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Pathophysiology of Autoimmune Bullous Diseases

      In immunobullous disease, the host immune system disrupts adhesive interactions in the skin, typically leading to clinical blister formation. The pathophysiology of these diseases has been an active area of investigation. The mechanisms by which these disorders lead to loss of adhesion are variable and disease dependent; however, general principles have been described.
      The term “subepidermal blistering disease” applies to several disorders that share the clinical appearance of vesicles and bulla, the histologic finding of subepidermal blistering, and in situ deposition of autoantibodies at the dermal–epidermal junction. This group of diseases includes bullous pemphigoid (BP), cicatricial pemphigoid, herpes gestationis, dermatitis herpetiformis, linear IgA disease, lichen planus pemphigoides, epidermolysis bullosa acquisita (EBA), and bullous systemic lupus erythematosus. Intraepidermal blistering diseases are characterized by acantholysis, loss of adhesion between adjacent epidermal keratinocytes, and deposition of immunoreactants at the keratinocyte cell membrane. The protypical intraepidermal autoimmune blistering diseases are pemphigus vulgaris (PV) and pemphigus foliaceus (PF).
      The autoimmune nature of these disorders began to be appreciated in the late 1960s when Jordon and Beutner used immunofluorescent techniques to demonstrate that BP patients have circulating and tissue-bound autoantibodies directed against antigens of the basement membrane zone. Use of these autoantibodies as a screening tool facilitated the identification of the target autoantigens. Using such an approach,
      • Stanley J.R.
      • Hawley-Nelson P.
      • Yuspa S.H.
      • Shevach E.M.
      • Katz S.I.
      Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia.
      ,
      • Stanley J.R.
      • Tanaka T.
      • Mueller S.
      • Klaus-Kovtun V.
      • Roop D.
      Isolation of complementary DNA for bullous pemphigoid antigen by use of patients’ autoantibodies.
      first characterized BP antigens at the molecular level and cloned the BP230 cDNA. Subsequently, cDNAs encoding BP180 (the autoantigen for BP, cicatricial pemphigoid, herpes gestationis, lichen planus pemphigoides, and linear IgA disease), laminin 5 (the autoantigen for cicatricial pemphigoid), and type VII collagen (the autoantigen for EBA and bullous systemic lupus erythematosus) were also cloned and characterized.

