New insights into the immunoultrastructural organization of cutaneous basement membrane zone molecules

Shimizu, Hiroshi

doi:10.1111/j.1600-0625.1998.tb00329.x

Cited by 22 publications

(15 citation statements)

References 53 publications

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“…Histologically, subepidermal blisters associated with inflammatory cell infiltration in the dermis are observed. BP is induced by autoantibodies against type XVII collagen (COL17, also called BP180 and BPAG2), a hemidesmosomal type II transmembrane protein that spans the lamina lucida and projects into the lamina densa of the dermal/epidermal junction (DEJ) (1)(2)(3)(4). Studies to map the epitopes on COL17 have revealed that the juxtamembranous extracellular noncollagenous 16A domain (NC16A) is preferentially recognized by autoantibodies in the sera of BP patients (5,6).…”

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confidence: 99%

Bullous Pemphigoid Autoantibodies Directly Induce Blister Formation without Complement Activation

Ujiie

Sasaoka

Izumi

et al. 2014

The Journal of Immunology

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109

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Complement activation and subsequent recruitment of inflammatory cells at the dermal/epidermal junction are thought to be essential for blister formation in bullous pemphigoid (BP), an autoimmune blistering disease induced by autoantibodies against type XVII collagen (COL17); however, this theory does not fully explain the pathological features of BP. Recently, the involvement of complement-independent pathways has been proposed. To directly address the question of the necessity of the complement activation in blister formation, we generated C3-deficient COL17-humanized mice. First, we show that passive transfer of autoantibodies from BP patients induced blister formation in neonatal C3-deficient COL17-humanized mice without complement activation. By using newly generated human and murine mAbs against the pathogenic noncollagenous 16A domain of COL17 with high (human IgG1, murine IgG2), low (murine IgG1), or no (human IgG4) complement activation abilities, we demonstrate that the deposition of Abs, and not complements, is relevant to the induction of blister formation in neonatal and adult mice. Notably, passive transfer of BP autoantibodies reduced the amount of COL17 in lesional mice skin, as observed in cultured normal human keratinocytes treated with the same Abs. Moreover, the COL17 depletion was associated with a ubiquitin/proteasome pathway. In conclusion, the COL17 depletion induced by BP autoantibodies, and not complement activation, is essential for the blister formation under our experimental system.

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confidence: 99%

Bullous Pemphigoid Autoantibodies Directly Induce Blister Formation without Complement Activation

Ujiie

Sasaoka

Izumi

et al. 2014

The Journal of Immunology

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109

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“…11 In patients with BP, the target epitopes for BMZ antibodies are located on the NC16A domain of BP180 antigen, ultrastructurally localized in the upper part of the lamina lucida, whereas the serum samples of most patients with MMP recognize the carboxyterminal domain of BP180 antigen at the lamina lucida-lamina densa border. 12 In some patients with MMP, autoantibodies are directed against the ␣ chain of laminin 5, localized in the upper part of the lamina densa.…”

Section: Discussionmentioning

confidence: 99%

“…This discrepancy is because of the presence of 2 different targeted antigens recognized in the serum samples of patients with MMP: the C domain of BP180 antigen, present in the lower part of the lamina lucida; and laminin 5 (also known as epiligrin), localized in the upper part of the lamina densa. 11,22,23 Thus, a direct salt-split pattern cannot be conclusive in patients with MMP.…”

Section: Commentmentioning

confidence: 99%

A Practical Technique for Differentiation of Subepidermal Bullous Diseases

Woźniak¹,

Kazama²,

Kowaléwski³

2003

Arch Dermatol

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“…Like other collagens, the molecule is able to trimerize by self assembly in such a way that the extracellular fragment forms a triple helix, ␣1[XVII] 3 (Balding et al, 1997;Hirako et al, 1996;Pas et al, 1999). The length of the rod domain is sufficient to traverse the lamina lucida, and the flexible carboxyl terminus has been seen within the lamina densa (Shimizu, 1998). Its as yet unidentified ligand(s) may reside within the lamina densa or lamina lucida.…”

