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Recent Advances in Understanding Pemphigus and Bullous Pemphigoid

      For many years, The Journal of Investigative Dermatology (JID) has been a leader in our understanding of many aspects of the major autoimmune blistering skin diseases, pemphigus and bullous pemphigoid. The purpose of this review is to highlight and summarize those advances by discussing the respective articles, published in the JID from 2015 to 2019. Seminal articles from elsewhere in the literature that set the stage for those advances, or that are “classics” in the area, are also included to provide context and a more complete picture.

      Pemphigus: clinical summary, epidemiology, co-morbidites, and HLA associations

      Pemphigus is a term that includes two major autoantibody-mediated diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF) (
      • Payne A.S.
      • Stanley J.R.
      Pemphigus.
      ). Pemphigus usually occurs in adults but can occur at all ages. PV is characterized by flaccid blisters that rupture easily leaving erosions in the mouth and on the skin. PF blisters occur only on skin and rupture quickly after forming, leaving mostly scaly crusted lesions. The histology of PV shows that blisters result from the loss of cell-cell adhesion deep in the epidermis just above the basal layer, whereas in PF, the loss of cell adhesion occurs in the superficial living epidermis in the granular layer. Direct immunofluorescence in both PV and PF shows IgG on the cell surface of keratinocytes.
      The incidence and prevalence of pemphigus depend on the population studied (
      • Hammers C.M.
      • Stanley J.R.
      Mechanisms of disease: pemphigus and bullous pemphigoid.
      ). A French study found a mean annual crude incidence of 1.85 cases of pemphigus per million inhabitants per year, with a mean age at diagnosis of 59.4 ± 18.7 years (
      • Jelti L.
      • Cordel N.
      • Gillibert A.
      • Lacour J.P.
      • Uthurriague C.
      • Doutre M.S.
      • et al.
      Incidence and mortality of pemphigus in France.
      ). Based on large cohorts retrieved from health insurance data, a prevalence of 94.8 patients per million inhabitants was calculated for PV and a prevalence of 10.0 per million for PF in Germany (
      • Hübner F.
      • Recke A.
      • Zillikens D.
      • Linder R.
      • Schmidt E.
      Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany.
      ).
      Surprisingly, a study from Germany looking for comorbid malignancies found that PV was associated with hematological and non-hematological cancers (e.g., oropharyngeal, gastrointestinal, and colon), whereas patients with PF did not show an association with hematological malignancies but did so for non-melanoma skin cancer (
      • Schulze F.
      • Neumann K.
      • Recke A.
      • Zillikens D.
      • Linder R.
      • Schmidt E.
      Malignancies in pemphigus and pemphigoid diseases.
      ). The limitations of this study, based on insurance data, include possible misdiagnosis (especially by non-dermatologists); possible inclusion of some patients with paraneoplastic pemphigus as pemphigus; ascertainment bias in the examination of areas of involvement in patients with pemphigus (vs. non-pemphigus controls); and confounding effects of immunosuppressive therapy. However, the results point to the importance of future population-based studies to understand co-morbidities.
      Confirming and extending previous data on the associations of certain leukocyte antigens (HLA) with pemphigus and the presentation of pemphigus antigen peptides (
      • Sinha A.A.
      • Brautbar C.
      • Szafer F.
      • Friedmann A.
      • Tzfoni E.
      • Todd J.A.
      • et al.
      A newly characterized HLA DQ beta allele associated with pemphigus vulgaris.
      ,
      • Veldman C.M.
      • Gebhard K.L.
      • Uter W.
      • Wassmuth R.
      • Grötzinger J.
      • Schultz E.
      • et al.
      T cell recognition of desmoglein 3 peptides in patients with pemphigus vulgaris and healthy individuals.
      ), a recent study from China identified HLA-DRB1*14:04 and also rs7454108 at the TAP2 gene (implicated in the presentation of intracellular proteins on major histocompatibility complex I HLAs) as associated with PV in a Han Chinese Population (
      • Gao J.
      • Zhu C.
      • Zhang Y.
      • Sheng Y.
      • Yang F.
      • Wang W.
      • et al.
      Association study and fine-mapping major histocompatibility complex analysis of pemphigus vulgaris in a Han Chinese population.
      ).

