Atsunari Tsuchisaka

Anti-desmocollin autoantibodies in nonclassical pemphigus.

Despite the established pathogenic role of anti‐desmoglein (Dsg) antibodies in classical pemphigus, the significance of autoantibodies to another desmosomal cadherin, desmocollin (Dsc) is at present unknown. No consistent immunoassay for immunoglobulin (Ig) G autoantibodies to Dscs has been developed.

Clinical and immunological findings in 104 cases of paraneoplastic pemphigus

Although there are many reports of sporadic patients with paraneoplastic pemphigus (PNP), only a few systematic studies on large cohorts of patients with PNP have been reported.

Anti-Alpha-2-Macroglobulin-Like-1 Autoantibodies Are Detected Frequently and May Be Pathogenic in Paraneoplastic Pemphigus

Paraneoplastic pemphigus (PNP) shows autoantibodies mainly to plakin and desmosomal cadherin family proteins. We have recently identified alpha-2-macroglobulin-like-1 (A2ML1), a broad range protease inhibitor, as a unique PNP antigen. In this study, we tested a large number of PNP sera by various methods. Forty (69.0%) of 58 PNP sera recognized A2ML1 recombinant protein expressed in COS7 cells by immunofluorescence (IF) and/or immunoprecipitation (IP)/immunoblotting (IB). IP/IB showed higher sensitivity than IF. In addition, 22 (37.9%) PNP sera reacted with A2ML1 by IB of cultured normal human keratinocytes (NHKs) under non-reducing conditions. Statistical analyses using various clinical and immunological data showed that the presence of anti-A2ML1 autoantibodies was associated with early disease onset and absence of ocular lesions. Next, to investigate the pathogenic role of anti-A2ML1 antibody, we performed additional functional studies. Addition of anti-A2ML1 polyclonal antibody to culture media decreased NHK cell adhesion examined by dissociation assay, and increased plasmin activity detected by casein zymography, suggesting that anti-A2ML1 antibody may decrease NHK cell adhesion through plasmin activation by inhibition of A2ML1. This study demonstrates that autoantibodies to A2ML1 are frequently and specifically detected and may have a pathogenic role in PNP.

Clinical and immunological profiles of anti-BP230-type bullous pemphigoid: Restriction of epitopes to the C-terminal domain of BP230, shown by novel ELISAs of BP230-domain specific recombinant proteins

ObjectivesTo confirm that sera from some BP patients reactive exclusively to the BP230 and to study the clinical and immunological characteristics of this condition.Materials and methodsBP patients were divided into three groups: BP reactive only to BP230 (BP230- BP), BP reactive to both BP180 and BP230 (BP180-BP230-BP) and BP reactive only to BP180 (BP180-BP), based on the results of standard ELISAs for BP180 and BP230. Clinical features were statistically analyzed among the three groups. Then, targeted epitopes in each group were studied by immunoblotting and novel ELISAs using three domainspecific BP230 recombinant proteins.ResultsForty-one, 65 and 47 of 153 BP patients were categorized as BP230-BP, BP180-BP230-BP and BP180-BP, respectively. Clinically, BP230-BP patients showed significantly lower severity, less need of systemic steroids and better responses to various treatments, suggesting that BP230-BP is a milder condition. Immunoblotting and ELISAs of domain-specific BP230 recombinant proteins indicated that, while BP180-BP230-BP sera reacted with all three domains of BP230, BP230-BP sera reacted more frequently with epitopes in the BP230 C-terminal domain.ConclusionWe propose a new disease entity, named anti-BP230-type BP, in which anti-BP230 antibodies might be pathogenic and react specifically with the BP230 C-terminal domain. While anti-BP230 antibodies in BP180-BP230-BP seem to be produced via intermolecular epitope spreading, anti-BP230 antibodies in BP230-BP are considered to be produced by different mechanisms.

