抗p200类天疱疮7例临床及免疫血清学特征分析

【摘要】 目的 总结抗p200类天疱疮患者的临床和免疫血清学特征。方法 收集2015年1月至2021年10月在中国医学科学院皮肤病医院确诊为抗p200类天疱疮的患者资料，回顾性分析其临床和免疫血清学特征。结果 纳入7例抗p200类天疱疮患者，盐裂皮肤-间接免疫荧光实验显示，7例患者血清IgG抗体均结合于盐裂皮肤的真皮侧，以真皮提取物为底物的免疫印迹显示，在相对分子质量200 000蛋白处有条带。4例呈经典型大疱性类天疱疮样损害，2例初起呈湿疹样损害，1例类似线状IgA大疱性皮病。6例循环IgG抗体可识别层粘连蛋白γ1-C端重组蛋白。4例患者接受不同剂量系统糖皮质激素治疗，其中1例对高剂量系统糖皮质激素（相当于泼尼松1.4 mg·kg-1·d-1）治疗抵抗；2例对米诺环素、氨苯砜治疗反应好；1例失访。4例患者在随访平均22.5个月时达到完全缓解停药；2例在随访平均8个月时达到最小剂量治疗保持完全缓解。结论 抗p200类天疱疮临床表现多样，重组Lnγ1-C端可作为可靠的抗原底物用于检测抗p200类天疱疮患者自身抗体；部分患者最终可达到完全缓解并停药。     

Two cases of subepidermal blistering disease with anti-p200 or 180-kD bullous pemphigoid antigen associated with psoriasis

We describe two patients with psoriasis vulgaris who subsequently developed a subepidermal blistering disease which disclosed IgG and C3 at the basement membrane zone in direct immunofluorescence. The first case was a 75-year-old Japanese man with herpetiform lesions. Histopathology showed neutrophil infiltration. IgG antibodies bound to the dermal side of the salt-split skin. Immunoblot analysis identified a 200-kD antigen in dermal extracts. The second case was a 70-year-old Japanese man. Histopathology showed eosinophil infiltration. IgG antibodies bound to the epidermal side of salt-split skin. Immunoblot analysis identified a 180-kD bullous pemphigoid (BP) antigen in epidermal extracts. We review the clinical and pathological features of psoriatic patients who presented a subepidermal blistering disease in which antigens were detected by immunoblot analysis; i.e., anti-p200 pemphigoid (14 cases) or BP (12 cases). There were few distinct clinical differences between two diseases. However, neutrophils were predominant in anti-p200 pemphigoid, while eosinophils were predominant in BP. After blister formation, ciclosporin was used effectively in addition to systemic steroids in the treatment of anti-p200 pemphigoid. On the other hand, ciclosporin was not used in the treatment of BP with psoriasis.     

Anti-p200 pemphigoid responding to dapsone

Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease. Clinical presentation is similar to standard bullous pemphigoid (BP) but mucous membranes and cephalic lesions are more frequent. Histology and direct immunofluorescence (IF) are identical to BP but indirect IF discloses linear deposits of immunoglobulin G (IgG) on the dermal side of artificial salt-split skin. Specific diagnosis is based on western immunoblotting that shows circulating IgG recognizing a 200-kDa protein localized on the dermal extract. The 200-kDa antigen was recently identified as laminin γ1. Anti-p200 pemphigoid should be considered before all atypical or topical steroid-resistant bullous disease, as well as mucous membranes pemphigoid or epidermolysis bullosa acquisita. Dapsone appears to be the most effective treatment and should be used as the first option in combination with topical steroids. In this report, we describe the case of a patient with a typical clinical and immunopathological anti-p200 pemphigoid, responding to a combination of topical steroids and dapsone.     

