Epidermolysis bullosa acquisita: What’s new?

Ishii, Norito; Hamada, Takahiro; Dainichi, Teruki; Karashima, Tadashi; Nakama, Takekuni; Yasumoto, Shinichiro; Zillikens, Detlef; Hashimoto, Takashi

doi:10.1111/j.1346-8138.2009.00799.x

Cited by 91 publications

(92 citation statements)

References 101 publications

(129 reference statements)

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“…A recent study reported that repeated IVIG (mean 23.1 cycles) resulted in discontinuation of concomitant therapies (corticosteroids, dapsone, and others), and that IVIG monotherapy led to long-term remission [9]. Other reports also showed that several cycles induced a sustained clinical remission [10]. In our case, although cutaneous lesions were refractory to dapsone, prednisolone, betamethasone, and DFPP, only 2 cycles of IVIG induced clinical remission.…”

Section: Discussionsupporting

confidence: 50%

Successful Treatment of Intravenous Immunoglobulins in a Patient with Intractable Epidermolysis Bullosa Acquisita with Autoantibodies to Type VII Collagen and Laminin Alpha-3

Osada

Yoshida²,

Kikuchi³

et al. 2014

J Clin Exp Dermatol Res

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Case Reportprogressive blistering skin lesions on the face, trunk, and extremities, which were treated with topical corticosteroids and antihistamines but showed no clinical improvement. On physical examination, severely pruritic erythemas and vesicles were diffusely distributed all over the body, most of which were eroded because of scratching ( Figure 1a). The erythematous rashes showed a variety of morphological patterns, erosions, flaccid bullae, and concentric erythemas with a wood-grainlike appearance (Figures 1b and 1c). Oral and conjunctival mucosal lesions were absent. The patient had no medical history, and the results of laboratory examinations were within normal ranges, except for mild hypercholesterolemia. Enzyme-linked immunosorbent assays showed negative results for all desmoglein 1 (Dsg1), Dsg3, bullous pemphigoid 180 (BP180) and BP 230.A skin biopsy specimen from an erythematous legion on the chest containing a vesicle showed subepidermal blistering and dense infiltration of neutrophils, eosinophils, and histiocytes in the superficial dermis (Figure 2a). The infiltrated cells were condensed in the papillary layer of the dermis (Figure 2b). Direct immunofluorescence (DIF) revealed linear deposition of IgG and C3 along the epidermal basement membrane zone (BMZ; Figure 2c). Indirect immunofluorescence (IIF) demonstrated circulating IgG anti-BMZ antibodies at a titer of 1:160, which bound to the dermal side of 1M NaCl-split normal human skin (data not shown).Immunoblot (IB) analysis of normal human dermal extracts revealed that IgG antibodies in the patient serum reacted with a 290-kDa protein band with the same mobility as an epidermolysis bullosa acquisita (EBA) antigen (type VII collagen; Figure 2d). IB of purified human laminin-332 (epiligrin or laminin-5) also detected IgG reactivity with the 165-kDa and 145-kDa forms of the alpha-3 subunit of laminin-332, which were also recognized by a positive control serum from a patient with anti-laminin-332-type mucous membrane pemphigoid (MMP) (Figure 2e). Other IB analyses of normal human epidermal extracts, the recombinant proteins of NC16a and the C-terminal domains of BP180, and a concentrated HaCaT cell culture supernatant showed no positive reactivity (data not shown).The patient was initially treated with dapsone (50 mg/day), which dramatically improved his pruritus, but failed to suppress the development of the erythemas and vesicles. Gradual increase in levels of liver transglutaminases led to cessation of dapsone. Because both pruritus and skin lesions were refractory to subsequent oral prednisolone (40 mg/day) or betamethasone (6 mg/day), double filtration plasmapheresis (DFPP) was performed. However, after 3 cycles of DFPP, the patient abruptly developed a high fever, showed deterioration of liver function, and showed increase in levels of white blood cells (12,800 cells/µL, normal<9,000 µL) and C-reactive protein (15.7 mg/dL, normal<0.3 mg/dL). Methicillin-resistant staphylococcal aureus (MRSA) was detected from a blood specimen and from a c...