      Role of Antibody Class and Subclass

      Although there began to be an established relationship between the presence of these targeted autoantibodies and blistering diseases, it was not until the early 1980s that a direct pathogenic role for these self-directed Igs was demonstrated.
      • Anhalt G.J.
      • Labib R.S.
      • Voorhees J.J.
      • Beals T.F.
      • Diaz L.A.
      Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease.
      pioneered the use of the passive transfer animal model to test the pathogenicity of pemphigus autoantibodies. Intraperitoneal injections of PV IgG and PF IgG induced intraepidermal blisters in neonatal mice, duplicating the key clinical and histological features of the human diseases. This passive transfer model provided a means to define in detail the humoral immune response. For example,
      • Rock B.
      • Martins C.R.
      • Theofilopoulos A.N.
      • Balderas R.S.
      • Anhalt G.J.
      • Labib R.S.
      • et al.
      The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem).
      used this system to demonstrate subclass specificity when they demonstrated that IgG4. subclass autoantibodies were pathogenic in pemphigus. Using IgG passive transfer experiments,
      • Amagai M.
      • Karpati S.
      • Prussick R.
      • Klaus-Kovtun V.
      • Stanley J.R.
      Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic.
      showed that IgG autoantibodies against desmoglein (Dsg)1 and Dsg3 are pathogenic and are important in inducing blister formation in pemphigus.
      The success of the passive transfer mouse model in pemphigus led to similar investigations in pemphigoid and EBA; however, when applied to pemphigoid, similar approaches failed to demonstrate the pathogenicity of pemphigoid autoantibodies due to the lack of cross-reactivity between murine and human autoantigens. As an alternative,
      • Liu Z.
      • Diaz L.A.
      • Troy J.L.
      • Taylor A.F.
      • Emery D.J.
      • Fairley J.A.
      • et al.
      A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180.
      generated rabbit anti-murine BP180 IgG, which induced BP in mice. With the same strategy, animal models for cicatricial pemphigoid and EBA were also developed by passive transfer of rabbit anti-laminin 5 and rabbit anti-type VII collagen IgG in mice, respectively (
      • Lazarova Z.
      • Yee C.
      • Darling T.
      • Briggaman R.A.
      • Yancey K.B.
      Passive transfer of antilaminin 5 antibodies induces subepidermal blisters in neonatal mice.
      ,
      • Sitaru C.
      • Mihai S.
      • Otto C.
      • Chiriac M.T.
      • Hausser I.
      • Dotterweich B.
      • et al.
      Induction of dermal–epidermal separation in mice by passive transfer of antibodies specific to type VII collagen.
      ). Subsequently, antilaminin 5, anti-type VII collagen, and anti-BP180 autoantibodies from patients were proved directly to be pathogenic in animal models (
      • Lazarova Z.
      • Hsu R.
      • Yee C.
      • Yancey K.B.
      Human anti-laminin 5 autoantibodies induce subepidermal blisters in an experimental human skin graft model.
      ,
      • Woodley D.T.
      • Ram R.
      • Doostan A.
      • Bandyopadhyay P.
      • Huang Y.
      • Remington J.
      • et al.
      Induction of epidermolysis bullosa acquisita in mice by passive transfer of autoantibodies from patients.
      ,
      • Nishie W.
      • Sawamura D.
      • Goto M.
      • Ito K.
      • Shibaki A.
      • McMillan J.R.
      • et al.
      Humanization of autoantigen.
      ). Besides IgG autoantibodies, anti-BP180 IgE antibodies were also shown to be pathogenic in human skin graft models (
      • Zone J.J.
      • Taylor T.
      • Hull C.
      • Schmidt L.
      • Meyer L.
      IgE basement membrane zone antibodies induce eosinophil infiltration and histological blisters in engrafted human skin on SCID mice.
      ,
      • Fairley J.A.
      • Burnett C.T.
      • Fu C.L.
      • Larson D.L.
      • Fleming M.G.
      • Giudice G.J.
      A pathogenic role for IgE in autoimmunity: bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice.
      ).

      Role of Complement

      Although local complement activation is universal in immunobullous diseases, PV and PF autoantibodies induce epidermal cell detachment in the mouse model independent of complement activation. In contrast, the classical pathway is required for experimental BP, whereas the alternative pathway is critical in experimental EBA.

      Antibody-Mediated Injury

      In the rabbit anti-mBP180 IgG-induced BP model, pathogenic antibodies trigger a complement-, mast cell-, and neutrophil-dependent inflammatory cascade, which causes a protease–protease inhibitor imbalance. Increased proteolytic enzymes then cleave BP180 and other extracellular matrix proteins, leading to dermal–epidermal junction separation. However, in the anti-laminin 5-induced dermal–epidermal junction separation, complement and mast cells are dispensable.

      Role of T Cells

      T lymphocytes are crucial in initiating autoimmune responses.
      • Wucherpfennig K.W.
      • Yu B.
      • Bhol K.
      • Monos D.S.
      • Argyris E.
      • Karr R.W.
      • et al.
      Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in pemphigus vulgaris.
      first demonstrated that T cells from PV patients with active disease responded to Dsg3 extracellular peptides. Subsequently,
      • Budinger L.
      • Borradori L.
      • Yee C.
      • Eming R.
      • Ferencik S.
      • Grosse-Wilde H.
      • et al.
      Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls.
      identified Th1 and Th2 responses against the BP180 ectodo-main in BP. Activation of autoreactive T cells is restricted by distinct HLA class II alleles that are prevalent in patients with these diseases. These T cells may be important in the activation and differentiation of B cells that produce pathogenic autoantibodies.

