Autoreactive T and B Cells from Bullous Pemphigoid (BP) Patients Recognize Epitopes Clustered in Distinct Regions of BP180 and BP230

Thoma-Uszynski, Sybille; Uter, Wolfgang; Schwietzke, Susanne; Borradori, Luca; Hertl, Michael

doi:10.4049/jimmunol.176.3.2015

Cited by 111 publications

(97 citation statements)

References 43 publications

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“…Of note, T and B cell reactivity against the NH 2 -terminal portion of the BP180 ectodomain was associated with severe BP, with widespread blisters and erosions, while the central portion was more frequently recognized in limited BP, with few blisters and erosions (37). In contrast, less than 50% of the studied BP patients showed a combined T and B cell response against the COOH- and NH 2 -terminal globular domains of BP230 (38). This finding is of particular interest in light of the current discussion as to whether the transmembranous adhesion molecule BP180 or the intracellular hemidesmosomal component BP230 is the major autoantigen of BP (Figure 1) (38).…”

Section: Autoreactive T Lymphocytes In the Pemphigoidsmentioning

confidence: 86%

“…A subset of healthy individuals who carried the BP-associated HLA class II allele DQβ1*0301 also showed BP180-specific T cell responses that were predominantly of the Th1 type (45). Distinct peptide-binding motifs of HLA-DQβ1* 0301 have not yet been defined, nor were the anchor motifs of T cell epitopes of BP180 characterized in detail (38). The presence of IgG autoantibodies against BP180 in the clinical BP variant mucous membrane pemphigoid seems to be associated with the presence of HLA-DQβ1*0301 (46).…”

Section: Autoreactive T Lymphocytes In the Pemphigoidsmentioning

confidence: 99%

“…Th2 and Th1 responses against the BP180 ectodomain were identified in the majority of the studied BP patients in 2 independent studies (34, 35). Recent studies showed that BP180-reactive Th cells and IgG autoantibodies recognized similar or identical epitopes clustered in distinct regions of the BP180 ectodomain and BP230 (36)(37)(38). Specifically, the majority of autoreactive Th2 and Th1 cells and B cells recognized epitopes within the NH 2 -terminal portion, followed by reactivity against the COOH-terminal and central portions, of the BP180 ectodomain (37).…”

Section: Autoreactive T Lymphocytes In the Pemphigoidsmentioning

confidence: 99%

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T cell control in autoimmune bullous skin disorders

Hertl¹

2006

Journal of Clinical Investigation

198

129

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Autoimmune bullous disorders are a group of severe skin diseases characterized clinically by blisters and erosions of skin and/or mucous membranes. A hallmark of these disorders is the presence of IgG and occasionally IgA autoantibodies that target distinct adhesion structures of the epidermis, dermoepidermal basement membrane, and anchoring fibrils of the dermis. This Review focuses on the potential role of autoreactive T cells in the pathogenesis of these disorders. Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are the best-characterized bullous disorders with regard to pathogenesis and T cell involvement. Activation of autoreactive T cells in PV and BP is restricted by distinct HLA class II alleles that are prevalent in individuals with these disorders. Autoreactive T cells are not only present in patients but can also be detected in healthy individuals. Recently, a subset of autoreactive T cells with remarkable regulatory function was identified in healthy individuals and to a much lesser extent in patients with PV, suggesting that the occurrence of autoimmune bullous disorders may be linked to a dysfunction of Tregs.Autoimmune bullous skin disorders are characterized by the presence of autoantibodies that target distinct adhesion molecules of the epidermis and dermoepidermal basement membrane zone, leading to a loss of adhesive function of the target antigen(s) and, clinically, to the appearance of blisters and erosions (1, 2) (Figures 1 and 2). Desmogleins are transmembranous components of desmosomes, adhesion units specialized in conferring epidermal keratinocyte cohesion and linked to intercellular molecules of the desmosomal plaque, which in turn interact with components of the cytoskeleton (Figure 1). In pemphigus, IgG autoantibodies against desmoglein 3 (Dsg3) and Dsg1 lead to loss of desmosomal adhesion of epidermal keratinocytes and intraepidermal blister formation (Figure 2). In the pemphigoids, IgG autoantibodies against components of the dermoepidermal basement membrane such as bullous pemphigoid (BP) antigen 180 (BP180; also referred to as BP antigen 2 and type XVII collagen), BP antigen 230 (BP230; also referred to as BP antigen 1), and laminin 5 interfere with the adhesion of basal epidermal keratinocytes to the dermoepidermal basement membrane zone (Figure 1). BP180 and BP230 are transmembranous and intracellular components, respectively, of hemidesmosomes of basal epidermal keratinocytes, while laminin 5 is a ligand of BP180 located in the lamina lucida of the basement membrane zone (Figure 1). The autoantigen of epidermolysis bullosa, type VII collagen, is the major component of anchoring fibrils that connect the dermoepidermal basement membrane with interstitial collagen bundles of the dermis (Figure 1). The autoantigen of dermatitis herpetiformis, epidermal transglutaminase, is targeted by autoantibodies of the IgA class in the papillary dermis (Figure 2).Based on the specificity of the targeted antigens, several clinically and immune serologically distinct bullous disorders have be...