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Section: Discussionsupporting

confidence: 50%

Successful Treatment of Intravenous Immunoglobulins in a Patient with Intractable Epidermolysis Bullosa Acquisita with Autoantibodies to Type VII Collagen and Laminin Alpha-3

Osada

Yoshida²,

Kikuchi³

et al. 2014

J Clin Exp Dermatol Res

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“…Collagen VII is the autoantigen of epidermolysis bullosa acquisita (Ishii et al 2010), and collagen XVII is the major autoantigen of the skin blistering disease bullous pemphigoid (Franzke et al 2005). The NC1 domain of the a3(IV) chain contains the epitopes recognized by the antiglomerular basement membrane antibodies found in patients with Goodpasture syndrome characterized by glomerulonephritis and lung (2010) hemorrhage (Khoshnoodi et al 2008).…”

Section: Genetic and Acquired Diseases Of Collagensmentioning

confidence: 99%

The Collagen Family

Ricard‐Blum¹

2010

Cold Spring Harbor Perspectives in Biology

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Collagens are the most abundant proteins in mammals. The collagen family comprises 28 members that contain at least one triple-helical domain. Collagens are deposited in the extracellular matrix where most of them form supramolecular assemblies. Four collagens are type II membrane proteins that also exist in a soluble form released from the cell surface by shedding. Collagens play structural roles and contribute to mechanical properties, organization, and shape of tissues. They interact with cells via several receptor families and regulate their proliferation, migration, and differentiation. Some collagens have a restricted tissue distribution and hence specific biological functions. THE COLLAGEN SUPERFAMILYThe collagen superfamily comprises 28 members numbered with Roman numerals in vertebrates (I -XXVIII) ( Table 1). A novel epidermal collagen has been called collagen XXIX (Söder-häll et al. 2007), but the COL29A1 gene was shown to be identical to the COL6A5 gene, and the a1(XXIX) chain corresponds to the a5(VI) chain (Gara et al. 2008). The common structural feature of collagens is the presence of a triple helix that can range from most of their structure (96% for collagen I) to less than 10% (collagen XII). As described in the following discussion, the diversity of the collagen family is further increased by the existence of several a chains, several molecular isoforms and supramolecular structures for a single collagen type, and the use of alternative promoters and alternative splicing.The criteria to name a protein collagen are not well defined and other proteins containing one triple-helical domain (Table 2) are not numbered with a Roman numeral so far and do not belong to the collagen family sensu stricto.

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“…After binding to their target Ag in the skin, a proinflammatory milieu is generated, leading to both neutrophil extravasation and activation. Reactive oxygen species and proteolytic enzymes released from neutrophils then lead to subepidermal blister formation (29)(30)(31).…”

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confidence: 99%

GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

Samavedam

Iwata

Müller

et al. 2014

The Journal of Immunology

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GM-CSF activates hematopoietic cells and recruits neutrophils and macrophages to sites of inflammation. Inhibition of GM-CSF attenuates disease activity in models of chronic inflammatory disease. Effects of GM-CSF blockade were linked to modulation of the effector phase, whereas effects on early pathogenic events, for example, Ab production, have not been identified. To evaluate yet uncharacterized effects of GM-CSF on early pathogenic events in chronic inflammation, we employed immunization-induced epidermolysis bullosa acquisita (EBA), an autoimmune bullous disease caused by autoantibodies to type VII collagen. Compared to wild-type mice, upon immunization, GM-CSF−/− mice produced lower serum autoantibody titers, which were associated with reduced neutrophil numbers in draining lymph nodes. The same effect was observed in neutrophil-depleted wild-type mice. Neutrophil depletion in GM-CSF−/− mice led to a stronger inhibition, indicating that GM-CSF and neutrophils have additive functions. To characterize the contribution of GM-CSF specifically in the effector phase of EBA, disease was induced by transfer of anti–type VII collagen IgG into mice. We observed an increased GM-CSF expression, and GM-CSF blockade reduced skin blistering. Additionally, GM-CSF enhanced reactive oxygen species release and neutrophil migration in vitro. In immunization-induced murine EBA, treatment with anti–GM-CSF had a beneficial effect on established disease. We demonstrate that GM-CSF modulates both autoantibody production and skin blistering in a prototypical organ-specific autoimmune disease.

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Epidermolysis bullosa acquisita: What’s new?

Cited by 91 publications

References 101 publications

Successful Treatment of Intravenous Immunoglobulins in a Patient with Intractable Epidermolysis Bullosa Acquisita with Autoantibodies to Type VII Collagen and Laminin Alpha-3

Successful Treatment of Intravenous Immunoglobulins in a Patient with Intractable Epidermolysis Bullosa Acquisita with Autoantibodies to Type VII Collagen and Laminin Alpha-3

The Collagen Family

GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

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