Immunofluorescence studies using skin sections of recessive dystrophic epidermolysis bullosa patients indicated that the antigen of anti-p200 pemphigoid is not a fragment of type VII collagen

BACKGROUND: There are a large number of autoimmune bullous diseases, which have distinct autoantibodies. Several reports on cases with IgG autoantibodies against a novel 200 kDa dermal protein have been published, for which we suggested the term, anti-p200 pemphigoid. However, the nature of this 200 kDa antigen has not been well characterized. OBJECTIVE: In this study, we examined the relationship between the 200 kDa protein and type VII collagen. METHODS: We collected sera from 12 cases of anti-p200 pemphigoid and skin sections from six cases of recessive dystrophic epidermolysis bullosa (RDEB). The reactivity of these sera was examined by indirect immunofluorescence using sections of the disease skin. RESULTS: we have shown that all the 12 anti-p200 pemphigoid sera could react with basement membrane zone of five cases of RDEB, while epidermolysis bullosa acquisita (EBA) sera were negative in these skins. In addition, in a case of RDEB, EBA sera reacted with intracytoplasmic deposition of type VII collagen, while no anti-p200 pemphigoid sera showed this reactivity. CONCLUSION: These results strongly suggested that the 200 kDa antigen is not a fragment of type VII collagen, but a specific autoantigen.     

A case of epidermolysis bullosa acquisita with autoantibody to anti-p200 pemphigoid antigen and exfoliative esophagitis

BACKGROUND: Some cases of a subepidermal blistering disease associated with autoantibodies to more than two antigens have been reported. OBSERVATION: A 52-year-old Japanese woman had pruritic blisters on almost the whole body as well as erosive lesions in the oral cavity and esophagus. A histological finding was subepidermal bullae. Direct immunofluorescence (IF) revealed a linear deposition of IgG, IgM and C3 at the epidermal basement membrane zone (BMZ). Indirect IF using human skin split by 1 M NaCl as a substrate showed IgG antibody reactive with the dermal side. By immunoblot analysis using normal human dermal extract, the 200-kDa and 290-kDa bands were detected. Indirect IF did not show any anti-BMZ antibody activity, when using the skin of the patient with recessive dystrophic epidermolysis bullosa as a substrate. CONCLUSION: We regarded our case as epidermolysis bullosa acquisita with autoantibody to anti-p200 pemphigoid antigen. This is the second case in the literature associated with autoantibodies to these two antigens.     

Anti-p200 pemphigoid: diagnosis and treatment of a case presenting as an inflammatory subepidermal blistering disease

Anti-p200 pemphigoid is a recently defined subepidermal immunobullous disease. It is characterized by the binding of circulating IgG autoantibodies to the dermal side of 1 M NaCl split skin and by reactivity of these autoantibodies to a unique 200-kd antigen on immunoblot of dermal extract. On immunoelectron microscopic examination, these autoantibodies deposit at the lamina lucida-lamina densa interface. We describe the clinical, histologic, and immunopathologic features in a patient with anti-p200 pemphigoid, as well as his favorable response to treatment with systemic glucocorticosteroids and dapsone.     

Relapse‐associated autoantibodies to BP180 in a patient with anti‐p200 pemphigoid

Anti‐p200 pemphigoid and bullous pemphigoid (BP) are autoimmune subepidermal blistering diseases characterized by autoantibodies to a 200‐kDa dermal antigen (p200) and two hemidesmosomal proteins (BP180 and BP230), respectively. We report a 70‐year‐old man with haemorrhagic blisters, widespread crusted erosions, and the immunopathological characteristics of anti‐p200 pemphigoid. Treatment with doxycycline, topical corticosteroids and immunoadsorption led to rapid clinical remission. However, 19 weeks later, a relapse occurred with generalized itchy urticarial erythema and tense blisters. At this time, both strong dermal and epidermal IgG staining was detected by indirect immunofluorescence microscopy on salt‐split skin, and autoantibodies against both p200 and the 16th noncollagenous (NC16A) domain of BP180 were found. Interestingly, the relapse was associated not only with the detection of autoantibodies to a second autoantigen (BP180), but also with an altered clinical phenotype. This case was a unique occasion to directly monitor the emergence of intermolecular epitope spreading during the course of an autoimmune bullous disorder.     

