decreased levels of soluble receptor for advanced glycation end products in patients with primary...
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Rheumatol Int (2008) 28:771–776
DOI 10.1007/s00296-008-0529-4ORIGINAL ARTICLE
Decreased levels of soluble receptor for advanced glycation end products in patients with primary Sjögren’s syndrome
Carol Stewart · Seunghee Cha · Robert M. Caudle · Kathleen Berg · Joseph Katz
Received: 15 October 2007 / Accepted: 5 January 2008 / Published online: 30 January 2008© Springer-Verlag 2008
Abstract The purpose of this study was to evaluate thelevels of sRAGE in primary Sjögren’s syndrome (SS), andto assess whether there is an association between sRAGElevels and disease characteristics. Thirteen patients wererandomly selected from three subgroups: primary SS,(n = 6), secondary Sjögren’s, (n = 4), and ANA(+) but lack-ing criteria for further disease classiWcation (n = 3). Levelsof serum sRAGE were measured in triplicate using anenzyme-linked immunosorbent assay kit. Mean sRAGElevels were signiWcantly lower in the primary Sjögren’sgroup. Logistic regression analysis indicated that plasmasRAGE level was a signiWcant predictor of diagnostic sta-tus. Analyses using routine serological tests for diagnosingautoimmune disorders failed to reach statistical signiW-cance. This preliminary study supports the hypothesis thatthe RAGE system might participate in the disease pathwayof primary SS, and that sRAGE may be a potential bio-marker to aid in the diagnosis of primary SS.
Keywords Sjögren’s syndrome · RAGE · sRAGE
Introduction
Sjögren’s syndrome (SS) is a chronic autoimmune disordercharacterized by the dysfunction and destruction of exo-crine glands associated with lymphocytic inWltrates [1, 2].
The chronic inXammation of the salivary glands may be aself-sustaining process promoting autoantibody productionagainst intracellular/cell surface antigens such as Ro, La[2–4] or muscarinic acetylcholine type-3 receptor (M3R)[5–10]. These processes interfere with normal glandularfunction and the mucosal surfaces become sites of chronicinXammation.
While the speciWc etiopathogenesis of SS is yetunknown, advanced glycation end products (AGEs), foundin increased levels in areas of chronic inXammation, and invessels and tissues of diabetics [11–15], have created ques-tions regarding possible roles in autoimmune inXammatorydiseases such as rheumatoid arthritis and SS. AGEs are aheterogeneous group of molecules that result from a seriesof chemical reactions formed from the nonenzymaticreduction of certain sugars. AGEs bind to a cell surfacereceptor (RAGE), a multi-ligand member of the Ig super-family, resulting in activation of pro-inXammatoryresponses and promotion of sustained inXammatory cellactivities [16–18].
RAGE is expressed by multiple cells types, includinginXammatory cells, neutrophils, mononuclear phagocytes,lymphocytes, and synovial cells [19], and has been reportedto play a role in the development of late diabetic complica-tions in mice models, such as neuropathy, nephropathy,macrovascular disease, and chronic inXammation [20].RAGE expression has been associated with chronic inXam-matory autoimmune diseases as well. RAGE is expressed atincreased levels in synovial Xuid of patients with rheuma-toid arthritis (RA) [21], and on the epithelial duct cells ofminor salivary glands of SS patients [22]. sRAGE, a trun-cated form of the receptor, is composed of only the extra-cellular ligand binding domain. It has the same ligandbinding speciWcity as RAGE, and acts as a competitivereceptor for cellular RAGE. In a sense, sRAGE functions as
C. Stewart (&) · S. Cha · R. M. Caudle · K. Berg · J. KatzCenter for Orphaned Autoimmune Disorders, Department of Oral and Maxillofacial Surgery and Diagnostic Sciences (OMSDS), University of Florida College of Dentistry (UFCD), Box 100414 JHMHC, Gainesville, FL 32610, USAe-mail: [email protected]
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a “decoy” for RAGE [23]. In humans, sRAGE is producedby alternative splicing of RAGE mRNA [24–27]. In addi-tion, it has also been shown that pericytes and endothelialcells produce and release sRAGE extracellularly, suggest-ing endogenous secretory RAGE is cytoprotective againstAGE [26]. Clinical studies have recently shown that higherplasma levels of sRAGE are associated with a reduced riskof coronary artery disease, hypertension, the metabolic syn-drome, arthritis and Alzheimer’s disease [28, 29]. Asreported in mouse models of arthritis, RAGE was upregu-lated in inXamed joints, and sRAGE reduced the jointinXammation [30]. In addition, a recent report stated thatplasma levels of sRAGE were reduced in subjects withrheumatoid arthritis compared with healthy controls withnon-inXammatory joint disease [23, 31].
