In vitro pemphigus vulgaris model using organotypic cultures of human epidermal keratinocytes

Using the Combi-ring-dish (CRD), a new culture device, organotypic cultures of human epidermal keratinocytes were grown on bovine eye lens capsules. In these highly differentiated cultures, typical suprabasal acantholysis was induced by pemphigus vulgaris antibodies. This in vitro pemphigus vulgaris model may be used to analyse keratinocyte-derived factors causing acantholysis in experimental pemphigus.     

Pemphigus foliaceus with neutrophilic spongiosis evolving to an atypical pemphigus phenotype

A 46-year-old Brazilian man, with initial pustular lesions, neutrophilic spongiosis and subcorneal cleavage evolved to an atypical pemphigus phenotype, with suprabasal acantholysis. Interestingly, his autoantibody profile, tested by immunofluorescence, immunoblotting, enzyme-linked immunosorbent assay, and immunoprecipitation revealed exclusive IgG anti-desmoglein 1 antibodies in all phases of the disease.     

Involvement of membrane attack complex of complement in UV-B-induced acantholysis in pemphigus

The initial acantholytic process induced by irradiation of UV-B on uninvolved skin of patients with pemphigus was immunohistologically studied using monoclonal antibodies that bind to antigenic determinants present in the C5b9 complex. Membrane attack complex of complement-related antigens in suprabasal intercellular sites could be detected after 5 hours of irradiation, at which time there was no acantholysis. At 24 hours, the staining intensity markedly increased and suprabasal clefts with acantholytic epidermal cells could be seen. In contrast, acantholysis did not develop in the absence of membrane attack complex formation at intercellular sites even 24 hours following UV-B irradiation. These findings suggest that UV-B can induce membrane attack complex assembly in the epidermis, which may itself be involved in the process of acantholysis and provide additional evidence for involvement of the complement system in pemphigus.     

Follicular acantholysis: a subtle clue to the early diagnosis of pemphigus vulgaris

The histologic hallmark of fully established pemphigus vulgaris (PV), a chronic autoimmune disease of the skin and mucosa, is the presence of acantholysis induced at the suprabasal level. This case report of acantholysis restricted to the follicular epithelium as a subtle histologic manifestation of the disease, draws attention to the pitfalls encountered in the histologic diagnosis of early cases of pemphigus vulgaris.     

A clinico-pathological study of 70 cases of pemphigus

A clinicopalhological study of 70 cases of pemphigus observed over a span of four and a half years from January 1992 to June 1996 at the Sir J.J. Group of Hospitals and Grant Medical College, Mumbai is reported. Pemphigus vulgaris constituted the single largest group of 43 cases, followed by pemphigus foliaceus (25 cases) and pemphigus vegetans (2 cases). Majority of the cases were seen in the age group of 21-60 years, with a slight male predominance. The youngest patient was 14 years while the eldest was aged 75 years. Mucosal involvement was seen in 31 cases of pemphigus vulgaris, as opposed to only 5 cases of pemphigus foliaceus. Flaccid bullae were present in 100% cases. Pruritus was complained of in 14 cases, though it was more common in pemphigus vegetans and vulgaris. Salient histopathological features of pemphigus vulgaris observed were (I) intraepidermal suprabasal blisters (35 cases), (2) presence of acantholytic cells (40 cases), (3) "Row of tombstone appearance" (I8 cases) and (4) acantholysis involving follicular sheath (20 cases). Main histopathological features of pemphigus foliaceus were (1) subcorneal blister (15 case), (2) acantholysis (24 cases) and (3) bulla cavity containing inflammatory infiltrate (12 cases). Both cases of pemphigus vegetans showed hyperkeratosis, papillomatosis and irregular acanthosis with intra-epidermal eosinophilic abscesses besides suprabasal lacunae.     

Histologic features of paraneoplastic pemphigus.

