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1.
Immunity ; 42(2): 309-320, 2015 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-25692704

RESUMO

The epidermis constantly encounters invasions that disrupt its architecture, yet whether the epidermal immune system utilizes damaged structures as danger signals to activate self-defense is unclear. Here, we used a C. elegans epidermis model in which skin-penetrating infection or injury activates immune defense and antimicrobial peptide (AMP) production. By systemically disrupting each architectural component, we found that only disturbance of the apical hemidesmosomes triggered an immune response and robust AMP expression. The epidermis recognized structural damage through hemidesmosomes associated with a STAT-like protein, whose disruption led to detachment of STA-2 molecules from hemidesmosomes and transcription of AMPs. This machinery enabled the epidermis to bypass certain signaling amplification and directly trigger AMP production when subjected to extensive architectural damage. Together, our findings uncover an evolutionarily conserved mechanism for the epithelial barriers to detect danger and activate immune defense.


Assuntos
Peptídeos Catiônicos Antimicrobianos/biossíntese , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/imunologia , Epiderme/imunologia , Epiderme/lesões , Fatores de Transcrição STAT/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Proteínas de Caenorhabditis elegans/imunologia , Moléculas de Adesão Celular/imunologia , Células Cultivadas , Hemidesmossomos/imunologia , Hemidesmossomos/patologia , Humanos , Imunidade Inata , Queratinócitos/imunologia , Queratinócitos/metabolismo , Transdução de Sinais/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
2.
Int J Mol Sci ; 22(22)2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34830116

RESUMO

BP180 is a type II collagenous transmembrane protein and is best known as the major autoantigen in the blistering skin disease bullous pemphigoid (BP). The BP180 trimer is a central component in type I hemidesmosomes (HD), which cause the adhesion between epidermal keratinocytes and the basal lamina, but BP180 is also expressed in several non-HD locations, where its functions are poorly characterized. The immunological roles of intact and proteolytically processed BP180, relevant in BP, have been subject to intensive research, but novel functions in cell proliferation, differentiation, and aging have also recently been described. To better understand the multiple physiological functions of BP180, the focus should return to the protein itself. Here, we comprehensively review the properties of the BP180 molecule, present new data on the biochemical features of its intracellular domain, and discuss their significance with regard to BP180 folding and protein-protein interactions.


Assuntos
Autoantígenos , Hemidesmossomos , Queratinócitos , Colágenos não Fibrilares , Penfigoide Bolhoso , Dobramento de Proteína , Autoantígenos/imunologia , Autoantígenos/metabolismo , Hemidesmossomos/imunologia , Hemidesmossomos/metabolismo , Humanos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Colágenos não Fibrilares/imunologia , Colágenos não Fibrilares/metabolismo , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/metabolismo , Colágeno Tipo XVII
3.
Exp Dermatol ; 22(6): 381-5, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23651418

RESUMO

Bullous pemphigoid (BP), an autoimmune subepidermal blistering skin disease, demonstrates tense blisters with or without widespread erythema, blistering along the lamina lucida, immunoglobulin G and/or complement deposits at the basement membrane zone, and the presence of circulating autoantibodies against hemidesmosomal molecules. These autoantibodies usually react against 180-kDa and/or 230-kDa proteins, designated as BP180 and BP230, respectively. The precise blistering mechanisms after autoantibodies bind to antigens are not fully understood. Immune complexes are thought to initially activate the complement cascade, which may induce activation of proteases and/or cytokines and cause dermal-epidermal separation. However, why does separation run specifically within the lamina lucida in a space as narrow as 500 nm wide? This review mainly focuses on the possible mechanisms of BP-specific blistering and how separation occurs along the lamina lucida, based on existing evidence.