Based upon developing theories regarding the role of thesRAGE/RAGE–ligand system, speciWcally in rheumatoidarthritis and SS, it seemed feasible to conduct a preliminaryinvestigation of serum sRAGE in primary SS patients. Thepurpose of this study was to evaluate the levels of sRAGEin patients with primary SS and to assess whether there isan association between sRAGE levels and disease charac-teristics in primary SS and two comparison groups. Thetwo comparison groups consisted of subjects with second-ary SS and subjects with a positive anti-nuclear antibody(ANA) titer, but lacking other published criteria for diseaseclassiWcation.
Materials and methods
Subjects
Thirteen patients were randomly selected from the Univer-sity of Florida Autoimmune Disease Center. The Center isa multispecialty center which includes rheumatologists,ophthamologists, nephrologists, pulmonologists, dermatol-ogists, pathologists, oral medicine specialists, and geneti-cists who collaborate to provide optimal patient care forcomplex patients with autoimmune diseases such as SS,systemic lupus erythematosus (SLE), and CREST/systemicsclerosis, polymyositis, and dermatomyositis. To be evalu-ated at the Center, a referral from a physician and at a mini-mum, a positive ANA titer is required. At the initialappointment, patient consent for inclusion into the study,demographic data, and medical history are obtained. Allprocedures were reviewed and approved by the UF HealthScience Center Institutional Review Board. Urine andserum were collected for diagnostic tests and aliquots werefrozen at ¡70°C for subsequent testing. Routine serologictests were performed and those used in this study were asfollows: anti-nuclear antibodies, anti Ro/SS-A, anti La/SS-B, rheumatoid factor, erythrocyte sedimentation rate, white
blood cell count (WBC) complement C3 and complementC4. Determination of a deWnitive diagnosis followed theAmerican College of Rheumatology criteria for SLE [32]and CREST/systemic sclerosis [33]. For diagnosis of pri-mary and secondary Sjögren’s syndrome, the 2002 Ameri-can/European Consensus criteria were applied [34]. For thisstudy, patients were randomly selected from three sub-groups as follows: primary SS (n = 6), secondary Sjögren’ssyndrome (n = 4), and only ANA positive (n = 3).
Measurement of serum sRAGE by ELISA
Collected blood was centrifuged at 2,000£g for 10 min,aliquoted, and stored at ¡70°C until used. Levels of serumsRAGE were measured in triplicates using an enzyme-linked immunosorbent assay kit (Quantikine; R&D Sys-tems, Minneapolis, MN, USA) as reported earlier [17]. Alltests for each sample were performed on the same day bytechnicians who were blinded as to the diagnosis of thegroups. This assay employs the quantitative sandwichenzyme immunoassay technique. According to the manu-facturer, the minimum detectable dose of sRAGE is 4 pg/ml, and there are no signiWcant cross-reactivities to EN-RAGE, HMGB1, S100A10 or S100Baa. A monoclonalantibody speciWc for RAGE (extracellular domain) hadbeen precoated into a microplate. Fifty microliters of stan-dards and samples were pipetted into the wells and avail-able RAGE was bound to the immobilized antibody. Afterwashing away any unbound substances, an enzyme-linkedpolyclonal antibody speciWc for extracellular domain forRAGE was added to the wells for 2 h incubation at roomtemperature. Following a wash to remove any unboundantibody–enzyme reagent, the color substrate solution wasadded, followed by a quencher. Color development, in pro-portion to the amount of sRAGE bound in the initial step,was measured by optical density according to manufac-turer’s recommendations.
