; 14 from pSS patients and 30 from normal subjects were negative. In a control group which included osteoarthritis, Crohn's disease and bacterial endocarditis patients, only two of 80 proved positive in this system. Validation of these sera by Western blotting generally revealed weak reactivity against a variety of HTLV-I antigens. PCR of genomic DNA derived from patients' peripheral blood mononuclear cells did not reveal the presence of HTLV-I and HIV-1 target sequences. CONCLUSIONS--This study shows that PCR precludes HTLV-I and HIV-1 infection as causative agents in these rheumatological diseases although a minority of patients possess antibodies that are weakly cross-reactive with retroviral antigens.
PMCID: PMC1005456  PMID: 7826136
4.  Is the blood B-cell subset profile diagnostic for Sjögren syndrome? 
Annals of the Rheumatic Diseases  2008;68(9):1447-1452.
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 ⩽13.5% for 84.0% sensitivity and 83.1% specificity, and, consequently, that of Bm2+Bm2′/eBm5+Bm5 at ⩾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.
PMCID: PMC2719083  PMID: 18782791
5.  Assessment of blood clot formation and platelet receptor function ex vivo in patients with primary Sjögren's syndrome 
BMJ Open  2013;3(5):e002739.
Primary Sjögren's syndrome (pSS) shares clinical features and pathogenetic mechanisms with systemic lupus erythematosus (SLE). SLE is associated with an increased thromboembolic risk; however, it is unclear whether pSS patients are susceptible to thromboembolic diseases. In this study, we examined ex vivo blood clot formation (clot strength, rates of clot formation and lysis) in pSS using thromboelastography (TEG) and platelet aggregation to common agonists using multiple electrode aggregometry (MEA). We also investigated the relationship between TEG/MEA parameters and clinical/laboratory features of pSS.
Case control.
Secondary care, single centre.
34 pSS patients, 11 SLE patients and 13 healthy volunteers (all women) entered and completed the study.
Primary and secondary outcome measures
Primary outcomes: TEG and MEA parameters between three subject groups. Secondary outcomes: The relationships between TEG/MEA and clinical/laboratory parameters analysed using bivariate correlation analysis with corrections for multiple testing.
All TEG and MEA parameters were similar for the three subject groups. After corrections for multiple testing, interleukin (IL)-1α and Macrophage inflammatory proteins (MIP)-1α remain correlated inversely with clot strength (r=−0.686, p=0.024 and r=−0.730, p=0.012, respectively) and overall coagulability (r=−0.640, p=0.048 and r=−0.648, p=0.048). Stepwise regression analysis revealed that several cytokines such as MIP-1α, IL-17a, IL-1α and Interferon (IFN)-γ may be key predictors of clot strength and overall coagulability in pSS.
Clot kinetics and platelet receptor function are normal in pSS. Several cytokines correlate with clot strength and overall coagulability in pSS.
PMCID: PMC3668418  PMID: 23793707
6.  Outcome of pregnancy in patients with autoimmune rheumatic disease before the disease onset. 
Annals of the Rheumatic Diseases  1988;47(12):982-987.
The outcomes of 419 pregnancies of 154 unselected patients with various auto-immune diseases, including 390 pregnancies before the disease onset, were studied retrospectively. The patients comprised 40 with systemic lupus erythematosus (SLE), 72 with rheumatoid arthritis, 21 with primary Sjögren's syndrome (1 degree SS), 14 with progressive systemic sclerosis (PSS), and seven with mixed connective tissue disease. The histories of 267 pregnancies of 98 healthy, age matched women served as controls. Our data indicate that compared with healthy controls autoimmune patients do not experience a higher incidence of fetal loss. The incidence of fetal loss before disease onset in the various groups of autoimmune patients (as well as after disease onset in patients with SLE and RA) was not significantly different from that of controls. Spontaneous abortions in patients with 1 degree SS and PSS before disease onset occurred significantly more frequently (p less than 0.05) than in controls. Nevertheless, it should be noted that this was not the case when the incidence per woman was considered. On the other hand, patients with SLE, both before and after disease onset, experienced a higher incidence of premature deliveries (p less than 0.05). Finally, the analysis of autoantibody profiles, including antibodies to nuclear antigens, to Ro(SSA) cellular antigen, to double stranded DNA, and to cardiolipin, could not demonstrate any association of autoantibodies with any particular pregnancy outcome.
