Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens
Xm. Yan et al., Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens, CLIN EXP IM, 122(2), 2000, pp. 170-179
AKR/N mice injected with fibroblasts expressing MHC class II (RT4.15HP cell
s) and the TSH receptor (TSHR) develop antibodies similar to those in Grave
s' disease. We were unable to analyse the subclass of these antibodies beca
use of unexpectedly high non-specific binding by ELISA or flow cytometry. T
he non-specific binding reflected generalized immune activation which occur
red even when the fibroblasts did not express the TSHR. However, the IgG su
bclasses were determined for thyroid peroxidase (TPO) antibodies induced us
ing TPO-expressing RT4.14HP cells and found to be IgG2a > IgG1. This Th1 pa
ttern is consistent with spontaneous secretion of interferon-gamma (but not
IL-4 or IL-10) by splenocytes from injected mice. The Th1 bias was related
to fibroblast injection because conventional immunization of the same mous
e strain with purified TPO and adjuvant induced a Th2 response (IgG1 > > Ig
G2a). Further, untransfected fibroblasts themselves induced powerful, non-s
pecific proliferative responses when used as antigen-presenting cells (APC)
in vitro. Flow cytometry revealed that the RT4.15HP fibroblasts (and TSHR-
and TPO-transfected derivatives) expressed B7-1. Unexpected constitutive e
xpression of this key molecule may bypass the requirement for up-regulation
of other costimulatory molecules involved in T cell stimulation. Our data
support the concept that RT4.15HP fibroblasts present the TSHR (or TPO), at
least for initiating the immune response. However, the accompanying genera
lized immune stimulation creates difficulties for analysis of TSHR-specific
T and B lymphocytes. On the other hand, extension of the model to TPO, an
easier antigen to study, will facilitate analysis of murine T cell response
s likely to resemble those in human thyroid autoimmunity.