Immunology of the skin and the eye

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<ul><li><p>he importance of regional im- </p><p>munity was highlighted by a </p><p>comparison of how general im- </p><p>munological mechanisms were </p><p>modified for diffcrrnt lissurs such a5 the </p><p>eye and the skin (W. Streilein, Boston, MA). </p><p>The conjunctive, the intraocular eye and the </p><p>skin are equipped with indigenous antigen- </p><p>presenting cells (APCsI, afferent and rffer- </p><p>ent routes for communication with the im- </p><p>mune system, draining lymphoicl organs and </p><p>unique microenvironments created by their </p><p>constituent parenchymal ceils (Table 1). The </p><p>ocular surface konjunctiva) resembles (and is in fact a component of) the mucosnl in-t- </p><p>mune system. Immune responses at this site differ from both conventional skin immunity </p><p>and ocular immune privilege by emphasiz- </p><p>ing IgA antibodies as effector molecules. </p><p>General immunology of skin and w= The type of immunity generated via the skin </p><p>is dominated by T cells that mediate de- </p><p>layed-type hypersensitivity (LITHI T helper 1 (Tl~lbtyx responses. By contrast, immun- itv generated via tile eye leads to a deviant </p><p>immune response dominated by CDS </p><p>T cells, often with a CD4 Th2 component. This aspect of ocular immune privilege has </p><p>been designated anterior-chamber-associ- </p><p>ated immune deviation CACAID) and de- pends upon many unique ocular factors, in- cluding constitutive intraocular expression of Fas ligand IFa&amp;), which may protnote </p><p>deletion of activated T cells in the eye. Thl- </p><p>type skin immune responses can be modified </p><p>by changes to the cutaneous microenviron- </p><p>ment: for example, ultraviolet-l3 radiation in- </p><p>duces keratinocytes to produce factors such </p><p>as ris-uranic acid, tumor necrosis factor a </p><p>(TNF-4 and interleukin 10 f&amp;IO) with the </p><p>abilitv to prevent cutaneous APCs from ac- </p><p>tivating naive T cells (1. Simon, Freiburg). </p><p>Similarly, ocular Th2-type responses and </p><p>ACAID can be abolished if ocular inflam- </p><p>mation is present at the time of antigen administration into the eye. </p><p>Maturation of skin dendrilic cells (I33 </p><p>during culture is characlerized by d cessation </p><p>of major histocompatibility complex IMHCI </p><p>class 11 syntlwsis. However, in contrast to macropltage mnturc3 tion and activa tinn, the </p><p>expression of MHC class 11 in association </p><p>with antigal is stable and long-lived. A fur- </p><p>ther characteristic is the early expression of </p><p>accessorv molecules, which may be required </p><p>for initial nonspecific T-cell chlstcring lvith </p><p>APCs. The importance of CD&amp;CD40 ligand </p><p>(CRLLOL) and Fas-FasL interactions during </p><p>this early phase of T-cell-APC interaction </p><p>was aiso emphasized and c!earlv has rele- i vance for intraoculLlr ACAlD mechanisms. </p><p>The role of t~tr;QceHular matrix ligands in ef- </p><p>fecting maturation was also highlighted in a </p><p>videotape analysis of DC motility in collagen </p><p>gels (E. K?impgec, Wiirzburg). </p><p>Ocular DCs occur in several different </p><p>sites including the c~~ijunctivvrt, the snterior </p><p>urea (iris/ciliary body), the posterior uvca (chorotd) artd the orbital adncme CJ. Forrester, Aberdeen). Conjunctival KS arc 111 many </p><p>ways similar to skin Langerlwns cells {LCs) </p><p>and migrate lo the draining submandibular </p><p>and cervical lymph node when activated by </p><p>antigen {see Table 1). Intraocular DCs and/ </p><p>or resident macrophages are presumed to </p><p>mediate ocular immune privilege via cyto- </p><p>kines such as transforming growth factor </p><p>p2 (TGF-P2). DCs in the posterior uveal </p><p>(choroidal) tract appear to be of two types </p><p>including a very