PMCID: PMC1003650  PMID: 3264698
7.  Decreased B cell activating factor receptor expression on peripheral lymphocytes associated with increased disease activity in primary Sjögren's syndrome and systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2006;66(6):790-797.
To analyse B cell activating factor (BAFF) receptor (BAFF‐R) expression on peripheral lymphocytes from patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE).
Patients and methods
Peripheral blood mononuclear cells from 20 patients with pSS, 19 patients with SLE and 15 controls were examined by flow cytometry to investigate BAFF‐R mean fluorescence intensity (MFI) on lymphocytes. BAFF‐R mRNA level from isolated blood B cells of nine patients with pSS and eight controls was assessed by real‐time quantitative reverse transcription‐PCR. BAFF serum level was determined by ELISA.
In all subjects, BAFF‐R was expressed on all naïve CD27− and memory CD27+ B‐cells and was present on <0.5% of T cells. The expression of BAFF‐R on B cells was significantly decreased in patients with pSS as compared with controls (MFI = 7.8 vs 10.6, p = 0.001), and was intermediate in patients with SLE (MFI = 9.5). Serum BAFF level was inversely correlated with BAFF‐R MFI (p = 0.007), but not because of competition between endogenous BAFF (at observed concentrations in patients) and the monoclonal antibody (11C1) detecting BAFF‐R. BAFF‐R mRNA levels did not differ between patients with pSS and controls (p = 0.48). BAFF‐R MFI decreased after overnight culture with recombinant human BAFF (from 32.5 to 25.4, p = 0.03). Contrary to the serum BAFF level, BAFF‐R expression was correlated with extraglandular involvement in pSS and SLE Disease Activity Index.
BAFF‐R expression is reduced on peripheral B cells of patients with pSS and SLE. This down‐regulation occurs through a post‐transcriptional mechanism and could be the consequence of chronic increase in BAFF. BAFF‐R levels on B cells could be a novel activity biomarker in autoimmune diseases.
PMCID: PMC1954659  PMID: 17185325
8.  Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases 
Annals of the Rheumatic Diseases  2004;64(6):913-920.
Objective: To assess the tolerance and efficacy of rituximab in patients with various autoimmune diseases seen in daily rheumatological practice.
Methods: 866 rheumatology and internal medicine practitioners were contacted by email to obtain the files of patients treated with rituximab for systemic autoimmune diseases. Patients with lymphoma were analysed if the evolution of the autoimmune disease could be evaluated.
Results: In all, 43 of 49 cases could be analysed, including 14 with rheumatoid arthritis (RA), 13 with systemic lupus erythematosus (SLE), six with primary Sjögren's syndrome (pSS), five with systemic vasculitis, and five with other autoimmune diseases. Rituximab was prescribed for lymphoma in two patients with RA and two with pSS. In the 39 other cases, rituximab was given because of the refractory character of the autoimmune disease. The mean follow up period was 8.3 months (range 2 to 26). There were 11 adverse events in 10 patients and treatment had to be discontinued in six. Efficacy was observed in 30 patients (70%): RA 11, SLE 9, pSS 5, vasculitis 2, antisynthetase syndromes 2, sarcoidosis 1. The mean decrease in corticosteroid intake was 9.5 mg/d (range 0 to 50) in responders. Seven patients experienced relapse after mean 8.1 months (5 to 15). Three patients died because of refractory autoimmune disease.
Conclusions: Despite absence of marketing authorisation, rituximab is used to treat various refractory autoimmune diseases in daily rheumatological practice. This study showed good tolerance and short term clinical efficacy, with marked corticosteroid reduction in patients with SLE, pSS, vasculitis, and polymyositis.
PMCID: PMC1755517  PMID: 15550531
9.  Preclinical validation of salivary biomarkers for primary Sjögren’s syndrome 
Arthritis care & research  2010;62(11):1633-1638.
Sjögren’s syndrome (SS) is a systemic autoimmune disease with a variety of presenting symptoms which may delay its diagnosis. We previously discovered a number of candidate salivary biomarkers for primary SS (pSS) using both mass spectrometry and expression microarray analysis (Arthritis Rheumatism, 2007;56(11):3588-3600). In this study, we aim to verify these candidate biomarkers in independent patient populations and to evaluate their predictive values for pSS detection.
In total, 34 patients with pSS, 34 patients with systemic lupus erythematosus (SLE) and 34 healthy individuals were enrolled for the validation studies. Salivary protein biomarkers were measured using either Western blotting or ELISA, and the mRNA biomarkers were measured using quantitative polymerase chain reaction (qPCR). Statistical analysis was performed using R2.9.