Assuntos
Autoanticorpos/imunologia , Vesícula/imunologia , Proteínas do Sistema Complemento/imunologia , Penfigoide Bolhoso/diagnóstico , Penfigoide Bolhoso/imunologia , Animais , Autoantígenos/imunologia , Membrana Basal/imunologia , Membrana Celular/metabolismo , Ativação do Complemento , Citocinas/metabolismo , Epiderme/imunologia , Hemidesmossomos/imunologia , Humanos , Imunoglobulina G/imunologia , Inflamação , Camundongos , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/fisiopatologia , Peptídeo Hidrolases/metabolismo , Colágeno Tipo XVII
4.
J Dermatol ; 47(4): 317-326, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32048350

RESUMO

Bullous pemphigoid (BP) is an autoimmune disease associated with subepidermal blistering due to autoantibodies directed against BP180 and BP230. BP180 is currently considered as the major pathogenic autoantigen. However, previous clinical findings suggested that anti-BP230 autoantibodies alone can cause skin lesions in animal models and many BP patients. The characteristics of BP230 and the pathogenic roles of anti-BP230 antibodies have been proposed. First, at the molecular level, BP230 mediates the attachment of keratin intermediate filaments to the hemidesmosomal plaque and interacts with other constituents of hemidesmosomes. Second, the presence of BP230 autoantibodies may correlate with specific clinical features of BP. The immunoglobulin (Ig)G autoantibodies from BP patients react mainly against the C-terminus of BP230, while the IgE autoantibodies are still inconclusive. Third, in vivo, autoantibodies against BP230 involved in the disease may not only induce the inflammatory response but also impair the structural stability of hemidesmosomes. This article reviews recently published work about the role of BP230 and its antibodies, including IgG and IgE, aiming to find clues of its clinical association and lay the foundation for the research on the pathogenicity of antibodies against BP230.


Assuntos
Autoanticorpos/imunologia , Distonina/imunologia , Penfigoide Bolhoso/imunologia , Pele/patologia , Autoanticorpos/metabolismo , Autoantígenos/imunologia , Distonina/metabolismo , Hemidesmossomos/imunologia , Hemidesmossomos/metabolismo , Hemidesmossomos/patologia , Humanos , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Filamentos Intermediários/imunologia , Filamentos Intermediários/metabolismo , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/patologia , Pele/imunologia , Colágeno Tipo XVII
5.
J Invest Dermatol ; 138(8): 1707-1715, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29530535

RESUMO

The basement membrane zone consists of multiple components, including collagen XVII (COL17), which is the target of bullous pemphigoid. To our knowledge, no research has addressed the differences in basement membrane zone components between the skin and oral mucosa; therefore, we investigated the basement membrane zone proteins, with a focus on COL17. The mRNA and protein expression levels of COL17 were significantly higher in oral keratinocytes than in skin keratinocytes. Hemidesmosomal COL17 expression was markedly higher in oral keratinocytes than in skin keratinocytes, and its level was associated with adhesion strength. Oral keratinocytes adhered to the extracellular matrix more tightly than did skin keratinocytes in vitro. Based on these results, we attempt to explain the clinical diversity of bullous pemphigoid. COL17 depletion was more prominent in skin keratinocytes than in oral keratinocytes after treatment with COL17-NC16A mAbs, which have in vivo pathogenicity. COL17 C-terminus mAbs, which are not pathogenic, facilitated COL17 depletion in combination treatment with COL17-NC16A mAbs in both types of keratinocytes. In summary, the greater amount of COL17 in oral keratinocytes than in skin keratinocytes is associated with the higher strength of oral keratinocyte hemidesmosomal adhesion at the basement membrane zone. Our results may explain why bullous pemphigoid blistering tends to be more prevalent in the skin than in the oral mucosa.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/metabolismo , Imunoglobulina G/imunologia , Mucosa Bucal/imunologia , Colágenos não Fibrilares/metabolismo , Penfigoide Bolhoso/imunologia , Adulto , Animais , Autoantígenos/genética , Autoantígenos/imunologia , Membrana Basal/imunologia , Membrana Basal/metabolismo , Vesícula/imunologia , Vesícula/patologia , Adesão Celular/imunologia , Linhagem Celular , Feminino , Voluntários Saudáveis , Hemidesmossomos/imunologia , Hemidesmossomos/metabolismo , Humanos , Queratinócitos/citologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Bucal/citologia , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Colágenos não Fibrilares/genética , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/patologia , Cultura Primária de Células , RNA Mensageiro/metabolismo , Pele/citologia , Pele/imunologia , Pele/metabolismo , Pele/patologia , Técnicas de Cultura de Tecidos , Colágeno Tipo XVII
6.
Adv Dermatol ; 23: 257-88, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18159905

