Epitopes Targeted by Bullous Pemphigoid T Lymphocytes and Autoantibodies Map to the Same Sites on the Bullous Pemphigoid 180 Ectodomain

Lin, Mong Shang; Fu, Chang Ling; Giudice, George J.; Olague-Marchan, Mónica; Lázaro, A. M.; Šťastný, Peter; Díaz, Luis A.

doi:10.1046/j.1523-1747.2000.00153.x

Cited by 77 publications

(70 citation statements)

References 43 publications

(46 reference statements)

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“…The NH 2 -terminal portion of the BP180 ECD was targeted by T and B cells to the greatest extent, whereas an overlapping T and B cell response to midportion and COOH terminus of BP180 was only seen in Ͼ50% of the patients (Table III). This finding is in line with a previous study by Lin et al (25) who detected both autoantibody and T cell reactivity directed against the NC16A-domain of BP180 in the majority of the patients investigated.…”

Section: Discussionsupporting

confidence: 93%

“…Previous reports only identified serum autoantibody (10, 21, 33, 34) and autoaggressive T cells (23) recognizing epitopes within the NH 2 -terminal region of the BP180 ECD in the majority of BP patients. Specifically, these studies focused on T cell recognition of the NC16A subdomain, which resides within the NH 2 -terminal region of BP180 (24,25,27,36). In fact, a considerable number of BP and Pg patients studied displayed NC16A-specific peripheral T cell responses, which were mainly of the Th2 type or of a mixed Th1/Th2 type (24,25,27,36).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, these studies focused on T cell recognition of the NC16A subdomain, which resides within the NH 2 -terminal region of BP180 (24,25,27,36). In fact, a considerable number of BP and Pg patients studied displayed NC16A-specific peripheral T cell responses, which were mainly of the Th2 type or of a mixed Th1/Th2 type (24,25,27,36). Specifically, Lin et al (24) identified autoreactive T cells directed against the NC16A region of the BP180 ECD in 12 patients with active BP and two patients with Pg.…”

Section: Discussionmentioning

confidence: 99%

“…Upon proper costimulation, Th cells become activated and secrete distinct cytokines, which stimulate B cells and thus foster plasma cell development and autoantibody production. Autoreactive Th cells that recognize regions of the BP180 ECD, including the immunodominant NC16A region, have been described in selected patients with BP and Pg (23)(24)(25)(26)(27). Clinically, BP has been associated with several MHC class II alleles, HLA-DQB1*0301, -*0305, -*0602, and -*0603 (28).…”

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confidence: 99%

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

Thoma-Uszynski

Uter

Schwietzke

et al. 2006

The Journal of Immunology

108

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Bullous pemphigoid (BP) is a well-characterized model of autoantibody-mediated autoimmunity, which presumably depends on autoreactive Th cells that promote the activation of autoreactive B cells. The two major autoantigens of BP are BP180 and BP230, two components of dermoepidermal adhesion complexes. Both, autoreactive Th cell responses and autoantibody profiles were characterized in 35 patients with acute onset BP using BP180 and BP230 proteins. Our findings indicate the following: 1) autoreactive Th cells recognized epitopes within the NH2-terminal (77.1%), COOH-terminal (65.7%), and central portion (57.1%) of the BP180 ectodomain; 2) IgG autoantibodies were found to exhibit similar or identical reactivity against the NH2-terminal (82.8%), COOH-terminal (77.1%), and central portion (37.1%) of the BP180 ectodomain; 3) T and B cell reactivity with the NH2-terminal portion of the BP180 ectodomain was associated with extensive BP, whereas the central portion was more frequently recognized in limited BP; 4) only 7 of 16 (43.7%) and 6 of 16 (37.5%) BP patients showed a Th cellular response against the COOH- and NH2-terminal regions of BP230, respectively, whereas 5) IgG reactivity against the COOH- and NH2-termini of BP230 was detected in 5 of 16 (31.3%) and 6 of 16 (37.5%) patients, respectively. These results demonstrate that Th and B cell reactivities against BP180, are, in contrast to BP230 reactivity, almost constantly detectable in BP patients, and differential epitope recognition of BP180 seems to be associated with distinct clinical severity. These observations support the concept that BP180, but not BP230, is the primary autoantigen of BP critical for disease development.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Thoma-Uszynski

Uter

Schwietzke

et al. 2006

The Journal of Immunology

108

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“…Th1/Th2 type, respectively (35,39). T cell recognition of BP180-NC16A seems to be rather heterogeneous since BP180-NC16A-specific T cell clones from the BP patients preferentially expressed a TCR different from the TCR expressed by T cell clones derived from a PG patient (40).…”

Section: Autoreactive T Lymphocytes In the Pemphigoidsmentioning

confidence: 99%

T cell control in autoimmune bullous skin disorders

Hertl¹

2006

Journal of Clinical Investigation

193

128

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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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Usefulness of BP180 NC16a Enzyme-Linked Immunosorbent Assay in the Serodiagnosis of Pemphigoid Gestationis and in Differentiating Between Pemphigoid Gestationis and Pruritic Urticarial Papules and Plaques of Pregnancy

Powell¹,

Sakuma-Oyama²,

Oyama³

et al. 2005

Arch Dermatol

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Background: Pemphigoid gestationis (PG) is a rare pregnancy-associated subepidermal immunobullous disease that targets hemidesmosomal proteins, particularly BP180. Clinically, PG can resemble the eruption known as polymorphic urticarial papules and plaques of pregnancy (PUPPP), and accurate differentiation between these 2 pruritic pregnancy dermatoses has important implications for fetal and maternal prognoses. Results of epitope mapping studies show that IgG autoantibodies in up to 90% of PG serum samples target the well-defined membrane-proximal NC16a domain of BP180.Objective: To examine the usefulness of a commercially available NC16a domain enzyme-linked immunosorbent assay in the serodiagnosis of PG and in the differentiation of PG from PUPPP.Participants: A total of 412 women consisting of pre-treatment patients with PG (n=82), patients with PUPPP (n=164), and age-and sex-matched controls (n=166).Methods: All serum samples were assayed in duplicate. Receiver operating characteristic analyses were performed to determine a cutoff value for the diagnosis of PG and for differentiation from PUPPP and controls.Results: A cutoff value of 10 enzyme-linked immunosorbent assay units was associated with specificity and sensitivity of 96%. Conclusions:The NC16a enzyme-linked immunosorbent assay is highly sensitive and highly specific in differentiating PG from PUPPP, and it is potentially a valuable tool in the serodiagnosis of PG.

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Epitopes Targeted by Bullous Pemphigoid T Lymphocytes and Autoantibodies Map to the Same Sites on the Bullous Pemphigoid 180 Ectodomain

Cited by 77 publications

References 43 publications

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

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

T cell control in autoimmune bullous skin disorders

Usefulness of BP180 NC16a Enzyme-Linked Immunosorbent Assay in the Serodiagnosis of Pemphigoid Gestationis and in Differentiating Between Pemphigoid Gestationis and Pruritic Urticarial Papules and Plaques of Pregnancy

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