Three protein biomarkers, cathepsin D, alpha-enolase and beta-2-microglobulin (B2M), and three mRNA biomarkers, myeloid cell nuclear differentiation antigen (MNDA), Guanylate binding protein 2 (GIP2) and low affinity IIIb receptor for the Fc fragment of IgG (FCGR3B), were significantly elevated in patients with pSS compared to both SLE patients and healthy controls. The combination of three protein biomarkers, cathepsin D, alpha-enolase and B2M, yielded a receiver operating characteristic (ROC) value of 0.99 in distinguishing pSS from healthy controls. The combination of protein biomarkers B2M and two mRNA biomarkers, MNDA and GIP2, reached an ROC of 0.95 in discriminating pSS from SLE.
We have successfully verified a panel of protein and mRNA biomarkers that can discriminate pSS from both SLE and healthy controls. If further validated in pSS patients and those with sicca symptoms but no autoimmune disease, these biomarkers may lead to a simple yet highly discriminatory clinical tool for diagnosis of pSS.
PMCID: PMC2995446  PMID: 20617533
10.  Autoantibodies against the Catalytic Domain of BRAF Are Not Specific Serum Markers for Rheumatoid Arthritis 
PLoS ONE  2011;6(12):e28975.
Autoantibodies to the catalytic domain of v-raf murine sarcoma viral oncogene homologue B1 (BRAF) have been recently identified as a new family of autoantibodies involved in rheumatoid arthritis (RA). The objective of this study was to determine antibody responses to the catalytic domain of BRAF in RA and other autoimmune diseases. The association between RA-related clinical indices and these antibodies was also assessed.
Methodology/Principal Findings
The presence of autoantibodies to the catalytic domain of BRAF (anti-BRAF) or to peptide P25 (amino acids 656–675 of the catalytic domain of BRAF; anti-P25) was determined in serum samples from patients with RA, primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE), and healthy controls by using indirect enzyme-linked immunosorbent assays (ELISAs) based on the recombinant catalytic domain of BRAF or a synthesized peptide, respectively. Associations of anti-BRAF or anti-P25 with disease variables of RA patients were also evaluated. Our results show that the BRAF-specific antibodies anti-BRAF and anti-P25 are equally present in RA, pSS, and SLE patients. However, the erythrocyte sedimentation rate (ESR) used to detect inflammation was significantly different between patients with and without BRAF-specific antibodies. The anti-BRAF-positive patients were found to have prolonged disease, and active disease occurred more frequently in anti-P25-positive patients than in anti-P25-negative patients. A weak but significant correlation between anti-P25 levels and ESRs was observed (r = 0.319, p = 0.004).
The antibody response against the catalytic domain of BRAF is not specific for RA, but the higher titers of BRAF-specific antibodies may be associated with increased inflammation in RA.
PMCID: PMC3236235  PMID: 22174938
11.  Effects of miglitol in platelet-derived microparticle, adiponectin, and selectin level in patients with type 2 diabetes mellitus 
Platelet-derived microparticles (PDMP), selectins, and adiponectin play an important role in the development of atherosclerosis in diabetes. Miglitol has been shown to have a beneficial effect on postprandial hyperglycemia in diabetic patients. However, its influence on platelet activation markers (PDMP and soluble CD40 ligand [sCD40L]), selectins, and adiponectin in these patients is poorly understood.
We investigated the effect of miglitol on circulating levels of PDMP, sCD40L, selectins, and adiponectin in patients with type 2 diabetes.
Miglitol (150 mg/day) was administered for 4 months. Levels of PDMP, sCD40L, soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble L-selectin (sL-selectin), and adiponectin were measured by enzyme-linked immunosorbent assay at baseline, and after 1 and 4 months of treatment.
The levels of PDMP, sCD40L, sP-selectin, sE-selectin, and sL-selectin were higher in diabetic patients than in hypertensive patients, while there were no significant differences between hypertensive and hyperlipidemic patients. Before miglitol treatment, the adiponectin level of diabetic patients was lower than that of hypertensive patients. Miglitol therapy significantly decreased the plasma PDMP and sCD40L levels relative to baseline. Miglitol also caused a significant decrease of sP-selectin, sE-selectin, and sL-selectin. On the other hand, miglitol therapy led to a significant increase in adiponectin after 4 months of administration compared with baseline. Furthermore, the reduction of platelet activation markers and selectins during miglitol therapy was significantly greater in the responder (adiponectin-improved) group than the nonresponder group of diabetic patients.
