How circulating autoimmune lymphocytes are able to recognize their
target tissue in naive hosts is still unknown. The need for activation
of T cells before transfer suggests that T-cell migration may depend on
inducible molecules. Indeed, it has been shown that activated T cells
of any antigen-specificity can penetrate the central nervous system but
that only T cells specific for antigens present in the tissue remain
there.
35 For experimental autoimmune uveitis Prendergast
et al.
38 have shown that distribution is independent of
T-cell specificity within the first 24 hours; however, a second peak of
T-cell influx is observed 96 to 120 hours after inoculation only when
activated experimental autoimmune uveitis–inducing T cells were
injected. Furthermore, Zhang
39 has shown that after the
encounter in vivo, transferred antigen-specific T cells expand 10- to
15-fold followed by a decline in number due to activation-induced
apoptosis. Zhang also showed that the remaining transferred cells were
fully unresponsive in vitro when cultured with their antigen, even in
the presence of added IL-2 and IL-4.
39 Whether these
observations on T-cell traffic apply to the cornea remains to be
investigated, because the cornea lacks blood vessels and MHC class II
expression.
40 It is therefore not clear how
cornea-specific T-cell lines might enter the cornea and mediate
keratitis. Irradiation of the eye may therefore be needed to cause
damage that “opens” the barrier between the cornea and circulating
immune cells. Liu
23 found that keratitis developed in
rabbits immunized to corneal antigens only if accompanied by uveitis
produced by injection of cytokines into the eye. Induction of uveitis
contributes to the breakdown of blood-ocular barriers and abrogation of
ocular immune privilege. In uveitis, reduced levels of TGF-β2 are
found in ocular fluids,
41 and TGF-β2 is a central factor
for the induction of anterior chamber-associated immune
deviation.
42 Likewise, local irradiation of the eye,
associated with development of transient edema, may break down ocular
barriers and increase the permeability of corneal stroma, allowing the
influx of macromolecules and possibly cells. Induction of cytokine
production by corneal cells could also be implicated in the
immunopathogenesis. It has been reported that 5 hours after sublethal
irradiation (7.0 Gy) in mice, upregulation of gene expression for
IL-1β, IL-3, IL-6, and G-CSF could be detected mouse
spleens.
43 Note that the ability of T-cell lines or clones
to cause arthritis in rats also required irradiation of the
recipients.
44 In the arthritis studies, however, it was
not feasible to discriminate between the effects of local and systemic
irradiation.