      Pemphigus: pathophysiology, autoantibodies, and autoantigens

      Classical and seminal studies showed that almost all patients with pemphigus have anti-desmoglein (Dsg) antibodies and anti-Dsg antibodies can cause typical pemphigus pathology (
      • Amagai M.
      • Klaus-Kovtun V.
      • Stanley J.R.
      Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion.
      ,
      • Stanley J.R.
      • Amagai M.
      Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome.
      ,
      • Stanley J.R.
      • Koulu L.
      • Klaus-Kovtun V.
      • Steinberg M.S.
      A monoclonal antibody to the desmosomal glycoprotein desmoglein I binds the same polypeptide as human autoantibodies in pemphigus foliaceus.
      ). Although other autoantibody reactivities may be found in patients with pemphigus and may exacerbate blistering, their contributions (and that of their respective antigens) have not been as well characterized (
      • Spindler V.
      • Eming R.
      • Schmidt E.
      • Amagai M.
      • Grando S.
      • Jonkman M.F.
      • et al.
      Mechanisms causing loss of keratinocyte cohesion in pemphigus.
      ).
      In PF, anti-Dsg1 antibodies cause the loss of cell adhesion in the superficial epidermis, and in PV, anti-Dsg3 or anti-Dsg3 with anti-Dsg1 antibodies cause blisters deep in the epidermis or mucosal epithelium (
      • Stanley J.R.
      • Amagai M.
      Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome.
      ) (Figure 1a and b). Disease pathophysiology by anti-Dsg antibodies has been shown by typical pemphigus pathology caused by cloned monoclonal and monovalent antibody fragments against Dsg1 (
      • Ishii K.
      • Lin C.
      • Siegel D.L.
      • Stanley J.R.
      Isolation of pathogenic monoclonal anti-desmoglein 1 human antibodies by phage display of pemphigus foliaceus autoantibodies.
      ), Dsg3 (
      • Hammers C.M.
      • Chen J.
      • Lin C.
      • Kacir S.
      • Siegel D.L.
      • Payne A.S.
      • et al.
      Persistence of anti-desmoglein 3 IgG(+) B-cell clones in pemphigus patients over years.
      ,
      • Payne A.S.
      • Ishii K.
      • Kacir S.
      • Lin C.
      • Li H.
      • Hanakawa Y.
      • et al.
      Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display.
      ,
      • Saleh M.A.
      • Ishii K.
      • Yamagami J.
      • Shirakata Y.
      • Hashimoto K.
      • Amagai M.
      Pathogenic anti-desmoglein 3 mAbs cloned from a paraneoplastic pemphigus patient by phage display.
      ), or both (
      • Payne A.S.
      • Ishii K.
      • Kacir S.
      • Lin C.
      • Li H.
      • Hanakawa Y.
      • et al.
      Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display.
      ). A pathogenic mouse PV IgG binds to the adhesive interface of Dsg3, suggesting that by interfering directly with Dsg-mediated adhesion, it can cause PV blisters (
      • Tsunoda K.
      • Ota T.
      • Aoki M.
      • Yamada T.
      • Nagai T.
      • Nakagawa T.
      • et al.
      Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3.
      ). The PF IgG can mediate pathogenicity even as monovalent Fab’ antibody fragments, resulting in typical PF blisters (
      • Rock B.
      • Labib R.S.
      • Diaz L.A.
      Monovalent Fab' immunoglobulin fragments from endemic pemphigus foliaceus autoantibodies reproduce the human disease in neonatal Balb/c mice.
      ). Finally, PF anti-Dsg1 antibodies can directly inhibit two interacting adhesion molecules, specifically Dsg1:desmocollin 1, at their adhesive interface (i.e., steric hindrance causing loss of adhesion) (
      • Evangelista F.
      • Roth A.J.
      • Prisayanh P.
      • Temple B.R.
      • Li N.
      • Qian Y.
      • et al.
      Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope.
      ), thus potentially disrupting the adhesion of keratinocytes and resulting in acantholysis.
      Figure thumbnail gr1
      Figure 1Pathophysiologic mechanisms in pemphigus. (a, b) PV and PF phenotypes correlate with the presence of anti-Dsg3 and/or anti-Dsg1 autoantibodies and the relative expression patterns of Dgs3 and Dsg1 in skin and mucous membranes (indicated by triangles and triangle widths). Where Dsg3 or Dsg1 cannot be compensated by the other Dsg, a blister occurs under autoantibody-mediated loss of function. (a, upper panel) In PV, anti-Dsg3 antibodies alone usually lead to mucosal blistering but not to skin blistering, because of the sufficient compensation of Dsg1 in the skin. (a, lower panel) When anti-Dsg3 and anti-Dsg1 antibodies are present, mucocutaneous blistering is observed because compensatory mechanisms are abrogated in both skin and mucous membranes. (b) In PF, only anti-Dsg1 antibodies are observed, leading to exclusive skin blistering because of the compensatory action of Dgs3 in mucous membranes. (c, yellow box) Binding of the autoantibodies to desmosomal Dsgs leads to steric hindrance of the Dsgs molecules and signaling-independent direct loss of adhesion, i.e., blistering. (c, red box) After this initial loss of adhesion, additional signaling-dependent processes may occur, which amplify acantholysis. Cis-cross linking of Dsgs may cause their signal-dependent endocytosis. For simplification, the heterophilic interactions of Dsgs with desmocollins or intracellular proteins interacting with Dsgs are not shown in (c). abs, antibodies; Dsg, desmoglein; PF, pemphigus foliaceus; PV, pemphigus vulgaris.
      Mice and human genetic studies confirm that the loss of function of desmogleins cause pemphigus blisters. Mice engineered to be genetically deficient in Dsg3 or Dsg1 develop PV or PF blisters, respectively (
      • Koch P.J.
      • Mahoney M.G.
      • Ishikawa H.
      • Pulkkinen L.
      • Uitto J.
      • Shultz L.
      • et al.
      Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris.
      ,
      • Kugelmann D.
      • Radeva M.Y.
      • Spindler V.
      • Waschke J.
      Desmoglein 1 deficiency causes lethal skin blistering.
      ). Recently, a human patient with a homozygous nonsense mutation in Dsg3 and typical PV mucosal lesions was reported (
      • Kim J.H.
      • Kim S.E.
      • Park H.S.
      • Lee S.H.
      • Lee S.E.
      • Kim S.C.
      A homozygous nonsense mutation in the DSG3 gene causes acantholytic blisters in the oral and laryngeal mucosa.
      ). Similarly, patients with homozygous Dsg1 mutations show PF-like acantholysis but also a syndrome that includes severe dermatitis, multiple allergies, and metabolic wasting, probably from barrier defects present from birth or early life (
      • Samuelov L.
      • Sarig O.
      • Harmon R.M.
      • Rapaport D.
      • Ishida-Yamamoto A.
      • Isakov O.
      • et al.
      Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.
      ). Interesting, humans with a heterozygous mutation in Dsg1 have striate palmoplantar keratoderma perhaps from weakened adhesion in areas of high friction from mechanical stress (
      • Hunt D.M.
      • Rickman L.
      • Whittock N.V.
      • Eady R.A.
      • Simrak D.
      • Dopping-Hepenstal P.J.
      • et al.
      Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma.
      ,
      • Lovgren M.L.
      • McAleer M.A.
      • Irvine A.D.
      • Wilson N.J.
      • Tavadia S.
      • Schwartz M.E.
      • et al.
      Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening.
      ).
      The previous studies strongly suggest that the inactivation of desmoglein function through steric hindrance by pemphigus antibodies would cause pemphigus blisters, as does the genetic inactivation of desmogleins.
      However, in some studies of blistering in pemphigus, it has been suggested that steric hindrance of the anti-Dsg antibodies causing loss of Dsg adhesion is not adequate in itself for the loss of keratinocyte adhesion, but that additional intracellular signaling is necessary for pathology (
      • Spindler V.
      • Eming R.
      • Schmidt E.
      • Amagai M.
      • Grando S.
      • Jonkman M.F.
      • et al.
      Mechanisms causing loss of keratinocyte cohesion in pemphigus.
      ,
      • Vielmuth F.
      • Waschke J.
      • Spindler V.
      Loss of desmoglein binding is not sufficient for keratinocyte dissociation in pemphigus.
      ). Other studies suggest that the steric hindrance of Dsg molecular adhesion and intracellular signaling may cooperate for blister formation in patients (
      • Saito M.
      • Stahley S.N.
      • Caughman C.Y.
      • Mao X.
      • Tucker D.K.
      • Payne A.S.
      • et al.
      Signaling dependent and independent mechanisms in pemphigus vulgaris blister formation.
      ,
      • Spindler V.
      • Eming R.
      • Schmidt E.
      • Amagai M.
      • Grando S.
      • Jonkman M.F.
      • et al.
      Mechanisms causing loss of keratinocyte cohesion in pemphigus.
      ), as evidenced by two important observations: (i) modulation of signaling can inhibit loss of adhesion, despite bound autoantibodies (
      • Berkowitz P.
      • Hu P.
      • Warren S.
      • Liu Z.
      • Diaz L.A.
      • Rubenstein D.S.
      P38MAPK inhibition prevents disease in pemphigus vulgaris mice.
      ,
      • Vielmuth F.
      • Waschke J.
      • Spindler V.
      Loss of desmoglein binding is not sufficient for keratinocyte dissociation in pemphigus.
      ), and (ii) clustering and endocytosis of Dsgs upon anti-Dsg autoantibody binding are processes that require, at least in part, signaling, and result in ultrastructurally changed desmosomes that become reduced in size and numbers and are more prone to splitting (
      • Sokol E.
      • Kramer D.
      • Diercks G.F.H.
      • Kuipers J.
      • Jonkman M.F.
      • Pas H.H.
      • et al.
      Large-scale electron microscopy maps of patient skin and mucosa provide insight into pathogenesis of blistering diseases.
      ,
      • Stahley S.N.
      • Warren M.F.
      • Feldman R.J.
      • Swerlick R.A.
      • Mattheyses A.L.
      • Kowalczyk A.P.
      Super-resolution microscopy reveals altered desmosomal protein organization in tissue from patients with pemphigus vulgaris.
      ).
      Our opinion is that anti-Dsg antibodies in pemphigus can result in blisters through direct inactivation of Dsg adhesion through the steric hindrance of adhesion sites, but that intracellular signaling (perhaps after this initial loss of adhesion) may enhance the blistering (Figure 1c).

