Absence of 4 1BB gene function exacerbates lacrimal gland inflammation in autoimmune-prone MRL-Faslpr mice.
OBJECTIVE
To define the role of endogenous 4-1BB (an important T-cell costimulatory molecule) in the regulation of ocular disease, MRL-Fas(lpr) mice deficient in 4-1BB were generated, and their lacrimal gland function was studied.


METHODS
4-1BB(-/-)MRL/MpJ-Tnfrs(lpr)/Tnfrs(lpr) (lpr/4-1BB(-/-)) mice were generated and used at the ninth backcross. Mice were killed at various times, and lacrimal gland cellularity was analyzed by flow cytometry. Tear and tissue samples were analyzed by Western blotting for the presence of aquaporin 5 (AQP5) and 120-kDa fragments of alpha-fodrin. Cytokine expression of lacrimal glands was assessed by flow cytometry and RT-PCR analysis.


RESULTS
Absence of the 4-1BB gene function in lpr mice resulted in early and increased infiltration of mononuclear cells into lacrimal glands compared with 4-1BB intact lpr mice. The severity of lesions in lpr/4-1BB(-/-) mice was closely associated with enhanced accumulation of primarily CD4(+) T cells within the lacrimal glands and with increased expression of IL-4. Elevated levels of AQP5 and cleaved 120-kDa fragments of alpha-fodrin were found in tears and lacrimal gland lysates, respectively, of lpr/4-1BB(-/-) but not lpr/4-1BB(+/+) mice.


CONCLUSIONS
Deletion of 4-1BB in lpr mice accelerates lacrimal gland lesions through increased CD4(+) T-cell infiltration and their production of immune modulators.
Vinay
Dass S
DS
LSU Eye Center, LSU Health Sciences Center School of Medicine, New Orleans, Louisiana, USA.
Kim
Jung D
JD
Asai
Tatsuhiko
T
Choi
Beom K
BK
Kwon
Byoung S
BS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003607:Dacryocystitis / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D020868:Gene Silencing / Q000502:physiology*; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007765:Lacrimal Apparatus / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics*; D015854:Up-Regulation
D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D015847:Interleukin-4; D007371:Interferon-gamma