Download - Immunology of the skin and the eye
he importance of ‘regional im-
munity’ was highlighted by a
comparison of how general im-
munological mechanisms were
modified for diffcrrnt lissurs such a5 the
eye and the skin (W. Streilein, Boston, MA).
The conjunctive, the intraocular eye and the
skin are equipped with indigenous antigen-
presenting cells (APCsI, afferent and rffer-
ent routes for communication with the im-
mune system, draining lymphoicl organs and
unique microenvironments created by their
constituent parenchymal ceils (Table 1). The
ocular surface konjunctiva) resembles (and
is in fact a component of) the mucosnl in-t-
mune system. Immune responses at this site
differ from both conventional skin immunity
and ocular immune privilege by emphasiz-
ing IgA antibodies as effector molecules.
General immunology of skin and
w= The type of immunity generated via the skin
is dominated by T cells that mediate de-
layed-type hypersensitivity (LITHI T helper
1 (Tl~lbtyx responses. By contrast, immun-
itv generated via tile eye leads to a deviant
immune response dominated by CDS’
T cells, often with a CD4’ Th2 component.
This aspect of ocular immune privilege has
been designated anterior-chamber-associ-
ated immune deviation CACAID) and de-
pends upon many unique ocular factors, in-
cluding constitutive intraocular expression
of Fas ligand IFa&), which may protnote
deletion of activated T cells in the eye’. Thl-
type skin immune responses can be modified
by changes to the cutaneous microenviron-
ment: for example, ultraviolet-l3 radiation in-
duces keratinocytes to produce factors such
as ris-uranic acid, tumor necrosis factor a
(TNF-4 and interleukin 10 f&IO) with the
abilitv to prevent cutaneous APCs from ac-
tivating naive T cells (1. Simon, Freiburg).
Similarly, ocular Th2-type responses and
ACAID can be abolished if ocular inflam-
mation is present at the time of antigen
administration into the eye’.
Maturation of skin dendrilic cells (I33
during culture is characlerized by d cessation
of major histocompatibility complex IMHCI
class 11 syntlwsis. However, in contrast to macropltage mnturc3 tion and activa tinn, the
expression of MHC class 11 in association
with antigal is stable and long-lived. A fur-
ther characteristic is the early expression of
accessorv molecules, which may be required
for initial nonspecific T-cell chlstcring lvith
APCs. The importance of CD&CD40 ligand
(CRLLOL) and Fas-FasL interactions during
this early phase of T-cell-APC interaction
was aiso emphasized’ and c!earlv has rele- i vance for intraoculLlr ACAlD mechanisms.
The role of t~tr;QceHular matrix ligands in ef-
fecting maturation was also highlighted in a
videotape analysis of DC motility in collagen
gels (E. K?impgec, Wiirzburg).
Ocular DCs occur in several different
sites including the c~~ijunctivvrt, the snterior
urea (iris/ciliary body), the posterior uvca
(chorotd) artd the orbital adncme CJ. Forrester,
Aberdeen). Conjunctival KS arc 111 many
ways similar to skin Langerlwns cells {LC’s)
and migrate lo the’ draining submandibular
and cervical lymph node when activated by
antigen {see Table 1). Intraocular DCs and/
or resident macrophages are presumed to
mediate ocular immune privilege via cyto-
kines such as transforming growth factor
p2 (TGF-P2). DCs in the posterior uveal
(choroidal) tract appear to be of two types
including a very large, tnntile veil-like cell
and rl smaller, migratory dendritiform cell.
ln addition, retin,ll pigment cpithclial (RPE)
cells modulate the function of choroidal
DCs depending on tile cocktail of cytokines
produced by resident cells. For example, in
response to IL-lp and TNF-a, RPE cells are
indtlccd to rclcnse graiiulocyt~2_macr(~pl~age
colony-slimulatil~g factor (GM-CSF) and
RANTES, which p remote APC clwmotaxis
and function, while in the presence of inter-
feron y (TFN-y) and TGF-P, tlw predominant
cytokine ruleasecl is IL-6 (Ref. 4.