Erythrokeratodermia variabilis with erythema gyratum repens-like lesions

A large pedigree with erythrokeratodermia variabilis (EKV) and erythema gyratum repens-like lesions is described. Clinical, laboratory, and histologic findings of this family are presented. The differential diagnoses of the following dermatoses with an erythematous and a hyperkeratotic component are discussed: erythrokeratodermia variabilis (Mendes da Costa), progressive symmetric erythrokeratoderma (Gottron), loricrin keratoderma, erythrokeratoderma en cocardes (Degos), Netherton syndrome, keratitis-ichthyosis-deafness (KID) syndrome, erythrokeratolysis hiemalis (Oudtshoorn disease), and nonbullous congenital ichthyosiform erythroderma.     

无水疱性类天疱疮一例

患者，男，70岁。全身泛发多形性红斑、丘疹伴瘙痒3个月，未见水疱。皮肤病理示真皮浅层血管周围轻度淋巴细胞、嗜酸粒细胞浸润。直接免疫荧光示表皮细胞间及基底膜IgG、C3、IgM、IgA阴性。间接免疫荧光示抗基底膜带IgG抗体1:40阳性。正常人皮肤盐裂间接免疫荧光示IgG表皮侧阳性。诊断为无水疱性类天疱疮，给予烟酰胺、四环素、雷公藤多苷口服，配合外用卤米松乳膏治疗，2个月后皮损基本消退。     

发生于特瑞普利单抗长期治疗后的大疱性类天疱疮二例

例1女,63岁,全身皮疹2个月伴瘙痒,表现为红斑基础上水疱大疱。2年前因直肠肛管恶性黑素瘤行肠周淋巴结清扫术,静脉注射特瑞普利单抗预防性治疗1年,停药后2周出现全身皮疹。上肢红斑处皮损直接免疫荧光示,IgG沿基底膜带沉积;血清盐裂间接免疫荧光,IgG沿表皮侧线状沉积。血清酶联免疫吸附试验示,BP180 > 200 U/...     

Case of subepidermal autoimmune bullous disease with psoriasis vulgaris reacting to both BP180 C‐terminal domain and laminin gamma‐1

A number of cases of psoriasis vulgaris developing bullous skin lesions have been diagnosed as either bullous pemphigoid with antibodies to the 180‐kDa bullous pemphigoid antigen (BP180) non‐collagenous 16a (NC16a) domain or anti‐laminin‐γ1 (p200) pemphigoid. We report a case of subepidermal bullous disease with psoriasis vulgaris, showing antibodies to both BP180 C‐terminal domain and laminin‐γ1. A 64‐year‐old Japanese man with psoriasis vulgaris developed exudative erythemas and tense bullae on the whole body but he did not have mucosal involvement. The blistering lesion showed subepidermal blisters histopathologically. In indirect immunofluorescence of 1 mol/L NaCl‐split skin, immunoglobulin (Ig)G antibodies reacted with both the epidermal and dermal side. Immunoblotting showed positive IgG with recombinant protein of BP180 C‐terminal domain and 200‐kDa laminin‐γ1 in normal human dermal extract.     

The autoantigen in anti-p200 pemphigoid is synthesized by keratinocytes and fibroblasts and is distinct from nidogen-2

Anti-p200 pemphigoid is a subepidermal immunobullous disorder associated with tissue-bound and circulating autoantibodies reactive with a 200 kDa protein on the dermal side of salt-split-skin. The autoantigen, named p200, is a non-collagenous glycoprotein located at the lamina lucida-lamina densa border of the epidermal basement membrane. However, its identity and cellular origin remain elusive. Here, we used biochemical and genetic approaches to characterize the autoantibody reactivity in three new patients with anti-p200 pemphigoid. We show that the target antigen p200 is synthesized by both keratinocytes and fibroblasts, is disulfide-bonded, and participates in calcium-dependent molecular interactions. Lack of collagen XVII (BP 180), collagen VII, or laminin 332 (laminin 5) from the dermal-epidermal junction does not destabilize p200. Colocalization within the basement membrane zone and an identical molecular weight suggested nidogen-2 as candidate autoantigen in anti-p200 pemphigoid, but biochemical analysis demonstrated that p200 is distinct from nidogen-2. In conclusion, the results define further the biochemical characteristics of p200 and demonstrate its in vitro-synthesis by keratinocytes and fibroblasts, thus providing a basis for identification and further characterization of this autoantigen.     

