Reduced thymic Aire expression and abnormal NF-kappa B2 signaling in a model of systemic autoimmunity.
The thymic stromal niche normally directs the production and export of a self-tolerant T cell repertoire. Many models of spontaneous autoimmunity, however, develop thymic architectural abnormalities before disease onset. Although this is suspected to affect central tolerance induction, creating an autoimmune predisposition, in-depth analysis of the microenvironment within these thymi is lacking, such that the mechanisms and likely direct effects on the T cell repertoire are unknown or speculative. Here we show that NZB mice, the first described model for systemic autoimmunity, demonstrate a complex thymic phenotype, including a lack of the autoimmune regulator (Aire), early defects in thymic epithelial cell (TEC) expansion, and evidence for altered NF-kappaB2 signaling. Analysis of medullary TEC revealed a numerical loss of the Aire-expressing MHC class II(high) (mTEC-high) subset as well reduced Aire protein and mRNA per cell. RelB expression was also reduced, while chemokines CCL19 and CCL21 were increased. Unexpectedly, the proportion of cortex and medulla in the NZB mice was normal from 36 wk, despite worsening architectural abnormalities. These data show that the NZB defect is more complex than previously appreciated, segregating into early numerical TEC deficiencies that correct with age, late degeneration of the niche architecture that does not affect TEC number, and a persistent reduction in Aire and RelB expression per cell acquired upon mTEC-high differentiation.
Fletcher
Anne L
AL
Immune Regeneration Laboratory, Monash University, Clayton, Victoria, Australia.
Seach
Natalie
N
Reiseger
Jessica J
JJ
Lowen
Tamara E
TE
Hammett
Maree V
MV
Scott
Hamish S
HS
Boyd
Richard L
RL
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016130:Immunophenotyping; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008814:Mice, Inbred NZB; D052003:NF-kappa B p52 Subunit / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic / Q000276:immunology; D000096927:AIRE Protein
D052003:NF-kappa B p52 Subunit; D014157:Transcription Factors; D000096927:AIRE Protein