immunology of the eye and the joint

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Immunology of the eye and the U I I I L

Manfred Zierhut, Bert Feltkamp, John Forrester, Johannes Saal and Giinther Dannecker

Involvement of the eye is not a rare phenomenon in arthritic diseases. The most common manifestation of this is intraocular inflammation (uveitis) and, less frequently, inflammation of the anterior eye segment (e.g. conjunctivitis, keratitis and scleritis). The generation of scleritis and keratitis is thought to be induced mainly by immune complexes, while T cells play an important role in rheumatoid arthritis (RA)-associated keratitis (M. Raizman, Boston), uveitis and RA. Established experimental models for autoimmune uveitis and arthritis h~ve provided insight into the immunoregulation of these dis- orders, although models induced by infectious antigens are not well established. Clinical studies have shown that the most common fea- ture of eye and joint involvement is the association with the major histocompatibility complex (MHC) HLA-B27 family of allelic variants.

Comparison of the immunoregulation of eye and joint

The similarity in the pathogenesis of the two broad types of uveitis and arthritis was one of the main features highlighted at this meeting (A. So, London; J. Forrester, Aberdeen). HLA-B27 and a variety of infective agents have been impli- cated in the immunopathology of acute anterior uveitis (AAU) and reactive arthritis (ReA), while macrophageff-cell-mediated vascu- litic reactions have been shown ro be involved in endogenous posterior uveitis and RA. Furthermore, the preferential usage of Vo8 + T-cell receptors (TCRs) has ~een observed in experimental models of autoimmune arthritis and uveitis 1 (V. Calder, London). Similarly, a study in humans has reported high

+ levels of Vo14 T-cell populations • . I .~ . m synowal fluid 2, although these data have not yet been confirmed

It is well known that polyarticular joint diseases such as rheumatoid arthritis, HLA-B27-associated arthritis and Borreliosis can be associated with eye diseases, such as uveitis, scleritis and keratitis. How- ever, the mechanisms underlying the involvement of these tissues remain unclear. A recent meeting* examined the immunoregulation of the eye and the joint in an at- tempt to determine their similarities

and differences.

(G. Pluschke, Basel). Unfortunately, studies of human uveitis have proved less informative (S. Whitcup, Bethesda), which may be due to the lack of reagents. In this respect, it is possible that the use of polymerase chain reaction (PCR)-anchor tech- niques may prove more fruitful in future studies (G. Pluschke).

Cytekines such as tumor necrosis factor ~ (TNF-a) and interleukin 6

vascular cell adhesion molecule 1 (VCAM-1) are active in chronic inflammation 4. It was suggested that, as lymphocytes ~ccumulate, cytokines such as interferon ~/ (IFN--,/) and IL-4 induce high endothelial venules (HEV) in the tissue. This has been shown in the joint and choroid by using specific antibodies to HEV (e.g. HECA-452). How- ever, no staining was found in chronically inflamed iris tissue.

The eye may have some immunoregulatory advantages over the joint through being an immunologically privileged site. While the anterior segment of the eye has long been recognized as having 'immunosuppressive' proper- ties, resident cells in the posterior segment also seem to have imrnunosuppressive effects s. These effects appear to be mediated by

(ILo6) appear to be important in prostaglar.din E 2 (PGE2) , although varioug fnrrn~ nf e Y n e r i m e n r ~ ! r h o r e d o n f n i t r i c , n v i A p i ~ ' J ; , ,

uveitis and arthritis (A. Kijlstra, Amsterdam). In endotoxin-induceci uveitis (EIU) in the Lewi: _"at, a bimodal secretion of TNF-a was observed, with high expression levels of IL-6 mRNMprotein and macrophage inflammatory protein- la (MIP-lot) mRNA (Ref. 3). By contrast, IL-6 was not detected after injection of endotoxin into the EIU-resistant BN rat. Interestingly, antibodies to TNF-ot appeared to exacerbate EIU, which is in contrast to their beneficial effect in some forms of arthritis.