Cytokine Regulation during Epidermal Differentiation and Barrier Formation

The role of structural components and cell adhesion molecules in the epidermis has not been fully studied in terms of the pathophysiology of atopic dermatitis (AD). In this issue, Omori-Miyake et al. (2014) report that IL-4 and IL-13, which are Th2 cytokines, downregulate the expression of keratins and desmosomal cadherins in a STAT6-dependent manner, leading to keratinocyte fragility in the face of mechanical stress. Th2 cytokine-induced instability of the epidermis may be considered to be one of the pathogenic mechanisms that have roles in AD.

Immunological and statistical studies of anti-BP180 antibodies in paraneoplastic pemphigus.

Abbreviations: BMZ, basement membrane zone; BP, bullous pemphigoid; HaCaT, concentrated culture supernatant of HaCaT cells; IB, immunoblotting; IF, immunofluorescence; PNP, paraneoplastic pemphigus; RP, recombinant protein

Linear IgA/IgG bullous dermatosis reacts with multiple laminins and integrins

BackgroundSince 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.ObjectivesTo determine autoantibodies and autoantigens in a new LAGBD case which showed atypical clinical and histopathological findings without apparent mucosal involvement.Materials and MethodsWe performed various indirect immunofluorescence and immunoblotting studies.ResultsIndirect 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-γ1 and integrin α6β4 in various patterns. Absorption study using recombinant proteins of laminin-γ1 indicated that the patient serum reacted with different epitopes between laminin-γ1 and laminin-γ2.ConclusionsThis study presented for the first time a LAGBD patient with IgG and IgA antibodies to various laminins and integrins.

B-cell activating factor detected on both naïve and memory B cells in bullous pemphigoid.

B‐cell activating factor (BAFF), an important immune regulatory cytokine, is involved in development of autoimmune diseases. Although BAFF is expressed in various cells, including dendritic cells (DCs) and monocytes, BAFF expression on B cells has not been well documented. In the present study, BAFF molecules on DCs and naïve and memory B cells in autoimmune bullous diseases, including pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid (BP), were analysed by flow cytometry. Compared with healthy controls (HC), BAFF expression on naïve and memory B cells increased significantly in BP. No difference in BAFF receptor expression in naïve and memory B cells was shown among all study groups. Furthermore, BAFF expression in both naïve and memory B cells of BP, but not HC, was detected by confocal microscopic analysis. These results implied that BAFF expressed by B cells may play a pathogenic role in autoimmune bullous diseases, particularly BP.

A case of oral mucous membrane pemphigoid with IgG antibodies to integrin α6β4

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Mouse bone marrow-derived dendritic cells can phagocytize the Sporothrix schenckii, and mature and activate the immune response by secreting interleukin-12 and presenting antigens to T lymphocytes

In sporotrichosis, dermal dendritic cells were considered to participate in induction of the immune responses against Sporothrix schenckii infection. However, it is still unclear whether and how dermal dendritic cells were involved in the progress. To clarify the pathogenic role of dermal dendritic cells (DC) in sporotrichosis, we examined the phagocytosis, maturation stages, cytokine production and antigen‐presenting ability of mouse bone marrow‐derived DC after stimulation with S. schenckii. By analysis of flow cytometry, electron microscope and confocal microscope, mouse bone marrow‐derived DC were proved to be able to phagocytize the S. schenckii. The increased expression of CD40, CD80 and CD86 on the surface of S. schenckii‐pulsed mouse bone marrow‐derived DC was detected by flow cytometer, indicating that the S. schenckii‐pulsed mouse bone marrow‐derived DC underwent the maturation program. The secretory enhancement of interleukin (IL)‐12, but not IL‐4, was found in S. schenckii‐pulsed mouse bone marrow‐derived DC, suggesting the possible activation of T‐helper 1 prone immune responses. Furthermore, S. schenckii‐pulsed mouse bone marrow‐derived DC were demonstrated to be capable of inducing the proliferation of T lymphocytes from BALB/c mice that were pre‐sensitized with S. schenckii. Together, all the results implied that dermal DC may participate in the induction of immune responses against S. schenckii infection in sporotrichosis.