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Introduction
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Pemphigus diseases
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Pemphigus vulgaris
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Pemphigus foliaceus
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Pemphigus variants
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Pemphigus herpetiformis
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Pemphigus erythematosus
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Drug‐induced pemphigus
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...Paraneoplastic pemphigus
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IgA pemphigus
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Pemphigoid diseases
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Bullous pemphigoid
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Pemphigoid gestationis
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Linear IgA disease
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Mucous membrane pemphigoid
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Anti‐p200 pemphigoid
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Epidermolysis bullosa acquisita
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Dermatitis herpetiformis Duhring
Autoimmune bullous diseases are associated with autoimmunity against structural components maintaining cell–cell and cell matrix adhesion in the skin and mucous membranes. Pemphigus diseases are characterized by autoantibodies against the intercellular junctions and intraepithelial blisters. In pemphigoid diseases and epidermolysis bullosa acquisita, sub‐epidermal blistering is associated with autoantibodies targeting proteins of the hemidesmosomal anchoring complex. The autoantigens in autoimmune blistering diseases have been extensively characterized over the past three decades. In general, the pathogenicity of autoantibodies, already suggested by clinical observations, has been conclusively demonstrated experimentally. Detection of tissue‐bound and circulating serum autoantibodies and characterization of their molecular specificity is mandatory for the diagnosis of autoimmune blistering diseases. For this purpose, various immunofluorescence methods as well as immunoassays, including immunoblotting, enzyme‐linked immunosorbent assay and immunoprecipitation have been developed. This review article describes the immunopathological features of autoimmune bullous diseases and the immunological and molecular tests used for their diagnosis and monitoring.
Autoimmune bullous skin diseases are characterized by autoantibodies and T cells specific to structural proteins maintaining cell-cell and cell-matrix adhesion in the skin. Existing clinical and ...experimental evidence generally supports a pathogenic role of autoantibodies for blister formation. These autoantibodies belong to several IgG subclasses, which associate with different functional properties and may thus determine the pathogenic potential of IgG antibodies. In pemphigus diseases, binding of IgG to keratinocytes is sufficient to cause intraepidermal blisters without engaging innate immune effectors and IgG4 autoantibodies seem to mainly mediate acantholysis. In contrast, in most subepidermal autoimmune blistering diseases, complement activation and recruitment and activation of leukocytes by autoantibodies are required for blister induction. In these conditions, tissue damage is thought to be mainly mediated by IgG1, but not IgG4 autoantibodies. This review summarizes the current knowledge on the pathogenic relevance of the IgG subclass of autoantibodies for blister formation. Characterization of the pathogenically relevant subclass(es) of autoantibodies not only provides mechanistic insights, but should greatly facilitate the development of improved therapeutic modalities of autoimmune blistering diseases.
Impaired regulatory T-cell function results in a severe chronic autoimmune disease affecting multiple organs in Scurfy mice and humans with the immune dysregulation, polyendocrinopathy, enteropathy, ...X-linked (IPEX) syndrome. Previous studies have shown that T helper cells but not cytotoxic T cells are critical for the disease pathology. Whether this T-cell subset is responsible directly for tissue inflammation or rather indirectly via the interaction with B cells or myeloid cells is largely unknown. To study this and to identify potential therapeutic targets for this lethal disease we investigated the contribution of B cells to this complex autoimmune phenotype. We show that B cells and the production of autoantibodies plays a major role for skin, liver, lung, and kidney inflammation and therapeutic depletion of B cells resulted in reduced tissue pathology and in prolonged survival. In contrast, the absence of B cells did not impact systemic T-cell activation and hyperreactivity, indicating that autoantibody production by B cells may be a major factor for the autoimmune pathology in mice deficient for regulatory T cells.
