title: Bullous pemphigoid antigen II (BP180) and its soluble extracellular domains are major autoantigens in mucous membrane pemphigoid: the pathogenic relevance to HLA class II alleles and disease severity.
abstract: BACKGROUND
  Mucous membrane pemphigoid (MMP), a chronic autoimmune subepithelial blistering disease, is associated with circulating IgG and/or IgA autoantibodies against several basement membrane zone antigens. The heterogeneity of clinical presentation and diversity of target autoantigens have contributed to difficulties in characterizing this condition immunologically.
  
  
  OBJECTIVE
  To analyse serum autoantibody profile and HLA class II alleles in MMP patients and to correlate this with the clinical presentation of disease.
  
  
  METHODS
  Well-defined subgroups consisting of 124 patients with MMP were examined for IgG and IgA reactivity with immunoblotting using human epidermal, dermal and placental amnion proteins. The results were further analysed on the basis of detailed clinical (sites of involvement and disease severity) and immunopathological criteria (immunofluorescence study and HLA class II alleles).
  
  
  RESULTS
  Immunoblot assay revealed that the majority of MMP patients had IgG (93 of 124, 75%) and/or IgA autoantibodies (63 of 124, 51%) to BP180 (including its soluble ectodomains, 120-kDa LAD-1 and 97-kDa LABD97 antigens). Other antigens targeted predominantly by IgG autoantibodies included: BP230 in 34 (27%), beta4 integrin in 26 (21%), and laminin 5 in three (2%). All the BP230+ sera and 23 (88%) beta4 integrin+ sera also reacted with at least one of the BP180 antigens. Over 85% of patients with reactivity to beta4 integrin had ocular involvement. In most cases of MMP, more severe clinical features were associated with antibody reactivity to multiple basement membrane zone antigens, as well as reactivity to multiple BP180 component antigens. Dual BP180/LAD-1 reactivity with IgG and IgA was associated with a more severe phenotype. In addition, the subset-dependent autoantibody reactivity correlated well with specific HLA class II alleles, DQB1*0301, DRB1*04 and DRB1*11.
  
  
  CONCLUSIONS
  Our results confirmed that BP180 is a major autoantigen targeted by the sera of patients with MMP. The disease-prevalent HLA class II alleles and humoral autoimmune response against the particular subsets of antigenic epitope(s) within BP180 ectodomain may contribute to the clinicopathological significance and disease severity of MMP.
authors.affiliation: Department of Dermatologic Immunopathology, Guy's, King's and St Thomas' School of Medicine, St Thomas' Hospital, London, UK. norider@wine.plala.or.jp
authors.forename: N
authors.initials: N
authors.lastname: Oyama
authors.forename: J F
authors.initials: JF
authors.lastname: Setterfield
authors.forename: A M
authors.initials: AM
authors.lastname: Powell
authors.forename: Y
authors.initials: Y
authors.lastname: Sakuma-Oyama
authors.forename: S
authors.initials: S
authors.lastname: Albert
authors.forename: B S
authors.initials: BS
authors.lastname: Bhogal
authors.forename: R W
authors.initials: RW
authors.lastname: Vaughan
authors.forename: F
authors.initials: F
authors.lastname: Kaneko
authors.forename: S J
authors.initials: SJ
authors.lastname: Challacombe
authors.forename: M M
authors.initials: MM
authors.lastname: Black
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000032:analysis / Q000276:immunology*; D001485:Basement Membrane / Q000276:immunology; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D000071821:Dystonin; D005260:Female; D005802:Genes, MHC Class II; D006801:Humans; D015151:Immunoblotting; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007797:Laminin / Q000276:immunology; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D010390:Pemphigoid, Benign Mucous Membrane / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D012720:Severity of Illness Index; D012867:Skin / Q000276:immunology; D000097805:Collagen Type XVII
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D000071821:Dystonin; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007797:Laminin; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII; C486268:DST protein, human; C095567:laminin alpha 3