title: CD4+CD25highFOXP3+ T regulatory cells as a biomarker of disease activity in systemic lupus erythematosus: a prospective study.
abstract: OBJECTIVE
  Several studies have reported low numbers of T regulatory cells (Tregs) in active systemic lupus erythematosus (SLE). However, it is not evident if these cells may be utilised as a biomarker in assessing disease activity.
  
  
  METHODS
  Tregs (CD4+CD25highFOXP3+) were prospectively assessed by flow cytometry in 285 separate blood samples from 100 white Caucasian SLE patients and 20 healthy controls. Patients were divided, according to disease activity (as measured by SLEDAI) into groups A (n=39, samples=94, SLEDAI=0), B (n=33, samples=92, SLEDAI=1-5), C (n=10, samples=53, SLEDAI=6-10) and D (n=18, samples=46, SLEDAI>10). Longitudinal measurements were performed in 131 cases (37 relapses, 44 remissions and 50 cases with stable disease activity) during three years. Statistics were performed by Student's t-test or one-way ANOVA; correlations with Pearson co-efficient, while p<0.05 was considered significant.
  
  
  RESULTS
  Tregs were found significantly lower in severely active disease (group D), compared to healthy controls, inactive disease, mild and moderate disease activity (0.57±0.16% vs. 1.49±0.19%, 1.19±0.34% and 1.05±0.36%, 0.72±0.21%, p<0.05, respectively). There was a strongly inverse correlation between Tregs and SLEDAI (r=-0.644, p<0.001). Alterations in disease activity were characterised by inverse alterations in Tregs: relapse (from 1.23±0.44% to 0.64±0.19%, p<0.001, mean change 0.59±0.41%), remission (from 0.65±0.27% to 1.17±0.30%, p<0.001, mean change 0.52±0.35%). In cases with unaltered disease activity, Treg numbers remained stable (from 0.98±0.35% to 1.03±0.34%, p=0.245). Tregs were practically halved during relapse (mean reduction 42.6±22.2%), and doubled during remission (mean increment 113±120.9%). Mean change of Tregs in stable disease was significantly lower (7.3±20.6%, p<0.001). A clinically significant change in SLEDAI (sum of cases with relapse and remission, n=81) was followed by a significant (>20%) inverse change in Tregs in 71/81 cases (sensitivity 87.7%). In 50 cases of stable disease activity, Tregs were significantly changed (>20%) in 13 cases (specificity 74%). Positive predictive value (PPV) was 84.5% and negative predictive value (NPV) was 78.7%.
  
  
  CONCLUSIONS
  CD4+CD25highFOXP3+ T regulatory cells displayed a strongly inverse correlation to disease activity in the long term. Treg alterations reflected changes in SLEDAI with high sensitivity. These cells may be a reliable biomarker for the assessment of disease activity in SLE by longitudinal measurements.
authors.affiliation: Clinical Immunology Unit, 2nd Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Greece. tselioskostas2@gmail.com.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tselios
authors.forename: Alexandros
authors.initials: A
authors.lastname: Sarantopoulos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gkougkourelas
authors.forename: Panagiota
authors.initials: P
authors.lastname: Boura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000097:blood*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000175:diagnosis* / Q000276:immunology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012074:Remission Induction; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit