Eur J Dermatol 2015; 25(5): 418-23

Investigative report Xiaoguang LI1,a Atsunari TSUCHISAKA1,a Hua QIAN1,a Kwesi TEYE1 Norito ISHII1 Ryosuke SOGAME1 Kazutoshi HARADA2 Daiki NAKAGOMI2 Shinji SHIMADA2 Chiharu TATEISHI3 Yoshiaki HIRAKO4 Takashi HASHIMOTO1 1

Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan 2 Department of Dermatology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan 3 Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan 4 Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan a These three authors contributed equally to this study.

Linear IgA/IgG bullous dermatosis reacts with multiple laminins and integrins Background: Since the original description by Zone et al in 1994, the disease entity and target antigens in linear IgA/IgG bullous dermatosis (LAGBD) have not been clarified in 20 years. Objectives: To determine autoantibodies and autoantigens in a new LAGBD case which showed atypical clinical and histopathological findings without apparent mucosal involvement. Materials and Methods: We performed various indirect immunofluorescence and immunoblotting studies. Results: Indirect immunofluorescence of 1M NaCl-split skin showed IgG and IgA reactivity with both epidermal and dermal sides. Immunoblotting studies using various antigen sources revealed circulating IgG and IgA antibodies reactive with laminin-332, laminin-␥1 and integrin ␣6␤4 in various patterns. Absorption study using recombinant proteins of laminin-␥1 indicated that the patient serum reacted with different epitopes between laminin-␥1 and laminin-␥2. Conclusions: This study presented for the first time a LAGBD patient with IgG and IgA antibodies to various laminins and integrins. Key words: linear IgA/IgG bullous dermatosis, integrin ␣6␤4, laminin332, laminin-␥1

Reprints: T. Hashimoto Article accepted on 20/2/2015

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IgG/IgA autoantibodies reacted with BP230, BP180, type VII collagen, LM-332, LM-␥1 and the 97kDa LAD-1 [1117]. The heterogeneity of autoantigens might cause the variable clinical and histopathological features. In this study, we report a LAGBD case with IgG and IgA autoantibodies reactive with LM-332, LM-␥1 and ITG ␣6␤4 in various patterns. In addition, absorption studies indicated that the patient serum reacted with different epitopes between LM-␥1 and LM-␥2.

Clinical manifestation An 80-year-old Japanese male, with complications of hypertension, hyperlipidemia, diabetes and prostatic hyperplasia, visited us because bullous skin lesions had developed on the limbs and soon spread to the trunk. Physical examination revealed scaly exudative erythemas with flaccid and tense blisters, erosions and pustules on the distal limbs and trunk (figures 1A, B). The skin lesions showed an annular arrangement in some areas. Erythemas were also found on the head. Although minimum erosions were seen on the lips and penis, apparent lesions were not seen either in the oral cavity or on the conjunctivae. Histopathology for a skin biopsy showed subepidermal blisters with inflammatory infiltration of numerous neutrophils and eosinophils (figures 1C, D). Direct immunofluorescence (IF) detected BMZ deposition of C3 but not IgG or EJD, vol. 25, n◦ 5, September-October 2015

To cite this article: Li X, Tsuchisaka A, Qian H, Teye K, Ishii N, Sogame R, Harada K, Nakagomi D, Shimada S, Tateishi C, Hirako Y, Hashimoto T. Linear IgA/IgG bullous dermatosis reacts with multiple laminins and integrins. Eur J Dermatol 2015; 25(5): 418-23 doi:10.1684/ejd.2015.2555

