Interferon-gamma:interleukin 4 ratios and associated type 1 cytokine expression in juvenile rheumatoid arthritis synovial tissue.
OBJECTIVE
To compare synovial tissue cytokine mRNA expression between patients with juvenile rheumatoid arthritis (JRA) and a heterogeneous group of non-autoimmune arthropathies (controls) with respect to type 1/type 2 balance.


METHODS
Thirty-five JRA (average 9.1 years' disease duration) and 13 control synovial tissues were studied. As a measure of the type 1/type 2 cytokine balance in a subset of the JRA and control tissues, interferon-gamma (IFN-gamma) and interleukin 4 (IL-4) mRNA levels were measured by competitive fragment reverse transcription-polymerase chain reaction. To quantitate additional cytokines relevant to this balance, multiprobe ribonuclease protection assays were employed measuring IL-5, IL-10, IL-13, IL-15, IL-18, and IL-12 (p35 and p40 subunits). Immunohistochemistry was performed on JRA tissues using antibodies specific for IL-15 and IL-18.


RESULTS
A higher IFN-gamma:IL-4 ratio (p = 0.034) was found in JRA tissues compared to controls. JRA tissues also displayed higher mRNA levels of IL-12p35 (p = 0.021), IL-15 (p = 0.002), and IL-18 (p = 0.017), but not IL-4 and IL-10. IFN-gamma expression in JRA, but not controls, correlated strongly with IL-12p35 (r = 0.63) and IL-12p40 (r = 0.73) levels. A subset of IL-15+ and IL-18+ cells was detected in JRA synovial tissues, largely within perivascular aggregates.


CONCLUSIONS
JRA synovial tissue cytokine expression patterns indicate a type 1 bias, even in the later stages of disease. The strong correlation between IFN-gamma and IL-12 in JRA suggests a prominent role for IL-12 in promoting the type I bias, while IL-15 and IL-18 may also indirectly increase IFN-gamma expression and further bias the immune response.
Scola
Michael P
MP
Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Thompson
Susan D
SD
Brunner
Hermine I
HI
Tsoras
Monica K
MK
Witte
David
D
Van Dijk
Marc A
MA
Grom
Alexei A
AA
Passo
Murray H
MH
Glass
David N
DN
D000293:Adolescent; D001171:Arthritis, Juvenile / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology
D019409:Interleukin-15; D020382:Interleukin-18; D012333:RNA, Messenger; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma