Mechanisms of spontaneous resolution versus fibrosis in granulomatous experimental autoimmune thyroiditis.
When granulomatous experimental autoimmune thyroiditis (G-EAT) was induced in CBA/J or DBA/1 mice, thyroid lesions resolved in less severe (3+) G-EAT in wild-type mice or severe (5+) G-EAT in IFN-gamma(-/-) mice, but progressed to fibrosis in 5+ G-EAT in wild-type mice. To define the mechanisms leading to these distinct outcomes, the expression of inflammatory and apoptotic molecules and infiltrating cells was evaluated using immunohistochemistry, RT-PCR, and confocal microscopy. The ratio of CD4(+)/CD8(+) T cells in thyroid infiltrates was one factor that predicted G-EAT outcome. CD4(+) T cells outnumbered CD8(+) T cells when lesions progressed to fibrosis, while CD8(+) T cells outnumbered CD4(+) T cells in thyroids that resolved. Fas, Fas ligand, FLIP, TNF-alpha, inducible NO synthase, TGF-beta, and IFN-gamma were highly expressed by infiltrating cells when G-EAT progressed to fibrosis. The expression of active caspase-3 was low, possibly contributing to the persistence of CD4(+) T cells in fibrosis. In contrast, FLIP was mainly expressed by thyrocytes in resolving G-EAT, the expression of active caspase-3 was high, and resolution correlated with apoptosis of infiltrating cells. There was also relatively less expression of TGF-beta, IFN-gamma, TNF-alpha, and inducible NO synthase and higher expression of IL-10 in resolving G-EAT than in G-EAT that progressed to fibrosis. These differences were particularly striking when comparing IFN-gamma(-/-) vs wild-type mice. These results suggest that several opposing biological mechanisms contribute to the outcome of an ongoing autoimmune response. These include differential expression of pro- and antiapoptotic molecules, cytokines, and the ratio of CD4(+) vs CD8(+) T cells.
Chen
Kemin
K
Department of Internal Medicine, University of Missouri School of Medicine, and Veterans Affairs Research Service, Columbia, MO 65212, USA.
Wei
Yongzhong
Y
Sharp
Gordon C
GC
Braley-Mullen
Helen
H
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D006099:Granuloma / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D013961:Thyroid Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013967:Thyroiditis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology*
D016207:Cytokines; D007371:Interferon-gamma