T cell cytokine imbalance towards production of IFN-gamma and IL-10 in NZB/W F1 lupus-prone mice is associated with autoantibody levels and nephritis.
OBJECTIVE
The role of T cell-derived cytokine production in lupus is poorly understood. We analysed the cytokine production of CD4(+) T cells in the NZB/W F1 mouse strain, the mouse model probably most closely resembling human systemic lupus erythematosus (SLE), and assessed whether a possible shift in the cytokines expressed is associated with age or disease activity.


METHODS
We used intracellular cytokine staining and flow cytometry to determine the cytokine expression of splenic CD4(+) T cells for interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-4 (IL-4) and IL-10. NZB/W F1 mice at different ages spanning 5 to 36 weeks were analysed, healthy Balb/cxNZW F1 (CWF1) mice were used as controls. Serum anti-double-stranded DNA (anti-dsDNA) antibody levels were determined by enzyme-linked immunosorbent assay (ELISA), and proteinuria and plasma creatinine were estimated using commercial test kits.


RESULTS
The cytokine profile of CD4(+) T cells was shifted towards T-helper 1 (Th1) cells and the frequencies of Th cells expressing IFN-gamma(+) correlated with age, anti-dsDNA-immunoglobulin G (IgG) titre and proteinuria. An increased percentage of IL-10 producers correlated positively with anti-dsDNA-IgG and proteinuria, and a small gain in IL-4 producers correlated with plasma creatinine. Neither the percentage of IL-10 producers nor IL-4 producers showed a significant correlation with age. There was no significant change observed in the frequency of TNF-alpha T cells. The IFN-gamma/IL-4 ratio demonstrated an increasing shift towards a Th1-type response during disease development that was not present in healthy mouse strains.


CONCLUSIONS
The association between the frequencies of T cells expressing IFN-gamma and IL-10 and clinical findings suggests a key role for these cells in the pathogenesis of lupus.
Enghard
P
P
Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany.
Langnickel
D
D
Riemekasten
G
G
D000367:Age Factors; D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D003401:Creatine / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D015759:Ionomycin; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism*; D008181:Lupus Nephritis / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D011507:Proteinuria; D013755:Tetradecanoylphorbol Acetate; D018417:Th1 Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001323:Autoantibodies; D015415:Biomarkers; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D015759:Ionomycin; D007371:Interferon-gamma; D004247:DNA; D003401:Creatine; D013755:Tetradecanoylphorbol Acetate