Miglitol has an adiponectin-dependent anti-atherothrombotic effect that may be beneficial for primary prevention of atherothrombosis in patients with type 2 diabetes.
PMCID: PMC3150178  PMID: 21845063
platelet activation markers; atherothrombosis; platelet-derived microparticles; PDMP
12.  Impact of interleukin-21 in the pathogenesis of primary Sjogren's syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands 
Arthritis Research & Therapy  2011;13(5):R179.
Interleukin (IL)-21 is a cytokine that controls the functional activity of effector T helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. To test whether IL-21 participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined.
Serum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured. Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass. LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry. Confocal microscopy was performed to further characterize the IL-21 positive cells.
Primary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1. Serum IgG1 levels correlated with anti-Ro antibody titers. Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens. The more the lymphocyte infiltrated, IL-21expression in LSGs showed a tendency to increase. Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5.
Primary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels. The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs. These observations suggest that IL-21 may play an important role in primary SS pathogenesis.
PMCID: PMC3308114  PMID: 22030011
IL-21; IL-21 receptor; Sjogren's syndrome; Immunoglobulin G1; Labial salivary gland
13.  Sjögren syndrome: Advances in the pathogenesis from animal models 
Journal of autoimmunity  2009;33(3-4):190-196.
Sjögren syndrome is an autoimmune disease characterized by hyposecretion of the lacrimal and salivary glands, resulting in dryness of the eyes and mouth. Individuals may experience primary Sjögren syndrome or a secondary form accompanying another rheumatic autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus. The pathogenic mechanisms of Sjögren syndrome remain largely unknown, in part a consequence of the heterogeneity of the disease. Animal models have shed light on the connections between specific pathways and symptoms, but an ideal system is wanting. Improved disease models will enable a better understanding of Sjögren syndrome, including how immune tolerance is lost and potential therapeutic interventions. Most importantly, an optimal model will enable detection of disease biomarkers, since injury to the salivary glands may precede lymphocytic infiltration. This review aims to characterize available mice models of Sjögren syndrome, including advantages and disadvantages, from the researcher’s perspective.
PMCID: PMC3439154  PMID: 19800762
Sjögren syndrome; Mouse models; Autoimmunity
14.  Circulating levels of soluble MER in lupus reflect M2c activation of monocytes/macrophages, autoantibody specificities and disease activity 
Arthritis Research & Therapy  2013;15(6):R212.
Systemic lupus erythematosus (SLE) is characterized by impaired efferocytosis and aberrant activation of innate immunity. We asked if shedding of MER receptor tyrosine kinase (MerTK) and AXL into soluble (s) ectodomains was related to immunological and clinical aspects of SLE.
Levels of sMER and sAXL in the plasma of 107 SLE patients and 45 matched controls were measured by ELISA. In 40 consecutive SLE patients, we examined potential correlations between either sMER or sAXL and plasma levels of sCD163, a marker of M2 activation. All three soluble receptors were measured in supernatants of monocytes/macrophages cultured in various immunological conditions. Membrane expression of MerTK, AXL and CD163 was assessed by flow cytometry.
Both sMER and sAXL were associated with anti-chromatin and anti-phospholipid autoantibodies, and with hematological and renal involvement. However, sMER and sAXL did not significantly correlate with each other; sAXL correlated with growth arrest-specific 6 (Gas6), whereas sMER correlated with reduced free protein S (PROS) levels. Only sMER showed significant associations with lupus-specific anti-dsDNA, anti-Sm, anti-ribonucleoprotein (anti-RNP) and anti-Ro60 autoantibodies. Strong correlations with disease activity indices (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), complement reduction, titer of circulating anti-dsDNA) were found for sMER, not for sAXL. Patients with active SLEDAI, nephritis, anti-dsDNA and anti-Ro60 positivity showed higher levels of sMER compared to controls. Levels of sMER, not sAXL, correlated with sCD163 levels, and these correlated with SLEDAI. Production of sMER and sCD163 occurred under “M2c” polarizing conditions, whereas sAXL was released upon type-I IFN exposure.
Alterations in homeostasis of anti-inflammatory and efferocytic “M2c” monocytes/macrophages may have a role in immunopathogenesis of SLE.
PMCID: PMC3978923  PMID: 24325951
15.  Ro/SSA and La/SSB specific IgA autoantibodies in serum of patients with Sjögren's syndrome and systemic lupus erythematosus 
Annals of the Rheumatic Diseases  1999;58(10):623-629.
