Immunoglobulin A (IgA) deposits in lesional skin of a patient with blepharochalasis

British journal oj Dcnmnology 1996: 155: 791-795. Immunoglobulin A (IgA) deposits in lesional skin of a patient with blepharochalasis A.GRASSEGGER. N.ROMANl. P.FRITSCH. J.SMOLLE* AND H.HINTNER" I^partrnent oj Dermatology. VniversiUj of Innsbruck. Anichstrasse 35. A'bO2O Innsbruck. Austria *lk})iirtmfiit of Dcnnatoloflil. Uiiiversitii of Cm:. Ausfriu ol Denntiioloifii. Gcucrcil Hiispiliii Salzburg. Austriu for publication 12 April 1996 Summary We describe a 21-year-old male patient with blepharochalasis. a form of localized acquired cutis laxa. He had a 13-year history of recurrent swelling attacks of the eyelids of unknown origin leading to periocular localized cutis laxa. Histology of lesional skin confirmed almost complete loss of elastic fibres in the reticular and papillary dermis. Immunotluorescence and immunoeiectron microscopy studies showed abundant immunoglobulin A (IgA) deposits around the remaining elastic fibres. Control skin of the forearm was negative. These findings support the hypothesis that immuno- pathogenetic mechanisms may contribute to the eiastolytic process of blepharochalasis. Blepharochalasis is a rare disorder that is considered to be a form of localized acquired cutis laxa confined to the periocular region. The disease usually begins in child- hood or adolescence with attacks of unilateral or bilateral swelling of the periocular region. Attacks last for 2 - J days and recur over many years with a decrease in frequency later in life. The clinical characteristics of blepharochalasis. such as the loss of elasticity of the eyelids, wrinkling, blepharoptosis and pseudoepi- canthus. are thought to be the result of these inflam- matory attacks.'"'' Hislological examination shows inflammatory infiltrates during the erythematous and oedemalous stages, whereas loss of elastic fibres is the predominant finding in the quiescent stage.^ We were able to study a patient who had suffered from blepharochalasis for several years. In order to obtain insight into the currently unknown pathogenesis of blepharochalasis. we performed routine histology, immunofluorescence and immunoeiectron microscopic studies. Case report A 21-year-old man had suffered from recurrent erythe- matous swelling attacks (three to five attacks every year) for 1 5 years. The inilammatory attacks were strictly confined to the periorbital region and lasted for 1-3 days. No trauma or infection were obvious. The patient had been tested extensively for an allergic cause of the swelling attacks. He had a history of mild pollinosis in chiIdh(K)d but had not had urticaria or bronchospasm. There was no family history of attacks of swelling, including angioedema. At the age of 12. he was seen by one of us (J.S.) during an attack (Fig. la). Systemic antihistamines had been given, together with cold compresses. Topical steroids had been applied occasionally, hut long-term topical steroid application was avoided. Mild atrophy and loss of elasticity of the eyelids was noted after the oedema had subsided. At that time, clinical and routine laboratory investigations. including Cl-esterase inhibitor level, were normal. Histology of lesional skin showed a perivascular inflam- matory infiltrate, dermal oedema and a decrease of elastic fibres in the reticular dermis (Fig. Ib). Unfortu- nately, no immunofluorescence studies had been per- formed. At the age of 21. the patient was seen again because of persisting attacks of eyelid swelling. He was aware of three attacks in the previous d months. On examination, the skin of the periorbitai region showed bilateral loss of elasticity with wrinkling. When held between the thumb and index finger, the skin tended to remain folded. Mild ptosis was evident but no abnormality of ocular and papillary movement was found (Fig. 2a). Skin elsewhere and physical and ophthalmological examinations, were normal. Plastic surgery is planned but had not been performed at the time of writing, since at least a 1-year interval free of swelling attacks is recommended prior to surgery. "^ Laboratory studies Routine laboratory tests including liver and kidney g 1996 British Associiition of Dermatologists 791 •92 A.GRASSEGGER etui. Figure I. (a) Acute sta[^e olbiepharochaleisis in uur piitiuol at the agi" of 12: note enormous symmetrical erythematous swelling of the periocular region, (b) Histology of the same stage: lymphohistiocytic pcrivascular and periaclnexiiil