Increased severity of murine lupus in female mice is due to enhanced expansion of pathogenic T cells.
A strong female predominance is a well-recognized feature of human lupus. The mechanism by which sex influences disease expression and severity is not fully understood. To address this question, we used the parent-into-F(1) (p-->F(1)) model of chronic graft-vs-host disease (cGVHD) in which lupus-like humoral autoimmunity and renal disease are induced in normal F(1) mice. An advantage of this model is that the pathogenic T cells driving disease (donor strain) can be studied separately from nonspecifically activated T cells (host strain). We observed that lupus-like disease using female donor and host mice (f-->F cGVHD) is characterized by more severe long-term disease (glomerulonephritis) than with male donor and host (m-->M cGVHD). Interestingly, differences in disease parameters could be seen at 2 wk after parental cell transfer, as evidenced by a 2- to 3-fold greater engraftment of donor CD4(+) T cells in f-->F cGVHD mice, which persisted throughout disease course. Enhanced engraftment of donor CD4(+) T cells in f-->F cGVHD mice was not due to differences in splenic homing, alloreactive precursor frequency, initial proliferation rates, or apoptotic rates, but rather to sustained high proliferation rates during wk 2 of disease compared with m-->M cGVHD mice. Crossover studies (m-->F, f-->M) demonstrated that enhanced donor CD4(+) T cell proliferation and engraftment segregate with the sex of the host. These results demonstrate that the sex of the recipient can influence the expansion of pathogenic T cells, thus increasing long-term the burden of autoreactive T cells and resulting in greater disease severity.
Lang
Thomas J
TJ
Research Service, Baltimore Veterans Affairs Medical Center, Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. tlang001@umaryland.edu
Nguyen
Phuong
P
Papadimitriou
John C
JC
Via
Charles S
CS
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002908:Chronic Disease; D005260:Female; D006082:Graft Enhancement, Immunologic / Q000379:methods; D007275:Injections, Intravenous; D007519:Isoantigens / Q000276:immunology; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012720:Severity of Illness Index; D012727:Sex Characteristics; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology*; D013997:Time Factors
D007519:Isoantigens