      Clinical studies and mechanisms of therapy in pemphigus

      Validated clinical disease scores have allowed the standard methods of evaluating disease activity and therapeutic response in pemphigus (
      • Hébert V.
      • Boulard C.
      • Houivet E.
      • Duvert Lehembre S.
      • Borradori L.
      • Della Torre R.
      • et al.
      Large international validation of ABSIS and PDAI pemphigus severity scores.
      ). Seminal studies have validated anti-CD20 antibody therapy with rituximab as a very effective therapeutic approach for both PV and PF (
      • Joly P.
      • Mouquet H.
      • Roujeau J.C.
      • D'Incan M.
      • Gilbert D.
      • Jacquot S.
      • et al.
      A single cycle of rituximab for the treatment of severe pemphigus.
      ), and it is now considered the first line therapy in many instances (
      • Harman K.E.
      • Brown D.
      • Exton L.S.
      • Groves R.W.
      • Hampton P.J.
      • Mohd Mustapa M.F.
      • et al.
      British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017.
      ,
      • Joly P.
      • Maho-Vaillant M.
      • Prost-Squarcioni C.
      • Hebert V.
      • Houivet E.
      • Calbo S.
      • et al.
      First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.
      ). The effectiveness of anti-CD20 antibody therapy, which targets B cells but not long-lived plasma cells, suggests that pemphigus antibodies are produced by short-lived plasmablasts that require continual renewal by memory B cells (
      • Colliou N.
      • Picard D.
      • Caillot F.
      • Calbo S.
      • Le Corre S.
      • Lim A.
      • et al.
      Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response.
      ). When the IgG B cells are depleted, the autoantibody titers go down or disappear. A recent study of the clonal repertoire of the IgG B cells in pemphigus and their recurrence with disease reappearance suggests that in effective therapy with long-term remission non-tolerant anti-Dsg B cell clones are completely eliminated, and few, if any, new ones emerge. However, in relapse after therapy, the re-emerging anti-Dsg IgG B cells are the same clonal B cells that were present before therapy (
      • Di Zenzo G.
      • Zambruno G.
      Clonal analysis of B-cell response in pemphigus course: toward more effective therapies.
      ,
      • Hammers C.M.
      • Chen J.
      • Lin C.
      • Kacir S.
      • Siegel D.L.
      • Payne A.S.
      • et al.
      Persistence of anti-desmoglein 3 IgG(+) B-cell clones in pemphigus patients over years.
      ). This observation suggests that the effectiveness of therapy depends on eliminating all non-tolerant B cells, and that, in general, there is not an ongoing loss of tolerance in patients with pemphigus that allows new anti-Dsg IgG B cell clones to emerge (Figure 2). The proteomic analysis of serum anti-Dsg antibodies from patients with pemphigus confirmed that the same clonal antibodies can recur over many years, with remissions and relapses (
      • Chen J.
      • Zheng Q.
      • Hammers C.M.
      • Ellebrecht C.T.
      • Mukherjee E.M.
      • Tang H.Y.
      • et al.
      Proteomic analysis of pemphigus autoantibodies indicates a larger, more diverse, and more dynamic repertoire than determined by B cell genetics.
      ,
      • Hammers C.M.
      • Tang H.Y.
      • Chen J.
      • Emtenani S.
      • Zheng Q.
      • Stanley J.R.
      Research techniques made simple: mass spectrometry for analysis of proteins in dermatological research.
      ). These studies also validated earlier studies in which immunoscope analyses, which assess the heavy chain CDR3 length distributions of antibody-producing clones, suggested that in recurrent disease after rituximab, the same clonal peaks reappeared (
      • Colliou N.
      • Picard D.
      • Caillot F.
      • Calbo S.
      • Le Corre S.
      • Lim A.
      • et al.
      Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response.
      ,
      • Mouquet H.
      • Musette P.
      • Gougeon M.L.
      • Jacquot S.
      • Lemercier B.
      • Lim A.
      • et al.
      B-cell depletion immunotherapy in pemphigus: effects on cellular and humoral immune responses.
      ). A recent study shows that, after depletion with rituximab, newly generated B cells have an increase in the surface expression of the potassium channel Kcnn4. In this study, this expression is a marker of a more naïve (and less memory-like) phenotype typical of more naïve B cells that appear after the recovery of the B cell repertoire after rituximab (
      • Caillot F.
      • Derambure C.
      • Berkani N.
      • Riou G.
      • Maho-Vaillant M.
      • Calbo S.
      • et al.
      Long-term increase of Kcnn4 potassium channel surface expression on B cells in pemphigus patients after rituximab treatment.
      ).
      Figure thumbnail gr2
      Figure 2Hypothetical mechanisms of relapse in pemphigus. Pemphigus may theoretically result either from a one-time (or time-limited) loss of tolerance of B cells to Dsg or by a chronic ongoing loss of B cell tolerance. Recurrences in the former case would result from the failure to destroy all non-tolerant B cell clones. Recurrence would then occur from the proliferation of the residual clones ultimately resulting in enough plasmoblasts to secrete detectable anti-Dsg antibodies. In the latter case, new non-tolerant B cell clones would be continually produced by the bone marrow and proliferate to cause disease. Current data favor the former mechanism, with no or few new clones evolving over the course of disease. Dsg, desmoglein.
      A recent study showing that anti-Dsg B cells may have a niche in the skin (
      • Takahashi H.
      Desmoglein 3-reactive B cells “hiding” in pemphigus lesions.
      ,
      • Yuan H.
      • Zhou S.
      • Liu Z.
      • Cong W.
      • Fei X.
      • Zeng W.
      • et al.
      Pivotal role of lesional and perilesional T/B lymphocytes in pemphigus pathogenesis.
      ) provides insight into why some pemphigus lesions persist after rituximab or can be present with no, or minimal, circulating antibodies.