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confidence: 99%

“…Its as yet unidentified ligand(s) may reside within the lamina densa or lamina lucida. A candidate ligand is laminin 5, which is mainly localized in the upper lamina densa (Shimizu, 1998). An interaction between the extracellular domain of type XVII collagen and laminin 5 has been reported (Reddy et al, 1998).…”

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confidence: 99%

Truncated Type XVII Collagen Expression in a Patient with Non-Herlitz Junctional Epidermolysis Bullosa Caused by a Homozygous Splice-Site Mutation

Leusden

Pas

Gedde‐Dahl

et al. 2001

Laboratory Investigation

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SUMMARY:Type XVII collagen (180-kDa bullous pemphigoid antigen) is a structural component of hemidesmosomes.Mutations in the type XVII collagen gene (COL17A1) have been established to be the molecular basis of non-Herlitz junctional epidermolysis bullosa (JEB-nH), an inherited skin blistering disorder. Here we report for the first time truncated type XVII collagen expression, caused by homozygosity for a COL17A1 donor splice-site mutation (4261ϩ1 g 3 c), which was identified by PCR amplification on genomic DNA. By RT-PCR and sequencing of cDNA derived from mRNA from the patient's cultured keratinocytes, we provide evidence of cryptic splicing and exon skipping, most abundantly of exon 52. JEB-nH patients with COL17A1 splice-site mutations resulting in an exon skip often have no immunologically detectable type XVII collagen. However, in our patient with the generalized atrophic benign epidermolysis bullosa subtype, a small amount of type XVII collagen was detectable in the skin, and immunoblotting of cultured keratinocytes revealed that the 180-kDa protein was 10 kDa shorter. We hypothesize that the function of this truncated type XVII collagen polypeptide, which is expressed at low levels, is impaired, explaining the JEB-nH phenotype. (Lab Invest 2001, 81:887-894).T ype XVII collagen (180-kDa bullous pemphigoid antigen; BP180, BPAG2), encoded by the COL17A1 gene, plays a critical role in adhesion of basal keratinocytes to the epidermal basement membrane zone (EBMZ). Its expression is restricted to hemidesmosomes, morphological structures that mediate the adhesion of basal keratinocytes to the underlying EBMZ in stratified and pseudostratified epithelia. Type XVII collagen interacts with other hemidesmosomal components (eg, the ␣6␤4 integrin and 230-kDa bullous pemphigoid antigen [BP230]), and thereby plays a role in the assembly and stabilization of hemidesmosomes (Hopkinson and Jones, 2000;Schaapveld et al, 1998). The molecule is a type II transmembrane protein whose carboxy terminal end is located outside the cell. This extracellular part contains 15 collagenous domains (COL1-15), interspaced by noncollagenous domains (NC1-16) (Giudice et al, 1992), which gives the molecule a certain flexibility. By electron microscopy, type XVII collagen is seen as a rigid central rod (COL15) followed by a movable tail (Hirako et al, 1996). Like other collagens, the molecule is able to trimerize by self assembly in such a way that the extracellular fragment forms a triple helix, ␣1[XVII] 3 (Balding et al, 1997;Hirako et al, 1996;Pas et al, 1999). The length of the rod domain is sufficient to traverse the lamina lucida, and the flexible carboxyl terminus has been seen within the lamina densa (Shimizu, 1998). Its as yet unidentified ligand(s) may reside within the lamina densa or lamina lucida. A candidate ligand is laminin 5, which is mainly localized in the upper lamina densa (Shimizu, 1998). An interaction between the extracellular domain of type XVII collagen and laminin 5 has been reported (Reddy et al, 1998). The globular...

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New insights into the immunoultrastructural organization of cutaneous basement membrane zone molecules

Cited by 22 publications

References 53 publications

Bullous Pemphigoid Autoantibodies Directly Induce Blister Formation without Complement Activation

Bullous Pemphigoid Autoantibodies Directly Induce Blister Formation without Complement Activation

A Practical Technique for Differentiation of Subepidermal Bullous Diseases

Truncated Type XVII Collagen Expression in a Patient with Non-Herlitz Junctional Epidermolysis Bullosa Caused by a Homozygous Splice-Site Mutation

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