BACKGROUND--We describe the histopathologic features of paraneoplastic pemphigus, a recently described autoimmune mucocutaneous disease associated with neoplasia. Complete evaluation for paraneoplastic pemphigus requires identification of the characteristic mucocutaneous eruption, tissue specimens for routine histologic and direct immunofluorescence evaluation, and identification of circulating autoantibodies with a unique specificity. Immunoprecipitation from keratinocytes reveals a characteristic complex of four proteins with the circulating antibodies. Various neoplasms have been identified in patients with paraneoplastic pemphigus. OBSERVATIONS--We reviewed 16 skin and oral mucous membrane biopsy specimens from six patients with paraneoplastic pemphigus confirmed by fulfillment of all criteria. Major features include epidermal acantholysis, suprabasal cleft formation, dyskeratotic keratinocytes, vacuolar change of the basilar epidermis, and epidermal exocytosis of inflammatory cells. Seven (44%) of 16 specimens displayed a unique combination of suprabasal acantholysis and dyskeratotic keratinocytes throughout the epidermis. These histologic findings correspond to those of the characteristic clinical lesions that are described as having features of pemphigus and erythema multiforme. CONCLUSIONS--Paraneoplastic pemphigus represents a unique clinical, histologic, and immunologic disease characterized by autoantibody production to desmoplakin I and desmoplakin II, bullous pemphigoid antigen, and, possibly, other antigens in the desmosomal complex. Recognition of the histologic features should prompt immunopathologic confirmation and evaluation for an occult neoplasm.     

Unusual presentation of pemphigus vulgaris

We report a case of a 50-year-old man who presented with a conjunctival erosion and lesions resembling acute paronychia of several fingers. The Tzanck preparation from the conjunctiva showed the presence of acantholytic cells. Skin biopsy showed suprabasal cleft formation with acantholysis. Direct immunofluorescence revealed intercellular epidermal staining with IgG and C3. Diagnosis of pemphigus vulgaris was therefore confirmed. Nail abnormalities that can be observed in pemphigus vulgaris are discussed.     

Bilateral herpes simplex virus keratitis in a patient with pemphigus vulgaris

Pemphigus is a group of chronic blistering diseases in which acantholysis and blister formation occur within the epidermis. Immunoglobulins and complement are found in the circulation and are bound to the cell surfaces of keratinocytes. Pemphigus is classified into several types hut may he divided into two major variants, pemphigus vulgaris and pemphigus foliaceus. The primary skin lesion of pemphigus vulgaris which was often fatal before the introduction of systemic glucocorticoid therapy, is a flaccid, fragile blister which can occur anywhere. The most common skin lesions arc erosions, which are often painful; suprabasal elefting within the epidermis is also present. In the majority of these patients, painful mucous membrane erosions will be the first symptom, while sometimes the conjunctiva is affected but corneal involvement is very rare.     

An immunohistological study of desmosomal components in pemphigus

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune diseases in which there is loss of cohesion between keratinocytes (acantholysis) and blistering within the epidermis. PV is characterized by acantholysis predominantly between the epidermal basal cells and suprabasal layers, whereas in PF intraepidermal cleavage is higher in the epidermis. Adhesion between keratinocytes is dependent on the function of transmembrane glycoproteins of the cadherin family present in specialized adhesion junctions, the desmosomes. The pathogenesis of acantholysis In pemphigus is uncertain, but the pemphigus autoantibodies bind to epithelial cadherins. We have used monoclonal antibodies to desmosomal components to investigate their distribution in different forms of pemphigus. Our results show that the localization of desmosomal components is abnormal in intact perilesional epidermis, intact epidermis above the blisters in PV and intact epidermis below the blisters in PF. We suggest that autoantibody binding may have a direct effect on the function of specific epithelial cadherins, but will only cause cell separation where the antigen is the principal adhesion molecule.     

In vivo enalapril-induced acantholysis.