doi:10.1684/ejd.2015.2555

n the progress of biochemical and molecular biological studies, most constituent proteins in the epidermal basement membrane zone (BMZ) have been identified as autoantigens for various subepidermal autoimmune bullous diseases [1]. These autoantigens include BP230 and BP180 in BP [2, 3], BP180 in pemphigoid gestationis and anti-BP180-type mucous membrane pemphigoid (MMP) [4], type VII collagen in epidermolysis bullosa acquisita (EBA) [5], the 120 kDa LAD-1, a truncated ecto-domain of BP180 in linear IgA bullous dermatosis (LABD) [6]. In addition to these autoantigens, autoantibodies to various subunits of both laminin (LM) and integrin (ITG) have been shown to be present in various diseases. Various subunits of LM-332 have been identified as autoantigens in antiLM-332-type MMP [7], while LM-␥1 was shown to be the autoantigen in anti-LM-␥1 pemphigoid [8]. In addition, IgG antibodies to the ITG ␤4 subunit were found in sera of ocular MMP [9], while IgG antibodies to the anti-ITG ␣6 subunit were found in sera of oral MMP [10]. Linear IgA/IgG bullous dermatosis (LAGBD), which was first proposed by Zone et al. in 1994 [11], is defined by in vivo bound and circulating anti-epidermal BMZ autoantibodies of both IgG and IgA classes [12]. However, its disease entity and pathogenesis are still obscure, although previous patients have shown clinical and histopathological features suggesting either BP or LABD. In addition, autoantigens in LAGBD have not been well elucidated. Thus, in previous reports of LAGBD cases,

A

C

E

D

F

B

Figure 1. Clinical, histopathological and immunofluorescence findings. A, B) Clinical features on the upper limbs and trunk. C, D) Histopathological findings. Magnifications: ×50 (C) and ×200 (D). E, F) Results of indirect immunofluorescence of 1M NaCl-split skin for IgA (E) and IgG (F) (×200).

IgA. ELISA kits for both BP180 and BP230 (MBL, Nagoya, Japan) showed negative results. Based on the immunological findings, the diagnosis of LAGBD was made, although clinical and histopathological features suggested a mixture of BP and LABD. Oral prednisolone 30 mg/day with topical corticosteroid did not improve the skin lesions. One month later, the dose of oral prednisolone was increased to 60 mg/day. Thereafter, new blister formation stopped and the erosions gradually improved. Subsequently, prednisolone was tapered to 25 mg/day over one month, which resulted in a recurrence of the erythema and blisters. The addition of minocycline 200 mg/day and nicotinamide 1200 mg/day showed no effectiveness. However, addition of colchicine 0.5 mg/day completely suppressed the relapse of skin lesions.

Materials and methods All studies followed guidelines of Medical Ethics Committees of Kurume University School of Medicine and were conducted according to Declaration of Helsinki Principles. Informed consents were obtained from all patients and control individuals.

Reagents, patient sera and antibodies All chemicals used for biochemical analyses were of analytical grade and were purchased from Sigma-Aldrich (St. Louis, MO) or nacalai tesque (Kyoto, Japan). Recombinant protein (RP) of LM-521 trimer was purchased from Biolamina (Sundbyberg, Sweden). RP of the extracellular domain (ECD) of ITG ␣6␤4 was purchased from R&D systems (Minneapolis, MN). To prepare RP of the intracellular domain (ICD) of the integrin␤4 subunit, cDNA encoding the correEJD, vol. 25, n◦ 5, September-October 2015

sponding sequence was amplified from cDNAs, which were prepared from DJM-1 cells, with a primer pair of AAAGAATTCAAGTACTGTGCCTGCTGCAAG (forward primer) and TTTCTCGAGGTGGTGGTGGTGGTGGTGAGTTTGGAAGAACTGTTG (reverse primer) (Hirako et al. unpulished data). The amplified cDNA was cloned into the EcoRV site of pT7Blue vector (Novagen) and then subcloned into EcoRI and XhoI sites of pGEX 4T-1 (GE healthcare) vector to obtain a GST-tag fusion protein. The nucleotide sequence of the coding region of the pGEX construct was determined using an ABI 3100 DNA sequencer and was found to be correct. Serum was obtained from the present patient before the treatments were initiated. Sera were also obtained from patients with each of pemphigus vulgaris, paraneoplastic pemphigus, BP, anti-BP180 MMP, LABD, EBA, anti-LM␥1 (p200) pemphigoid and anti-LM-332 MMP, as disease controls. Sera from three healthy volunteers were used as normal controls. All sera were stored at -30 ◦ C or -80 ◦ C, and aliquots with 0.1% sodium azide as a preservative were kept at 4 ◦ C during the experiments. LM-␣3 mAb was purchased from Cosmo BIO CO.LTD (Tokyo, Japan), and LM-␤3 mAb, LM-␥2 mAb, ITG ␣6 mAb and ITG ␤4 ECD pAb were purchased from Santa Cruz Biotechnology (Dallas, TX). ITG ␤4 ICD mAb (clone 1A3) was reported previously [18]. His-tag mAb were purchased from Medical & Biological Laboratories CO., LTD (Nagoya, Japan). Horseradish peroxidase-conjugated goat antibodies to human and rabbit IgG for second antibodies in IB were obtained from Dako (Glostrup, Denmark).