Epidermolysis bullosa acquisita (EBA) is a subepidermal blistering disorder associated with tissue-bound and circulating autoantibodies specific to type VII collagen, a major constituent of the ...dermal-epidermal junction. Previous attempts to transfer the disease by injection of patient autoantibodies into mice have been unsuccessful. To study the pathogenic relevance of antibodies specific to type VII collagen in vivo, we generated and characterized rabbit antibodies specific to a murine form of this antigen and passively transferred them into adult nude, BALB/c, and C57BL/6 mice. Immune rabbit IgG bound to the lamina densa of murine skin and immunoblotted type VII collagen. Mice injected with purified IgG specific to type VII collagen, in contrast to control mice, developed subepidermal skin blisters, reproducing the human disease at the clinical, histological, electron microscopical, and immunopathological levels. Titers of rabbit IgG in the serum of mice correlated with the extent of the disease. F(ab')(2) fragments of rabbit IgG specific to type VII collagen were not pathogenic. When injected into C5-deficient mice, antibodies specific to type VII collagen failed to induce the disease, whereas C5-sufficient mice were susceptible to blister induction. This animal model for EBA should facilitate further dissection of the pathogenesis of this disease and development of new therapeutic strategies.
Epidermolysis bullosa acquisita (EBA) is an antibody-mediated blistering skin disease associated with tissue-bound and circulating autoantibodies to type VII collagen (COL7). Transfer of antibodies ...against COL7 into mice results in a subepidermal blistering phenotype, strictly depending on the complement component C5. Further, activation predominantly by the alternative pathway is required to induce experimental EBA, as blistering was delayed and significantly ameliorated only in factor B
mice. However, C5 deficiency not only blocked the activation of terminal complement components and assembly of the membrane attack complex (MAC) but also eliminated the formation of C5a. Therefore, in the present study, we first aimed to elucidate which molecules downstream of C5 are relevant for blister formation in this EBA model and could be subsequently pharmaceutically targeted. For this purpose, we injected mice deficient in C5a receptor 1 (C5aR1) or C6 with antibodies to murine COL7. Importantly,
mice were significantly protected from experimental EBA, demonstrating that C5a-C5aR1 interactions are critical intermediates linking pathogenic antibodies to tissue damage in this experimental model of EBA. By contrast,
mice developed widespread blistering disease, suggesting that MAC is dispensable for blister formation in this model. In further experiments, we tested the therapeutic potential of inhibitors of complement components which were identified to play a key role in this experimental model. Complement components C5, factor B (fB), and C5aR1 were specifically targeted using complement inhibitors both prophylactically and in mice that had already developed disease. All complement inhibitors led to a significant improvement of the blistering phenotype when injected shortly before anti-COL7 antibodies. To simulate a therapeutic intervention, anti-fB treatment was first administered in full-blown EBA (day 5) and induced significant amelioration only in the final phase of disease evolution, suggesting that early intervention in disease development may be necessary to achieve higher efficacy. Anti-C5 treatment in incipient EBA (day 2) significantly ameliorated disease during the whole experiment. This finding is therapeutically relevant, since the humanized anti-C5 antibody eculizumab is already successfully used in patients. In conclusion, in this study, we have identified promising candidate molecules for complement-directed therapeutic intervention in EBA and similar autoantibody-mediated diseases.
Experimental models reproducing an autoimmune response resulting in skin blistering in immunocompetent animals are lacking. Epidermolysis bullosa acquisita (EBA) is a bullous skin disease caused by ...autoantibodies to type VII collagen. In this study, we describe an active disease model of EBA by immunizing mice of different strains with murine type VII collagen. All mice developed circulating IgG autoantibodies that recognized type VII collagen and bound to the lamina densa of the dermal-epidermal junction. Importantly, subepidermal blisters developed in 82% of SJL-1, 56% of BALB/c mice, and 45% of Fc gammaRIIb-deficient mice, but not in SKH-1 mice. In susceptible animals, deposits of IgG1, IgG2, and complement C3 were detected at the dermal-epidermal junction. In contrast, in the nondiseased mice, tissue-bound autoantibodies were predominantly of the IgG1 subclass and complement activation was weak or absent. This active disease model reproduces in mice the clinical, histopathological, and immunopathological findings in EBA patients. This robust experimental system should greatly facilitate further studies on the pathogenesis of EBA and the development of novel immunomodulatory therapies for this and other autoimmune diseases.
Abstract Autoantibodies interact with the innate immune system, including the complement network and Fc receptors (FcRs) bearing effector cells, resulting in the induction of tissue injury. It was ...suggested that these two pro-inflammatory pathways might mediate distinct effector responses, and that only one or the other effector arm may usually dominate an inflammatory response. Recent studies, however, support the notion that autoantibody-induced tissue injury may depend on both, FcRs and selected pathways of the complement network. This review summarizes our current knowledge on the interactions between autoantibodies, FcRs and complement components as essential triggers of tissue injury in autoimmune diseases like rheumatoid arthritis, anti-glomerular basement membrane glomerulonephritis and subepidermal blistering diseases. Manipulation of these connective pathways might be of therapeutic use to control antibody-mediated autoimmune diseases.
IgG4 autoantibodies induce dermal–epidermal separation Mihai, Sidonia; Chiriac, Mircea T.; Herrero‐González, Josep E. ...
Journal of cellular and molecular medicine,
September/October 2007, Letnik:
11, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Bullous pemphigoid (BP) is a sub‐epidermal autoimmune blistering disease associated with autoantibodies to the dermal–epidermal junction (DEJ). Patients’ autoantibodies induce dermal–epidermal ...separation when co‐incubated with cryosections of human skin and leucocytes from healthy volunteers. IgG autoantibodies trigger complement and/or leucocyte activation resulting in specific pathology in several autoimmune conditions. In these diseases, IgG1 and IgG3 isotypes, but not the IgG4 subclass, are thought to trigger inflammatory pathways resulting in tissue damage. The capacity of IgG4 autoantibodies to mediate tissue damage has not yet been demonstrated. In this study, we isolated IgG1 and IgG4 autoantibodies from bullous pemhigoid patients'serum and analysed their blister‐inducing potential in our cryosection assay. As expected, complement‐fixing IgG1 autoantibodies induced sub‐epidermal splits in this experimental model. Purified IgG4 did not fix complement, but, interestingly, like IgG1, activated leucocytes and induced dermal–epidermal separation. The potential of IgG4 autoantibodies to induce Fc‐dependent dermal–epidermal separation was significantly lower compared to IgG1. Our results demonstrate that IgG4 autoantibodies are able to activate leucocytes and point to a hitherto less recognized function of IgG4. Moreover, for the first time, we clearly demonstrate that BP IgG4 autoantibodies have the capacity to induce leucocyte‐dependent tissue damage.
Intravenous immunoglobulin (IVIg) therapy is widely used to treat a variety of autoimmune diseases including immunothrombocytopenia, chronic inflammatory demyelinating polyneuropathy, and more ...recently autoimmune skin blistering diseases. Despite this well‐documented clinical success, the precise molecular and cellular mechanisms underlying this immunomodulatory activity are discussed controversially. In particular, the clinically relevant therapeutic pathway of IVIg‐mediated immune modulation has not been studied in detail. In the present study, we use four independent in vivo model systems of auto‐Ab‐mediated autoimmune disease to identify a common pathway explaining IVIg activity under therapeutic conditions in vivo. We show that irrespective of the in vivo model system, IVIg activity is strictly dependent on the presence of terminal sialic acid residues and the inhibitory FcγRIIB under preventive as well as therapeutic treatment conditions. In contrast, specific ICAM3 grabbing nonintegrin related 1, previously demonstrated to be essential under preventative treatment conditions, showed a disease‐specific impact on IVIg‐mediated resolution of established autoimmune disease.
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