Statistical analysis
Because sRAGE levels were not normally distributed, statisti-cal analysis of the data was carried out using nonparametricprocedures. DiVerences between groups were assessed usingthe Mann–Whitney U test, and associations between studyvariables were examined using the Spearman rank-order cor-relation coeYcient. Logistic regression analyses were alsoperformed to determine the predictive value of sRAGE levelsand other serological measures to diagnostic status. For theseanalyses, sRAGE concentrations were collapsed into fourordered categories, each representing a range of 300 pg/ml.Titers for ANA, RF, anti-SS-A/Ro and anti-SS-B/La weredichotomized as positive and negative outcome. StatisticalsigniWcance was set at the P < 0.05 level.
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Results
Serologic parameters and demographic characteristics foreach of the subjects in the study are shown in Table 1. All13 patients in the sample were female. Patients in the ANApositive group were younger and reported a more recentonset of symptoms than those diagnosed with primary andsecondary Sjögren’s syndrome, but neither age nor durationof symptoms diVered signiWcantly across the three groups.Eighty-Wve percent were Caucasian, and nearly half (47%)reported greater than a high school education.
As stated in Table 2, mean sRAGE levels were lowest inthe primary Sjögren’s group, [primary Sjögren’s 1,117.5,secondary Sjögren’s 1,401.2, and ANA (+) 1,616.3]. Thesedata are plotted in bar graphs in Fig. 1. An initial test indi-cated that serum sRAGE levels were not signiWcantlydiVerent for secondary Sjögren’s and ANA positivepatients, and therefore, these groups were combined in sub-sequent analyses. Figure 2 depicts the scattergram plot ofsRAGE for primary SS and the combined group. Results ofa Mann–Whitney U test conWrmed that the diVerence insRAGE concentrations for primary SS and the comparisongroup was statistically signiWcant (P < 0.025). A binarylogistic regression analysis with diagnostic category as thecriterion indicated that plasma sRAGE levels signiWcantlypredicted a diagnosis of primary SS (likelihood ratio �2
(1) = 4.38, P < 0.05). The odds ratio was 6.03, indicatingthat the probability of a primary Sjögren’s diagnosisincreased by a factor of 6 for each decrease of 300 pg/ml inthe level of sRAGE. Similar analyses using levels of com-
plement C3, C4, and the presence of ANA, RF, SS-A/Roand SS-B/LA autoantibodies as predictors failed to reachstatistical signiWcance (Table 3).