Similarities in the mechanisms of inflammatory-cell homing to the eye and joint have also been demonstrated (A. Duijvestijn, Maastricht). E-selectin appears to be important in acute inflammation, while mechanisms mediated by very late antigen 4 (VLA-4) and

*The workshop 'Immunology of the Joint and the Eye' was held in Ettal,

Germany, on 6-7 October 1993.

this system is currently under active investigation (j. Forrester, Aberdeen). It is possible that similar downregulatory mechanisms also exist in the joint.

Role of HLA-B27 in arthritis and uveitis

The whole spectrum of HLA-B27- associated diseases was presented by J. Wollenhaupt (Hanover). The association between HLA-B27 and ankylosing spondylitis (AS), ReA such as Reiter's syndrome, and AAU, thereby greups these diseases together. Indeed, one in three AS patients have or have had AAU, and half of the AAU patients also have AS or Re?,. However, mild joint diseases in AAU patients do ~,ot show a tendency to worsen over the years, and the ophthalmo- logical prognosis is generally good (A. Linssen, Amsterdam).

Other genetic factors, besides HLA-B27, may be of pathogenetic importance: for instance, the

© 1994, Elsevier Science Ltd 0167-5699/94/507.00

Immunology Today 249 Vol. 15 No. 6 1994

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Campylobacter Chlamydia Klebsiella

Salmonella Shigelia Yersinia

Exogenous factors

HLA-B27/B60 overly or poorly presents

peptide to CTLs

~ +)

[ Other genetic factors I

Arthritis I Other Uveitis Other in some I joints in one eye

i

joints [normal eye normal

Fig. 1. Model for the central role of MHC HLA-B27 in the patbogenesis of arthritis and uvettis. HLA-B27 may provide the link betu,een a number of exogenous factors and several clinical pbenomena, altbougb the precise local role of exogenous factors is not clear. HLA-B27 probably combines with HLA-B60 m this interaction. Other genetic factors may also be highly impo~;dmo HLA-827- A~ and I4I A - R ) 7 - A,~ll a r o . . . . . . . . . . . . . . . . . . . . . . .

probably diseases that show a st,ong resemblance to their counterparts in HLA-B27 ~ individuals, but with a different patbogenesis. The reason why only one eye is affected by AA U may be due to local differences in levels of anti-inflammatory cytokines (T.E.W. Feltkamp, Antsterdam). Abbreviaiions: MHC, major bistocompatibility complex; AS, ankylosing spondylitis; AAU, acute anterior t, veitis; ReA, reactive

arthritis; CTL, cytotoxic T lympbocytes.

co-inheritance of HLA-B60. How- ever, other potential genetic factors have not yet been identified, and no individual HLA-B27 subtype has been " ' ' parncumny associated with any of the diseases. Therefore, HLA-B2;" is itself considered to be of major pathogenetic importance (T.E.W. Feltkamp, Amsterdam). This is underlined by the aberrations observed in transgenic rats that express a large number of HLA- B27 copies 6, and by the increased frequency of ankylosing entesop- athy in HLA-B27-transgenic mice (P. Ivanyi, Amsterdam). It has been suggested that HLA-B27 functions

as a common pathway in the pathogenesis of these diseases (Fig. 1). HLA-B27 can present peptides of Gram-negative bacteria to cytotoxic T lymphocytes (CTLs) (Ref. 7), and it is possible that if HLA- B27 overly or poorly presents peptide, then this might lead to disease. The finding that AAU is typically a unilateral disease and that, in HLA- B27-associated joint diseases, some joints are affected more than others, suggests that unknown local factors also play a pathogenetic role (T.E.W. Feltkamp, Amsterdam).

Role of microorganisms The role of microorganisms in

inducing autoimmune disease was discussed with regard to heat-shock proteins (HSPs), superantigens (SAgs), Borreliosis and Epstein-Barr virus (EBV). Responses to HSPs have bee,', found in a number of human autoimmune diseases, although not in uveitis (U. Feige, Basel). Using a rat model of mycobacteria-induced arthritis, mycobacteria-reactive T cells were found to transfer disease, and arthrito- genic T-cell clones were shown to be responding to Hsp65. Although the dominant epitope (amino acids 180-188) could not induce disease, it could suppress or modify manifestation of disease. Thus, since Hsp65 could be used to prevent disease in a number of animal models, it might provide a tool for therapy. However, the role of HSPs as a causative agent of autoimmune diseases remains unanswered.