OBJECTIVE—To investigate the occurrence of IgA autoantibodies to Ro 52 kDa, Ro 60 kDa and La antigen in serum of patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE).
METHODS—Recombinant Ro 52 kDa, Ro 60 kDa and La antigens were used to analyse autoantibodies in serum from 25 patients with pSS, 30 patients with SLE and 20 controls using a semiquantitative immunoblotting approach.
RESULTS—Among the patients with pSS, 21 (84%) had detectable IgA autoantibodies to Ro 52 kDa, 13 (52%) to Ro 60 kDa and 20 (80%) to La antigen. The corresponding results for the patients with SLE were 22 (73%), 14 (47%) and 20 (67%), respectively. No IgA autoantibodies against the three antigens were detected in 20 normal controls. A comparison of several clinical features with the titres of IgA antibodies to Ro 52 kDa, Ro 60 kDa and La, revealed a significant relation between IgA anti-Ro 52 and IgA anti-La to sicca (p< 0.05). Semiquantitative data suggest that IgG is the dominating antibody to the three antigens followed by IgM > IgA in both SLE and pSS patients. Specificity studies of IgA autoantibodies with different subfragments of Ro 52 kDa and Ro 60 kDa antigens showed that IgA antibodies did not differ from IgG and IgM in their recognition pattern.
CONCLUSION—These results suggest that besides IgM and IgG, IgA autoantibodies are also detected at high frequency in patients with pSS and SLE. Further studies are necessary to evaluate the contribution of these IgA autoantibodies to inflammation as well as their diagnostic value.

PMCID: PMC1752767  PMID: 10491361
16.  Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjögren's syndrome 
B cell activation may result in an increased secretion of immunoglobulin free light chains (FLCs) in autoimmune diseases.
To analyse serum FLC levels in patients with rheumatoid arthritis and in those with primary Sjögren's syndrome (pSS).
Patients and methods
Blood samples were collected from 80 healthy blood donors, 50 patients with rheumatoid arthritis and 139 patients with pSS. Serum FLC level was measured using a new quantitative immunoassay.
Mean (standard error (SE)) serum κ and λ FLC levels were significantly higher in patients with rheumatoid arthritis and in those with pSS than in controls (κ : 18.9 (1.1) and 16.3 (1.4) v 10.5 (0.4) mg/l, p<0.001 and p = 0.001, respectively; λ: 16.7 (1.2) and 19.3 (1.5) v 11.6 (0.6) mg/l, p<0.001 for both). 18 (36%) patients with rheumatoid arthritis and 31 (22.3%) patients with pSS had abnormal serum FLC levels (increased κ or λ levels and abnormal ratio of κ:λ). Serum κ and λ levels were correlated with other B cell activation markers in both diseases. FLC levels increased with disease activity, because, unlike total gammaglobulin and immunoglobulin G levels, they were significantly correlated with Disease Activity Score 28 in patients with rheumatoid arthritis (p = 0.004 for κ, p = 0.05 for λ) and with extraglandular involvement in pSS (p = 0.01 for κ, p = 0.04 for λ).
FLC levels are increased and correlate with disease activity in patients with rheumatoid arthritis and in those with pSS, two diseases in which increased risk of lymphoma could result from persistent B cell activation and disease activity. Further studies are required to determine whether FLC assessment could represent a relevant biomarker for response to treatment (especially B cell depletion) and for the risk of lymphoma in autoimmune diseases.
PMCID: PMC1798389  PMID: 16569685
17.  Selective polyclonal increase of immunoglobulin G1 subclass: a link with Sjögren's syndrome. 
Annals of the Rheumatic Diseases  1990;49(6):373-377.
A selective polyclonal increase in IgG1 has been described previously in a group of patients with connective tissue disease; nine of the 16 patients had a prior diagnosis of systemic lupus erythematosus (SLE). A detailed clinical and serological study of 32 patients with this immunoglobulin abnormality has now been made. Most cases showed a characteristic autoantibody profile of antinuclear antibody, rheumatoid factor, and antibodies to Ro and La. Sjögren's syndrome was diagnosed as 'definite' in 16 cases and 'possible' in seven cases by Fox's criteria. The remainder had unclassified connective tissue disease (three), rheumatoid arthritis with dry eyes (two), SLE (one), scleroderma (two), and Raynaud's disease (one). Extraglandular features were invariably present in patients with primary Sjögren's syndrome. The highest concentrations of IgG1 were found in patients with the shortest disease duration. Selective polyclonal increase of IgG1 should alert the doctor to the development of Sjögren's syndrome, usually with extraglandular disease and antibodies to Ro and La.