infliimmatory infiltrate and oedema (haematoxylin and eosin: x2()()). J Figure 2. Uil Uuiesfent stage ol'blepharochiilasis: al ihe age of 21 loss of skin elasticity led to wrinkling, lilepharoptosis. Ib) Histology of this stage shows loss of elastic fibres in the papillary and reticular dennis but none or only minimal perivascular inflammatory infiltrates (elas- tica; x20()). function tests, protein electrophoresis and blood count, were normal. Antinuclear antibodies were negative. Complement components. C3 and C4. and Cl-esterase inhibitor levels were normal as was caeruloplasmin. serum copper, a i -antitrypsin levels and thyroid studies. Urinary Bence-Jones protein was negative. Total IgE level was 245U/ml (normal < lOOU/ml): serum IgA. IgM and IgG were within normal limits. IgM and IgG antibodies against Bonrlia antigens were not detect- able. Skin testing to recall antigens showed a normal T-cell mediated immune status. Electrocardiography and chest X-ray were normal. Abdomen sonography did not show any pathological changes. Ristopathology (Eig. 2b) Rebiopsy at the age of 21. during the quiescent stage, depicted only mild perivascular infiltrates and slight oedema of the dermis. Negative Congo red and thioflavin-T staining excluded the presence of amyloid deposits. Elastica and Gomori staining showed a marked decrease of elastic and reticular fibres throughout the reticular dermis. including the periadnexal areas. Within blood vessel walls, normal-appearing elastic fibres were present. Collagen fibres were inconspicuous and no calcification was observed using the von Kossa staining. Immunofluon'sci'mc studies Direct immunofluorescence investigation of lesional skin revealed abundani tlbrillar IgA deposits in and around blood vessels, eccrine sweat glands and on the remnants of elastic fibres throughout the papillary dermis. Deposits of IgG and IgM were not found. Con- trols from non-lesional skin (forearm) showed no specific itiimunotluorescence (Fig. 5). Indirect immuno- fluorescence (IgM, IgG and IgA) did not show circu- lating antibodies directed against epidermal or dermal structures. (r 1 9Sfi British Association of Dermatologists. Brilish jounMl of Denyiatolot]}!. 115, 791-795 igA DEPOSITS IN BLEPHAROCHALASIS 793 [-igiire J. (a. b) [mmuiioilLiore.scL'nl findings during ihf quiescent stygeof blL'iiliarncli;it;isis, Alniiulani inirnimiiginlHiIni A (igA) deposiLs arc located around ciastic fibres ot'vessifi walls |a) and reniiiindcrs oi dcrmai eiaslif fibres lib); e. epidermis: d, derinisl | x 4 0 0 l . Imiuunoi'lirtron microscopy Direct immunoptToxidase staining was pertbrmed on 10//m standard cryostat sections. The pre-embedding techniqne was used and sections were processed as described.' Using horseradish peroxidase-conjugated antihiiman IgA antibodies, the reaction product was found on elastic iibres but not on collagen libres. They were located in the papillary dermis. In longitudinally sectioned fibres, the reaclion product seemed to be concentrated at the margin ol the elastic libre, whereas the central amorphous elastin core was entirely free of immunoglobulin deposits. No elastic fibres were found in the reticular dermis (I'ig. 4}. Discussion A prerequisite of tissue elasticity is the three- dimensional network of crosslinked elastic Hbers. The crosslinking process is catalysed by the copper- dependent enzyme lysyloxidase. The degradation of elastic fibres is mediated by classic elastases (i.e. serine proteases) and by metallo-elastases (matrix metallopro- teases), Inhibitors of elastases such as Oj-antitrypsin. Oj-macroglobulin. elatin and tissue inhibitor metailo- proteinases. contribute to the homeostasis of elastic fibre turnover.*^^ Consequently, impairment of elastic fibre architecture (elastic Hbre homoeostasisi may result in various connective tissue diseases.'^ In particular. increase of elastic fibre degradation occurs in congenital and acquired cntis laxa with or without internal organ involvement.'""'"^ In addition, inflammatory inliltrates. especially leucocytes and macrophages. are associated with elastase activity,''"" explaining, at least in part, the enhanced, localized degradation of elastic fibres secondary to various diseases such as sarcoidosis, necrobiosis lipoidica. nodular amyloidosis. acroderma- titis chronica atrophicans. lymphocytoma or. most frequently, discoid lupus erythematosus." ' ' '** Several varieties of postinflammatory elastolysis seem to exist including anetoderma'""'^' ' ''' and mid-dermal elastolysis."""