Indirect IF Indirect IF studies of normal human skin and 1M NaCl-split normal human skin were performed as described previously [8].

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Routine IB studies of various antigen sources IB analyses were performed by the previously described methods, using normal human epidermal extract [2], RP of BP180 NC16a domain [3], RP of BP180 C-terminal domain [4], concentrated culture supernatant of HaCaT cells [19], normal human dermal extract [5] and purified human LM332 [7]. Hirako et al. recently established a method to prepare a hemidesmosome-rich fraction from cultured DJM-1 cells, human squamous cell carcinoma cell line [20]. We have recently developed a novel IB using the hemidesmosomerich fraction [20].

IB studies of RPs of LM-521 trimer, ECD of ITG ␣6␤4 and ICD of ITG ␤4 subunit We have recently developed novel IB using RP of LM-521 trimer, which was purchased from Biolamina (Sundbyberg, Sweden) [21]. We have also recently developed novel IB studies using RPs of ECD of ITG ␣6␤4 and ICD of ITG ␤4 subunit (Li et al, manuscript submitted). RPs of ECD of human ITG ␣6␤4 were purchased from R&D systems (Minneapolis, MN, USA). ICD of ITG␤4 was prepared by Hirako et al (unpublished). Briefly, for these studies, 150 ng LM-521 trimer RP, 80ng RP of ITG a6␤4 ECD and 80ng ITG ␤4 ICD RP were added with 2× sample buffer, boiled for 2min and applied onto 7.5% SDS-PAGE e-PAGEL(ATTO, Tokyo, Japan). After being blotted onto nitrocellulose membrane by the iBlot Gel Transfer device (Invitrogen, Carlsbad, CA), immunostaining for the blotted membrane was performed by the same methods as for our routine IB studies.

Immunoprecipitation (IP)-IB study of RP of ITG ␣6␤4 ECD IP-IB was also performed using RP of ITG ␣6␤4 ECD. Briefly, the RP was first immunoprecipitated by incubation with the patient serum and protein G (Life Technologies, Grand Island, NY) at 4 ◦ C overnight. After being boiled in a sample buffer, the immunoprecipitates were subjected to IB using anti-His-tag mAb followed by incubation with HRP-conjugated anti-mouse IgG pAb

Absorption study using RPs of LM-␥1 Fragments of cDNA of human LM-␥1 were isolated by PCR using cDNA library from normal epidermis and appropriate primers (Ohata et al, manuscript in preparation). RP of I and II C-terminal domains and V and VI N-terminal domains of human LM-␥1 were prepared using a mammalian expression system in CHO cells. For absorption studies, the patient serum (1:20 dilution for IgG and 1:10 dilution for IgA) was first incubated with 1 ug RP of either I and II domains or V and VI domains of human LM-␥1 in ELISA plate for 4.5 hrs (3 wells, 90 mins each, sequentially) at room temperature. As a positive control, the serum was incubated in ELISA plate without RP. The absorbed serum was then examined by IB of both normal human dermal extract and purified human LM-332.

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Results Indirect IF Indirect IF of normal human skin showed negative results for both IgA and IgG antibodies. However, indirect IF of 1M NaCl-split human skin detected IgA and IgG antibodies reactive with both epidermal and dermal sides (figures 1E, F).

