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Autoimmune Bullous Diseases: Historical Perspectives

      The first major finding that allowed us to progress in our understanding of autoimmune blistering skin diseases was that chronic blistering diseases of the skin could be differentiated. The initial major clinical differentiation was between pemphigus and pemphigoid and, still today, our major progress in understanding these diseases comes from patients with pemphigus and pemphigoid. Therefore, in this review of historical perspectives, we will focus on pemphigus and pemphigoid. The early history and the clinical and histological differentiation of pemphigus, pemphigoid, and related diseases is beautifully described in a classic monograph by a giant in the field, Walter
      • Lever W.F.
      Pemphigus and Pemphigoid.
      . Although many contributed to the differentiation at the histological and clinical level, Walter Lever, informed by his own patients and their histology, was a major figure in synthesizing and distilling the essence of this information.

      Pemphigus

      According to
      • Lever W.F.
      Pemphigus and Pemphigoid.
      , MacBride may have carefully described the first cases of pemphigus vulgaris in 1777. Cazenave is credited with identifying the pemphigus foliaceus subtype in 1844 (
      • Lever W.F.
      Pemphigus and Pemphigoid.
      ). What really allowed unambiguous differentiation of the autoimmune bullous diseases was the characterization of their histology. In his classic work in 1943, Civatte discovered acantholysis (loss of cell-cell adhesion) in pemphigus and differentiated this histology from the subepidermal blisters of what was probably bullous pemphigoid and/or dermatitis herpetiformis (1943). Another approximately 20 years went by before the seminal discovery of Beutner and Jordon (then a medical student) that the sera of patients with pemphigus vulgaris have IgG autoantibodies against the cell surface of keratinocytes as determined by indirect immunofluourescence (1964). The discovery of these autoantibodies led to the important understanding that pemphigus is an IgG-mediated autoimmune disease (Figure 1). That the autoantibodies actually cause the blister of pemphigus was shown in human skin organ culture by
      • Schiltz J.R.
      • Michel B.
      Production of epidermal acantholysis in normal human skin in vitro by the IgG fraction from pemphigus serum.
      and by passive transfer to neonatal mice by Anhalt, Diaz and co-workers (
      • 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.
      ). Finally, pemphigus antigens were discovered to be desmosomal cadherins. By immunochemical methods pemphigus foliaceus antigen was shown to be a desmosomal glycoprotein, now called desmoglein 1 (
      • Koulu L.
      • Kusumi A.
      • Steinberg M.S.
      • Klaus Kovtun V.
      • Stanley J.R.
      Human autoantibodies against a desmosomal core protein in pemphigus foliaceus.
      ), and by cDNA cloning pemphigus vulgaris autoantibodies defined a new desmosomal cadherin, desmoglein 3 (
      • Amagai M.
      • Klaus-Kovtun V.
      • Stanley J.R.
      Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion.
      ). These studies demonstrated that the autoantibodies in pemphigus are directed against molecules in cell adhesion structures, a conclusion particularly gratifying in diseases whose pathology is caused by loss of cell adhesion. Such discoveries also have allowed new diagnostic methods for these diseases (
      • Ishii K.
      • Amagai M.
      • Hall R.P.
      • Hashimoto T.
      • Takayanagi A.
      • Gamou S.
      • et al.
      Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins.
      ) and will ultimately lead to more targeted therapy.
      Figure thumbnail gr1
      Figure 1Pemphigus historical timeline. IF, immunofluorescence.

