Localization of Bullous Pemphigoid Antigen (BPA) in Isolated Human Keratinocytes

215

156

Antibodies against the extracellular domain of bullous pemphigoid antigen 2 (BPAG2) are thought to play a key role in the pathogenesis of bullous pemphigoid (BP), the most frequent autoimmune bullous disease of the skin. Autoreactive T cell responses to BPAG2 were investigated in 16 BP patients and 24 healthy controls by coculture of PBMC with two recombinant BPAG2 proteins (extracellular domain of BPAG2). Primary in vitro T cell responses to BPAG2 were observed in 10/12 BP patients expressing the BP-associated HLA-DQB1*0301 allele and 8/10 DQB1*0301 positive healthy individuals. DQB1*0301 also restricted three autoreactive T cell lines from two BP patients and a healthy donor. In contrast, PBMC from 14 normal patients carrying HLA class II alleles other than DQB1*0301 were not stimulated by BPAG2. Autoreactive BPAG2-specific CD4 ϩ T cell lines and clones from five BP patients produced both Th1 and Th2 cytokines, whereas three autoreactive T cell lines from three DQB1*0301 positive normal patients produced exclusively IFN-␥ . The absence of BPAG2-specific Th2 cells in healthy individuals strongly suggests that autoreactive Th2 responses to BPAG2 are restricted to BP patients and may thus be critical in the pathogenesis of BP. (

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls.

Büdinger¹,

Borradori²,

Yee³

et al. 1998

215

156

“…In the skin lesions of BP patients, hemidesmosomes cannot be visualized by electron microscopy (1,2). Immunoelectron microscopic studies have demonstrated that circulating BP autoantibodies bind specifically to the hemidesmosomes of normal epidermis (3)(4)(5)(6)(7); however, it is important to note that direct evidence ofthe pathogenicity ofthese antihemidesmosomal autoantibodies is lacking.…”

Section: Introductionmentioning

confidence: 99%

Identification of two collagen domains within the bullous pemphigoid autoantigen, BP180.

Giudice¹,

Squiquera²,

Elias³

et al. 1991

124

Bullous pemphigoid (BP) is an autoimmune disease characterized by subepidermal vesicles and the presence of autoantibodies directed against the epidermal basement membrane zone. Previous studies have identified two protein components of the hemidesmosome, BP180 and BP230, as the primary antigenic targets of BP autoantibodies. We have recently reported the isolation of a 1.0-kb BP180 cDNA. Sequence analysis presented in this report reveals that this partial BP180 cDNA encodes two protein domains which have primary structures that are characteristic of the triple helical domains of collagens, i.e., glycine appears at every third position and over one-third of the remaining residues are proline. The two collagen domains have lengths of 242 and 30 amino acids and are separated by a noncollagen stretch of 12 amino acids. Collagenase digestion of the BP180 cDNA-encoded fusion protein generated a peptide fragment with a size that was consistent with the predicted locations of the collagenase digestion sites. A possible physiological function for the collagen domains of the BP180 hemidesmosomal protein may be to form stable interactions with constituents of the extracellular matrix of the cutaneous basement membrane zone. Such interactions may provide the molecular framework for the adhesion between the basal keratinocyte and the basal lamina. (J. Clin. Invest. 1991.87:734-738.)

“…However, because the molecular composition of hemidesmosomes has not been determined, the association of BP antibodies and hemidesmosomes has been determined by immunoelectron microscopy (43)(44)(45)(46). Because BP autoantibodies bind hemidesmosomes, they can be used as tools to define some of their molecular constituents.…”

Section: Immunopathologymentioning

confidence: 99%

Pemphigus and pemphigoid as paradigms of organ-specific, autoantibody-mediated diseases.

Stanley¹

1989

190

114

The blistering skin diseases pemphigus and pemphigoid can be considered paradigms of antibody-mediated, organ-specific autoimmune diseases. These diseases not only demonstrate mechanisms whereby autoantibodies can mediate tissue damage, but are also examples ofhow autoantibodies from patients can be used as tools to further our understanding ofthe molecular structure of normal tissue. In this Perspectives article, I will briefly describe the clinical, histologic, and immunopathologic features of these diseases. I will then discuss in more detail the newer data regarding the pathophysiology of these diseases, as well as the molecules defined by the autoantibodies from these patients. Clinical and histologic featuresThe clinical and histologic aspects of pemphigus and pemphigoid are well established (Table I) (1). There are two major types of pemphigus, called pemphigus vulgaris (PV)' and pemphigus foliaceus (PF). Patients with PV almost always develop, and often present with, mucous membrane erosions. Skin lesions, which are seen as flaccid blisters or erosions, tend to gradually enlarge at the edges. PV, ifleft untreated, is almost always fatal. The histology ofa PV lesion shows that the blister (or erosion) forms because of separation of epidermal cells from each other (a process called acantholysis) just above the basal cell layer. In contrast to PV patients, PF patients rarely have mucous membrane lesions. They usually present with scaly and crusted skin lesions, which, unlike PV lesions, do not tend to form extensive and enlarging erosions, but are fixed and well demarcated. Fogo selvagem (also called Brazilian PF) is a form of PF that is endemic in rural areas of Brazil and often affects children and young adults (2). The histology of a PF lesion demonstrates blister formation due to acantholysis in the superficial epidermis at the granular layer. With these histologic findings in mind, both major types of pemphigus, PV and PF, can May 1989May , 1443May -1448 In contrast to the flaccid blisters, erosions, and crusted lesions seen in pemphigus patients, bullous pemphigoid (BP) patients classically present with tense blisters on normal-appearing or erythematous skin. Whereas pemphigus lesions are due to intraepidermal blisters, histology of a BP lesion indicates a subepidermal blister with an infiltrate containing eosinophils in the superficial dermis and at the epidermal basement membrane zone (BMZ). Clinically and histologically similar to BP, herpes gestationis (also called pemphigoid gestationis) is a subepidermal, autoantibody-associated blistering disease that occurs during the second or third trimester of pregnancy, and spontaneously resolves in the months after delivery. ImmunopathologyOver 20 years ago, Beutner and Jordon established that BP and pemphigus were associated with autoantibodies (3). Both direct immunofluorescence of patients' lesional and perilesional skin and indirect immunofluorescence with patients' sera on normal skin substrates, have demonstrated antibody binding to the same ar...