Routine IB studies of various antigen sources IB of normal human epidermal extract did not detect IgA or IgG antibodies to any of BP230, BP180, envoplakin, periplakin, desmoglein 1 (Dsg1) and Dsg3 (figure 2A). IB of RPs of both NC16a and C-terminal domains of BP180 showed negative reactivity with these RP for both IgA and IgG antibodies (figures 2B, C). IB of concentrated culture supernatant of HaCaT cells failed to detect IgA or IgG antibodies to the 120 kDa LAD-1 (figure 2D). In IB of normal human dermal extract, control EBA serum reacted with the 290 kDa type VII collagen and control anti-LM-␥1 pemphigoid (p200) serum reacted with the 200 kDa LM-␥1 (figure 2E). The patient serum showed positive reactivity with LM-␥1 clearly for IgG antibodies and faintly for IgA antibodies (figure 2E). In IB of purified human LM-332, control anti-LM-332-type MMP serum reacted with the 165 kDa and 145 kDa forms of LM-␣3, the 140 kDa LM-␤3 and the 105 kDa LM-␥2 (figure 2F). Patient IgG and IgA antibodies also reacted with all of LM-␣3, LM-␤3 and LM-␥2, although IgA reactivity with LM-␣3 was very weak (figure 2F). In recently developed IB of hemidesmosome-rich fraction, all mAbs reacted with corresponding antigens: i.e., the 205 kDa ␤4 subunit of ITG, the 190 kDa and 160 kDa forms of LM-␣3, the 150 kDa LM-␥2, the 140 kDa LM-␤3 and the 120 kDa ␣6 subunit of ITG (figure 2G). Because of the relatively low sensitivity of some of the mAbs in IB, we used higher concentrations for both mAbs and the second antibodies, which caused several non-specific bands. Nevertheless, IgG and IgA antibodies in the patients sera, but not those in normal sera, also reacted with all of the five antigens, except for negative reactivity with the 160 kDa form of LM-␣3, although the reactivity of IgG antibodies to LM-␤3 and IgA antibodies to ITG-␣6 was also relatively weak.

Novel IB studies using RPs To further confirm the reactivity of our patient serum with various subunits of LMs and ITGs, we performed novel IB studies using of RPs of LM-521 trimer, ECD of ITG ␣6␤4 and ICD of ITG ␤4 subunit. In IB of LM-521 trimer RP, IgG, but not IgA, antibodies reacted with LM-␥1 (figure 3A). The negative IgA reactivity was probably due to extremely weak reactivity with LM-␥1 in IB of dermal extract. In IB of RP of ECD of ITG ␣6␤4, IgG antibodies of the patient serum reacted with 120 kDa RP of ECD of the ITG ␣6 subunit but not 100 kDa RP of ECD of the ITG ␤4

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(A)

IB of epidermal extract 1 2 3 4 5

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(C) IB of BPI80-C-terminal

IB of BPI80-NC16a 1 2 3 4

(D) IB of HaCaT cells

1 2 3 4

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230 kDa BP230 210 kDa EPL 190 kDa PPL

120 kDa LAD-1

180 kDa BP180

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(G) Hemidesmosome-rich fraction

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290 kDa VII collagen 165 kDa LMa3 145 kDa LMa3 140 kDa LMb3

200 kDa LMg1

Patient (lgA) Patient (lgG) Normal (lgA) LAD control (lgA)

Patient (lgA) Patient (lgG) Normal MMP control

Patient (lgA) Patient (lgG) Normal BP control

Patient (lgA) Patient (lgG) BP control PNP control PV control

(E) IB of dermal extract

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205 kDa ITGb4 190 kDa LMa3

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160 kDa LMa3 150 kDa LMg2 140 kDa LMb3 120 kDa ITGa6

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LMb3 mAb LMa3 mAb ITGa6 mAb

ITGb4 ICD mAb

105 kDa LMg2

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Patient (lgA) Patient (lgG) MMP control

Patient (lgA) Patient (lgG) p200 control EBA control

Figure 2. Results of immunoblotting analyses. A) IB of normal human epidermal extract. B) IB of RP of BP180 NC16a domain. C) IB of RP of BP180 C-terminal domain. D) IB of concentrated culture supernatant of HaCaT cells. E) IB of normal human dermal extract. F) IB of purified human LM-332. G) IB of hemidesmosome-rich fraction.

subunit (figure 3B). The patient IgA antibodies reacted clearly with both RPs (figure 3B). In IB of RP of ICD of the ITG ␤4 subunit, both IgG and IgA antibodies in the patient serum reacted with the 150 kDa RP (figure 3C).