      Bullous Pemphigoid

      Although Civatte and others had noted that some bullous diseases were subepidermal and therefore distinct from pemphigus, Lever, in analyzing previous data and studying his own patients, clearly defined bullous pemphigoid as a distinct disease (1953) from pemphigus and also from dermatitis herpetiformis as defined by Duhring (Figure 2). In pemphigoid patients, IgG directed against epidermal basement membrane was found in serum by indirect immunofluorescence, and in skin by direct immunofluorescence (
      • Beutner E.H.
      • Lever W.F.
      • Witebsky E.
      • Jordon R.
      • Chertock B.
      Autoantibodies in pemphigus vulgaris.
      ). This discovery, by Beutner, Lever, Jordon, and others, provided an immunologic basis for differentiating pemphigoid from pemphigus. Skin organ culture and passive transfer models did not work well in pemphigoid. More complicated in vitromodels indicated that not only IgG but complement and inflammatory cells were necessary for blister formation in pemphigoid (
      • Gammon W.R.
      • Lewis D.M.
      • Carlo J.R.
      • Sams Jr., W.M.
      • Wheeler Jr., C.E.
      Pemphigoid antibody mediated attachment of peripheral blood leukocytes at the dermal-epidermal junction of human skin.
      ). Surprisingly, two different bullous pemphigoid antigens were identified and cloned, called BP230 (
      • 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 cDNA for bullous pemphigoid antigen by use of patients’ autoantibodies.
      ) and BP180 (
      • Labib R.S.
      • Anhalt G.J.
      • Patel H.P.
      • Mutasim D.F.
      • Diaz L.A.
      Molecular heterogeneity of the bullous pemphigoid antigens as detected by immunoblotting.
      ,
      • Diaz L.
      • Ratrie H.
      • Saunders W.S.
      • Futamura S.
      • Squiquera H.L.
      • Anhalt G.J.
      • et al.
      Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera.
      ), according to their molecular weight in kilodaltons. Mouse models of disease indicated that the BP180 is the pathogenic antigen and that IgG, complement, and inflammatory cells are necessary for disease (
      • 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.
      ). Both of these antigens are part of the hemidesmosome, an adhesion structure that anchors the basal keratinocyte to the basement membrane, a logical and satisfying finding in a disease in which that adhesion is lost.
      Figure thumbnail gr2
      Figure 2Bullous pemphigoid historical timeline. IF, immunofluorescence.
      As in pemphigus, these discoveries have allowed new diagnostic tests (
      • Giudice G.J.
      • Wilske K.C.
      • Anhalt G.J.
      • Fairley J.A.
      • Taylor A.F.
      • Emery D.J.
      • et al.
      Development of an ELISA to detect anti-BP180 autoantibodies in bullous pemphigoid and herpes gestationis.
      ) and insight into new targets to treat disease.

      Other Autoimmune Blistering Skin Diseases

      Characterization of the pathology and pathophysiology of pemphigus and bullous pemphigoid led to our being able to categorize other related autoimmune blistering diseases that are distinct. Dermatitis herpetiformis, originally described by
      • Duhring L.A.
      Dermatitis herpetiformis (reprinted from JAMA 3:225–229, 1884).
      , was not histologically differentiated from pemphigoid for many years (
      • Pierard J.
      • Whimster I.
      The histological diagnosis of dermatitis herpetiformis, bullous pemphigoid and erythema multiforme.
      ), and was finally absolutely differentiated by its immunological finding of granular immunoglobulin deposition, specifically IgA, in the papillary dermal tips (
      • Cormane R.H.
      Immunofluorescent studies of the skin in lupus erythematosus and other diseases.
      ,
      • van der Meer J.B.
      Granular deposits of immunoglobulin in the skin of patients with dermatitis herpetiformis. An immunofluorescence study.
      ). Subsequently linear IgA at the basement membrane zone was discovered (
      • Chorzelski T.P.
      • Beutner E.H.
      • Jablonska S.
      • Blaszczyk M.
      • Triftshauser C.
      Immunofluorescence studies in the diagnosis of dermatitis herpetiformis and its differentiation from bullous pemphigoid.
      ) in some patients who now are felt to have linear IgA disease, which can mimic dermatitis herpetiformis. Benign mucosal pemphigoid (a term coined by
      • Lever W.F.
      Pemphigus.
      ), also called cicatricial pemphigoid, first reported (according to
      • Lever W.F.
      Pemphigus and Pemphigoid.
      ) by Wichmann in 1794 (
      • Wichmann J.E.
      Ideen zur diagnostick.
      ), was differentiated from bullous pemphigoid mainly by its clinical course of erosive lesions in mucous membranes with scarring (
      • Lever W.F.
      Pemphigus.
      ) in spite of similar histology and immunofluorescence findings (
      • Bean S.F.
      • Waisman M.
      • Michel B.
      • Thomas C.I.
      • Knox J.M.
      • Levine M.
      Cicatricial pemphigoid. Immunofluorescent studies.
      ). Epidermolysis bullosa acquisita was originally defined by its mechanobullous nature that resembled inherited epidermolysis bullosa (
      • Roenigk Jr., H.H.
      • Ryan J.G.
      • Bergfeld W.F.
      Epidermolysis bullosa acquisita. Report of three cases and review of all published cases.
      ); however, when it was discovered that the IgG seen at the epidermal basement membrane (
      • Kushniruk W.
      The immunopathology of epidermolysis bullosa.
      ) could be localized to the base of 1 molar sodium chloride split skin, it became apparent that some patients previously diagnosed with bullous pemphigoid actually had epidermolysis bullosa acquisita of an inflammatory type (
      • Gammon W.R.
      • Briggaman R.A.
      • Woodley D.T.
      • Heald P.W.
      • Wheeler Jr., C.E.
      Epidermolysis bullosa acquisita – a pemphigoid-like disease.
      ). The antigen in epidermolysis bullosa was found to be type VII collagen (
      • Woodley D.T.
      • OKeefe E.J.
      • Reese M.J.
      • Mechanic G.L.
      • Briggaman R.A.
      • Gammon W.R.
      Epidermolysis bullosa acquisita antigen, a new major component of cutaneous basement membrane, is a glycoprotein with collagenous domains.
      ).