Immunomapping in localized bullous pemphigoid

A 70-year-old Caucasian patient is described, who presented with a bullous dermatosis on an amputation stump. The bullous lesions had developed after practice with a Kondylen-Bettung-Münster (KBM) prosthesis. The lesions disappeared completely after prednisone therapy and replacement of the prosthesis with a Thomas splint. The patient has remained free of symptoms ever since, even though prednisone was completely withdrawn after 9 months. According to skin immunofluorescence criteria, the patient suffered from pemphigoid, rather than epidermolysis bullosa acquisita as strongly suggested by the anamnesis. In particular, the presence of linear IgG at the level of the lamina lucida of the epidermal basement membrane zone and the localization of laminin antigen at the blister floor are highly suggestive of pemphigoid.     

Erythema gyratum repens with pulmonary tuberculosis

A 63-year-old man presented with erythema gyratum repens of 7 months' duration. A cavitating mass at the right lung apex was resected and proved to be tuberculous. Following the resection, the skin lesions cleared within a few days. Erythema gyratum repens has not previously been described in association with non-malignant visceral pathology. The pathogenesis remains obscure but cannot be related specifically to a response to tumour cells or their products in view of the association reported here. The condition bears no resemblance to any known tuberculide.     

类天疱疮的分型及几种新的亚型

类天疱疮是一组常见的自身免疫性大疱性皮肤病.近年来随着免疫印迹技术的发展,发现几种新的类天疱疮,如抗p200类天疱疮、抗p105类天疱疮及抗p450类天疱疮等.介绍类天疱疮的临床分型、盐裂皮肤间接免疫荧光分型和分子免疫学分型,并对新近命名的抗p200类天疱疮、抗p105类天疱疮及抗p450类天疱疮的临床特征及诊断治疗进行介绍.     

Episodic erythema gyratum repens with ichthyosis and palmoplantar hyperkeratosis without signs of internal malignancy

Two patients with typical lesions of erythema gyratum repens, peripheral ichthyosis, palmoplantar hyperkeratosis and nail changes are described. A non-specific erythrodermic eruption of several weeks' duration had preceded the typical lesions. No signs of internal malignancy were found and the typical gyrate lesions disappeared within some weeks with full restitution of all skin lesions within 6-8 months.     

Subepidermal blistering disease with autoantibodies against a novel dermal 200-kDa antigen

A number of autoimmune subepidermal blistering diseases are characterized by the distinct autoantigens of the cutaneous basement membrane zone. Recently, a few cases with autoantibodies against a novel 200-kDa dermal protein have been reported. We collected nine cases of subepidermal blistering disease with IgG antibodies against this 200-kDa antigen. In this report, we describe the clinical and immunological appearances in these cases. Five cases showed bullous pemphigoid-like features, one case resembled dermatitis herpetiformis, and another case showed mixed features of bullous pemphigoid and linear IgA bullous dermatosis. It was interesting to note that psoriasis coexisted in four cases. By indirect immunofluorescence on 1 M NaCl split skin, IgG antibodies from all sera reacted with the dermal side of the split. By immunoblot analysis, IgG antibodies recognized a 200-kDa protein of dermal extract. IgG affinity-purified antibodies on the 200-kDa immunoblot membrane stained the dermal side of 1 M NaCl split skin. Various examinations suggested that the 200-kDa antigen is not identical to any chains of laminins-1, -5 or -6. This autoimmune subepidermal blistering disease against the dermal 200-kDa protein may form a new distinct entity, which often associates with psoriasis.     