      Bullous pemphigoid: clinical summary, epidemiology, associated diseases, and HLA associations

      Bullous pemphigoid (BP) is an autoantibody-mediated disease that usually occurs in the elderly but may be seen at all ages (
      • Culton D.A.
      • Liu Z.
      • Diaz L.A.
      Bullous pemphigoid.
      ). It is characterized by tense large blisters on skin and in a minority of cases, oral erosions. Blisters may be on normal-appearing or inflamed skin. Some cases can start (or persist) with only urticarial-like lesions. The histology typically shows a subepidermal blister with a superficial infiltrate containing eosinophils, and fewer, if any, neutrophils. Direct immunofluorescence shows IgG and C3 (the third component of complement) at the basement membrane zone.
      As in pemphigus, the incidence and prevalence of BP depends on the population studied (
      • Hammers C.M.
      • Stanley J.R.
      Mechanisms of disease: pemphigus and bullous pemphigoid.
      ). The prevalence of BP in Germany was found to be 259.3 patients per million inhabitants, about 2.5 times that of pemphigus, with a disease duration of 6–8 years (
      • Hübner F.
      • Recke A.
      • Zillikens D.
      • Linder R.
      • Schmidt E.
      Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany.
      ).
      Based on insurance data, BP was associated with hematological malignancies, such as lymphoma and leukemia, in about 7% of the cases, but no association with non-hematological malignancies was seen (
      • Schulze F.
      • Neumann K.
      • Recke A.
      • Zillikens D.
      • Linder R.
      • Schmidt E.
      Malignancies in pemphigus and pemphigoid diseases.
      ). However, no association of BP with cancer was seen in another recent study (
      • Langan S.M.
      • Groves R.W.
      • West J.
      The relationship between neurological disease and bullous pemphigoid: a population-based case-control study.
      ).
      However, this latter study confirmed and extended recent findings of the association of BP with neurologic diseases, specifically, stroke, dementia, Parkinson ’s disease, and multiple sclerosis. This association is thought to occur in part because BP antigens may be found in the central nervous system. It is well established that BP antigen 1 (BPAG1, BP230, see below) has an alternatively spliced neural form, including one in the brain (
      • Bouameur J.E.
      • Favre B.
      • Borradori L.
      Plakins, a versatile family of cytolinkers: roles in skin integrity and in human diseases.
      ,
      • Guo L.
      • Degenstein L.
      • Dowling J.
      • Yu Q.C.
      • Wollmann R.
      • Perman B.
      • et al.
      Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration.
      ,
      • Leung C.L.
      • Zheng M.
      • Prater S.M.
      • Liem R.K.
      The BPAG1 locus: alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles.
      ). Although the BP180 antigen (see below) has been reported to be found in the brain (
      • Seppänen A.
      • Autio-Harmainen H.
      • Alafuzoff I.
      • Särkioja T.
      • Veijola J.
      • Hurskainen T.
      • et al.
      Collagen XVII is expressed in human CNS neurons.
      ), a recent comprehensive study using various methods could not detect it (
      • Barrick B.J.
      • Ida C.M.
      • Laniosz V.
      • Jentoft M.E.
      • Sominidi-Damodaran S.
      • Wieland C.N.
      • et al.
      Bullous pemphigoid, neurodegenerative disease, and hippocampal BP180 expression: A retrospective postmortem neuropathologic study.
      ).
      Analyzing demographic, clinical, and serological features, no differences, except for age, were found in patients with BP and preceding neurological disease and in patients with BP and no neurological disease. Those patients having BP after the diagnosis of neurologic conditions were significantly older (
      • Messingham K.N.
      • Miller A.D.
      • Narayanan N.S.
      • Connell S.J.
      • Fairley J.A.
      Demographics and autoantibody profiles of pemphigoid patients with underlying neurologic diseases.
      ). A surprising proportion, 53.6%, of patients with multiple sclerosis (MS) had serum antibodies that bound the full length BP180 antigen on immunoblots. However, only about 8% of the MS sera reacted against the major BP180 disease epitope, BP180-NC16A, by ELISA, or against the cutaneous membrane zone by indirect immunofluorescence. These studies indicate that epitopes differ between the BP and MS anti-BP180 sera, suggesting that epitope spreading may be necessary to initiate BP (
      • Tuusa J.
      • Lindgren O.
      • Tertsunen H.M.
      • Nishie W.
      • Kokkonen N.
      • Huilaja L.
      • et al.
      BP180 autoantibodies target different epitopes in multiple sclerosis or Alzheimer's disease than in bullous pemphigoid.
      ).
      Another association with BP might be dermatitis herpetiformis (DH). Patients with DH have a 22-fold increased risk to develop subsequent BP, with a mean time of 3 years in between diagnoses of DH and BP (
      • Varpuluoma O.
      • Jokelainen J.
      • Försti A.K.
      • Timonen M.
      • Huilaja L.
      • Tasanen K.
      Dermatitis herpetiformis and celiac disease increase the risk of bullous pemphigoid.
      ). However, in our experience, DH followed by BP is still a very unusual event.
      A Chinese study to detect HLA associations with BP showed that the haplotype DQB1*03:01 was the only significant association for BP. A total of 49.65% of their patients had this HLA allele compared with 35.25% of the healthy controls.The DQB1*03:03 and DQB1*06:01 alleles had protective associations (
      • Sun Y.
      • Liu H.
      • Wang Z.
      • Fu X.
      • Wang C.
      • Mi Z.
      • et al.
      The HLA-DQB1*03:01 is associated with bullous pemphigoid in the Han Chinese population.
      ).