      Conclusion

      These diseases have provided remarkable insight into the cell biology of adhesion in stratified squamous epithelia. The first hemidesmosomal molecules as well as new desmosomal molecules were discovered because of the antibodies from these patients. These antibodies also provided direct evidence of the function of these molecules. Finally, and most importantly, probing the pathophysiology of these diseases has allowed improved diagnosis and therapy of these severe and disfiguring conditions.

      Conflict of Interest

      The authors state no conflict of interest.

      References

        • Amagai M.
        • Klaus-Kovtun V.
        • Stanley J.R.
        Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion.
        Cell. 1991; 67: 869-877
        • 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.
        N Engl J Med. 1982; 306: 1189-1196
        • Bean S.F.
        • Waisman M.
        • Michel B.
        • Thomas C.I.
        • Knox J.M.
        • Levine M.
        Cicatricial pemphigoid. Immunofluorescent studies.
        Arch Dermatol. 1972; 106: 195-199
        • Beutner E.H.
        • Jordon R.E.
        Demonstration of skin antibodies in sera of pemphigus vulgaris patients by indirect immunofluorescent staining.
        Proc Soc Exp Biol Med. 1964; 117: 505-510
        • Beutner E.H.
        • Lever W.F.
        • Witebsky E.
        • Jordon R.
        • Chertock B.
        Autoantibodies in pemphigus vulgaris.
        JAMA. 1965; 192: 682-688
        • Chorzelski T.P.
        • Beutner E.H.
        • Jablonska S.
        • Blaszczyk M.
        • Triftshauser C.
        Immunofluorescence studies in the diagnosis of dermatitis herpetiformis and its differentiation from bullous pemphigoid.
        J Invest Dermatol. 1971; 56: 373-380
        • Civatte A.
        Diagnostic histopathologique de la dermatite polymorphe douloureuse ou maladie de Duhring-Brocq.
        Ann Dermatol Syph. 1943; 3: 1-30
        • Cormane R.H.
        Immunofluorescent studies of the skin in lupus erythematosus and other diseases.
        Pathologia Europ. 1967; 2: 170-180
        • Diaz L.
        • Ratrie H.
        • Saunders W.S.
        • Futamura S.
        • Squiquera H.L.
        • Anhalt G.J.
        • et al.
        Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera.
        J Clin Invest. 1990; 86: 1088-1094
        • Duhring L.A.
        Dermatitis herpetiformis (reprinted from JAMA 3:225–229, 1884).
        JAMA. 1983; 250: 212-216
        • Gammon W.R.
        • Briggaman R.A.
        • Woodley D.T.
        • Heald P.W.
        • Wheeler Jr., C.E.
        Epidermolysis bullosa acquisita – a pemphigoid-like disease.
        J Am Acad Dermatol. 1984; 11: 820-832
        • Gammon W.R.
        • Lewis D.M.
        • Carlo J.R.
        • Sams Jr., W.M.
        • Wheeler Jr., C.E.
        Pemphigoid antibody mediated attachment of peripheral blood leukocytes at the dermal-epidermal junction of human skin.
        J Invest Dermatol. 1980; 75: 334-339
