Summary
Background
Although many new disease entities of autoimmune bullous disease (AIBD) have recently been recognized, satisfactory immunological diagnostic methods and comprehensive ...classifications for various AIBDs have not been established.
Objectives
To identify immunological diagnostics and comprehensive classifications for AIBDs.
Methods
We selected and examined 4774 patients with various AIBDs from our cohort of 5063 patients with difficult AIBDs, whose sera and information were sent for our diagnostic method from other institutes in either Japan or other countries over the last 19 years. We examined the sera by our immunological diagnostic methods including various immunofluorescence, immunoblotting and enzyme‐linked immunosorbent assay tests to make final diagnoses.
Results
By our immunological diagnostic methods, we successfully made final diagnoses for approximately three‐quarters of the difficult cases of AIBD, although the remaining cases could not be diagnosed. Using the results, we suggest the most extensive and newest classification of AIBDs, and also propose the most efficient algorithm of immunological tests for the diagnosis of various AIBDs.
Conclusions
The results in this study of 4774 patients with various AIBDs indicate that our immunological diagnostic method is useful for making diagnoses for most patients with AIBD. However, we need further improvements including new immunological techniques to establish more satisfactory methods.
What's already known about this topic?
There are many different autoimmune bullous diseases (AIBDs) that are diagnosed by immunological tests, in addition to clinical and histopathological examinations.
As one of the centres for diagnosis of AIBDs in Japan, we have collected sera and information for more than 5000 difficult cases of various AIBDs over the last 19 years, and have performed various serological tests.
What does this study add?
This study presents the current classification and algorithm for immunological diagnosis in AIBDs.
This study also presents the final diagnoses for our 4774 patients with AIBDs, which were made by our immunological diagnostic method.
What is the translational message?
This study proposes a comprehensive novel classification of AIBDs, which should be useful for precise and detailed diagnoses of various AIBDs in the clinical field.
The large number of immunological and molecular methods described in this study should also facilitate clinical practice, such as for diagnoses and appropriate selection of treatments, for various AIBDs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Background
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.
Objectives
The aim of this study was to develop reliable assays to detect anti‐Dsc autoantibodies.
Methods
We expressed soluble recombinant proteins (RPs) of human Dsc1–3 in mammalian cells and examined sera of various types of pemphigus, including 79 paraneoplastic pemphigus (PNP) sera, by novel enzyme‐linked immunosorbent assays (ELISAs) using the RPs. We also performed ELISAs of Dsc baculoproteins and used the complementary DNA (cDNA) transfection method, and compared the results with those of mammalian ELISAs.
Results
Through mammalian ELISAs, IgG autoantibodies to Dsc1, Dsc2 and Dsc3 were detected in 16·5%, 36·7% and 59·5% of PNP sera, respectively, and considerable numbers of pemphigus herpetiformis (PH) and pemphigus vegetans (PVeg) sera reacted strongly with Dsc1 and Dsc3. Mammalian ELISAs were highly specific and more sensitive than baculoprotein ELISAs or the cDNA transfection method. Several Dsc‐positive sera, particularly PH sera, showed no reactivity with Dsgs. The reactivity of PNP serum and PVeg serum with Dscs was not abolished by pre‐absorption with Dsg RPs.
Conclusions
The results of these novel ELISAs indicated that IgG anti‐Dsc autoantibodies were frequently detected and potentially pathogenic in nonclassical pemphigus.
What's already known about this topic?
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 IgG autoantibodies to Dscs has been developed.
What does this study add?
We have successfully established new sensitive and specific mammalian Dsc immunoglobulin (Ig) G enzyme‐linked immunosorbent assays.
Our data show that IgG anti‐Dsc autoantibodies are frequently detected and potentially pathogenic in particular types of nonclassical pemphigus.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Background Oral mucosal lesions develop in pemphigus vulgaris, but not in pemphigus foliaceus. This clinical phenomenon is explained by the ‘desmoglein (Dsg) compensation theory’. Dsg3 and ...Dsg1 are major autoantigens for pemphigus vulgaris and pemphigus foliaceus, respectively. Dsg3 is overexpressed and Dsg1 is weakly expressed on the oral mucosa. Thus, on the oral mucosa, suppression of Dsg3 function by anti‐Dsg3 autoantibodies is not compensated by weakly expressed Dsg1 in pemphigus vulgaris, while suppression of Dsg1 function by anti‐Dsg1 autoantibodies is perfectly compensated by richly expressed Dsg3 in pemphigus foliaceus.
Objectives We present five Japanese patients with pemphigus who deviate from this theory, i.e. all patients showed oral lesions (three also had cutaneous lesions) and reacted only with Dsg1, but not with Dsg3, by enzyme‐linked immunosorbent assay.
Methods To confirm whether the unique clinical phenotypes in our patients were due to a different immunological profile from that in classical pemphigus, we examined the reactivity of the patient sera by immunoprecipitation‐immunoblotting analysis using five Dsg1/Dsg2 domain‐swapped molecules.
