A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice.
The tight skin (Tsk/+) mouse represents a murine model of heritable fibrosis with some similarities to the skin fibrosis seen in human scleroderma. Tsk/+ animals display alterations in connective tissue in some internal organs. Skin fibrosis can be adoptively transferred to normal recipients with Tsk/+ bone marrow or spleen cells and older Tsk/+ animals develop autoantibodies against topoisomerase suggesting that some of the pathogenesis in the Tsk/+ mouse may be mediated by autoimmunity. To determine the role of T cell subsets in the pathogenesis of fibrotic disease, Tsk/+ mice were bred with CD4- and CD8-deficient (CD4-/- and CD8-/-) mice. Tsk/+ CD4-/- mice showed a marked reduction in skin fibrosis as well as decreased cellularity and only mild collagen disorganization as compared to Tsk/+ CD4+ CD8+ control mice yet did not differ from Tsk controls in the level of serum anti-topoisomerase activity. In contrast, Tsk/+ CD8-/- mice exhibited the same histology in the skin as Tsk/+ controls yet had significantly reduced levels of serum anti-topoisomerase activity. Lung pathology, i.e. emphysema, was unaffected by both the CD4 or CD8 mutations. These data show that only some of the pathological effects of the Tsk mutation are T cell dependent and that different T cell subsets affect different parameters in this multi-organ model of fibrotic disease.
Wallace
V A
VA
Amgen Institute, Department of Immunology, University of Toronto, Ontario, Canada.
Kondo
S
S
Kono
T
T
Xing
Z
Z
Timms
E
E
Furlonger
C
C
Keystone
E
E
Gauldie
J
J
Sauder
D N
DN
Mak
T W
TW
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000276:immunology; D008168:Lung / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D012867:Skin / Q000473:pathology*
D001323:Autoantibodies; D004264:DNA Topoisomerases, Type I