(A)

IB of LM521 1 2 3 4 5

IP-IB of RP of ECD of ITG ␣6␤4 To further confirm the IgG reactivity of the patient serum with intact form of ITG ␣6␤4, we also performed IP-IB using this RP of ECD of ITG ␣6␤4. Both mAb to ITG ␣6 subunit and pAb to ITG ␤4 subunit, but not mAb to ITG ␤4

(B) IB of ITGα6β4 ECD (C) IB of ITGβ4 ICD (D) IP-IB of ITGα6β4 ECD 1 2 3 4 5 6

120 kDa ITGα6 ECD

1 2 3 4 5

150 kDa ITGβ4 ICD

LMγ1 100 kDa ITGβ4 ECD

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Normal control (lgG) Patient (lgG) ITGβ4 ECD pAb ITGβ4 ICD mAb ITGα6 mAb

Normal control (lgA) Patient (lgA) Normal control (lgG) Patient (lgG) ITGβ4 ICD mAb

Normal control (lgA) Patient (lgA) Normal control (lgG) Patient (lgG) ITGβ4 ECD mAb ITGα6 mAb

p200 control

Normal control (lgA) Patient (lgA) Normal control (lgG) Patient (lgG)

Figure 3. A) IB of LM521 trimer RP. B) IB of RP of ECD of ITG ␣6␤4. C) IB of RP of ICD of ITG ␤4 subunit. D) IP-IB of RP of ECD of ITG ␣6␤4. EJD, vol. 25, n◦ 5, September-October 2015

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subunit, immunoprecipitated 120 kDa ECD RP of the ITG ␣6 subunit (figure 3D). Detection of the sole protein band of 120 kDa ECD RP was reasonable, because only the RP of the ITG ␣6 subunit, not the RP of the ITG ␤4 subunit, had His-tag. The patient serum also showed a relatively weak band for the 120 kDa ECD RP, confirming that the patient IgA could react with the intact dimer form of ITG ␣6␤4.

Absorption study using RPs of LM-␥1 In absorption experiments for IB of normal human dermal extract, the reactivity of both IgG and IgA antibodies with LM-␥1 did not reduce after incubation with RP of either I and II domains or V and VI N-terminal domains of human LM-␥1 (figure 4A). Similarly, in absorption experiments for IB of purified human LM-332, the reactivity of both IgG and IgA antibodies with LM-␥1 did not reduce after incubation with RP of either I and II domains or V and VI N-terminal domains of human LM-␥1 (figure 4B).

Discussion To the best of our knowledge, this is the first LAGBD case with IgA/IgG antibodies to three subunits of LM-332, LM␥1 and two subunits of ITG ␣6␤4. Particularly, IgA/IgG antibodies to ITG ␣6␤4 were first disclosed in LAGBD. In this study, in addition to several conventional IB studies, we also performed newly established IB studies using hemidesmosome-rich fraction and various RPs of LMs and ITGs. The studies confirmed well the reactivity of IgG and IgA antibodies in the patient serum with various LMs and ITGs. These novel IB studies should facilitate the detec-