      BP: pathophysiology, autoantibodies, and autoantigens

      Seminal studies have demonstrated antibodies to two major antigens in BP, BP230 (BPAG1/BPAG1e), and BP180 (BPAG2, Collagen XVII), the latter most associated with disease activity (
      • Diaz L.A.
      • 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. Immunolocalization of this protein to the hemidesmosome.
      ,
      • Giudice G.J.
      • Emery D.J.
      • Diaz L.A.
      Cloning and primary structural analysis of the bullous pemphigoid autoantigen BP180.
      ,
      • Schmidt E.
      • Obe K.
      • Bröcker E.B.
      • Zillikens D.
      Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid.
      ,
      • 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.
      ). Both these antigens are components of the basement membrane zone (Figure 3a), specifically the hemidesmosome. BP230 is part of the intracellular hemidesmome plaque, whereas BP 180 is a transmembrane collagenous protein.
      Figure thumbnail gr3
      Figure 3Pathophysiologic mechanisms in bullous pemphigoid. (a) Key adhesion molecules of basal hemidesmosomes with BP230 positioned intracellularly and BP180 as a transmembrane protein. (b) Pathophysiologic pathways of bullous pemphigoid summarized in this review. BMZ, basement membrane zone; Col, collagen; EC, ectodomain; GzmB, granzyme B; KIF, keratin intermediate filament; Lam332, laminin 332; MC, mast cell; NE, neutrophil elastase.
      Many of the pathophysiologic pathways involved have been demonstrated in murine models, with some notable differences compared with the human situation (
      • Hammers C.M.
      • Stanley J.R.
      Mechanisms of disease: pemphigus and bullous pemphigoid.
      ). For example, in mice, activated neutrophils figure prominently in the initiation of subepidermal blistering, whereas in humans, one of the histologic hallmarks of BP is an eosinophil-rich infiltrate in the dermis and at the dermal-epidermal junction. In this regard, the importance of eosinophils in the pathophysiology of blistering has been demonstrated recently using a humanized murine model (
      • Lin L.
      • Hwang B.J.
      • Culton D.A.
      • Li N.
      • Burette S.
      • Koller B.H.
      • et al.
      Eosinophils mediate tissue injury in the autoimmune skin disease bullous pemphigoid.
      ). In previous mouse models in which neutrophils figured predominantly, BP IgG was the only immunoglobulin tested. However, the use of BP IgE in a mouse expressing the human FcεRI, more faithfully models the human disease condition in which patients have IgE anti-NC16A antibodies and eosinophils with the proper high affinity receptor for IgE. This allows eosinophils to be activated by IgE bound to the basement membrane, and it allows mast cells with anti-NC16A IgE on their surface to be activated by fragments of BP180 released from the basement membrane (
      • Hammers C.M.
      • Stanley J.R.
      Mechanisms of disease: pemphigus and bullous pemphigoid.
      ). Figure 3b summarizes how IgG, complement (see below), IgE, eosinophils, and mast cells may be involved in the pathophysiology of BP.
      Further supporting the importance of the BP180 antigen in disease pathogenesis, a provocative mouse model demonstrated that the genetic alteration of the BP180 antigen could cause a model of BP, with the mice displaying itch, erosions, eosinophilic infiltrates, IgG autoantibodies with subepidermal reactivity, and elevated serum IgE levels (
      • Hurskainen T.
      • Kokkonen N.
      • Sormunen R.
      • Jackow J.
      • Löffek S.
      • Soininen R.
      • et al.
      Deletion of the major bullous pemphigoid epitope region of collagen XVII induces blistering, autoimmunization, and itching in mice.
      ,
      • Yancey K.B.
      Itch, eosinophils, and autoimmunity: a novel murine model of bullous pemphigoid.
      ).
      The autoantibody response in BP has been dissected at a finer level. Most patients with BP have inflammatory disease with antibodies binding to the NC16A major pathologic epitope of BP180, but a recent study analyzed a group of 14 patients with BP (out of 121 patients) with non-inflammatory disease (
      • Izumi K.
      • Nishie W.
      • Mai Y.
      • Wada M.
      • Natsuga K.
      • Ujiie H.
      • et al.
      Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid.
      ). These patients’ antibodies bound the mid-portion of extracellular BP180 and not the NC16A epitope, and most of the patients had disease associated with taking a dipeptidyl peptidase-IV (DPP-4) inhibitor for diabetes. Another study of BP180 epitopes showed that the antibody response to certain epitopes on BP180 was associated with degrees of pathogenicity (
      • Wada M.
      • Nishie W.
      • Ujiie H.
      • Izumi K.
      • Iwata H.
      • Natsuga K.
      • et al.
      Epitope-dependent pathogenicity of antibodies targeting a major bullous pemphigoid autoantigen collagen XVII/BP180.
      ). Specifically, antibodies against NC16A were pathogenic in mouse skin expressing human BP180, whereas antibodies against a more extracellular BP180 domain bound the skin but were non-pathogenic. The pathogenicity may be related to the observation that the anti-NC16A antibodies could cause the internalization of BP180 (and the presumed depletion of BP180 in the hemidesmosome), whereas the other non-pathogenic antibodies could not.
      Finally, the amount of serum BP180 autoantibodies in patients with Alzheimer’s disease has been associated with their degree of dementia (
      • Kokkonen N.
      • Herukka S.K.
      • Huilaja L.
      • Kokki M.
      • Koivisto A.M.
      • Hartikainen P.
      • et al.
      Increased levels of the bullous pemphigoid BP180 autoantibody are associated with more severe dementia in Alzheimer's disease.
      ). Patients with these anti-BP180 antibodies did not have BP, and their serum anti-BP180 antibodies did not bind the epidermal basement membrane zone, similar to findings discussed previously in patients with MS (
      • Messingham K.N.
      • Miller A.D.
      • Narayanan N.S.
      • Connell S.J.
      • Fairley J.A.
      Demographics and autoantibody profiles of pemphigoid patients with underlying neurologic diseases.
      ).
      Recently, fine mapping has been applied to characterize immunodominant T helper type 2 (Th2)-cell epitopes in patients with BP by screening 22 overlapping peptides spanning the BP180-NC16A domain (
      • Zhang J.
      • Fang H.
      • Shen S.
      • Dang E.
      • Li Q.
      • Qiao P.
      • et al.
      Identification of immunodominant Th2-cell epitopes in Chinese patients with bullous pemphigoid.
      ). Two peptides were identified that caused HLA-DR-restricted proliferation of CD4+ T cells, Th2 IL-4 cytokine production, and autoantibody production by B cells.