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Section: Autoreactive T Lymphocytes In the Pemphigoidsmentioning

confidence: 86%

Section: Autoreactive T Lymphocytes In the Pemphigoidsmentioning

confidence: 99%

Section: Autoreactive T Lymphocytes In the Pemphigoidsmentioning

confidence: 99%

See 1 more Smart Citation

T cell control in autoimmune bullous skin disorders

Hertl¹

2006

Journal of Clinical Investigation

198

129

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“…These results strongly suggest that CD4 + T cells play a pivotal role in the production of the autoantibodies through the presentation of the endogenous autoantigen. In human BP, the presence of autoreactive CD4 + T cells has been reported, indicating the contribution of CD4 + T cells to the pathogenesis of human BP (38)(39)(40). In addition, particular MHC class II alleles are more frequent in BP patients (41).…”

Section: Discussionmentioning

confidence: 99%

A Novel Active Mouse Model for Bullous Pemphigoid Targeting Humanized Pathogenic Antigen

Ujiie

Shibaki

Nishie

et al. 2010

The Journal of Immunology

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Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). To establish an active stable BP animal model that demonstrates the persistent inflammatory skin lesions initiated by the anti-human COL17 Abs, we used COL17-humanized (COL17m−/−,h+) mice that we recently produced. First, we generated immunodeficient Rag-2−/−/COL17–humanized mice by crossing Rag-2−/− mice with COL17-humanized mice. Then, splenocytes from wild-type mice that had been immunized by grafting of human COL17-transgenic mouse skin were transferred into Rag-2−/−/COL17–humanized mice. The recipient mice continuously produced anti-human COL17 IgG Abs in vivo and developed blisters and erosions corresponding to clinical, histological, and immunopathological features of BP, although eosinophil infiltration, one of the characteristic histological findings observed in BP patients, was not detected in the recipients. Although the depletion of CD8+ T cells from the immunized splenocytes was found to produce no effects in the recipients, the depletion of CD4+ T cells as well as CD45R+ B cells was found to inhibit the production of anti-human COL17 IgG Abs in the recipients, resulting in no apparent clinical phenotype. Furthermore, we demonstrated that cyclosporin A significantly suppressed the production of anti-human COL17 IgG Abs and prevented the development of the BP phenotype in the treated recipients. Although this model in an immunodeficient mouse does not exactly reproduce the induction mechanism of BP in human patients, this unique experimental system targeting humanized pathogenic Ag allows us to investigate ongoing autoimmune responses to human molecules in experimental animal models.