        • Giudice G.J.
        • Wilske K.C.
        • Anhalt G.J.
        • Fairley J.A.
        • Taylor A.F.
        • Emery D.J.
        • et al.
        Development of an ELISA to detect anti-BP180 autoantibodies in bullous pemphigoid and herpes gestationis.
        J Invest Dermatol. 1994; 102: 878-881
        • Ishii K.
        • Amagai M.
        • Hall R.P.
        • Hashimoto T.
        • Takayanagi A.
        • Gamou S.
        • et al.
        Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins.
        J Immunol. 1997; 159: 2010-2017
        • Koulu L.
        • Kusumi A.
        • Steinberg M.S.
        • Klaus Kovtun V.
        • Stanley J.R.
        Human autoantibodies against a desmosomal core protein in pemphigus foliaceus.
        J Exp Med. 1984; 160: 1509-1518
        • Kushniruk W.
        The immunopathology of epidermolysis bullosa.
        Can Med Assoc J. 2007; 108: 1143-1146
        • Labib R.S.
        • Anhalt G.J.
        • Patel H.P.
        • Mutasim D.F.
        • Diaz L.A.
        Molecular heterogeneity of the bullous pemphigoid antigens as detected by immunoblotting.
        J Immunol. 1986; 136: 1231-1235
        • Lever W.F.
        Pemphigus.
        Medicine. 1953; 32: 1-123
        • Lever W.F.
        Pemphigus and Pemphigoid.
        Charles C. Thomas, Springfield, IL1965
        • 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.
        J Clin Invest. 1993; 92: 2480-2488
        • Pierard J.
        • Whimster I.
        The histological diagnosis of dermatitis herpetiformis, bullous pemphigoid and erythema multiforme.
        Br J Dermatol. 1961; 73: 253-266
        • Roenigk Jr., H.H.
        • Ryan J.G.
        • Bergfeld W.F.
        Epidermolysis bullosa acquisita. Report of three cases and review of all published cases.
        Arch Dermatol. 1971; 103: 1-10
        • Schiltz J.R.
        • Michel B.
        Production of epidermal acantholysis in normal human skin in vitro by the IgG fraction from pemphigus serum.
        J Invest Dermatol. 1976; 67: 254-260
        • 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.
        Cell. 1981; 24: 897-903
        • Stanley J.R.
        • Tanaka T.
        • Mueller S.
        • Klaus-Kovtun V.
        • Roop D.
        Isolation of cDNA for bullous pemphigoid antigen by use of patients’ autoantibodies.
        J Clin Invest. 1988; 82: 1864-1870
        • van der Meer J.B.
        Granular deposits of immunoglobulin in the skin of patients with dermatitis herpetiformis. An immunofluorescence study.
        Br J Dermatol. 1969; 81: 493-503
        • Wichmann J.E.
        Ideen zur diagnostick.
        Helwing, Hannover1794
        • Woodley D.T.
        • OKeefe E.J.
        • Reese M.J.
        • Mechanic G.L.
        • Briggaman R.A.
        • Gammon W.R.
        Epidermolysis bullosa acquisita antigen, a new major component of cutaneous basement membrane, is a glycoprotein with collagenous domains.
        J Invest Dermatol. 1986; 86: 668-672