Roles of CCR2 and CXCR3 in the T cell-mediated response occurring during lupus flares.
OBJECTIVE
Infiltrating lymphocytes have been demonstrated to play an important role in the tissue injury that occurs in systemic lupus erythematosus (SLE). Inflammatory chemokines control lymphocyte traffic through their interaction with T cell chemokine receptors. In this study we assessed the expression of chemokine receptors on T cell subsets of patients with active or inactive SLE.


METHODS
Forty-four SLE patients (40 women and 4 men) were included in the study. The patients were divided according to their SLE Disease Activity Index (SLEDAI), which resulted in a group of patients with inactive SLE (n = 27) and a group with active SLE (n = 17). The control group was composed of 22 healthy blood donors. A disease control group consisted of 18 patients infected with human immunodeficiency virus. Expression of chemokine receptors CCR1, CCR2, CCR5, CXCR3, CXCR4, and CX3CR1 was assessed on whole blood samples by immunofluorescence analysis.


RESULTS
On T lymphocytes, significant differences between the SLE patients and controls were observed only in the expression of CCR2 and CXCR3. On monocytes, no significant differences in CCR2 expression were observed between the healthy controls and the SLE patients. The proportion of CD8+,CCR2+ T cells was significantly lower in the SLE patients compared with the controls (mean +/- SD 2.3 +/- 1.3% and 3.5 +/- 3.2% in the active and inactive SLE groups, respectively, versus 21 +/- 24% in controls; P < 0.0001 for both). The CD4+,CCR2+ subset was represented similarly among the controls and patients with inactive SLE (16.7 +/- 5.8% and 12.8 +/- 8.1%, respectively) but was depleted in patients with active SLE (7.1 +/- 4.4%; P < 0.0001 versus controls). The active SLE group expressed significantly lower circulating levels of CD4+,CCR2+ T cells than did the inactive disease group (P = 0.007). A negative correlation was found between the proportion of CD4+,CCR2+ T cells and the SLEDAI (r = -0.43, P = 0.005, by Spearman's correlation). Proportions of CD8+,CXCR3+ T cells were similar between the SLE groups and the control group (58 +/- 22.6% in active SLE, 47.1 +/- 20% in inactive SLE, and 59.4 +/- 17.3% in controls). The proportion of CXCR3-expressing CD4+ T cells was decreased in the active disease group (23.5 +/- 3.2% versus 39.9 +/- 12.5% in controls; P = 0.008) but not in the inactive disease group (34.8 +/- 9.5%). A trend toward a significant negative correlation was observed between the decreased proportion of CD4+,CXCR3+ T cells and the SLEDAI (P = 0.08). Following in vitro activation of purified CD4 T cells, only CCR2 was internalized, whereas expression of CXCR3 was retained in activated CD4 cells.


CONCLUSIONS
The numbers of circulating CD4+,CXCR3+ and CD4+,CCR2+ T cells are selectively decreased during SLE flares. A decrease in the number of circulating CD4+ T cells expressing CCR2 and/or CXCR3 could serve as a biomarker of the SLE flare.
Amoura
Zahir
Z
Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France. zahir.amoura@psl.ap-hop-paris.fr
Combadiere
Christophe
C
Faure
Sophie
S
Parizot
Christophe
C
Miyara
Makoto
M
Raphaël
Darren
D
Ghillani
Pascale
P
Debre
Patrice
P
Piette
Jean-Charles
JC
Gorochov
Guy
G
D000328:Adult; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D004247:DNA / Q000276:immunology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000175:diagnosis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D012074:Remission Induction
D001323:Autoantibodies; D015415:Biomarkers; C515334:CCR2 protein, human; C515187:CXCR3 protein, human; D008024:Ligands; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D004247:DNA