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“…␤ 3 -and ␥ 2 -chains from the squamous carcinoma cell line SCC25), recombinant 230-kDa BP antigen (BP230) and 180-kDa BP antigen (BP180; baculoprotein expression system) as previously described [4] . By ELISA, there was strong IgG reactivity against laminin 332 and reactivity against a distinct BP180 epitope (midportion of the BP180 ectodomain, aa residues 809-1106).…”

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confidence: 99%

Brunsting-Perry Pemphigoid of the Scalp with Antibodies against Laminin 332

et al. 2011

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Letter to Dermatology␤ 3 -and ␥ 2 -chains from the squamous carcinoma cell line SCC25), recombinant 230-kDa BP antigen (BP230) and 180-kDa BP antigen (BP180; baculoprotein expression system) as previously described [4] . By ELISA, there was strong IgG reactivity against laminin 332 and reactivity against a distinct BP180 epitope (midportion of the BP180 ectodomain, aa residues 809-1106). The lesion healed with topical corticosteroids. Three years later, the patient was in complete remission, and a control ELISA no longer showed IgG reactivity against laminin 332, BP180 or BP230 antigens. Case 2A 74-year-old man had a 2-year history of erosions and crusts of the scalp. At presentation, he had an erosive and crusty lesion 10 cm in diameter on the top of his head while other parts of the body or mucous membranes were not affected ( fig. 1 b). The biopsy showed actinic damage of the epidermis; the diagnosis of actinic keratosis was established, and the lesion was treated with liquid nitrogen with only temporary effect. A second biopsy of lesional skin showed subepidermal cleavage and an inflammatory infiltrate composed of lymphocytes and histiocytes in the dermis suggestive of CP ( fig. 1 c). DIF of lesional skin was negative, IIF on monkey oesophagus showed granular antinuclear auto-antibodies at a titre of 1: 80 and weak linear positivity with anti-IgG, -A and -M antibodies; salt split skin was negative. By ELISA, the patient's serum showed IgG reactivity against laminin 332. Topical treatment with corticosteroids led to a temporary healing of the lesion. Two years later, the patient still needs intermittent topical corticosteroid treatment. DiscussionBrunsting-Perry pemphigoid typically affects elderly men as multiple erosive and scarring lesions in the head and neck region, rarely as a solitary plaque [5] . In case of a solitary lesion the diagnosis may be extremely difficult. These cases can be misdiagnosed as actinic keratosis, pyoderma or dermatitis artefacta. The lesion is often eroded; thus, no subepidermal blister is detected, eosinophils are usually absent, immunofluorescence studies, if done, can be negative.A case of Brunsting-Perry pemphigoid similar to ours with a solitary lesion of the scalp was described by Poon and McGrath [6] , which was negative by DIF and IIF. Monihan et al. [7] described 3 cases of CP simulating basal cell carcinoma. Murata et al. [8] detected immunoglobulin deposits between basal keratinocytes and the lamina lucida of the dermal-epidermal junction by immuno-electron microscopy in a case of Brunsting-Perry pemphigoid supporting the concept that this disorder is closely related to CP. Key WordsAuto-immune bullous diseases ؒ Brunsting-Perry pemphigoid ؒ Cicatricial pemphigoid ؒ Laminin 332 A scarring disease localized to the head and neck without mucosal involvement, described by Brunsting and Perry in 1957 [1] , is considered as a variant of cicatricial pemphigoid (CP), bullous pemphigoid (BP) or epidermolysis bullosa acquisita (EBA), although the target antigen has not yet be...

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Autoreactive T and B Cells from Bullous Pemphigoid (BP) Patients Recognize Epitopes Clustered in Distinct Regions of BP180 and BP230

Cited by 111 publications

References 43 publications

T cell control in autoimmune bullous skin disorders

T cell control in autoimmune bullous skin disorders

A Novel Active Mouse Model for Bullous Pemphigoid Targeting Humanized Pathogenic Antigen

Brunsting-Perry Pemphigoid of the Scalp with Antibodies against Laminin 332

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