RESUMO

There has been a considerable progress in the understanding of the physiopathology of BP during the past 2 decades. The insights into the humoral and cellular immune response against BP180 and BP230 have increased significantly. Nevertheless, the factors underlying the initiation of the disease leading to a disruption of self-tolerance remain unclear. Clinically, the disease shows protean presentations, and diagnostic delay is common. A practical, relevant, and unresolved question is how to identify patients suffering from BP at an early stage of the disease, when direct immunofluorescence microscopy findings still may be negative. The characterization of markers allowing the differentiation of BP from other pruritic eruptions occurring in the elderly population would be extremely helpful in daily practice. Finally, despite the knowledge that potent topical steroids are efficient in controlling the disease, management of BP sometimes remains difficult and requires systemic therapies. It is hoped that a better knowledge of the regulation of the autoimmune response in BP also will facilitate the design of novel immunomodulatory therapeutic approaches devoid of the severe side effects of current immunosuppressive treatments.


Assuntos
Penfigoide Bolhoso , Autoanticorpos/imunologia , Autoantígenos/imunologia , Proteínas de Transporte/imunologia , Proteínas do Citoesqueleto/imunologia , Distonina , Hemidesmossomos/imunologia , Humanos , Testes Imunológicos , Imunossupressores/uso terapêutico , Proteínas do Tecido Nervoso/imunologia , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/diagnóstico , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/fisiopatologia , Penfigoide Bolhoso/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Colágeno Tipo XVII
8.
J Invest Dermatol ; 122(1): 103-10, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14962097

RESUMO

Bullous pemphigoid is a subepidermal bullous disease of skin and mucosae associated with autoantibodies to BP180. To characterize the humoral response to BP180, we generated a random BP180 epitope library displayed on lambda bacteriophage. After validation of the library by epitope mapping of three BP180-specific monoclonal antibodies, 15 novel or known BP180 epitopes were identified using 10 bullous pemphigoid serum samples. Fifty-seven bullous pemphigoid and 81 control sera were then assayed against the selected epitopes. Thirty-one out of 57 (54%) bullous pemphigoid sera reacted with at least an additional antigenic site other than the NC16A, within the extracellular (37%) and intracellular (28%) domains of BP180. In addition, the reactivity with extracellular epitopes of BP180 contained within the residue stretches 508-541 and 1331-1404 appeared to be related to the presence of both skin and mucosal involvement. Finally, a preliminary analysis of the epitope pattern in the disease course indicated that bullous pemphigoid patients exhibit a specific reactivity pattern, and that binding to intracellular epitopes of BP180, in addition to NC16A, may be detectable at an early clinical stage. Our findings provide novel insights into the pathophysiology of bullous pemphigoid and show the potential of the utilized approach as a tool for a rapid diagnosis of bullous pemphigoid patients and their management.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Mapeamento de Epitopos , Penfigoide Bolhoso/diagnóstico , Penfigoide Bolhoso/imunologia , Anticorpos Monoclonais/imunologia , Hemidesmossomos/imunologia , Humanos , Queratinócitos/imunologia , Mucosa/imunologia , Colágenos não Fibrilares , Biblioteca de Peptídeos , Fenótipo , Pele/imunologia , Colágeno Tipo XVII
9.
J Invest Dermatol ; 119(5): 1065-73, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12445194

RESUMO

Bullous pemphigoid, the most common autoimmune subepidermal bullous disorder, is associated with autoantibodies targeting antigenic sites clustered within the extracellular domain of BP180. To investigate epitope and subclass specificity of autoantibodies in bullous pemphigoid, we developed an enzyme-linked immunosorbent assay utilizing baculovirus-expressed recombinant forms of the NH2- and COOH-terminal regions of the extracellular domain of BP180 and examined sera obtained from patients with active bullous pemphigoid (n=116) and controls (n=100). Ninety-three (80%) and 54 (47%) of the 116 bullous pemphigoid sera recognized the NH2- and COOH-terminal regions, respectively, of the extracellular domain of BP180. Detailed analysis demonstrates that (i) this novel enzyme-linked immunosorbent assay is highly specific (98%) and sensitive (93%) as 108 of 116 bullous pemphigoid sera reacted with at least one of the baculovirus-derived recombinants, (ii) in active bullous pemphigoid, autoantibodies against the NH2-terminus of the extracellular domain of BP180 were predominantly of the IgG1 class, whereas a dual IgG1 and IgG4 response to this region was related to a more severe skin involvement, (iii) autoreactivity against both the NH2- and COOH-terminal regions was more frequently detected in patients with mucosal lesions, and (iv) levels of IgG (and IgG1) against the NH2-terminal, but not against the COOH-terminal portion of the extracellular domain of BP180, reflected disease severity indicating that autoantibodies against the NH2-terminus are critical in the pathogenesis of bullous pemphigoid. In conclusion, this novel enzyme-linked immunosorbent assay represents a highly sensitive and specific assay for rapid diagnosis of bullous pemphigoid and related disorders and may provide predictive parameters for the management of bullous pemphigoid patients.


Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Penfigoide Bolhoso/imunologia , Autoantígenos/química , Autoantígenos/genética , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Hemidesmossomos/imunologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Mucosa/imunologia , Colágenos não Fibrilares , Fenótipo , Estrutura Terciária de Proteína , Índice de Gravidade de Doença , Pele/imunologia , Colágeno Tipo XVII
10.
J Biochem ; 133(2): 197-206, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12761182

RESUMO

Bullous pemphigoid antigen 180 (BP180)/type XVII collagen is a transmembrane hemidesmosomal protein. Previously, we demonstrated that the collagenous ectodomain of BP180 can be cleaved within the extracellular non-collagenous (NC) 16A domain adjacent to the cell membrane and released from the cell surface. Here, we report that the BP180 cleavage is mediated by a membrane-associated metalloprotease expressed in epithelial cells. A tissue inhibitor of metalloprotease 1 (TIMP-1), but not TIMP-2, like the synthetic metalloprotease inhibitor KB-R8301, significantly reduced the cleavage. Within epithelial cells cultured for more than 36 h past confluency, antibodies to BP180 showed a reduced hemidesmosomal staining. Observed for the first time, addition of KB-R8301 to the cell culture preserved this staining. To examine the effect of the extracellular cleavage of BP180 on molecular interactions among hemidesmosomal components, we eliminated its collagenous extracellular portion, except for the NC16A domain, by collagenase digestion. Interestingly, this collagenase treatment caused partial disassembly of hemidesmosomal components in cultured human keratinocytes. Moreover, a monoclonal antibody specific for the cleaved extracellular fragment detected a unique tissue distribution of the fragment that might reflect an association of the cleavage process with the mitotic activity of epithelial tissues. Our observations demonstrate that the cleavage of BP180 occurring within the NC16A domain is mediated by a membrane-associated metalloprotease and suggest a possible involvement of the cleavage in hemidesmosomal disassembly.


Assuntos
Autoantígenos/metabolismo , Autoantígenos/fisiologia , Hemidesmossomos/metabolismo , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/farmacologia , Proteínas de Transporte , Bovinos , Linhagem Celular , Colagenases/farmacologia , Proteínas do Citoesqueleto , Distonina , Células Epiteliais/química , Hemidesmossomos/imunologia , Metaloproteases/metabolismo , Metaloproteases/fisiologia , Proteínas do Tecido Nervoso , Colágenos não Fibrilares , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Distribuição Tecidual , Inibidor Tecidual de Metaloproteinase-1/farmacologia , Colágeno Tipo XVII
11.
Immunol Allergy Clin North Am ; 32(2): 217-32, v, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22560135

RESUMO

Bullous pemphigoid (BP) represents the most common autoimmune subepidermal blistering disease. BP typically affects the elderly and is associated with significant morbidity. It has usually a chronic course with spontaneous exacerbations. The cutaneous manifestations of BP can be extremely protean. While diagnosis of BP in the bullous stage is straightforward, in the non-bullous stage or in atypical variants of BP signs and symptoms are frequently non-specific with eg, only itchy excoriated, eczematous, papular and/or urticarial lesions that may persist for several weeks or months. Diagnosis of BP critically relies on immunopathologic examinations including direct immunofluorescence microscopy and detection of serum autoantibodies by indirect immunofluorescence microscopy or BP180-ELISA.


Assuntos
Autoantígenos/imunologia , Hemidesmossomos/imunologia , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/diagnóstico , Fatores Etários , Idoso , Autoanticorpos/imunologia , Autoantígenos/metabolismo , Vesícula/imunologia , Vesícula/patologia , Comorbidade , Diagnóstico Diferencial , Hemidesmossomos/metabolismo , Humanos , Incidência , Colágenos não Fibrilares/metabolismo , Penfigoide Bolhoso/epidemiologia , Penfigoide Bolhoso/patologia , Colágeno Tipo XVII
12.
J Autoimmun ; 31(4): 331-8, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18922680

RESUMO

Bullous pemphigoid (BP) is a cutaneous autoimmune inflammatory disease associated with subepidermal blistering and autoantibodies against BP180, a transmembrane collagen and major component of the hemidesmosome. Numerous inflammatory cells infiltrate the upper dermis in BP. IgG autoantibodies in BP fix complement and target multiple BP180 epitopes that are highly clustered within a non-collagen linker domain, termed NC16A. Anti-BP180 antibodies induce BP in mice. In this study, we generated a humanized mouse strain, in which the murine BP180NC14A is replaced with the homologous human BP180NC16A epitope cluster region. We show that the humanized NC16A (NC16A+/+) mice injected with anti-BP180NC16A autoantibodies develop BP-like subepidermal blisters. The F(ab')(2) fragments of pathogenic IgG fail to activate the complement cascade and are no longer pathogenic. The NC16A+/+ mice pretreated with mast cell activation blocker or depleted of complement or neutrophils become resistant to BP. These findings suggest that the humoral response in BP critically depends on innate immune system players.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Hemidesmossomos/imunologia , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/imunologia , Pele/imunologia , Animais , Degranulação Celular/imunologia , Modelos Animais de Doenças , Humanos , Mastócitos/imunologia , Camundongos , Camundongos Transgênicos , Penfigoide Bolhoso/patologia , Pele/patologia , Colágeno Tipo XVII
14.
Clin Exp Dermatol ; 33(2): 183-5, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18093242

RESUMO

Bullous pemphigoid (BP) is an acquired bullous disease with an increasing prevalence among elderly people worldwide, including in Greece. Blister formation in most patients with BP is caused by autoantibodies against structural components of the basement membrane zone of the skin, predominantly BP180NC16a and BP230 antigens on the hemidesmosome adhesion complex. Routine diagnostic methods such as histological examination and direct and indirect immunofluorescence are combined to determine diagnosis. In this study, an ELISA was used to measure levels of both anti-BP180NC16A and anti-BP230 autoantibodies in the blister fluid of 13 patients with newly diagnosed BP, before starting treatment. The aim of the study was to evaluate this method as a diagnostic tool in BP. Our results indicate that blister-fluid examination by ELISA can be a useful tool to diagnose bullous pemphigoid, especially in elderly patients who refuse biopsy or have poor venous access.


Assuntos
Autoanticorpos/análise , Autoantígenos/imunologia , Vesícula/imunologia , Proteínas de Transporte/imunologia , Proteínas do Citoesqueleto/imunologia , Hemidesmossomos/imunologia , Proteínas do Tecido Nervoso/imunologia , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/diagnóstico , Idoso , Distonina , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Indireta de Fluorescência para Anticorpo/métodos , Grécia , Humanos , Masculino , Penfigoide Bolhoso/imunologia , Sensibilidade e Especificidade , Colágeno Tipo XVII
15.
Clin Exp Dermatol ; 31(2): 252-9, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16487105

RESUMO

Maintenance of an intact epidermis depends on secure adhesion between adjacent keratinocytes, and between basal keratinocytes and the underlying epidermal basement membrane. The major adhesion units that achieve this are the hemidesmosomes and desmosomes, but when these structures are disrupted, e.g., by gene mutations or autoantibodies, the resilience of the epidermis is lost and blisters develop. Recently, there have been considerable advances in our knowledge of the proteins and glycoproteins that contribute to maintaining keratinocyte adhesion via hemidesmosomes and desmosomes, as well as new insights into the molecular pathogenesis of several inherited and autoimmune blistering skin diseases. These new basic scientific data are clinically relevant, helping to improve patient management and to provide a rationale for developing better and more specific treatments for patients with inherited or acquired blistering skin diseases. In addition, there have also been improvements in our understanding of the organization and assembly of these adhesion structures, and their involvement in signalling pathways, intricately linked to skin development, wound healing and tumour invasion. This review provides an update on the structure and organization of hemidesmosomes and desmosomes, and on the molecular pathology of their various components that result in bullous skin diseases.