      Drug-induced BP

      Epidemiologic evidence from large cohorts from France and Finland has shown an association of patients taking DPP-4 inhibitors (i.e., gliptins) for diabetes and BP (
      • Nishie W.
      • Tasanen K.
      Gliptin-associated bullous pemphigoid: A valuable model of the mechanism of breakdown of immune tolerance against BP180.
      ,
      • Plaquevent M.
      • Tétart F.
      • Fardet L.
      • Ingen-Housz-Oro S.
      • Valeyrie-Allanore L.
      • Bernard P.
      • et al.
      Higher frequency of dipeptidyl peptidase-4 inhibitor intake in bullous pemphigoid patients than in the French general population.
      ,
      • Varpuluoma O.
      • Försti A.K.
      • Jokelainen J.
      • Turpeinen M.
      • Timonen M.
      • Huilaja L.
      • et al.
      Vildagliptin significantly increases the risk of bullous pemphigoid: A Finnish Nationwide Registry study.
      ). In Chinese patients, the haplotype HLA-DQB1*03:01, which had also been described as a significant risk factor for BP (
      • Sun Y.
      • Liu H.
      • Wang Z.
      • Fu X.
      • Wang C.
      • Mi Z.
      • et al.
      The HLA-DQB1*03:01 is associated with bullous pemphigoid in the Han Chinese population.
      ), was found to be a biomarker for genetic susceptibility to gliptin-induced BP (
      • Ujiie H.
      • Muramatsu K.
      • Mushiroda T.
      • Ozeki T.
      • Miyoshi H.
      • Iwata H.
      • et al.
      HLA-DQB1*03:01 as a biomarker for genetic susceptibility to bullous pemphigoid induced by DPP-4 inhibitors.
      ). As discussed above, a non-inflammatory type of BP with an atypical (i.e., not NC16A) BP180 epitope was associated in several patients with gliptin-associated BP (
      • Izumi K.
      • Nishie W.
      • Mai Y.
      • Wada M.
      • Natsuga K.
      • Ujiie H.
      • et al.
      Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid.
      ).

