The Immunological Features and Pathophysiology of Ocular Cicatricial Pemphigoid

THE IMMUNOLOGICAL FEATURES AND PATHOPHYSIOLOGY OF OCULAR CICATRICIAL PEMPHIGOID

MARK J. ELDER1•2 and SUSAN LIGHTMANl.2 London

SUMMARY knowledge about the immune basis and pathophysiology Ocular cicatricial pemphigoid is an uncommon but of ocular cicatricial pemphigoid. severe and potentially blinding systemic disease. It shares BULLOUS SKIN DISEASES many pathophysiological features with the other bullous skin diseases such as dermatitis herpetiformis, bullous All of the bullous skin diseases may be associated with pemphigoid and pemphigus vulgaris. All of these diseases cicatricial conjunctival changes but they are uncommon, have circulating antibodies that bind to the basement mild and frequently asymptomatic. These diseases membrane of mucous membranes. The individual dis include dermatitis herpetiformis,I,1 epidermolysis bull eases differ by each having a specific component of the osa,1,4-10 pemphigus vulgarus 1,3,11--16 and bullous pemphi - basement membrane complex as its antigen. In acute goid, 17 22 As a family of diseases, they all have circulating ocular cicatricial pemphigoid, the conjunctiva is infil antibodies to skin and mucous membrane basement mem trated with neutrophils, macrophages, Langerhans cells brane. Antibodies and complement are bound to the base and CD8+ and CD4+ T-cells while in the chronic disease ment membrane of lesional and non-Iesional skin, the conjunctiva is infiltrated mainly by CD8+ T-cells. However, the diseases differ by each having a unique CD4+ There is evidence of activation of these T-cells as component of the basement membrane as its antigen cells as shown by expression of the interleukin-2 receptor (Table I). The exceptions to this are that dermatitis herpeti and increased expression of major histocompatibility formis does not have a circulating antibod/ and the anti class II antigens within the tissue. The aetiology of the gen in pemphigus vulgaris is the intercellular cement fibrosis is unknown but increased amounts of several substance.12,13_ls The disease with the most severe ocular fibrogenic growth factors are demonstrable by consequences is ocular cicatricial pemphigoid. 1 immunohistochemistry. CLINICAL FEATURES OF OCULAR Clinically, cicatrising conjunctivitis may range from CICATRICIAL PEMPHIGOID asymptomatic subtarsal or canthal fibrosis to a complete obliteration of the fornices with total keratinisation of the Ocular cicatricial pemphigoid (OCP) affects elderly 58-69 ocular surface. 1 The cicatrisiation may have a wide range patients, with a mean age at presentation of 66-77% of aetiologies including physical, chemical, pharmaceuti years.23-26 Ocular involvement occurs in of 7 cal, infectious, inflammatory and immune stimuli. 1 This cases.23-2 In an ophthalmic series, skin lesions were pres 9% cicatrisation may impair corneal function by a variety of ent in of cases.2S Other mucous membrane involve (15%), (12%) mechanisms. These include a dysfunction in any of the ment included the mouth nose and (9% three tear film layers, abnormal lid-globe contact or oeosphagus ).2S There is an association with HLA 1 *0301) movement, trichiasis, exposure, and a predisposition to DQw7 (DQB 28 and affected patients have a four blepharitis and keratitis. This paper summarises current fold increase in the prevalence of other autoimmune dis eases (p<0,01) - mainly rheumatoid arthritis but also From: 'Moorfields Eye Hospital, London; 'Institute of systemic lupus erythematosus and polyarteritis nodosa.2s Ophthalmology, London, UK. Correspondence to: Mark Elder, MoorfieldsEye Hospital, City Road, The disease may be acute and associated with inflam London EC I V 2PD, UK. mation, or chronic and not associated with inflammation,

Table I. The immune-related cicatrising conjunctivitides brane are detected in about 50% of patients.30,32,34-38 This antibody is directed against basement membrane antigens Disease Antibody binding site of 230 kDa and/or 160-180 kDa. There is some cross Ocular cicatricial pemphigoid Lamina lucida of BMZ reactivity with bullous pemphigoid antigen.'8,33,39 Immu Dermatitis herpetiformis Sublamina densa region of BMZ noglobulins G and A and complement are bound to Epidermolysis bullosa Type VII procollagen in BMZ Pemphigus vulgarus Intercellular cement substance conjunctival basement membrane in up to 67% of Bullous pemphigoid 220 kDa glycoprotein in BMZ cases.25,33,36,40 The binding is strictly linear and is along the Stevens-Johnson syndrome Blood vessel wall superficial and deep aspects of the lamina lucida.'8 Vari