tion of various autoantigens in distinct autoimmune bullous diseases in the future studies. We inferred that antibodies to ITG ␣6␤4 were responsible for the reactivity with the epidermal side of 1M NaCl-split skin and antibodies to LM-332 and LM-␥1 were responsible for reactivity with the dermal side. Negative results for IgG and IgA in direct IF might be due to unsuitable sampling of the skin biopsy, in which only C3 deposition might be strong and detectable. In addition, as is well known, indirect IF of 1M NaCl-split skin is more sensitive than that of intact normal human skin. Previous autoantigen-identification studies have detected LM-332 in anti-LM-332-type MMP, the ITG ␤4 subunit of ITG ␣6␤4 in ocular MMP, the ␣6 subunit in oral MMP and LM-␥1 in anti-LM-␥1 (p200) pemphigoid [1]. In addition, we recently reported that three LAGBD cases with oral mucosal lesions showed IgA/IgG antibodies to LM-332 and LM-␥1 [12]. Therefore, antibodies to LM-332 and ITG ␣6␤4 are pathogenic for the production of mucosal lesions in MMP. However, our case showed no mucosal lesions, suggesting that the antibodies to LM-332 and ITG ␣6␤4 in our case had different pathogenic effects from those in MMP. Thus, our study implicates a complicated pathogenesis in LAGBD. In addition, the results of studies of RPs of the ECD of ITG ␣6␤4 and the ICD of the ITG ␤4 subunit indicated that IgA antibodies reacted with both the ECD and ICD of the ITG ␤4 subunit and IgG antibodies reacted only with the ICD of the ITG ␤4 subunit. The significance of this difference between IgG and IgA antibodies is currently unknown. However, the difference in reactivity between IgG and IgA antibodies might be caused by the same mechanism that is involved in the different antigenic reactivity between IgG antibodies in bullous pemphigoid and IgA antibodies in LABD.

(A) IB of dermal extract lgG

(B) IB of laminin-332 RP

lgA

lgG

1 2 3 4 5 6 7 8 9

lgA

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165 kDa LMα3 200 kDa LMγ1

145 kDa LMα3 140 kDa LMβ3

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Absorbed with domain V/VI of LMγ1 Absorbed with domain I/II of LMγ1 No RP

Patient Absorbed with domain V/VI of LMγ1 Absorbed with domain I/II of LMγ1 No RP Patient Anti-LM332-type MMP control

Absorbed with domain V/VI of LMγ1 Absorbed with domain I/II of LMγ1 No RP patient Absorbed with domain V/VI of LMγ1

Absorbed with domain I/II of LMγ1 No RP Patient

p200 control

Figure 4. Absorption study using the patient serum and RPs of I/II and V/VI domains of LMg1. A) IB of normal human dermal extract for IgG and IgA antibodies of the patient serum, which was absorbed with RP of either I/II or V/VI domains of LMg1. B) IB of purified human LM-332 for absorbed serum.

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We also performed IP-IB of dimer RP of ITG ␣6␤4, which showed clear IgG reactivity with the intact form of ITG ␣6␤4. IgG antibodies to the ITG ␣6 subunit were more likely to mediate this reactivity, because IB of the same ITG ␣6␤4 ECD RP also showed positive reactivity with the ␣6, but not the ␤4 subunit in IB of this RP. However, we could not completely exclude the possibility that IgG antibodies with conformational epitopes on the ECD of the ITG ␤4 subunit, which could not be detected in IB, might mediate the reactivity with the intact dimer RP of ITG ␣6␤4. Thus, the results in this IP-IB study further suggest that the patient antibodies really bound to the intact ITG ␣6␤4 in the patient skin and exerted a pathogenic role. Finally, it was intriguing whether the patient serum reacted with common epitopes or different epitopes between LM-␥1 and LM-␥2, because LM-␥1 and LM-␥2 have considerably similar cDNA sequences. Therefore, we performed absorption studies using RPs of different domains of human LM-␥1. There was no reduction of reactivity of either IgG or IgA antibodies in the patient serum with either LM-␥1 or LM-␥2, suggesting that both IgG and IgA antibodies reacted with different epitopes on LM-␥1 and LM-␥2. These results might also indicate that IgG antibodies to LM-␥2 in anti-LM-332 MMP and IgG antibodies to LM-␥1 in anti-laminin-␥1 (p200) pemphigoid do not react with common epitopes on each laminin-␥ molecule.  Disclosure. Acknowledgements: We gratefully appreciate the secretarial work of Ms. Tomoko Tashima and Ms. Mami Nishida. We also thank the participation of the patients. Financial support: none. Conflict of interest: none.