Assuntos
Desmossomos/patologia , Hemidesmossomos/patologia , Dermatopatias Vesiculobolhosas/patologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Adesão Celular , Desmossomos/genética , Desmossomos/imunologia , Epiderme/imunologia , Epiderme/patologia , Hemidesmossomos/genética , Hemidesmossomos/imunologia , Humanos , Dermatopatias Vesiculobolhosas/genética , Dermatopatias Vesiculobolhosas/imunologia
16.
Hybridoma (Larchmt) ; 25(3): 158-62, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16796463

RESUMO

Type XVII collagen, also referred to as bullous pemphigoid antigen 2 (BPAG2) or bullous pemphigoid antigen 180 (BP180), is a transmembrane protein of the hemidesmosomal complexes of keratinocytes. Type XVII collagen has an unusual type II orientation with its N-terminus intracellularly located and with a large extracellular domain that spans lamina lucida of the dermal-epidermal junction. Type XVII collagen is an autoantigen in patients with pemphigoid diseases and its gene is mutated in patients with junctional epidermolysis bullosa. In the present work, we generated new monoclonal antibodies (MAbs) against the intracellular domain of type XVII collagen. We further characterized reactivity and fine specificity of an MAb (clone V58) from this panel of antibodies. The epitope recognized by the mAb V58 was mapped to a stretch of type XVII collagen corresponding to residues 234-398 of its sequence. Possible applications of this new MAb include antigen mapping in patients with hereditary epidermolysis bullosa and immunoaffinity purification of cell-derived type XVII collagen.


Assuntos
Anticorpos Monoclonais/biossíntese , Autoantígenos/imunologia , Hemidesmossomos/imunologia , Líquido Intracelular/imunologia , Colágenos não Fibrilares/imunologia , Animais , Anticorpos Monoclonais/química , Autoantígenos/química , Proteínas de Transporte , Linhagem Celular Tumoral , Células Cultivadas , Proteínas do Citoesqueleto , Distonina , Epitopos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso , Colágenos não Fibrilares/química , Estrutura Terciária de Proteína , Colágeno Tipo XVII
17.
Blood ; 107(3): 1063-9, 2006 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-16234355

RESUMO

Bullous pemphigoid (BP) is an autoimmune disease associated with autoantibodies directed against the hemidesmosomal antigens anti-BP230 and anti-B180. Neonatal mice injected with rabbit anti-mouse BP180 (mBP10) IgG develop a BP-like disease. Complement, immune complexes, mast cells, and neutrophils play a key role in subepidermal blistering in this animal model. In this study we investigated the role of beta2 integrins in experimental BP. Wild-type (WT) mice pretreated with neutralizing antibody against CD11a (LFA-1), CD11b (Mac-1), CD11a plus CD11b, or CD18 alone failed to develop BP when injected with pathogenic anti-mBP180 IgG. This was associated with a significant reduction in neutrophil accumulation in neutralizing antibody-treated mice. Mac-1-deficient (Mac-1 knockout [KO]) mice were resistant to experimental BP despite normal complement deposition and mast cell and neutrophil degranulation. Neutrophil infiltration in Mac-1 KO mice was severely impaired at 24 hours. However, more neutrophils accumulated in the skin of Mac-1 KO mice compared with WT mice at early time points (2-4 hours), which was associated with an increase in their survival as determined by apoptosis markers. These data suggest that beta2 integrins play differential roles in experimental BP: LFA-1 is required for neutrophil recruitment, while Mac-1 mediates late neutrophil accumulation and apoptosis of infiltrating neutrophils.