•' Blepharochalasis is currently accepted to be a variant of localized postinflammatory acquired cutis laxa . ' "" Similar to primary anetoderma and other postinflam- matory elastolytic processes.~"~~^ blepharochalasis is preceded by inflammatory attacks, possibly leading to degradation of the elastic fibres. Overwhelming elastase activity and/or impaired elastase inhibitor function may be responsible for the elastolytic process.'^""^ Our patient presents with the typical clinical findings of blepharochalasis. Although angioedema with numerous triggering mechanisms leading to blephar- ochalasis was described previously."" (indings such as a negative family history and the normal Cl-esterase inhibitor and serum complement levels in our patient exclude hereditary angioedema. The clinical aspect of erythema during the attacks of swelling and the C) iyy6 British Association of t)ermiiti)fiigists. British loiinud of Iknmloloiiii. 135, 791-7-795 794 A.GRASSEGGER ct E \^ Figure 4. Imniunoelectronmicrnscnpy of periocular lesional skin. Demonstration of immLinoglobulin A (IgAl dcposilion on elastic tibres in ihe papillary dermis. Nole tlitit the peroxidase reaction product is localized on the microlibrillar portion of eiastie tibres (arrows). The amorphous elastic core as well as collagen fibres (C), basement meinhrane | arrowheads I, and epidermal cells (Kl arc negative | x 24.000. bar = 1 /(ill). Inset shows one of the libres at higher magnification (x S1.000, inset bar = histology demonstrating a marked perivascular infil- trate early in the disease, support inflammation rather than mere angioedema. In addition, no other symptoms suggestive of a type I allergic reaction occurred during the attacks of swelling. Nevertheless, a history of polli- nosis and slightly elevated serum IgE levels indicate atopy in our patient. It should be noted that short-term topical steroid application was reported by the patient but he denied long-term usage. Since collagen fibres of lesional skin appeared normal histologically. an adverse effect to topical steroids seemed unlikely. Primary or familial aniyloidosis is sometimes associated with blepharochalasis"*'"' but could be excluded in our patient by histology and the normal laboratory para- meters. Thus, the cause of our patient's attacks of swelling remains unclear. There is some evidence thai immunological mechan- isms are involved in the pathogenesis of at least some variants of postinflammatory elastolysis.^^ ""• Comple- ment C5 and IgM deposits were found in a granular and fibrillar pattern at the basement membrane zone and between collagen fibres in patients with aneto- dernia. 17-14 In addition. Hodak et al. described various autoimmune abnormalities associated with primary anetoderma."'"^ Some investigators have detected ele- vated plasma IgA levels with localized"'' or generalized acquired cutis laxa.'^ In our patient, no autoimmune diseases or elevation of the serum IgG. IgM or TgA levels could ha detected. However, our finding of IgA deposits in lesional skin suggests the involvement of immuno- pathogenetic mechanisms. To our knowledge, there is no previous report describing localized IgA deposits in blepharochalasis or other forms of postinflammatory elastolysis. As was shown by others, the antigenic effects of elastin disintegration products can be seen ill vitro during mechanical stretching of elastic libres.""'^' ' This observation indicates that, during the swelling of elastic tissue, a change of the elastic fibre structure may create antigenic sites in vivo fol- lowed by an immune response. This point of view may be supported by our finding that no IgA deposits could be found in unaffected skin in our patient. In summary, we have demonstrated for the first time that involvement of IgA may contribute to the develop- ment of blepharochalasis. Our findings are in agreement with previous reports suggesting immunopathogenetic © 199(1 British Association of Dermaliilogists. Hritisli lournal of Dcnniitohgii. 1 i5 . 791-795 IgA DEPOSITS IN BLEPHAROCHALASIS 795 mechanisms in the spectrum of cutis laxa con- ditions.'^"^"" '" but are unique in that IgA. rather than other classes of immunoglobulins. were found in close association with the remnants of elastic libres. IgA deposits may reflect an epipbenomenon, or indicate latent autoimmune activation. It is not clear, bowever. why IgA deposits outlast the inflammatory infiltrate. 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