References

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4. Nie Z, Hashimoto T. IgA antibodies of cicatricial pemphigoid sera specifically react with C-terminus of BP180. J Invest Dermatol 1999; 112: 254-5. 5. Ishii N, Yoshida M, Hisamatsu Y, et al. Epidermolysis bullosa acquisita sera react with distinct epitopes on the NC1 and NC2 domains of type VII collagen: study using immunoblotting of domainspecific recombinant proteins and postembedding immunoelectron microscopy. Br J Dermatol 2004; 150: 843-51. 6. Dmochowski M, Hashimoto T, Bhogal BS, et al. Immunoblotting studies of linear IgA disease. J Dermatol Sci 1993; 6: 194-200. 7. Hisamatsu Y, Nishiyama T, Amano S, et al. Usefulness of immunoblotting using purified laminin 5 in the diagnosis of anti-laminin 5 cicatricial pemphigoid. J Dermatol Sci 2003; 33: 113-9. 8. Dainichi T, Kurono S, Ohyama B, et al. Anti-laminin gamma-1 pemphigoid. Proc Natl Acad Sci U S A 2009; 106: 2800-5. 9. Letko E, Bhol K, Foster SC, et al. Influence of intravenous immunoglobulin therapy on serum levels of anti-beta 4 antibodies in ocular cicatricial pemphigoid. A correlation with disease activity. A preliminary study. Curr Eye Res 2000; 21: 646-54. 10. Malik M, Gurcan HM, Christen W, et al. Relationship between cancer and oral pemphigoid patients with antibodies to alpha6integrin. J Oral Pathol Med 2007; 36: 1-5. 11. Zone JJ, Pazderka Smith E, Powell D, et al. Antigenic specificity of antibodies from patients with linear basement membrane deposition of IgA. Dermatology 1994; 189(Suppl 1): 64-6. 12. Sakaguchi M, Bito T, Oda Y, et al. Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332. JAMA Dermatol 2013; 149: 1308-13. 13. Chan LS, Traczyk T, Taylor TB, et al. Linear IgA bullous dermatosis. Characterization of a subset of patients with concurrent IgA and IgG anti-basement membrane autoantibodies. Arch Dermatol 1995; 131: 1432-7. 14. Honoki K, Muramatsu T, Tsubakimoto A, et al. Linear IgA bullous dermatosis with circulating IgG autoantibodies to the 230 kD epidermal antigen. J Dermatol 1998; 25: 503-9. 15. Hertl M, Budinger L, Christophoridis S, et al. IgG and IgA antibodies in linear IgA/IgG bullous dermatosis target the ectodomain of bullous pemphigoid antigen 2. Br J Dermatol 1999; 140: 750-2. 16. Metz BJ, Ruggeri SY, Hsu S, et al. Linear IgA dermatosis with IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen (BP180): evidence for a distinct subtype. Int J Dermatol 2004; 43: 4436. 17. Shimizu S, Natsuga K, Shinkuma S, et al. Localized linear IgA/IgG bullous dermatosis. Acta Derm Venereol 2010; 90: 621-4. 18. Hirako Y, Usukura J, Uematsu J, et al. Cleavage of BP180, a 180-kDa bullous pemphigoid antigen, yields a 120-kDa collagenous extracellular polypeptide. J Biol Chem 1998; 273: 9711-7. 19. Ishii N, Ohyama B, Yamaguchi Z, et al. IgA autoantibodies against the NC16a domain of BP180 but not 120-kDa LAD-1 detected in a patient with linear IgA disease. Br J Dermatol 2008; 158: 1151-3. 20. Miyamoto S, Chikazu D, Yasuda T, et al. A case of oral mucous membrane pemphigoid with IgG antibodies to integrin alpha6beta4. Br J Dermatol 2014; 171: 1555-7. 21. Li X, Qian H, Takizawa M, et al. N-linked glycosylation on laminin gamma1 influences recognition of anti-laminin gamma1 pemphigoid autoantibodies. J Dermatol Sci 2015; 77: 125-9.

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IgG bullous dermatosis reacts with multiple laminins and integrins.

Since the original description by Zone et al in 1994, the disease entity and target antigens in linear IgA/IgG bullous dermatosis (LAGBD) have not bee...
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