BMZ, basement membrane zone, ous components of complement are bound to the basement membrane including Clq, C3, C4 and properdin/o,31,39,40 Progression of the ocular cicatrisation occurs in 75% of and complement may be activated via both the classical patients not receiving treatment.26,29 The cicatrisation may and the alternative pathway.41 Lysis of the desmosomal occur as a gradual event not associated with inflammation attachments of the basal layer of the epithelium causes the or in a stepwise manner during periods of acute inflam subepithelial bullae, which may be clinically manifest, mation.24,30,31 Surgically induced inflammation can cause especially involving the skin or mouth.42,43 rapid progression, such as may occur with entropion cor Further evidence for an autoimmune basis of the , - rection or cryotherapy. 26 30 33 disease comes from the development of an animal model Clinically, the sequence of progression is usually that of in rabbits,45 The injection of a monoclonal antibody into progressive shrinkage of the conjunctiva with symblepha basement membrane of conjunctival epithelium (MAb63) ron, development of cicatricial entropion of both upper causes conjunctival inflammation, neutrophil infiltration and lower lids, trichiasis, obliteration of the fornices, and basement membrane deposition of IgG in a pattern ocular surface keratinisation, diminution of the tear film similar to that seen in acute OCP. and eventual keratopathy. At any point there may be an Immunohistochemical studies25,33,40,44 have shown that exacerbation of conjunctival inflammation. the acute, ulcerative phase affects both the conjunctival IMMUNE FEATURES IN OCULAR epithelium and the substantia propria. The stromal CICATRICIAL PEMPHIGOID Circulating antibodies to conjunctival basement mem-

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Fig. 2. Subacute ocular cicatricial pemphigoid stromal con Fig. 1. Acute ocular cicatricial pemphigoid showing intense junctiva showing T-cells staining positive for interleukin 2 infiltration with neutrophils in the conjunctival stroma and epi receptor suggesting activation. x500, (Courtesy of Dr W. thelium. x125. (Courtesy of Dr W. Bernauer.) Bernauer.) 198 M. J. ELDER AND S. LIGHTMAN

with a growth factor similar to the effect produced by TGF-�, PDGF, TNF or IL-l. This is consistent with immu nohistochemical findings of raised levels of TGF-� in acute disease and of TGF-�, PDGF and fibroblastgrowth factor in subacute OCP.33 The origin of these fibrogenic cytokines is unknown, but it is probable that they are pro duced by both acute and chronic inflammatory cell types.

CLINICAL RESPONSE TO SYSTEMIC DRUGS Further insight into the mechanisms involved in fibrosis can be gleaned from the response to various drug treat ments in OCP. Both dapsone25,37,49,5o and cyclophospha mide25,29,5o have been shown to reduce inflammation and impair or halt the progression of the fibrosis compared Fig. 3. Chronic ocular cicatricial pemphigoid stromal conjunctiva showing CD4+ T-cell infiltration. x312. (Courtesy with untreated controls. of Dr W Bernauer.) Dapsone is a sulphone and both inhibits the myelo peroxidase in polymorphonuclear leucocytes and stabil changes in acute disease are characterised by a marked ises lysosomal membranes. This reduces the release of infiltration of neutrophils (Fig. 1), macrophages, Langer lysosomal enzymes.51 It also suppresses migration of neu hans/dendritic cells and T lymphocytes compared with trophils to extravascular sites through inhibition of the normal controls. In addition, there is significantly adhesion required for neutrophil recruitment.52 Therefore, increased expression of the major histocompatibility class a response to dapsone is mainly due to inhibition of neu II antigen (HLA-DR), there are equal numbers of CD4+ trophil recruitment and function. and CD8+ T-cells and 4-10% of the T-cells stain positive Moderate doses of cyclophosphamide suppress both for interleukin 2 receptor, suggesting that they are acti B-cell and CD4+ and CD8+ T-cells. This leads to a sup vated33,40,44 (Fig. 2). Staining for transforming growth fac pression of both T-cell-mediated and humoral responses.53 tor-beta (TGF-�) is significantly increased. Therefore fibrosismay be inhibited by suppressing any or The subacute phase of the disease is histologically all of these cell lines. This points to a complex set of mech similar to acute disease although the CD4+/CD8+ ratio anisms that are involved in the aetiology of the fibrosis in drops to 0.4. The chronic phase is characterised by an infil OCP. This is further complicated by the number of growth tration with T lymphocytes (Fig. 3), HLA-DR expressing factors demonstrated by immunohistochemistry.33Further cells and macrophages which are mildly increased in research is necessary to dissect in detail the mechanisms number. The CD4+/CD8+ ratio is 0.5.33 Mild to severe of cicatrisation in these inflammatory processes. This subepithelial fibrosis may be found in any of the three would be expected to lead to much more effective thera clinical phases. peutic regimes that may have fewer systemic side effects. For the conjunctival epithelium, the acute disease reveals marked infiltration with neutrophils and Langer The authors are thankful to Dr W. Bernauer for his permission to hans cells. In chronic disease there is a similar cell profile include his work in this paper.

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