      Mechanisms of therapy and new therapeutic approaches for BP

      Intensive potent topical corticosteroids are effective with fewer side effects than oral corticosteroids, the usual therapy for these patients (
      • Joly P.
      • Roujeau J.C.
      • Benichou J.
      • Delaporte E.
      • D'Incan M.
      • Dreno B.
      • et al.
      A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study.
      ,
      • Joly P.
      • Roujeau J.C.
      • Benichou J.
      • Picard C.
      • Dreno B.
      • Delaporte E.
      • et al.
      A comparison of oral and topical corticosteroids in patients with bullous pemphigoid.
      ). Rituximab is also probably effective (
      • Hall 3rd, R.P.
      • Streilein R.D.
      • Hannah D.L.
      • McNair P.D.
      • Fairley J.A.
      • Ronaghy A.
      • et al.
      Association of serum B-cell activating factor level and proportion of memory and transitional B cells with clinical response after rituximab treatment of bullous pemphigoid patients.
      ), but the evidence is not as convincing as with pemphigus. Intravenous immunoglobulin (IVIG) is also effective (
      • Amagai M.
      • Ikeda S.
      • Hashimoto T.
      • Mizuashi M.
      • Fujisawa A.
      • Ihn H.
      • et al.
      A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.
      ). The latter is thought to exert its beneficial effects by saturating the neonatal Fc receptor, thus increasing the catabolism of IgG, including the pathogenic circulating autoantibodies (
      • Li N.
      • Culton D.
      • Diaz L.A.
      • Liu Z.
      Modes of action of intravenous immunoglobulin in bullous pemphigoid.
      ). IVIG not only ameliorates disease activity by reducing circulating autoantibodies but in a murine model, also decreases IL-6 and increases IL-10, two cytokines that are thought to be associated with disease activity (
      • Sasaoka T.
      • Ujiie H.
      • Nishie W.
      • Iwata H.
      • Ishikawa M.
      • Higashino H.
      • et al.
      Intravenous IgG reduces pathogenic autoantibodies, serum IL-6 levels, and disease severity in experimental bullous pemphigoid models.
      ).
      New therapeutic approaches for BP are under development. The inhibition of fixation and activation of complement, as suggested for other complement-mediated diseases (
      • Ricklin D.
      • Lambris J.D.
      Complement in immune and inflammatory disorders: therapeutic interventions.
      ), would be a logical targeted approach to therapy because complement components serve as initiators of inflammation in BP (e.g., by the degranulation of mast cells and chemotaxis of eosinophils and neutrophils) (
      • Nelson K.C.
      • Zhao M.
      • Schroeder P.R.
      • Li N.
      • Wetsel R.A.
      • Diaz L.A.
      • et al.
      Role of different pathways of the complement cascade in experimental bullous pemphigoid.
      ) (Figure 3b). In experimental BP, the classical pathway of complement activation has been shown to be critical with the amplification of disease from the alternative pathway (
      • Nelson K.C.
      • Zhao M.
      • Schroeder P.R.
      • Li N.
      • Wetsel R.A.
      • Diaz L.A.
      • et al.
      Role of different pathways of the complement cascade in experimental bullous pemphigoid.
      ). Furthermore implicating complement in pathogenesis, C5a receptor-deficient mice are protected from blistering in experimental BP (
      • Heimbach L.
      • Li Z.
      • Berkowitz P.
      • Zhao M.
      • Li N.
      • Rubenstein D.S.
      • et al.
      The C5a receptor on mast cells is critical for the autoimmune skin-blistering disease bullous pemphigoid.
      ). A preclinical study of complement inhibition by TNT003, an anti-C1s mouse monoclonal antibody, evaluated its effect on complement deposition by BP sera on the basement membrane of normal human skin. It showed dose-dependent reductions of C3 fixation and liberation of the anaphylatoxin C5a (
      • Kasprick A.
      • Holtsche M.M.
      • Rose E.L.
      • Hussain S.
      • Schmidt E.
      • Petersen F.
      • et al.
      The anti-C1s antibody TNT003 prevents complement activation in the skin induced by bullous pemphigoid autoantibodies.
      ). The use of the humanized IgG4 version of TNT003 (designated TNT009 or BIVV009) was evaluated in a phase 1 trial (NCT02502903) in humans. This therapy resulted in complete or partial reduction of complement fixation at the basement membrane zone in four of the five patients included; however, clinical symptoms were not evaluated (
      • Freire P.C.
      • Muñoz C.H.
      • Derhaschnig U.
      • Schoergenhofer C.
      • Firbas C.
      • Parry G.C.
      • et al.
      Specific inhibition of the classical complement pathway prevents C3 deposition along the dermal-epidermal junction in bullous pemphigoid.
      ). With the FDA’s designation of BIVV009’s orphan drug status for BP, further clinical development is likely (
      • Kushner C.J.
      • Payne A.S.
      Increasing the complement of therapeutic options in bullous pemphigoid.
      ).
      In addition to IL-6 and IL-10, a new cytokine, macrophage, and/or monocyte-derived tumor necrosis factor-related weak inducer of apoptosis (TWEAK), was recently discovered to be implicated in BP pathophysiology (
      • Liu Y.
      • Peng L.
      • Li L.
      • Liu C.
      • Hu X.
      • Xiao S.
      • et al.
      TWEAK/Fn14 activation contributes to the pathogenesis of bullous pemphigoid.
      ) (Figure 3b). TWEAK was increased in BP lesional skin and serum (with a positive correlation to BP180 IgG levels). Futhermore, TWEAK reduced BP180 expression in vitro, an effect possibly mediated by binding to its Fn14 receptor with subsequent signaling via the NF-κB and extracellular signal–regulated kinase. These finding suggest that the TWEAK pathway might be a druggable target in BP.