PMCID: PMC1004103  PMID: 2116774
18.  Evaluation of genetic association between an ITGAM non-synonymous SNP (rs1143679) and multiple autoimmune diseases 
Autoimmunity Reviews  2011;11(4):276-280.
Many autoimmune diseases (ADs) share similar underlying pathology and have a tendency to cluster within families, supporting the involvement of shared susceptibility genes. To date, most of the genetic variants associated with systemic lupus erythematosus (SLE) susceptibility also show association with others ADs. ITGAM and its associated ‘predisposing’ variant (rs1143679, Arg77His), predicted to alter the tertiary structures of the ligand-binding domain of ITGAM, may play a key role for SLE pathogenesis. The aim of this study is to examine whether the ITGAM variant is also associated with other ADs. We evaluated case-control association between rs1143679 and ADs (N=18,457) including primary Sjögren’s syndrome, systemic sclerosis, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, celiac disease, and type-1 diabetes. We also performed meta-analyses using our data in addition to available published data. Although the risk allele ‘A’ is relatively more frequent among cases for each disease, it was not significantly associated with any other ADs tested in this study. However, the meta-analysis for systemic sclerosis was associated with rs1143679 (pmeta=0.008). In summary, this study explored the role of ITGAM in general autoimmunity in seven non-lupus ADs, and only found association for systemic sclerosis when our results were combined with published results. Thus ITGAM may not be a general autoimmunity gene but this variant may be specifically associated with SLE and systemic sclerosis.
PMCID: PMC3224188  PMID: 21840425
ITGAM; autoimmune diseases; genetic susceptibility
19.  Identification of autoantibody biomarkers for primary Sjögren's syndrome using protein microarrays 
Proteomics  2011;11(8):1499-1507.
Sjögren's syndrome (SS) is a chronic, progressive autoimmune disease primarily affecting women. Diagnosis of SS requires an invasive salivary gland tissue biopsy and a long delay from the start of the symptoms to final diagnosis has been frequently observed. In this study, we aim to identify salivary autoantibody biomarkers for primary SS (pSS) using a protein microarray approach. Immune-response protoarrays were used to profile saliva autoantibodies from patients with pSS (n=14), patients with systemic lupus erythematosus (SLE, n=13), and healthy control subjects (n=13). We identified 24 potential autoantibody biomarkers that can discriminate patients with pSS from both patients with SLE and healthy individuals. Four saliva autoantibody biomarkers, anti-transglutaminase, anti-histone, anti-SSA, and anti-SSB, were further tested in independent pSS (n=34), SLE (n=34), and healthy control (n=34) subjects and all were successfully validated with ELISA. This study has demonstrated the potential of a high-throughput protein microarray approach for the discovery of autoantibody biomarkers. The identified saliva autoantibody biomarkers may lead to a clinical tool for simple, noninvasive detection of pSS at low cost.
PMCID: PMC3209962  PMID: 21413148
Autoantibody biomarker; Protein arrays; Protein microarray; Sjögren's syndrome
20.  Sicca symptoms and secondary Sjögren's syndrome in systemic lupus erythematosus: comparison with rheumatoid arthritis and correlation with disease variables 
Annals of the Rheumatic Diseases  2001;60(12):1103-1109.
OBJECTIVE—Firstly, to study the prevalence of ocular and oral sicca symptoms, reduced tear and saliva production, and the minimum frequency of secondary Sjögren's syndrome (sSS) in systemic lupus erythematosus (SLE). Secondly, to compare sicca symptoms and findings with those of matched patients with rheumatoid arthritis (RA), and sicca symptoms with those in healthy controls. Finally, to study possible associations of clinical variables with sicca symptoms and sSS in SLE.
METHODS—Self reported sicca symptoms were recorded in 81 patients with SLE aged ⩽70, 81 matched patients with RA, and 81 matched healthy controls. Other study variables included Schirmer-I test (S1T), unstimulated whole saliva, health status measures (in SLE and RA), disease activity, accumulated organ damage, and serological markers (in SLE).
RESULTS—A significantly higher proportion of patients with SLE reported sicca symptoms than healthy controls. Further, a significantly higher proportion reported ocular sicca symptoms (43 and 21%, respectively) and had pathologically reduced S1T compared with RA (46 and 21%, respectively). No difference was seen in oral sicca symptoms and saliva production. In SLE, sicca symptoms were associated with fatigue, and sSS with anti-SSB or anti-SSA antibodies, or both.
