Autologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves' ophthalmopathy.
OBJECTIVE
Graves' ophthalmopathy (GO) affects 50% to 60% of patients with Graves' hyperthyroidism, resulting in exophthalmos, periorbital edema, pain, double vision, optic neuropathy, and loss of vision. Fibroblasts are a key autoimmune target in GO and have effector functions that contribute to GO-associated pathologic conditions, including proliferation, production of excess glycosaminoglycans, and fat deposition. GO is also characterized by autoimmune inflammation of orbital connective tissue with mononuclear cell infiltration, including T cells.


METHODS
To determine whether autologous T cells can drive proliferation of orbital fibroblasts and thus contribute to GO, a novel reverse autologous mixed-cell reaction (rAMCR) was performed. Fibroblasts cultured from orbital tissue of patients with GO that was removed during orbital decompression surgery were mixed with autologous T cells, and fibroblast proliferation was determined.


RESULTS
Autologous T cells stimulated proliferation of orbital fibroblasts. Fibroblasts derived from blepharoplasty fat of two different patients did not proliferate, demonstrating that the effect is specific to cells derived from deep orbital fat. Proliferation was dependent on cell contact and on major histocompatibility complex (MHC) class II and CD40-CD154 (CD40 ligand) signaling.


CONCLUSIONS
The results suggest that T cells and orbital fibroblasts participate in an antigen-dependent positive feedback loop in which presentation of autoantigens by fibroblasts via MHC class II and CD40-CD40L signaling results in T-cell activation. These activated T cells stimulate fibroblast proliferation, leading to fibroblast-associated diseases in GO. Thus, therapies that interfere with CD40-CD40L signaling, antigen expression by fibroblasts, or T-cell function may be effective in preventing progression of GO symptoms.
Feldon
Stephen E
SE
Department of Ophthalmology, University of Rochester, NY 14642, USA.
Park
D J John
DJ
O'Loughlin
Charles W
CW
Nguyen
Vu T
VT
Landskroner-Eiger
Shira
S
Chang
Donald
D
Thatcher
Thomas H
TH
Phipps
Richard P
RP
D017951:Antigen Presentation; D001324:Autoantigens / Q000502:physiology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D049970:Graves Ophthalmopathy / Q000473:pathology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D009915:Orbit / Q000473:pathology*; D013601:T-Lymphocytes / Q000502:physiology*
D001324:Autoantigens; D019013:CD40 Antigens; D000949:Histocompatibility Antigens Class II; D023201:CD40 Ligand