There is IIO~Y accumulating evidence to sup-
port the cllncept of atopic dermatitis as a
paradigm cd an IgE-mediated DTH reac-
tion, \\*herr FceRI-expressing LCs represent
the pivotal Jsment (T. Siebcr, Munich)‘.
While nt~mal LCs qwess low amounts of
l&RI, the expression is strongly and specifi-
cally increased t ” Atopic dermatitis. Besides
the rcle<Isc of proinflammatory cytokines,
LCs use FceRI for antigen focusing for effi-
cicnt stimulation of T cells with minute
amounts nf allergens. Eosinophiis are also
believed to be of major importance as effec-
tor cells mediating the pathogenetically rel-
evant late-phase reaction, which is associ-
ated with a significant destruction of the
surrounding tissue in atopic dermatitis (A.
Kapp, HannoverIh. Toxic proteins that are
detected in this disease, such as eosinophil
c&ionic protein (ECP~, might play an im-
portant role by propagating the allergic in-
flammatory process and by modulating the
immune response. In addition, ECP levels
cumhtcd with ilw disease activity.
There are five allqic eye dlseascs: sea-
sonal allergic conjunctivitis, perennial aller-
gic conjunctivitis, giant papillary conjunc-
tivitis, vernal keratoconjunctivitis (VKC) and
atopic keratoconjunctivitis (AKC). VKC and
AKC are chronic, complex in mechanism,
and carry major blinding potential
ii,i 9 I ,’ -<- {‘l,,iy(,ji, >
IMMUNOLOGY TODAY
0X. Foster, Boston, MA). Like their derma-
tological counterparts, cells of an immediate
and a late-phase reaction are detectable,
While mast-cell mediators are important
contributors to the ocular damage, eviderze
now indicates that, in patients with VKC and
AKC, cytokines released from eosinophils in
the late phase catise damage to ocular cells
leading to cornea1 involvement. Although
mast-cell stabilizers represent an advance in
the development of drugs that can help pre-
vent blinding in VKC and AK (Ref. 7), more
attention to eosinophil modulation is clearly
needed. Cyclosporin A might be effective in
reducing the immunological damage, but its
effects are incomplete and are not uniform.
IL-13 and IL-4 are equally potent in
inducing IgE-synthesis (E. Wierenga,
Amsterdam). In contrast to Thl cells, Th2
celIs express a rather low killing capacity.
The secretory repertoire of APCs such as
monocytes and DCs might be crucial in
skewing the T-cell profile. Lipopolysac-
charide (LPS)-stimulated monocytes pro-
duce IL-12 within 8 h but prostaglandin E,
@‘GE,) is released after 24 h. IL-12 and PGE,
can direct the outcome of the differentiation
of naive T cells towards Thl and Th2 cells,
respectively. However, IL-12 can exacerbate
ongoing Th2 responses, so that its use in
therapy of allergic diseases is questionable
(I? Jeannin, Geneva). Similarly, there is some
evidence that strategies aimed at down-
regulating IgE synthesis by altering
CD4OXD40L interaction with recombinant
molecules lack promise. By contrast, some
hope could be invested in N-acetyl-cystein
(NAC), which is known to interfere with
apoptosis. Indeed, results b vitro suggest
that NAC decreases IL-4 production by
T cells and thereby inhibits the transcription
of mature IgE transcripts. Furthermore,
feeding rats with NAC strongly modulates
IgE synthesis in vivo.