      Role of Signal Transduction

      In pemphigoid, binding of antibody to BP180 initiates a series of extracellular inflammatory events that leads to proteolysis of BP180 by human neutrophil elastase. In contrast, in pemphigus antibody binding to Dsg does not require inflammatory components to mediate blister formation. Binding of pemphigus IgG to Dsg appears to initiate a series of events within the target keratinocyte that leads to subsequent loss of cell–cell adhesion.
      Several key observations support the idea that energy-requiring cellular events are required for PV or PF IgG to induce acantholysis. In cultured cells, Kowalczyck’s group showed that PV IgG-mediated disruption of keratinocyte adhesion and Dsg3 internalization were temperature dependent, occurring at 37 °C, but not at 4 °C, despite the fact that PV IgG continued to bind to the keratinocyte cell surface at 4 °C (
      • Calkins C.C.
      • Setzer S.V.
      • Jennings J.M.
      • Semmers S.
      • Tsunoda K.
      • Amagai M.
      • Kowalczyk A.P.
      Desmoglein endocytosis and desmosomal disassembly are coordinated responses to pemphigus autoantibodies.
      ). Additional evidence that energy-dependent processes within live cells are required for pemphigus IgG to induce loss of adhesion comes from the investigation of the effects of PF IgG on the binding of Dsg1-coated beads to cultured Ha-Cat cells. Only when PF IgG bound to metabolically active keratinocytes was bead release observed; bead release did not occur if the metabolically inert Dsg1-coated beads were first incubated with Dsg1-specific PF IgG (
      • Waschke J.
      • Bruggeman P.
      • Baumgartner W.
      • Zillikens D.
      • Drenckhahn D.
      Pemphigus foliaceus IgG causes dissociation of desmoglein 1-containing junctions without blocking desmoglein 1 transinteraction.
      ).
      In 1995 Kitajima proposed that binding of pemphigus IgG to human squamous-cell carcinoma cell lines activated intracellular signaling (
      • Seishima M.
      • Esaki C.
      • Osada K.
      • Mori S.
      • Hashimoto T.
      • Kitajima Y.
      Pemphigus IgG, but not bullous pemphigoid IgG, causes a transient increase in intracellular calcium and inositol 1, 4, 5-triphosphate in DJM-1 cells, a squamous cell carcinoma line.
      ). Using a biochemical screen, subsequent studies by our group demonstrated that binding of PV IgG to keratinocyte cell-surface Dsg3 activated phosphorylation of p38MAPK and heat-shock protein 27 within the target keratinocyte both in vitro and in vivo. Inhibition of p38MAPK blocked the ability of PV IgG to induce cytoskeletal changes that precede acantholysis. In the passive transfer mouse model of PV, inhibition of p38MAPK blocked the ability of PV IgG to induce blistering in vivo, suggesting a causal role for signaling in the mechanism by which these antibodies induce loss of cell–cell adhesion and further suggesting that blockade of this enzyme in patients might prove an effective strategy for treating pemphigus (
      • Berkowitz P.
      • Hu P.
      • Warren S.
      • Liu Z.
      • Diaz L.A.
      • Rubenstein D.S.
      p38MAPK inhibition prevents disease in pemphigus vulgaris mice.
      ). Both the GTPase RhoA and plakoglobin have been mechanistically implicated in the cascade of intracellular events induced by pemphigus IgG. Keratinocytes from plakoglobin knockout mice do not retract their keratin intermediate filaments or lose adhesion when exposed to PV IgG, suggesting a critical role for this catenin in PV IgG-mediated acantholysis (
      • Caldelari R.
      • de Bruin A.
      • Baumann D.
      • Suter M.M.
      • Bierkamp C.
      • Balmer V.
      • et al.
      A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris.
      ). Waschke et al.’s observations that (1) incubation of cultured cells with PV or PF IgG reduced the activity of Rho A, (2) the Rho A activator cytotoxic necrotizing factor-y blocked pemphigus IgG-induced skin splitting, and (3) modulation of RhoA activity by PF IgG is p38MAPK dependent collectively suggest that RhoA may be a downstream target of p38MAPK in this signaling cascade (
      • Waschke J.
      • Spindler V.
      • Bruggeman P.
      • Zillikens D.
      • Schmidt G.
      • Drenckhahn D.
      Inhibition of Rho A activity causes pemphigus skin blistering.
      ).
      Over 5 decades of active investigation by numerous labs around the world have contributed to our current understanding of autoimmune blistering diseases. Although much work remains in order to precisely define how these autoimmune responses develop and cause tissue injury, detailed maps of the pathophysiologic mechanisms are beginning to emerge and provide opportunities for developing specific targeted therapies.

      Conflict of Interest

      The authors delcare no conflict of interest.

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