Assuntos
Antígenos CD18/imunologia , Penfigoide Bolhoso/imunologia , Animais , Antígenos CD/imunologia , Apoptose/imunologia , Autoanticorpos/administração & dosagem , Autoanticorpos/imunologia , Proteínas do Sistema Complemento/imunologia , Modelos Animais de Doenças , Hemidesmossomos/imunologia , Hemidesmossomos/patologia , Imunoglobulina G/administração & dosagem , Imunoglobulina G/imunologia , Antígeno de Macrófago 1/genética , Antígeno de Macrófago 1/imunologia , Mastócitos/imunologia , Mastócitos/patologia , Camundongos , Camundongos Knockout , Ativação de Neutrófilo/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Neutrófilos/patologia , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/patologia
18.
Oral Dis ; 11(4): 197-218, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15984952

RESUMO

Mucous membrane pemphigoid (MMP) is a sub-epithelial vesiculobullous disorder. It is now quite evident that a number of sub-epithelial vesiculobullous disorders may produce similar clinical pictures, and also that a range of variants of MMP exist, with antibodies directed against various hemidesmosomal components or components of the epithelial basement membrane. The term immune-mediated sub-epithelial blistering diseases (IMSEBD) has therefore been used. Immunological differences may account for the significant differences in their clinical presentation and responses to therapy, but unfortunately data on this are few. The diagnosis and management of IMSEBD on clinical grounds alone is impossible and a full history, general, and oral examination, and biopsy with immunostaining are now invariably required, sometimes supplemented with other investigations. No single treatment regimen reliably controls all these disorders, and it is not known if the specific subsets of MMP will respond to different drugs. Currently, apart from improving oral hygiene, immunomodulatory-especially immunosuppressive-therapy is typically used to control oral lesions. The present paper reviews pemphigoid, describing the present understanding of this fascinating clinical phenotype, summarising the increasing number of subsets with sometimes-different natural histories and immunological features, and outlining current clinical practice.


Assuntos
Doenças Autoimunes , Doenças da Gengiva/imunologia , Penfigoide Mucomembranoso Benigno , Corticosteroides/uso terapêutico , Autoanticorpos/imunologia , Doenças Autoimunes/classificação , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Vesícula , Células Epiteliais/imunologia , Doenças da Gengiva/tratamento farmacológico , Hemidesmossomos/imunologia , Humanos , Imunossupressores/uso terapêutico , Penfigoide Mucomembranoso Benigno/classificação , Penfigoide Mucomembranoso Benigno/tratamento farmacológico , Penfigoide Mucomembranoso Benigno/imunologia
19.
Clin Exp Dermatol ; 30(3): 277-81, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15807689

RESUMO

Histopathology demonstrates disruption of the basal layer of the epidermis in lichen planus (LP) and altered expression of basement membrane zone (BMZ) components occurs in cutaneous and oral LP. This is the first study in erosive LP of the vulva to investigate the expression of components of the BMZ and extracellular matrix by indirect immunofluorescence. Six biopsies from lesional vulval erosive LP were compared with two biopsies from normal vulva and five biopsies from normal skin. In erosive vulval LP there was widespread disruption of several BMZ components compared to normal skin. The hemidesmosome antigens were disrupted and attenuated, or absent. Expression of lamina lucida proteins and anchoring filaments also showed some alteration. Lamina densa components were altered and in particular there was very marked thickening, streaking and fragmentation of the anchoring fibrils. Some dermal extracellular matrix proteins were increased. This study has demonstrated widespread damage to the BMZ in erosive LP of the vulva, in particular the hemidesmosomes (alpha6beta4 integrin, BP230, BP180) and anchoring fibrils (collagen VII). This suggests an alteration in antigenic expression in the BMZ that may lead to exposure of epitopes and thus make these proteins vulnerable to attack by autoantibodies.


Assuntos
Matriz Extracelular/imunologia , Hemidesmossomos/imunologia , Líquen Plano/imunologia , Pele/imunologia , Doenças da Vulva/imunologia , Autoantígenos/metabolismo , Autoimunidade , Membrana Basal/imunologia , Membrana Basal/metabolismo , Membrana Basal/patologia , Moléculas de Adesão Celular/metabolismo , Colágeno Tipo VII/metabolismo , Matriz Extracelular/metabolismo , Feminino , Hemidesmossomos/metabolismo , Humanos , Laminina/metabolismo , Líquen Plano/metabolismo , Líquen Plano/patologia , Pele/metabolismo , Doenças da Vulva/metabolismo , Doenças da Vulva/patologia , Calinina
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