Anti‐p200‐Pemphigoid – Eine neue blasenbildende Autoimmundermatose

Anti‐p200 pemphigoid is an autoimmune skin disease characterized by tense blisters, subepidermal split formation, and mainly neutrophilic inflammatory infiltration of the dermal‐epidermal junction (DEJ). Direct immunofluorescence microscopy of perilesional skin biopsies demonstrates linear deposits of IgG and C3 along the DEJ, while by indirect immunofluorescence microscopy on NaCl‐split human skin, patients' IgG labels the dermal side. The antigenic target of the autoantibodies is a 200 kD protein (p200) of the lower lamina lucida that can be detected in human dermal extracts by immunoblotting. While p200 is thought to be important for cell‐matrix adhesion, its exact identity is unknown. To date, the p200 autoantigen has been demonstrated to be distinct from bullous pemphigoid antigens 180 und 230, laminin 1, 5, and 6, α6β4 integrin, and type VII collagen. Biochemical characterization of the p200 molecule revealed a noncollagenous N‐glycosylated acidic protein with an isoelectric point of approximately 5.5. We provide an overview on pathogenesis, clinical features, diagnosis, and treatment of this unique autoimmune dermatosis.     

Antiepiligrin cicatricial pemphigoid: an underdiagnosed entity within the spectrum of scarring autoimmune subepidermal bullous diseases?

BACKGROUND: Antiepiligrin cicatricial pemphigoid (AECP) is a chronic autoimmune subepidermal blistering disease characterized by autoantibodies to laminin 5 and clinical features of cicatricial pemphigoid. Only a few patients with AECP have been described to date. The aim of the present study was to analyze the relative frequency of AECP among patients with the clinical phenotype of cicatricial pemphigoid. OBSERVATIONS: Serum from 16 consecutive patients with the clinical phenotype of cicatricial pemphigoid were included in this study. Nine patients had circulating IgG autoantibodies by indirect immunofluorescence on sodium chloride-split skin; patients' IgG bound to the epidermal side (n = 2), dermal side (n = 5), or both sides (n = 2) of this test substrate. Interestingly, all 5 cases with dermal binding immunoprecipitated laminin 5 from extracts and media of cultured keratinocytes, and 4 of these serum samples reacted with the alpha3 subunit of laminin 5 by immunoblotting. None of the patients with dermal binding of IgG demonstrated autoantibodies to type VII collagen. CONCLUSION: Our data suggest that, among patients with the clinical phenotype of cicatricial pemphigoid, AECP may be more frequent than previously assumed.     

Histopathology of anti-p200 pemphigoid

Anti-p200 pemphigoid is an autoimmune subepidermal blistering disease characterized by circulating and tissue-bound antibodies against a 200-kd glycoprotein (p200) of the human dermis. We reviewed 10 lesional biopsies from seven patients with anti-p200 pemphigoid in an attempt to define typical histopathologic features of this disease. All biopsy specimens showed subepidermal blistering and a moderate to dense inflammatory infiltrate in the upper dermis. Immunohistochemical analysis localized type IV collagen to the dermal side of the blister, suggesting that split formation occurred within the lamina lucida of the cutaneous basement membrane. The inflammatory infiltrate was composed almost exclusively of neutrophils in six biopsies and contained a mixture of neutrophils and eosinophils in the remaining four. In three specimens, microabscess formation in the papillary dermis adjacent to the blister cavity was noted. Neutrophilic and eosinophilic spongiosis was found in five and three biopsies, respectively. We conclude that histopathology of anti-p200 pemphigoid is characterized by subepidermal blistering and a superficial inflammatory infiltrate, which is usually dominated by neutrophils but occasionally contains significant numbers of eosinophils. While this microscopic picture mimics that of linear IgA disease, dermatitis herpetiformis, or bullous pemphigoid, it should also alert a histopathologist to the possibility of anti-p200 pemphigoid and prompt immunofluorescence and immunoblotting studies for definite diagnosis or exclusion of this autoimmune subepidermal blistering disease.