The role of SAgs is also unclear (G. Dannecker, Tiibingen). SAgs can activate a large proportion of T cells in organisms that express a particular V~ TCR sequence. The activation and proliferation of T cells is followed by depletion or hyporesponsiveness of these cells s. Since SAgs can also induce poly- clonal antibody responses, it has been suggested that they may play a role in the pathogenesis of autoimmune diseases. Furthermore, SAg-induced depletion of T cells or hyporesponsiveness could be used for treatment. In animal models, gAgs have been shown to inhibit induction of disease, although relapses or reactivation have also been .4escribed. There is evidence for the involvement of a SAg in RA

(Ref. 2), altb_ ugh conflicting results have been reported. Clearly, it is too early to correlate specific autoimmune diseases with specific SAgs (Ref. 9). Furthermore, no association between HSPs or SAgs and uveitis is yet known.

Lyme-Borreliosis is an established clinical entity both in rheumatology and ophthalmology. H.D. Kramer (Heidelberg) focused on the interaction of Borrelia burg- dorferii with the immune system. Monoclonal antibodies (mAbs) were used to clone the different antigens from Borrelia. Such mAbs can be used to subtype Borrdia and, hope- fully, will reduce the well-known problems associated with serological testing in Lyme disease. Severe combined imm,modeficiency (SCID) mice develop classical borreliosis, but no uveitis. Transfer of serum from immune animals was shown to protect susceptible animals, as did transfer of one of the mAbs (anti- Osp A). The antigen itself is a possible candidate for a vaccine, and a phase I clinical trial showing serum conversion has been performed.

Certain viruses may be involved in the pathogenesis of autoimmune diseases. J.G. Saal (Tiibingen) sum- marized studies of EBV in RA patients. Patients with RA have higher titers of antibodies against Epstein-Barr nuclear antigen (EBNA) and show defects in the T- cell control of EBV. EBV type A DNA could be detected in the syn- ovial membranes of 37% of RA patients (and 8% of other kinds of arthritis), and HLA-DR4+EBV ÷ individuals had a 39-fold higher risk of developing RA than did patients without this marker com- bination. A considerable degree of molecular mimicry between EBV- encoded proteins and host determi- nants has been found, the most interesting being the mimicry between EBV gp110 and the RA- associated HLA-DR-131 amino acid sequence G~.-a-Lys-Arg-Ala-Ala.

New therapeutic strategies Currently, a number of studies

are investigating the effect of vari- ous mAb strategies for the treatment of RA. Encouraging results have been reported using anti-CD4 mAbs and anti-TNF-a mAbs (Ref. 10). One of the problems in selecting


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a suitable antibody for therapy is the establishment of an in vitro assay, and mice transgenic for human CD4 may prove helpful in this respect (F. Emmrich, ErlangenJ.

For the treatment of AAU in patients with AS, it has been suggested that sulphasalazine might reduce the recurrence rate of AAU (Ref. 11), and this rewards filr~her study. Treatment of human uveitis mainly utilizes steroid and immunosuppressive therapy, and mAbs have not yet been used in controlled studies. In experimental autoimmune uveitis (EAU), antibodies to intercellular adhesion molecule 1 (ICAM-1) and CD4 can prevent disease, and it seems reasonable to use one of these in severe cases of human uveitis. An extremely interesting study in progress at the National Eye Institute at Bethesda is aimed at the induction of a state of tolerance after oral administration of retinal-S antigen or other ocular autoa,tigen~'Z. In contrast to uveitis, anterior-segment involvement (especially in RA-associated

keratitis) sometimes responds well to topical cyclosporin A, suggesting an important role for T cells rather than immune complexes in anterior-segment inflammation (M. Zierhut, Tiibingen).