large, tnntile veil-like cell </p><p>and rl smaller, migratory dendritiform cell. </p><p>ln addition, retin,ll pigment cpithclial (RPE) </p><p>cells modulate the function of choroidal </p><p>DCs depending on tile cocktail of cytokines </p><p>produced by resident cells. For example, in </p><p>response to IL-lp and TNF-a, RPE cells are </p><p>indtlccd to rclcnse graiiulocyt~2_macr(~pl~age </p><p>colony-slimulatil~g factor (GM-CSF) and </p><p>RANTES, which p remote APC clwmotaxis </p><p>and function, while in the presence of inter- </p><p>feron y (TFN-y) and TGF-P, tlw predominant </p><p>cytokine ruleasecl is IL-6 (Ref. 4. </p><p>There is IIO~Y accumulating evidence to sup- </p><p>port the cllncept of atopic dermatitis as a </p><p>paradigm cd an IgE-mediated DTH reac- </p><p>tion, \\*herr FceRI-expressing LCs represent </p><p>the pivotal Jsment (T. Siebcr, Munich). </p><p>While nt~mal LCs qwess low amounts of </p><p>l&amp;RI, the expression is strongly and specifi- </p><p>cally increased t Atopic dermatitis. Besides the rcle</p></li><li><p>IMMUNOLOGY TODAY </p><p>0X. Foster, Boston, MA). Like their derma- </p><p>tological counterparts, cells of an immediate </p><p>and a late-phase reaction are detectable, </p><p>While mast-cell mediators are important contributors to the ocular damage, eviderze </p><p>now indicates that, in patients with VKC and </p><p>AKC, cytokines released from eosinophils in </p><p>the late phase catise damage to ocular cells </p><p>leading to cornea1 involvement. Although </p><p>mast-cell stabilizers represent an advance in </p><p>the development of drugs that can help pre- </p><p>vent blinding in VKC and AK (Ref. 7), more </p><p>attention to eosinophil modulation is clearly </p><p>needed. Cyclosporin A might be effective in </p><p>reducing the immunological damage, but its </p><p>effects are incomplete and are not uniform. </p><p>IL-13 and IL-4 are equally potent in </p><p>inducing IgE-synthesis (E. Wierenga, </p><p>Amsterdam). In contrast to Thl cells, Th2 </p><p>celIs express a rather low killing capacity. </p><p>The secretory repertoire of APCs such as </p><p>monocytes and DCs might be crucial in </p><p>skewing the T-cell profile. Lipopolysac- </p><p>charide (LPS)-stimulated monocytes pro- duce IL-12 within 8 h but prostaglandin E, </p><p>@GE,) is released after 24 h. IL-12 and PGE, </p><p>can direct the outcome of the differentiation </p><p>of naive T cells towards Thl and Th2 cells, respectively. However, IL-12 can exacerbate </p><p>ongoing Th2 responses, so that its use in </p><p>therapy of allergic diseases is questionable (I? Jeannin, Geneva). Similarly, there is some </p><p>evidence that strategies aimed at down- </p><p>regulating IgE synthesis by altering </p><p>CD4OXD40L interaction with recombinant </p><p>molecules lack promise. By contrast, some hope could be invested in N-acetyl-cystein </p><p>(NAC), which is known to interfere with </p><p>apoptosis. Indeed, results b vitro suggest </p><p>that NAC decreases IL-4 production by </p><p>T cells and thereby inhibits the transcription of mature IgE transcripts. Furthermore, </p><p>feeding rats with NAC strongly modulates </p><p>IgE synthesis in vivo. </p><p>!kcsicSosis </p><p>Besides lung infiltration, sarcoidosis can </p><p>lead to various forms of skin and eye mani- </p><p>festations. Cutaneous sarcoidosis has vari- </p><p>ous clinical appearances: for example, typi- </p><p>cal nodules and plaques, erythema nodosum or the characteristic lupus pernio tK. Degitz, Munich). Skin and ocular sarcoidosis </p><p>Ie I. erties of the skib an </p><p>Cornea and Skin Conjunctiva intraocular tissue </p><p>LCs {epidermis); LCS DCs, macrophages </p><p>None {cornea): DCs. macrophages </p><p>(dermis) (uveal tract) </p><p>Component </p><p>Local APCs </p><p>Homing CLA+; L-selectin Unknown Unknown _ </p><p>Afferent route Lymphatics Lymphatics Aqueous drainage </p><p>via veins </p><p>Blaockissue barrier Fenestrated </p><p>Lymphoid organ Regionai lymph </p><p>node </p><p>Fenestrated Tight junctions </p><p>Regional lymph Spleen node </p><p>Abbreviations: APCs, ant&amp;en-presenting; cells; CLA, cutaneous lymphocyte antigen; DCs, dendritic cells; LCs, Langerhans cell;. _ </p><p>(uveitis) (M. Zierhut, Tiibingen) can mimic </p><p>various other disorders both clinically and </p><p>imrnunohistologically, raising the possibility </p><p>that sarcoidosis could be a more general </p><p>inflammatory response to several antigens. </p><p>No single suspected antigen seems to be re- sponsible in the majority of cases, and re- </p><p>cent studies trying to identify mycobacterial </p><p>DNA by polymerase chain reaction in sarcoid </p><p>lesions have gtlderally been disappointing. The characteristic lymphopenia in sar- </p><p>coidosis reflects a redistribution of lympho- </p><p>cytes to sites of inflammation. Depending </p><p>on the organ, the CD4:CDB ratio is elevated, </p><p>reaching 1O:l in the choroid of uveitis pa- </p><p>tients. Activated macrophages and Thl cells </p><p>are the predominant cells in the lesions. The </p><p>role of Thl and Th2 cells has been studied </p><p>exclusively in the lung (E. Fireman, Tel Aviv): </p><p>Th2 cells favor fibrosis whereas Thl cells </p><p>can lead to resolution. A low ratio of Thl :Th2 </p><p>cells therefore carries a bad prognosis. In </p><p>the lung, an overexpression of T-cell recep- </p><p>tor (TCR) yl has been found, but T cells in </p><p>the lacrimal gland also show an abundance </p><p>of TCR variable (V)Sl, VS2, Vyl and Vy3 (Ref. 8). Therapy with IFNy, which shifts </p><p>the balance to Thl cells, has already shown </p><p>promising results in pulmonary disease, but has not been used in ocular sarcoidosis. </p><p>Pigment cells and tumors of the skin and eye Pigment cells of the skin and eye can gener- </p><p>ate malignant neoplasms. However, the </p><p>behavior of melanomas that originate from skin differs markedlv from that of ocular melanomas. More importantly, the immune </p><p>system participates in the pathogenesis of </p><p>both types of melanomas, but in different ways. Bv contrast to skin melanomas, OCU- i lar melanoma5 arise in ai immunologically </p><p>privileged site (B. Ksander, Boston, MA). Although the primary ocular tumors grow Slowly, more than 50% of patients develop </p><p>distant metastases (chiefly liver) for which there is no cure. However, since the intcr- val between primarv and distant m&amp;stases </p><p>is often verv Long, there is time for immune </p><p>intervention, such as the use of tumor- specific vaccines. Experiments have been </p><p>aimed at creating such a vaccine by trans- </p><p>fecting 87 and IL-12 into tumor cells from human primary ocular melanomaP. Trans- </p><p>fected cells readily activate tumor-specific, HLA-restricted cytotoxic T cells. Moreover, metastatic cells from ocular melanomas ex- </p><p>press abundant class 1 molecules, rendering them susceptible to killer-cell lysis. Thus, the </p><p>potential exists that a vaccine derived from primary ocular melanomas might induce im- </p><p>munity of a type able to prevent metastases from estabiishing residence in distant organs. </p><p>In contrast to ocular melanoma, primary </p><p>cutaneous melanoma frequently undeigoes </p><p>partial regression, and is coms1~~11y infil- trated by T cells and macrophages. k~- </p><p>ever, the paradox is the coexistence of mela- noma-specific immunity IVitli mclanonia </p><p>pqyession. Several mechanisms have been </p><p>found in melanoma that explain its escape </p></li><li><p>from immune recognition and destruction </p><p>(E. Br&amp;ker, W iirzburg) (reviewed in Ref. 11). These include: genetic instability leading </p><p>to early antigenic heterogeneity; loss of ex- pression of MHC class i antigen during local and systemic progression; release of