Enalapril is a widely used antihypertensive drug with a very powerful in vitro acantholytic effect. It has been known to potentially induce pemphigus in genetically predisposed subjects. The action mechanism is complex and still only partially understood. We describe the case of a 66-year-old man, affected with intermediary basal cell carcinoma, in whom the histological examination showed suprabasal acantholytic clefts in the perilesional epidermis. Surprisingly a second biopsy taken from the apparently healthy skin of his back confirmed the presence of acantholytic changes. Clinical signs of pemphigus were absent. The patient's history did not reveal any relevant data but a mild arterial hypertension that had been treated for 1 year with 10 mg enalapril. Taking into account the patient's history (enalapril long-term administration), the absence of any bullous or erosive lesions and the histological findings, a diagnosis was made of in vivo enalapril-induced acantholysis.     

Benign familial chronic pemphigus and pityriasis rosea. Clinical aspects and histology of the coexistence of both dermatoses

We report the course of benign familial pemphigus (Hailey-Hailey disease) in a 45-year-old woman. While this condition was in remission the patient started to suffer from pityriasis rosea. A biopsy of this coexisting dermatosis revealed the typical features of Hailey-Hailey disease (suprabasal acantholysis) and of pityriasis rosea within the same lesion.     

History of pemphigus

The modern concept of pemphigus divides it into variants: pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus (Senear-Usher syndrome), and pemphigus herpetiformis. These conditions are all related by the fact that they are all bullous diseases at some time during their clinical course and are histologically characterized by acantholysis. In pemphigus vulgaris and pemphigus vegetans, acantholysis is generally above the basilar cell layer (suprabasilar) or in the lower half of stratum spinosum. In pemphigus foliaceus, pemphigus herpetiformis and pemphigus erythematosus, acantholysis occurs in the granular cell layer or upper stratum spinosum. Autoantibodies to the intercellular cement substance of the epidermis are present in all the variants.

The changes in the concept of pemphigus over time has been reviewed.^1,2 The term “pemphigus,” itself, was first proposed by Boissier de Sauvages in his classification of skin diseases.³ He described pemphigus maior as an acute, febrile, blistering disease lasting only two weeks. Today, the diagnosis would probably be erythema multiforme.

Wichmann^4,5 was the first to describe pemphigus as a chronic bullous disease; he used the term, febris bullosa, to describe bullous eruptions of short duration. Unfortunately, few authors agreed with Wichmann's more restricted concept, and continental dermatologists continued to use the term pemphigus for a wide range of vesicular or bullous diseases. For example, Gilibert,⁶ in his monograph on pemphigus, included almost every disease with bullae in his classification. His “chronic pemphigus” most closely corresponds to the modern concept of pemphigus. Von Martius⁷ had an equally liberal definition of pemphigus, dividing it into 97 types.

Willan had a much more restricted view of the disease. In his classification of skin diseases, pemphigus vulgaris was a febrile, bullous eruption of short duration.⁸ He applied the term “pompholyx duitinus” to a chronic, bullous eruption, without inflammation and fever, similar to the modern concept of pemphigus vulgaris.     

Organ culture studies of pemphigus antibodies. II. Ultrastructural comparison between acantholytic changes in vitro and human pemphigus lesions.

The ultrastructural and light microscopic features of acantholysis produced in organ culture were compared with those of human pemphigus lesions. In both, an intraepidermal split was seen an typical suprabasal acantholytic cells were present. These cells contained small bundles of tonofilaments, usually located away from the cell periphery. Desmonsomal plaques with inserted tonofilaments frequently remained along the periphery of acantholytic cells and along the upper portion of the periphery of basal cells. The ultrastructural similarity between in vitro and in vivo lesions provides additional evidence to suggest that organ cultures may provide a valid model for studying the dynamics of pemphigus lesion formation.     