Man[red Zierhut is at the Dept of Ophthalmology, University of Tiibingen, 72076 Tiibingen, Germany; Bert Feltkamp is at The Netherlands Ophthalmic Research Institute, 1100 AC Amsterdam, The Netherlands; John Forrester is at the Dept o[ Ophthalmology, Universi~ o[ Aberdeen, Aberdeen, UK AB9 2ZD; ]ohannes Saal is at the Dept o[ Internal Medicine, University of Tiibingen, 72076 Fiibingen, Germany; Giinther Dannecker is at the Dept o[ Pediatric Rheumatology, University o[ Tiibingen, 72076 Tiibingen, Germany.

References 1 Merryman, C.F., Doaoso, L.A., Zhang, X.M., Heber-Katz, E. and Gregerson, D.S. (1991) J. lmmunoL 146, 75-80

2 Paliard, X., West, S.G., Lafferty, J.A. et ,11. ( 1991 ) Science 253, 325-329 3 Hoekzema, R., Murray, i'.l. and Kijlstra, A. (1990) Curr. Eye Res. 9, 207-211 4 Kuppner, M.C., Liversidge, J., McKillop-Smith, S, Lumsden, I.. and Forrester, J.V. (1993) Curr. Eye Res. 12, 923-934 5 Liversidge, J.. McKay, D., Mullen. G. and Forre~ter, !.V. (! qq~) Cell. lmmunoL 149, 315-330 6 Taurog, J.D., Maika, S.D., Simmons, W.A., Breban, M. and Hammer, R.E. (1993) ]. hnmunol. 150. 4168-4178 7 Hermann, E., Yu, D.T.H., Meyer zum Biischenfelde, K.H. and Fleischer, B. (1993) Lancet 324, 646-650 8 Dannecker, G., Mecheri, S., Staiano-Coico, L. and Hoffman, M.K. ( 1991 ) J. Immunol. 146, 2083-2087' 9 Acha-Orbea, H. (1993) Ann. Rheum. Dis. 52, $6-S16 10 Breedveld, F.C. and De Vries, R.R.P. (1992) Clin. Exp. Rheumatol. 10, 325-326 11 Dougados, M., Berenbaum, F., Maetzel, A. and Amor, B. (1993) Rev. Rheum. 60, 80-82 12 Nussenblatt, R.B., Caspi, R.R., Mahdi, R. et al. (1990)J. Imnmnol. 144, 1689-1695

The role of cell adhesion molecules in immunopathology

Andrzej G6rski

Much of current knowledge of the strt, cture and function of human endothelial cells (ECs) has been derived from the st~ldy of human umbilical vein ECs (HUVECs). However, such data can only be partially extrapolated to other type, of endothelium, and to in vivo situations, since HUVECs are dividing embryonic vascular cells. Moreover, ECs derived from different vessels are phenotypically and functionally different. Not only do large- and small-vessel ECs differ in their growth requirements, tube- forming ability and the production of active mediators [such as interleukin 1 (IL-1), IL-4, IL-8, inter- ferons (IFN), colony-stimulating

The number o[ papers abstracted in Medline that can be accessed with the keyword 'adhesion' has risen approximately 3000-fold over the past 20 years. The inten- tion of a recent symposium* was to update current progress in the

area o f cell adhesion molecules.

factors and prostaglandins], but also in the regulation of expression of cell adhesion molecules (CAMs). This may explain the differences in the pathophysiology and clinical characteristics between large- and

*The symposium 'The Role of Cell Adhesion Molecules in Immuno- pathology' was held in Warsaw,

Poland, 14-16 November 1993. © 1994 , Elsevier Science L td 0167-56991941507.00

small-vessel inflammatory responses. Furthermore, similar differences have been noted between venous and arterial ECs. For example, cytokines upregulate intercellular adhesion molecule 1 (ICAM-I), both on human lilac venous and arterial ECs, a,ad induce the syn- thesis and expression of E-selectin on both cell types. By contrast,

I I • vascular' c~ll aaneslon moiecuk i (VCAM-1) is induced only on venous ECs. Furthermore, cytokines upregulate expression of ICAM-1 and induce weak expression of VCAM-1, but not E-selectin, on human mesangial cells (I. Hauser, Nurnberg; Z. Ruszczak, Minden).


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