Immunology of the skin and the eye

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  • 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 {LCs)

    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


    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.


    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)


    Local APCs

    Homing CLA+; L-selectin Unknown Unknown _

    Afferent route Lymphatics Lymphatics Aqueous drainage

    via veins

    Blaockissue barrier Fenestrated

    Lymphoid organ Regionai lymph


    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 cekz.

    These mechanisms should thus be the targets of immunotherapy in skin and eye


    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.


    1 Griffith, T.S., Brunner, T., Fletcher, SM.,

    Green, D-R. and Ferguson, T-A. (1995) Scieme


    2 Streilein, J.W., Bradley, D., Sane Y. and

    Sonoda, Y. (1996) hwst. Og~htl~dJ~20I. Vis. Sci. 37,


    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 CD3CDS 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


    PII 10161.5699(96)30054.6