      Conclusions and future directions

      The development of chimeric autoantibody receptor (CAAR) T cells to cure experimental pemphigus has been a major recent development (
      • Ellebrecht C.T.
      • Bhoj V.G.
      • Nace A.
      • Choi E.J.
      • Mao X.
      • Cho M.J.
      • et al.
      Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease.
      ). This approach destroys B cells expressing anti-Dsg receptors, thus preventing the development of plasmoblasts that secrete autoantibodies and potentially curing disease. If effective for pemphigus, it has the potential of curing other autoantibody-mediated autoimmune diseases in which the antigen is known.
      As discussed above, rituximab is very effective for pemphigus, but disease often recurs, probably from the expansion of B cell clones that were not totally eliminated (Figure 2). If this is true, then modified anti-CD20 antibodies, which more effectively eliminate all CD20+ B cells, might be more effective at inducing permanent remission (
      • Du F.H.
      • Mills E.A.
      • Mao-Draayer Y.
      Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment.
      ).
      The relationship of BP to neurologic diseases and antidiabetic DPP-4 inhibitors has been well established as discussed above. BP has also been precipitated by check point inhibitors (
      • Lopez A.T.
      • Khanna T.
      • Antonov N.
      • Audrey-Bayan C.
      • Geskin L.
      A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors.
      ) However, the pathophysiologic pathways leading to these associations will need to be worked out.
      New therapeutic targets and approaches, in addition to those discussed above, are being identified in BP. New methods of inhibiting complement activation (
      • Gutjahr A.
      • Heck F.
      • Emtenani S.
      • Hammers A.K.
      • Hundt J.E.
      • Muck P.
      • et al.
      Bullous pemphigoid autoantibody-mediated complement fixation is abolished by the low-molecular-weight heparin tinzaparin sodium.
      ) may be applied to therapy. IgE and eosinophils are important mediators of disease in BP (
      • Freire P.C.
      • Muñoz C.H.
      • Stingl G.
      IgE autoreactivity in bullous pemphigoid: eosinophils and mast cells as major targets of pathogenic immune reactants.
      ,
      • Lin L.
      • Hwang B.J.
      • Culton D.A.
      • Li N.
      • Burette S.
      • Koller B.H.
      • et al.
      Eosinophils mediate tissue injury in the autoimmune skin disease bullous pemphigoid.
      ). Therefore, therapy with inhibitors of IgE binding to mast cells, for example omalizumab (
      • Yu K.K.
      • Crew A.B.
      • Messingham K.A.
      • Fairley J.A.
      • Woodley D.T.
      Omalizumab therapy for bullous pemphigoid.
      ), and the inhibition of eosinophils and eosinophil-derived IL-31, which may contribute to pruritus (
      • Lin L.
      • Hwang B.J.
      • Culton D.A.
      • Li N.
      • Burette S.
      • Koller B.H.
      • et al.
      Eosinophils mediate tissue injury in the autoimmune skin disease bullous pemphigoid.
      ,
      • Rüdrich U.
      • Gehring M.
      • Papakonstantinou E.
      • Illerhaus A.
      • Engmann J.
      • Kapp A.
      • et al.
      Eosinophils are a major source of interleukin-31 in bullous pemphigoid.
      ), are future avenues of therapy for study. Eotaxin and IL-5, also elevated in the BP lesions (
      • Shrikhande M.
      • Hunziker T.
      • Braathen L.R.
      • Pichler W.J.
      • Dahinden C.A.
      • Yawalkar N.
      Increased coexpression of eotaxin and interleukin 5 in bullous pemphigoid.
      ,
      • Wakugawa M.
      • Nakamura K.
      • Hino H.
      • Toyama K.
      • Hattori N.
      • Okochi H.
      • et al.
      Elevated levels of eotaxin and interleukin-5 in blister fluid of bullous pemphigoid: correlation with tissue eosinophilia.
      ), are also attractive therapeutic targets, as are other eosinophil-related mediators (
      • Amber K.T.
      • Valdebran M.
      • Kridin K.
      • Grando S.A.
      The role of eosinophils in bullous pemphigoid: A developing model of eosinophil pathogenicity in mucocutaneous disease.
      ). The inhibition of proteases, such as granzyme B that localize to the basement membrane in BP and cleave basement membrane adhesion molecules, may be promising approaches to therapy (
      • Russo V.
      • Klein T.
      • Lim D.J.
      • Solis N.
      • Machado Y.
      • Hiroyasu S.
      • et al.
      Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction.
      ). We also hypothesize that the forced expression of the adhesion molecule BP180 by experimental drugs, such as apocynin or Y-27632, could be developed into new therapeutics for use in BP, as evidenced by compelling experimental data from stem cell research (
      • Liu N.
      • Matsumura H.
      • Kato T.
      • Ichinose S.
      • Takada A.
      • Namiki T.
      • et al.
      Stem cell competition orchestrates skin homeostasis and ageing.
      ).
      As evidenced from this introduction to the JID COLLECTION, creative basic and translational research, much of it published in the JID, has led to a profound understanding of the major autoimmune skin diseases pemphigus and BP and their effective therapies.

      Additional reading: reviews on pemphigus and BP

      There are many mouse models for not only pemphigus and BP but also the other autoimmune blistering skin diseases (
      • Culton D.A.
      • McCray S.K.
      • Park M.
      • Roberts J.C.
      • Li N.
      • Zedek D.C.
      • et al.
      Mucosal pemphigus vulgaris anti-Dsg3 IgG is pathogenic to the oral mucosa of humanized Dsg3 mice.
      ,
      • Pollmann R.
      • Eming R.
      Research techniques made simple: mouse models of autoimmune blistering diseases.
      ). These murine models have been invaluable in helping to dissect pathophysiology, as well as therapeutic approaches to these diseases.
      A recent meeting, summarized by a meeting report (
      • Schmidt E.
      • Spindler V.
      • Eming R.
      • Amagai M.
      • Antonicelli F.
      • Baines J.F.
      • et al.
      Meeting Report of the Pathogenesis of Pemphigus and Pemphigoid Meeting in Munich, September 2016.
      ), highlighted many of the recent advances in both pemphigus and pemphigoid.
      Additional recent reviews summarize the diagnosis, mechanisms of disease and therapeutic approaches for these diseases in more detail (
      • Hammers C.M.
      • Stanley J.R.
      Mechanisms of disease: pemphigus and bullous pemphigoid.
      ,
      • Schmidt E.
      • Zillikens D.
      Pemphigoid diseases.
      ,
      • Spindler V.
      • Eming R.
      • Schmidt E.
      • Amagai M.
      • Grando S.
      • Jonkman M.F.
      • et al.
      Mechanisms causing loss of keratinocyte cohesion in pemphigus.
      ).

      Conflict of Interest

      CMH is a consultant to Argenx and viDA Therapeutics. JRS is a consultant for Argenx. CMH and JRS have a patent and a provisional patent for using pemphigus and BP monoclonal antibodies to deliver biologic agents to the epidermis and the basement membrane zone.

      Acknowledgments

      This work was supported by grants to CMH from the DFG ( RTG1727 , CRU303 , CSSL ) and from the Section of Medicine at the University of Luebeck ( CS06-2019 ).

      Author Contributions

      Conceptualization: CMH, JRS; Writing – Original Draft, CMH, JRS; Writing – Editing and Review, CMH and JRS.

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