!kcsicSosis
Besides lung infiltration, sarcoidosis can
lead to various forms of skin and eye mani-
festations. Cutaneous sarcoidosis has vari-
ous clinical appearances: for example, typi-
cal nodules and plaques, erythema nodosum
or the characteristic lupus pernio tK. Degitz,
Munich). Skin and ocular sarcoidosis
Ie I. erties of the skib an
Cornea and Skin Conjunctiva intraocular tissue
LCs {epidermis); LCS DCs, macrophages
None {cornea): DCs. macrophages
(dermis) (uveal tract)
Component
Local APCs
Homing CLA+; L-selectin’ Unknown Unknown _
Afferent route Lymphatics Lymphatics Aqueous drainage
via veins
Blaockissue barrier Fenestrated
Lymphoid organ Regionai lymph
node
Fenestrated Tight junctions
Regional lymph Spleen
node
Abbreviations: APCs, ant&en-presenting; cells; CLA, cutaneous lymphocyte antigen; DCs, dendritic cells; LCs, Langerhans cell;. _ ”
(uveitis) (M. Zierhut, Tiibingen) can mimic
various other disorders both clinically and
imrnunohistologically, raising the possibility
that sarcoidosis could be a more general
inflammatory response to several antigens.
No single suspected antigen seems to be re-
sponsible in the majority of cases, and re-
cent studies trying to identify mycobacterial
DNA by polymerase chain reaction in sarcoid
lesions have gtlderally been disappointing.
The characteristic lymphopenia in sar-
coidosis reflects a redistribution of lympho-
cytes to sites of inflammation. Depending
on the organ, the CD4:CDB ratio is elevated,
reaching 1O:l in the choroid of uveitis pa-
tients. Activated macrophages and Thl cells
are the predominant cells in the lesions. The
role of Thl and Th2 cells has been studied
exclusively in the lung (E. Fireman, Tel Aviv):
Th2 cells favor fibrosis whereas Thl cells
can lead to resolution. A low ratio of Thl :Th2
cells therefore carries a bad prognosis. In
the lung, an overexpression of T-cell recep-
tor (TCR) yl has been found, but T cells in
the lacrimal gland also show an abundance
of TCR variable (V)Sl, VS2, Vyl and Vy3
(Ref. 8). Therapy with IFNy, which shifts
the balance to Thl cells, has already shown
promising results in pulmonary disease, but
has not been used in ocular sarcoidosis.
Pigment cells and tumors of the skin and eye Pigment cells of the skin and eye can gener-
ate malignant neoplasms. However, the
behavior of melanomas that originate from
skin differs markedlv from that of ocular
melanomas. More importantly, the immune
system participates in the pathogenesis of
both types of melanomas, but in different
ways. Bv contrast to skin melanomas, OCU- i lar melanoma5 arise in ai immunologically
privileged site (B. Ksander, Boston, MA).
Although the primary ocular tumors grow
Slowly, more than 50% of patients develop
distant metastases (chiefly liver) for which
there is no cure”. However, since the intcr-
val between primarv and distant m&stases
is often verv Long, there is time for immune
intervention, such as the use of tumor-
specific vaccines. Experiments have been
aimed at creating such a vaccine by trans-
fecting 87 and IL-12 into tumor cells from
human primary ocular melanomaP. Trans-
fected cells readily activate tumor-specific,
HLA-restricted cytotoxic T cells. Moreover,
metastatic cells from ocular melanomas ex-
press abundant class 1 molecules, rendering
them susceptible to killer-cell lysis. Thus, the
potential exists that a vaccine derived from
primary ocular melanomas might induce im-
munity of a type able to prevent metastases
from estabiishing residence in distant organs.
In contrast to ocular melanoma, primary
cutaneous melanoma frequently undeigoes
partial regression, and is coms1~~11y infil-
trated by T cells and macrophages. k~-
ever, the paradox is the coexistence of mela-
noma-specific immunity IVitli mclanonia
pqyession. Several mechanisms have been
found in melanoma that explain its escape
from immune recognition and destruction
(E. Br&ker, W iirzburg) (reviewed in Ref. 11).
These include: genetic instability leading
to early antigenic heterogeneity; loss of ex-
pression of MHC class i antigen during local
and systemic progression; release of secre-
tory intercellular adhesion molecule 1
(sICAM-I ) by melanoma cells, thereby
blocking tumor-leukocyte interactions; pro-
duction of immunosuppressive cytokines
such as TGF-PI and IL-10 by melanoma
cells; and induction of anergy by melanoma
cells in CQ4’ autologous T cek’z.
