Activity of childhood lupus nephritis is linked to altered T cell and cytokine homeostasis.
OBJECTIVE
Standard therapy for lupus nephritis is based on non-specific immunosuppression. We aimed to identify specific alterations in T cell and cytokine homeostasis and possible associations with disease activity in children with lupus nephritis (LN).


METHODS
The phenotype of circulating T cells from children with LN and healthy controls (HC) was analyzed by flow cytometry. Intracellular expression of IL-17 and INF-γ was assessed after stimulation with anti-CD3 and anti-CD28. Serum concentrations of IP10, CCL2, TGF-β, IL-17, and IL-23 were measured by ELISA. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 update (SLEDAI-2K).


RESULTS
Children with active LN displayed increased frequencies of effector memory CD4(+)CD45RO(+)CCR7(-) and terminal differentiated CD4(+)CD45RA(+)CCR7(-) T cells and reduced naive CD4(+)CD45RA(+)CCR7(+) T cells compared to those with inactive LN or HC. Circulating CD4(+)CXCR3(+) and CD4(+)CCR2(+) T cells correlated inversely with the renal SLEDAI-2K, whereas IP10 and CCL2 showed a positive correlation. Reduced CD4(+)Foxp3(+) T cells and serum TFG-β levels in active LN were associated with high serum IL-17 and IL-23 levels and correlated inversely with the renal SLEDAI-2K (r = -0.5855, p = 0.0013 and r = -0.6246, p = 0.0005, respectively), whereas IL-17 and IL-23 correlated positively (r = 0.5516, p = 0.0029 and r = 0.6116, p = 0.0007, respectively). Expansion of Th17 and Th1/Th17 cells in children with LN was significantly greater than in HC (p = 0.0304 and p = 0.0067, respectively).


CONCLUSIONS
Children with active LN display high levels of pro-inflammatory cytokines associated with an increase in effector T cells and reduction of regulatory T cells. Therapeutic regulation of the aberrant cytokine profile might specifically interrupt pathogenic mechanisms.
Department of Pediatrics I, Innsbruck Medical University, Anichstr. 35, 6020, Innsbruck, Austria. monika.edelbauer@i-med.ac.at
Monika
M
Edelbauer
Sudhir
S
Kshirsagar
Magdalena
M
Riedl
Heiko
H
Billing
Burkhard
B
Tönshoff
Dieter
D
Haffner
Gerard
G
Cortina
Oliver
O
Amon
Sophia
S
Ross
Jörg
J
Dötsch
Gottfried
G
Wechselberger
Lutz T
LT
Weber
Martin
M
Dablander
Markus
M
Anliker
Andrea
A
Griesmacher
Elisabeth
E
Steichen-Gersdorf
D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018932:Chemokine CCL2 / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D005260:Female; D006706:Homeostasis; D006801:Humans; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008181:Lupus Nephritis / Q000097:blood / Q000276:immunology*; D008297:Male; D054390:Receptors, CCR2 / Q000276:immunology; D054367:Receptors, CXCR3 / Q000276:immunology; D018121:Receptors, Cytokine / Q000276:immunology
C111835:CCL2 protein, human; C515334:CCR2 protein, human; C515187:CXCR3 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; C104577:IP10-Mig receptor; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D018121:Receptors, Cytokine