CONCLUSIONS—An increased prevalence of sicca symptoms was found in patients with SLE compared with controls, and a higher prevalence of ocular sicca symptoms and reduced tear production in SLE compared with RA. Sicca problems should be considered in the care of patients with SLE, especially those with anti-SSB and/or anti-SSA antibodies who have sicca symptoms and fatigue.

PMCID: PMC1753445  PMID: 11709451
21.  The soluble CD40 ligand sCD154 in systemic lupus erythematosus 
Journal of Clinical Investigation  1999;104(7):947-955.
We found that the plasma of patients with active systemic lupus erythematosus (SLE) could induce a human B-cell line (Ramos) to express high levels of immune accessory molecules that are commonly found on blood B cells of patients with active SLE. The ability of SLE plasma to induce such phenotypic changes could be abrogated by neutralizing antibodies specific for the CD40 ligand (CD154) but not by antibodies to TNF-α. Immunoprecipitation studies with anti-CD154 identified a 20-kDa protein in the plasma of SLE patients with active disease, but not in plasma of normal donors, indicating that such plasma contained soluble CD154 (sCD154). Using a quantitative ELISA method, we found that the plasma of patients with active disease had levels of sCD154 that were significantly higher than those found in plasma of normal donors. Levels of CD154 transcripts in SLE blood lymphocytes correlated with the relative concentrations of sCD154 found in SLE plasma. Furthermore, plasma levels of sCD154 correlated with the titers of anti–double-stranded DNA autoantibody and with clinical disease activity. These studies indicate that sCD154 of patients with SLE may act as a functional ligand for CD40 that is associated with SLE disease activity.
PMCID: PMC408556  PMID: 10510335
22.  No evidence for a putative involvement of platelet-activating factor in systemic lupus erythematosus without active nephritis. 
Mediators of Inflammation  2003;12(2):101-105.
BACKGROUND: Platelet-activating factor (PAF) seems to be implicated in systemic lupus erythematosus (SLE) patients with associated renal diseases. AIMS: In this study, we ensured the role of PAF in SLE patients without renal complications. METHODS: Blood PAF and acetylhydrolase activity, plasma soluble phospholipase A(2), and the presence of antibodies against PAF were investigated in 17 SLE patients without active nephritis and in 17 healthy controls. RESULTS: Blood PAF levels were not different (p=0.45) between SLE patients (6.7+/-2.8 pg/ml) and healthy subjects (9.6+/-3.1 pg/ml). Plasma acetylhydrolase activity (the PAF-degrading enzyme) was significantly (p=0.03) elevated in SLE patients (57.8+/-6.4 nmol/min/ml) as compared with controls (37.9+/-2.6 nmol/min/ml). Plasma soluble phospholipase A(2) (the key enzyme for PAF formation) was not different (p=0.6) between SLE patients (59.1+/-5.1 U/ml) and controls (54.7+/-2.4 U/ml). Antibodies against PAF were detected only in 3/17 SLE patients. Flow cytometry analysis did not highlight PAF receptors on circulating leukocytes of SLE patients. CONCLUSION: This clinical study highlights no evidence for a putative important role of PAF in SLE patients without active nephritis.
PMCID: PMC1781601  PMID: 12775360
23.  Increased Soluble CD4 in Serum of Rheumatoid Arthritis Patients Is Generated by Matrix Metalloproteinase (MMP)-Like Proteinases 
PLoS ONE  2013;8(5):e63963.
Higher soluble CD4 (sCD4) levels in serum have been detected in patients of infectious and chronic inflammatory diseases. However, how and why sCD4 is produced remains poorly understood. We establish sensitive ELISA and WB assays for sCD4 detection in conditioned medium of in vitro cell culture system and serum of chronic inflammatory patients. Serum samples from patients with systemic lupus erythematosus (SLE) (n = 79), rheumatoid arthritis (RA) (n = 59), ankylosing spondylitis (AS) (n = 25), gout (n = 31), and normal controls (n = 99) were analyzed using ELISA for sCD4 detection. Results from each assay were analyzed by the Kruskal-Wallis test. Dunn’s multiple comparison post-test was then applied between groups. We confirm that cells expressing exogenous CD4 produce sCD4 in a constitutive and PMA-induced manner. Importantly, sCD4 production in a heterologous expression system is inhibited by GM6001 and TAPI-0, suggesting receptor shedding by matrix metalloproteinase (MMP)-like proteinases. Moreover, similar findings are recapitulated in human primary CD4+ T cells. Finally, we show that serum sCD4 levels are increased in patients of chronic inflammatory diseases including RA and SLE, but not in those with gout. Intriguingly, sCD4 levels in RA patients are correlated positively with the disease activities and higher sCD4 levels seem to associate with poor prognosis. Taken together, we conclude that CD4 is shed from cell surface by a MMP-like sheddase and sCD4 level is closely related with the inflammatory condition in certain chronic diseases. Hence, sCD4 might be considered an important parameter for RA disease progression with potential diagnostic importance.
PMCID: PMC3660307  PMID: 23700441
24.  Anti-ribosomal P protein antibodies detected by immunoblotting in patients with connective tissue diseases: their specificity for SLE and association with IgG anticardiolipin antibodies 
Annals of the Rheumatic Diseases  2000;59(12):975-981.
OBJECTIVE—To assess the prevalence and clinical and serological associations of anti-ribosomal P protein antibodies (anti-P antibodies) in patients with connective tissue diseases (CTDs) and investigate the immunobiological nature of autoantibody clustering in which anti-P antibodies play a part.
METHODS—IgG anti-P antibodies in the sera of 267 patients with CTDs and 31 healthy subjects were analysed by immunoblotting performed on cytoplasmic extract of Raji cells. 60 patients with systemic lupus erythematosus (SLE), 32 systemic sclerosis, 46 primary Sjögren's syndrome, 16 poly/dermatomyositis, 11 rheumatoid arthritis, 8 undifferentiated CTD, 72 overlap CTD, and 22 primary antiphospholipid syndrome were studied. Anti-P antibodies were affinity purified by elution from nitrocellulose bound antigen and tested by ELISA for their binding activity to cardiolipin.
RESULTS—Anti-P antibodies were detected in 16 (6%) patients and in none of the controls: 12/60 SLE (20%) and 4/80 undifferentiated/overlap patients with CTD (5%). A close association of IgG antibodies with P proteins and with cardiolipin was seen in lupus sera (p=0.0009, odds ratio 18.33). Anti-P antibodies from 9 of 12 anti-P lupus serum samples could be affinity purified and none of the affinity purified fractions cross reacted with ELISA plate coated cardiolipin.
CONCLUSIONS—Anti-P immunoreactivity is a specific marker of SLE and lupus-like disease and its detection is recommended as a powerful diagnostic tool. Anti-P antibodies are strongly clustered with IgG anticardiolipin antibodies in lupus sera, even if they are independently elicited. This suggests that their cognate autoantigens play a part in a common pathogenetic pathway in SLE.

PMCID: PMC1753043  PMID: 11087701
25.  Effects of pitavastatin on plasminogen activator inhibitor-1 in hyperlipidemic patients 
The effects of statins on two platelet activation markers, plasiminogen activator inhibitor (PAI)-1 and adiponectin, were investigated in 68 patients with hyperlipidemia. The patients were treated with pitavastatin with a dosage of 2 mg daily. The plasma levels of platelet-derived microparticles (PDMP), soluble CD40 ligand (sCD40L), sP-selectin, PAI-1, and adiponectin were measured at baseline and after 6 months of treatment in both groups. In hyperlipidemic patients, the plasma levels were higher in PDMP, sCD40L, sP-selectin, and PAI-1, and lower in adiponectin, compared to the normolipidemic controls. Plasma PDMP and sCD40L were positively correlated, while plasma adiponectin was negatively correlated with the plasma levels of PAI-1. No significant differences were observed in the plasma levels of PDMP, sCD40L, sP-selectin, and PAI-1 before and after treatment. A significant increase in plasma adiponectin levels was observed after 6 months of treatment with pitavastatin. When the patients treated with pitavastatin were divided into two groups according to the adiponectin response to pitavastatin treatment, significant decreases in plasma PAI-1, PDMP, and sCD40L levels were observed after pitavastatin treatment in the responder group. These findings suggest that PDMP, sCD40L, and PAI-1 may participate in the development of atherothrombosis in patients with hyperlipidemia, and that pitavastatin may exert an adiponectin-dependent anti-atherothrombotic effect in hyperlipidemic patients.
PMCID: PMC3396113  PMID: 22807641
hyperlipidemia; PAI-1; pitavastatin; adiponectin; atherothrombosis

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