These mechanisms should thus be the targets of immunotherapy in skin and eye
melanoma.
Conchding remarks By comparing the eye and the skin, this meet-
ing highlighted how tissues modulate the
immune response: immunological mecha-
nisms in allergic responses in the skin and
in the conjunctiva have many features in
common, mediated by similar populations
of APCs. By contrast, tumor reponses are
quite different, e.g. for skin and eye mda-
noma, in which ACAID appears to have a
major modulating effect. However, ACAID
might not be wholly protective for T-cell
mediated responses since conditions such as
systemic sarcoidosis can affect all ocular com-
ponents. Clearly, selective tissue immuno-
regulatory mechanisms can be bypassed
if the microenvironmental condition5 are
changed appropriately. Current research is
aimed at determining how these changes
are induced.
References
1 Griffith, T.S., Brunner, T., Fletcher, SM.,
Green, D-R. and Ferguson, T-A. (1995) Scieme
270,1189-1192
2 Streilein, J.W., Bradley, D., Sane Y. and
Sonoda, Y. (1996) hwst. Og~htl~dJ~20I. Vis. Sci. 37,
413-424
3 Ktimpgen, E., Gold, R., Egg&, A. et nl.
(1995) 1. Crll. BiocRrrli. CSuppl.) 21h, 12
4 Kuppner, MC., McKillop-Smith, S. and Forrester, J.V. (1995) Iwnr~rw~log!/ 84, 265-271
5 Bieber, T. Clrl-I. O@. Iwwtrr~oI. (in press)
6 Kapp, A. (1993) AIfqy 48, 1-5
7 Foster, C.S. and Calonge, M. (19901
Ophflinlw~oloS!/ 97, 992-1000
8 Smith, J.A.. Whitcup, S., Mahdi, R.M.,
Nussenblatt, R.B. and Egwuagu, C.E. (1995)
!JKkYf. Ophh~hJ~~. Vis. Pi. 36, 537
9 Zimmermann, L,E. and McLean, J.W. 11979)
AJII. 1. Ophtkahol. 87, 741
10 Ksander, B.R,, Rubsamen, I?, Olsen, K.,
Cousins, S.W. and Streilein, J.W. I19911 Iwest.
O,t~l~!l~r?lf?rol. Vis. 5-i. 32, 3198-3208
11 Riinger, T.M., Klein, CL, Becker, J.C. and
Brticker, E.B. (1994) C~,rr. Ollii~. O~~cu~. 6,
18% 1% 12 Becker, J.C., Brablctz,T., Conrad, C.T.,
BrGcker, E.B. and R&&Id, R.A. (1995) Proc.
Nntl. Ad. SC-i. U. S. A. 92, 2375-2378
Emmanna Ciccone, Carlo Enrico Grossi and Andrea Velardi
t has been shown recently that a
subset of CD3’CDS’ cytotoxic
T lymphocytes (CTLs) egress surface
.moIecules of the immunoglobulin
superfamily that function as receptors for
human major histocompatibility complex
[MHC) HLA class I alleles and exert in-
hibitory effects on cell-mediated cytoly-
sislW3. These receptors, which are typically
found on a large proportion of CD3- T-celi
receptor (TCR)- natural killer (NKl cellsJ,5,
have been tentatively termed kiIl?r-cell ir
hibitory receptors UURsY’, and can be sub-
divided into GL183 (Refs 1, 2) specific for
(see Table 1). In normal subjects, this CTL
subsrt accounts for less than 5% of the pti-
ripheral blood T cells, but it is expanded
considerably 040%) in the reconstitution
phase that follows bone marrow transplan-
tation (BMT) from three loci-incompatible
donors7. CTLs also express activatory TCRs
that are capable of triggering the cytolytic
program of these cells.
Thus, there is convincing evidence for
the existence of a subpopulation of CTLs
that express two distinct sets of receptors for
HLA class I molecules that mediate opposite
functions.
PII 10161.5699(96)30054.6