Results The sera of two patients who had only oral lesions tended to react with the extracellular (EC) 5 domain of Dsg1, the domain that is considered nonpathogenic in classical pemphigus foliaceus. Sera of three patients with mucocutaneous lesions reacted with EC1 domain or with both EC1 and EC2 domains of Dsg1, like classical pemphigus foliaceus.
Conclusions These results indicate that antigenic diversity of anti‐Dsg1 antibodies in these patients may cause the unique oral mucosal and cutaneous lesions, although further studies are required to elucidate the pathomechanisms.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Background
Drug‐induced pemphigus (DIP) shows clinical, histopathological and immunological features of pemphigus. However, little is known about immunological profiles in DIP.
Objectives
To ...characterize clinical and immunological profiles in patients with DIP.
Methods
We studied 17 Japanese patients with DIP who were treated at Kurume University Hospital or who consulted from other hospitals between 1997 and 2012. Complicated diseases, clinical and histopathological manifestations, responsible drugs and findings in immunofluorescence, enzyme‐linked immunosorbent assays (ELISAs), immunoblotting (IB) and prognosis were analysed.
Results
Eight of the 17 patients with DIP showed pemphigus foliaceus‐like appearance, three showed pemphigus herpetiformis‐like appearance, and six showed atypical bullous lesions. Responsible drugs were thiol‐containing drugs in 16 patients (bucillamine in nine cases, d‐penicillamine in four cases, and cetapril, thiopronine and captopril in one patient each), and a nonthiol drug, sulfasalazine, in one patient. By ELISAs and/or IB analyses, nine patients reacted only with desmoglein 1 (Dsg1), four reacted with Dsg1 and Dsg3, and four showed no specific reactivity. By IB of normal human epidermal extracts, in addition to positive reactivity with Dsg1, four patients with no detectable malignancy showed paraneoplastic pemphigus‐like reactivity with the 210‐kDa envoplakin and the 190‐kDa periplakin. Four cases showed anti‐Dsg3 antibodies without mucosal lesions. While 11 cases recovered after discontinuation of the causative drugs, six patients had a very protracted or intractable disease course, and might develop true pemphigus.
Conclusions
The present study indicated that the majority of the patients with DIP studied showed a pemphigus foliaceus‐type phenotype with anti‐Dsg1 autoantibodies, caused by thiol‐containing drugs.
What's already known about this topic?
Drug‐induced pemphigus (DIP) is a rare type of drug eruption. Most patients with DIP show pemphigus foliaceus‐like clinical and histopathological features.
To date, approximately 200 cases of DIP have been described.
It has been reported that thiol‐containing drugs cause pemphigus foliaceus, while nonthiol drugs cause pemphigus vulgaris.
What does this study add?
We report characteristics of 17 patients with DIP for their background, clinical and histopathological manifestations, causative drugs and the results of immunofluorescence, enzyme‐linked immunosorbent assays and immunoblotting.
The present study indicated that the majority of the patients with DIP studied showed a pemphigus foliaceus‐type phenotype with antidesmoglein 1 autoantibodies, caused by thiol‐containing drugs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Background Pemphigus foliaceus (PF) is a blistering skin disease mediated by antibodies to desmoglein (Dsg) 1. The two major subtypes are nonendemic and endemic PF. A previous study in ...endemic PF demonstrated that changes in antibody epitope could modulate disease relapse and remission.
Objectives To characterize the frequency of immunoreactivity to various Dsg1 extracellular (EC) domains in nonendemic PF and to study if there is any change in epitope profile across various activity stages.
Methods Sera from 34 patients with nonendemic PF were selected. To map the conformational epitopes by immunoprecipitation‐immunoblotting, we constructed five Dsg1/Dsg2 domain‐swapped molecules, with each molecule representing one EC domain of Dsg1 on a backbone of Dsg2.
Results Dsg1 EC1, EC2, EC3, EC4 and EC5 domains were recognized by 88%, 50%, 13%, 22% and 0% of active PF sera, respectively. Immunoreactivity to EC3 or EC4 often cosegregated with that to either EC1 or EC2. Longitudinal follow‐up of 21 patients with PF for a median of 16 months revealed that, in most cases, immunoreactivity to the amino‐terminus of Dsg1 persisted across various activity stages; only two patients lost their EC1 reactivity upon remission and changed their major epitope(s) to EC2 ± EC3.
Conclusions Most of the anti‐Dsg1 antibodies in nonendemic PF bind to the amino‐terminus of Dsg1, a region critical for intercellular adhesion of cadherins, and this skewed amino‐terminal immunoreactivity prevails across various activity stages in most patients, even upon remission. These findings are valuable for understanding the biology of Dsg‐mediated cellular adhesion as well as for the development of epitope‐based monitoring and therapeutic strategies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