Suprabasal acantholytic dermatologic toxicities associated checkpoint inhibitor therapy: A spectrum of immune reactions from paraneoplastic pemphigus‐like to Grover‐like lesions

Checkpoint inhibitors (CPIs) restore the function of effector immunocytes to target and destroy cancer cells. Immune‐related adverse events (irAEs) are a consequence of immune reactivation, with unpredictable inflammatory response, loss of self‐tolerance, and development of autoimmunity. Adverse events from CPIs that present as dermatologic toxicities have diverse clinical and histopathologic features. CPI‐associated dermatologic toxicities may exhibit histopathologic features of lichenoid dermatitis, bullous pemphigoid, and granulomatous/sarcoid‐like reactions. Suprabasal acantholytic dermatologic toxicities associated with CPIs are particularly rare but represent an emerging histopathologic pattern and include lichenoid dermatitis with suprabasal acantholysis/vesicle formation to Grover disease (transient acantholytic dermatosis). Here, we report two patients who developed suprabasal acantholytic dermatologic toxicities during CPI therapy. One patient exhibited a CPI‐associated autoimmune blistering disease with paraneoplastic pemphigus (PNP)‐like features restricted to histopathology and immunofluorescence, while the other patient had Grover‐like lesions. A review of the literature revealed a spectrum of suprabasal acantholytic dermatologic toxicities associated CPIs that may present as lichenoid dermatitis with acantholysis/vesicle formation, Grover‐like eruptions, and lesions with PNP‐like features restricted to histopathology and immunofluorescence. It is important for clinicians and pathologists to recognize the types of dermatologic toxicities associated with CPIs to direct appropriate therapeutic strategies.     

Pemphigus vulgaris and intraepithelial neoplasia localized to the vagina

BACKGROUND: Involvement of the vaginal mucosa in pemphigus vulgaris is a rare occurrence. Here we report an original case that resulted in discovery of intra-epithelial neoplasia at the same site. PATIENTS AND METHODS: A 63 year-old woman was followed for 18 years for pemphigus vulgaris treated with prednisone, initially in combination with azathioprine. An erosive lesion was discovered in the pouch of Douglas during routine gynecological examination and demonstrated the histological features of pemphigus, despite remission of the disease at other sites. In spite of resumption of azathioprine and prednisone, the vaginal lesion continued to spread. A further biopsy revealed intra-epithelial vaginal neoplasia together with images of suprabasal cleavage and acantholysis. Surgical removal was carried out. DISCUSSION: Intra-epithelial carcinoma associated with pemphigus vulgaris has been described in rare cases in the cervix but never in the vagina.     

A study of keratin expression in benign familial chronic pemphigus.

We studied keratin expression in the involved and uninvolved skin of six benign familial chronic pemphigus (BFCP) patients, using monoclonal antibodies specific for various keratin polypeptides and immunohistopathologic techniques. Normal and psoriatic (i.e., hyperproliferative) skin specimens served as controls. The uninvolved BFCP epidermis showed keratin profiles identical to that of normal epidermis. In the acantholytic epidermal segments of the involved BFCP skin, some of the lower suprabasal acantholytic cells failed to express keratin polypeptides 10 and 11 (Moll's catalog). This delay in expression of suprabasal keratins was not accompanied by an expression of hyperproliferative keratin polypeptide 16. Also, some of the lower suprabasal acantholytic cells of the involved BFCP epidermis retained staining by the antikeratin KS-1A3 antibody, which in the normal, psoriatic, and uninvolved epidermis was limited to the basal cell layer. Staining for keratin polypeptide 18 was negative in the epidermis of all four types of specimens. We believe that the delay in suprabasal keratin expression in the involved BFCP epidermis was more likely secondary to the acantholysis (i.e., "arrest of differentiation" due to acantholysis) rather than due to a primary defect in keratin expression.     

Pemphigus vulgaris and pemphigus foliaceus antibodies are pathogenic in plasminogen activator knockout mice.