secre- </p><p>tory intercellular adhesion molecule 1 </p><p>(sICAM-I ) by melanoma cells, thereby blocking tumor-leukocyte interactions; pro- duction of immunosuppressive cytokines </p><p>such as TGF-PI and IL-10 by melanoma </p><p>cells; and induction of anergy by melanoma cells in CQ4 autologous T cekz. </p><p>These mechanisms should thus be the targets of immunotherapy in skin and eye </p><p>melanoma. </p><p>Conchding remarks By comparing the eye and the skin, this meet- ing highlighted how tissues modulate the immune response: immunological mecha- </p><p>nisms in allergic responses in the skin and </p><p>in the conjunctiva have many features in common, mediated by similar populations </p><p>of APCs. By contrast, tumor reponses are </p><p>quite different, e.g. for skin and eye mda- </p><p>noma, in which ACAID appears to have a </p><p>major modulating effect. However, ACAID might not be wholly protective for T-cell </p><p>mediated responses since conditions such as </p><p>systemic sarcoidosis can affect all ocular com- ponents. Clearly, selective tissue immuno- regulatory mechanisms can be bypassed </p><p>if the microenvironmental condition5 are </p><p>changed appropriately. Current research is </p><p>aimed at determining how these changes </p><p>are induced. </p><p>References </p><p>1 Griffith, T.S., Brunner, T., Fletcher, SM., </p><p>Green, D-R. and Ferguson, T-A. (1995) Scieme </p><p>270,1189-1192 </p><p>2 Streilein, J.W., Bradley, D., Sane Y. and </p><p>Sonoda, Y. (1996) hwst. Og~htl~dJ~20I. Vis. Sci. 37, </p><p>413-424 </p><p>3 Ktimpgen, E., Gold, R., Egg&amp;, A. et nl. (1995) 1. Crll. BiocRrrli. CSuppl.) 21h, 12 </p><p>4 Kuppner, MC., McKillop-Smith, S. and Forrester, J.V. (1995) Iwnr~rw~log!/ 84, 265-271 </p><p>5 Bieber, T. Clrl-I. O@. Iwwtrr~oI. (in press) </p><p>6 Kapp, A. (1993) AIfqy 48, 1-5 </p><p>7 Foster, C.S. and Calonge, M. (19901 </p><p>Ophflinlw~oloS!/ 97, 992-1000 </p><p>8 Smith, J.A.. Whitcup, S., Mahdi, R.M., </p><p>Nussenblatt, R.B. and Egwuagu, C.E. (1995) </p><p>!JKkYf. Ophh~hJ~~. Vis. Pi. 36, 537 </p><p>9 Zimmermann, L,E. and McLean, J.W. 11979) </p><p>AJII. 1. Ophtkahol. 87, 741 </p><p>10 Ksander, B.R,, Rubsamen, I?, Olsen, K., </p><p>Cousins, S.W. and Streilein, J.W. I19911 Iwest. </p><p>O,t~l~!l~r?lf?rol. Vis. 5-i. 32, 3198-3208 </p><p>11 Riinger, T.M., Klein, CL, Becker, J.C. and </p><p>Brticker, E.B. (1994) C~,rr. Ollii~. O~~cu~. 6, </p><p>18% 1% 12 Becker, J.C., Brablctz,T., Conrad, C.T., BrGcker, E.B. and R&amp;&amp;Id, R.A. (1995) Proc. </p><p>Nntl. Ad. SC-i. U. S. A. 92, 2375-2378 </p><p>Emmanna Ciccone, Carlo Enrico Grossi and Andrea Velardi </p><p>t has been shown recently that a subset of CD3CDS cytotoxic </p><p>T lymphocytes (CTLs) egress surface </p><p>.moIecules of the immunoglobulin superfamily that function as receptors for </p><p>human major histocompatibility complex </p><p>[MHC) HLA class I alleles and exert in- hibitory effects on cell-mediated cytoly- </p><p>sislW3. These receptors, which are typically </p><p>found on a large proportion of CD3- T-celi receptor (TCR)- natural killer (NKl cellsJ,5, have been tentatively termed kiIl?r-cell ir </p><p>hibitory receptors UURsY, and can be sub- divided into GL183 (Refs 1, 2) specific for </p><p>(see Table 1). In normal subjects, this CTL </p><p>subsrt accounts for less than 5% of the pti- </p><p>ripheral blood T cells, but it is expanded </p><p>considerably 040%) in the reconstitution phase that follows bone marrow transplan- </p><p>tation (BMT) from three loci-incompatible </p><p>donors7. CTLs also express activatory TCRs </p><p>that are capable of triggering the cytolytic </p><p>program of these cells. Thus, there is convincing evidence for </p><p>the existence of a subpopulation of CTLs </p><p>that express two distinct sets of receptors for HLA class I molecules that mediate opposite </p><p>functions. </p><p>PII 10161.5699(96)30054.6 </p></li></ul>