,*
* Neurocrine Biosciences, Inc., San Diego, California;
BD Biosciences, San Diego, California; and
Department of Medicine, Rheumatology Section, E550, Boston University Medical Center, Boston, Massachusetts
Correspondence: Dr. David Alleva, Neurocrine Biosciences, Inc., 10555 Science Center Dr., San Diego, CA 92121-1102. E-mail: dalleva{at}neurocrine.com
Genetic susceptibility of the SJL mouse to experimental autoimmune
encephalomyelitis (EAE) appears, in part, to be a result of genes that
promote abnormal development of the pathogenic Type 1 (Th1) phenotype
of neuroantigen-specific T-cells. Because antigen-presenting/accessory
cells (APCs) produce cytokines that can modulate the development of Th1
and Th2 phenotypes, we addressed whether APCs from SJL mice were
genetically programmed for elevated expression of the Th1-promoting
cytokine, IL-12. Activated peritoneal macrophages (M
; i.e., APC)
from naïve SJL mice produced levels of TNF-
, IL-1, IL-6,
IL-10, and TGF-ß within the range of six normal strains. In contrast,
SJL IL-12p40 (in addition to IL-12p70) production was consistently
five- to 20-fold greater than that of any normal strain tested, which
arose from elevated expression of the IL-12p40 but not the IL-12p35
gene, because p40 mRNA levels were eight- to 15-fold greater than those
of normal strains. This aberrancy in IL-12p40 expression appears
identical to that observed in the NOD mouse, another strain prone to
organ-specific autoimmunity. A genetically programmed bias toward
elevated expression of IL-12 in M from the SJL and NOD strains of
autoimmunity provides a conserved mechanism for the dominant Th1
development of naïve, autoantigen-specific T-cells in these
strains. This study is the first demonstration of a genetically
programmed aberrant phenotype that is intrinsically expressed within a
cell type in the SJL mouse and provides insight into its predisposition
for EAE.
Key Words: EAE • diabetes • antigen-presenting cell • multiple sclerosis • cytokines
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