Correlation analyses were carried out to examine therelationship between serum sRAGE and other serologicalmarkers. These revealed that low levels of sRAGE were
Table 1 Demographic and serological measures for 13 patients
Primary SS (n = 6)
Secondary SS (n = 4)
ANA positive (n = 3)
Age (years)
Mean 56.8 57.5 37.3
SD 18.8 15.2 3.5
Duration of Symptoms (years)
Mean 10.0 7.2 5.0
SD 6.0 6.1 7.8
Race (N)
White 5 3 3
Non-white 1 1 0
Education (years)
Mean 13.8 12.2 11.7
SD 1.8 1.2 1.5
Plasma sRAGE (pg/ml)
Mean (SD) 1,117.5 (238.3) 1,401.2 (353.5) 1,616.3 (405.9)
Median 1,127.5 1,485.0 1,409.0
Range 851–1,349 912–1,723 948–2,084
Table 2 Demographic and serological measures for 13 patients
Predictor SigniWcance Odds ratio
sRAGE P < 0.05 6.03
ANA P < 0.50 0.00
RF P < 0.20 5.00
Ro(SSA) P < 0.20 6.67
La(SSB) P > 0.50 1.25
C3 P > 0.50 0.99
C4 P> 0.50 0.98
Fig. 1 Bar graph demonstrating mean sRAGE in the three groups: pri-mary Sjögren’s Syndrome, secondary Sjögren’s syndrome, and ANA (+)
spuorG tneitaP
0
004
008
0021
0061
0002
0042
evitisop ANASSyradnoceSSSyramirP
Pla
sma
sRA
GE
( p
g/m
l)
Fig. 2 Scatter gram of mean plasma sRAGE levels for subjects in twogroups, PSS and combined secondary Sjögren’s syndrome andANA(+)
sRAGE in Primary SS and Comparison Groups
500
1000
1500
2000
2500
Pla
sma
sRA
GE
pg
/ml
Primary SS Comparison
p < .025
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reliably associated with high levels of complement C4(r = ¡0.58, P < 0.05). The correlation between sRAGE andcomplement C3 approached statistical signiWcance(r = ¡0.50, P = 0.08), but no substantial correlations werefound for ESR, WBC count, or the presence of SS-A/Ro orSS-B/La antibodies.
Discussion
Primary SS is a relatively common autoimmune diseasecharacterized by the dysfunction and destruction of severaltypes of exocrine glands associated with lymphocytic inWl-trates [16]. The current biomarkers for diagnosis and pro-gression of PSS are not optimally speciWc or sensitive. Todate, major initiatives to develop such benchmarks havebeen unsuccessful.
In the present study, we found that primary SS patientshave signiWcantly decreased serum levels of sRAGE ascompared with secondary SS and patients with only a posi-tive ANA titer. Furthermore, sRAGE level was a signiWcantpredictor of diagnostic category. The odds ratio for thediagnosis of PSS was 6.03, indicating that the probability ofa primary Sjögren’s diagnosis increased by a factor of 6 foreach decrease of 300 pg/ml in the level of sRAGE. Similaranalyses using ANA titers, anti-SS-A/Ro, anti-SS-B/La andRF titers as predictors failed to reach statistical signiW-cance. Low levels of sRAGE were also reliably associatedwith high levels of complement C4.
Advanced glycation end products and RAGE are oftenconcentrated in joints of subjects with rheumatoid arthritis(RA), and amplify the immune/inXammatory response inthis disease process [19]. It has been demonstrated that
human synovial Wbroblasts constitutively expressed RAGE,mainly in synovial intima [35]. Recent studies have sug-gested that AGEs may form in inXammatory foci as a resultof oxidation or activated myeloperoxidase pathways.AGEs, through RAGE, may prime pro-inXammatory mech-anisms in endothelial cells, thereby amplifying inXamma-tory eVects in atherogenesis and chronic inXammatorydisorders. Furthermore, RAGE induces the expression ofvarious cytokines and growth factors to mediate the trans-diVerentiation of epithelial cells to form myoWbroblasts,resulting in the loss of epithelia E cadherin staining [36].Previously, we have demonstrated that primary SS minorsalivary glands express RAGE to a larger extent than nor-mal salivary tissue [22].
The American European Consensus Committee hasestablished criteria for the diagnosis of primary and second-ary Sjögren’s syndrome [34]. Using these criteria, a sensi-tivity of 96.1% and speciWcity of 94.2% for diagnosis ofprimary SS was reported. In patients with another well-deW-ned connective tissue disease such as SLE or RA, the pres-ence of item I (ocular symptoms) or item II (oralsymptoms) plus any 2 from among items III (Ocular signs)IV (Histopathology), and V (Objective salivary glandinvolvement) were considered as indicative of secondarySS. These criteria showed a sensitivity of 97.2% and speci-Wcity of 90.2% secondary SS.
For a diagnosis of primary SS, antibodies anti-SS-A/Ro,anti-SS-B/La, or a positive labial salivary gland biopsy arerequired. However, some patients decline the lip biopsy dueto post-op discomfort and potential lip paresthesia. If SS-A/SS-B antibodies are negative and the lip biopsy is not per-formed, the diagnosis could be missed or signiWcantlydelayed. In some cases, diYculty may arise in distinguishing
Table 3 Results of logistic regression analysis predicting a diagnosis of primary Sjögren’s Syndrome
a Positive labial salivary gland biopsy focus score = 3
Patient Diagnosis Age (years)
Sex Symptom Duration (years)
Race Comp C3
Comp C4
ESR RF ANA SSA SSB WBC sRAGE (pg/ml)
1 Prim SS 50 F 6 White 150 21 29 (+) (+) (+) (+) 6,000 1,304
2 Prim SS 28 F 4 White 136 28 25 (+) (+) (+) (+) 12,300 905
3 Prim SS 75 F 5 White 148 22 4 (+) (+) (+) (¡) 9,100 951
4a Prim SS 64 F 11 White 131 35 10 (¡) (+) (¡) (¡) 10,200 851
5 Prim SS 77 F 19 White 97 3 66 (+) (¡) (+) (¡) 4,700 1,349
6 Prim SS 47 F 15 Latin 111 36 76 (¡) (+) (+) (¡) 1,700 1,345
7 SLE/SS 60 F 6 White 124 21 21 (+) (+) (+) (+) 4,400 1,723
8 SLE/SS 52 F 2 White 99 18 23 (+) (+) (+) (+) 3,300 1,580
9 SLE/SS 41 F 5 Black 172 49 36 (¡) (+) (+) (¡) 7,000 912
10 Crest/SS 77 F 16 White 135 23 22 (¡) (+) (¡) (¡) 7,500 1,390
11 ANA pos 37 F 14 White 106 29 7 (¡) (+) (¡) (¡) 6,800 1,409
12 ANA pos 34 F 0 White 122 19 5 (¡) (+) (¡) (¡) 13,900 2,084
13 ANA pos 41 F 1 White 162 21 37 (¡) (+) (¡) (¡) 9,300 1,356
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between primary SS and SLE when hematologic and renaldisorders are absent, antibodies for SS-A, SS-B, DNA, andSm are negative, and the labial salivary gland biopsy isdeclined or inconclusive. Another marker, such as sRAGElevels could be helpful in establishing a diagnosis. For sec-ondary SS, neither the labial salivary gland biopsy nor SS-A/SS-B antibodies is required. IdentiWcation of a newmarker that might help distinguish between primary SS,secondary SS, and ANA (+), with no further classiWcationcould be helpful for diagnostic purposes. Soluble RAGEcould also be a future intervention target such as suggestedfor diabetic vascular disease and inXammatory condition[24, 37].
The overexpression of RAGE on the ductal epithelialcells in the minor salivary glands of primary SS may alsorepresent increased signaling through the receptors associ-ated with increased inXammatory response. The relativedecrease of sRAGE in primary SS serum can explain thereduced capacity of the immune system to negate this eVectby the binding of sRAGE to RAGE ligands and preventinginXammatory signaling through the cellular RAGE. In addi-tion, cell-bound RAGE functions as a counter-receptor forleukocyte integrins, thereby being directly involved in leu-kocyte recruitment, especially in inXammatory conditionswhen the receptor expression increases [36].
In summary, the present preliminary study supports thehypothesis that the RAGE system might be involved in thepathogenesis of primary SS and that sRAGE may be used asa potential biomarker for diagnosis of primary SS. Additionalstudies with larger subject cohorts will be important to con-Wrm these Wndings. Because our study is cross-sectional indesign, we are unable to suggest whether the reduced level ofsRAGE in primary SS is part of the initiation or rather a con-sequence of the disease. Further longitudinal studies will benecessary to determine the relationship between plasmasRAGE levels and progression of primary SS and for theidentiWcation of speciWc sRAGE protein ligands.
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