Previous studies have suggested that urokinase plasminogen activator is required for blister formation in pemphigus vulgaris and pemphigus foliaceus. Other studies, however, have shown that downregulation of plasminogen activator does not inhibit blisters induced by pemphigus immunoglobulin G. To eliminate the possibility that small amounts of urokinase plasminogen activator might be sufficient for blister formation, we passively transferred pemphigus immunoglobulin G to urokinase plasminogen activator knockout neonatal mice. Pemphigus foliaceus and pemphigus vulgaris immunoglobulin G caused gross blisters and acantholysis in the superficial and suprabasal epidermis, respectively, to the same degree in knockout and control mice, demonstrating that urokinase plasminogen activator is not absolutely required for antibody-induced blisters. Some studies have shown elevated tissue-type plasminogen activator in pemphigus lesions. Tissue-type plasminogen activator, however, is not necessary for blister formation, because pemphigus foliaceus and pemphigus vulgaris immunoglobulin G caused blisters to the same degree in tissue-type plasminogen activator knockout and control mice. To rule out that one plasminogen activator might compensate for the other in the knockout mice, we bred urokinase plasminogen activator, tissue-type plasminogen activator double knockouts. After passive transfer of pemphigus foliaceus and pemphigus vulgaris immunoglobulin G these mice blistered to the same degree as the single knockout and control mice, and histology indicated blisters at the expected level of the epidermis. These data definitively demonstrate that plasminogen activator is not necessary for pemphigus immunoglobulin G to induce acantholysis in the neonatal mouse model of pemphigus.     

慢性家族性良性天疱疮发病机制的研究进展

Hailey-Hailey病(HHD),又称为慢性家族性良性天疱疮,是一种少见的常染色体显性遗传病,以表皮棘层松解为特征,具体发病机制尚不清楚。HHD由钙依赖性ATP酶基因遗传缺陷引起,该基因编码人类分泌途径钙离子转运ATP酶1型(SPCA1),在角质形成细胞内高度表达。本文就近年来有关HHD发病机制的研究进展进行综述,为今后该病相关研究提供理论基础。     

Castleman's disease associated pemphigus. A form of paraneoplastic pemphigus

We report a patient with Castleman's disease (angio-follicular lymph node hyperplasia) associated with a pemphigus vulgaris-Iike disorder. The patient had the hyaline-vascular mediastinal type of Castleman's disease and developed painful oral erosions and penile lesions.
Histologic examination revealed an interface dermatitis including vacuolar changes, necrotic keratinocytes and a lichenoid infiltrate. In addition there was suprabasal vesiculation with acantholysis, reminiscent of pemphigus vulgaris. Direct immunoperoxidase staining for intercellular igG was positive.
HLA typing revealed that the patient did not have an HLA haplotype known to he associated with susceptibility to pemphigus.
Until now, Castleman's disease Associated Pemphigus (CDAP) has been regarded as a unique entity presenting as atypical pemphigus vulgaris. However, a review of the literature reveals that the clinical and histologic signs of CDAP are virtually identical to those of paraneoplastic pemphigus and that both entities are associated with a lymphoproiiferative disorder. We suggest that CDAP is a form of paraneoplastie pemphigus.     

Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome

Paraneoplastic pemphigus is the term used for an exclusive subset of pemphigus. The clinical lesions may resemble pemphigus, pemphigoid, erythema multiforme, graft-vs.-host disease, or lichen planus. A common denominator in all patients is the concomitant occurrence of either occult or confirmed systemic neoplasm. It is imperative to confirm the diagnosis through microscopy, where intraepidermal suprabasal cleavage, epidermal acantholysis, dyskeratotic keratinocytes and vacuolar changes in the basal epidermis, interfacial dermatitis, and epidermal exocytosis can be seen. Furthermore, the deposition of immunoglobulin G (IgG) and complement in the epidermal intercellular spaces, detected by direct and/or indirect immunofluorescence, is equally crucial for confirming the diagnosis.