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Bullous pemphigoid (BP) is the most common autoimmune blistering disorder of the skin that usually affects the elderly. It is characterized by circulating and tissue-bound IgG autoantibodies directed against structural components of the dermo-epidermal basement membrane zone, BP180 and BP230. Clinically, it presents with generalized tense subepidermal blisters arising on apparently normal or erythematous skin.
The goal of this study was to determine whether there is a correlation of clinical and immunological disease parameters in BP. This analysis included 50 patients diagnosed with BP who were seen in the departments of dermatology in Erlangen and Marburg within 6.6 years. The data was assessed retrospectively. In order to quantify the documented skin and mucosae lesions our group developed a new score, which allowed retrospective assessment of disease activity. Therefore the pros and cons of established BP- and pemphigus-scores were taken into account. In summary our new scoring system divides the body surface area into 10 regions. Depending on weighing factors for quality (erosive/bullous versus crusty lesions) and quantity (multiple versus single lesions) of the reported lesions each area is scored with 0 to 1 point. As a result, this score reaching from 0 to 10 can be attributed to every patient. The autoantibody reactivity was measured by ELISA based on five BP180 and BP230 recombinant proteins.
At the time of first diagnosis almost all patients showed antibody reactivity against one or more BP180 domains, while only 66% of the sera recognized at least one BP230 recombinant protein. Correlating clinical and serological parameters we could show a statistically significant positive association between disease activity of BP assessed by the score and IgG reactivity against the entire extracellular domain of BP180 (recombinant BP180-ex) as well as against the NC16A domain of BP180 (covered by the recombinant BP180-N1). In contrast there was no association between disease activity and IgG reactivity against BP230-C1. The correlation remained unclear for antibody reactivity against BP180-C1 and BP230-N recombinant proteins due to small numbers of measurements. Both the antibody profiles and the analysis of a group of six patients in the course of time under treatment confirmed these results.
In summary our results suggest that the autoantibody reactivity against BP180 has a strong association to disease activity in newly diagnosed patients while the antibody reactivity against BP230 plays a secondary role. This is in line with the theory of “epitope spreading” which describes the current concept of autoimmune diseases. According to this theory it has been postulated that the immune response is not restricted to a unique immunodominant epitope, but spreads to involve additional secondary epitopes within the same protein or distinct molecules. That means that the extracellular epitopes of the transmembrane protein BP180 are certainly critical for the initial stage of autoimmune response in BP while processes of intra- and intermolecular epitope spreading involve intracellular epitopes of BP180 and the intracellular located BP230 subsequently in the progress of disease.
It has been postulated that the NC16A domain, which is the largest non-collagenous extracellular domain of BP180, is the immunodominant region in the pathogenesis of BP. We could show that not only the antibody reactivity against BP180-N1, which covers the NC16A domain, but also against the entire ectodomain of BP180 strongly correlated with disease activity. Thus our results provide further support to the concept that the ectodomain of BP180 presents additional epitopes besides NC16A that are pathogenic and therefore associated with disease activity. In contrast, autoantibody reactivity against BP230 seems to play a secondary role in the pathogenesis and consequently shows no association to disease activity.
In terms of correlating clinical and serological data our results reveal a big consensus to results that were obtained in previous studies. In the majority these were based on less detailed evaluations of disease activity but partly also based on precise analysis. Thus we think that our new scoring system is a valid tool in assessing disease activity in BP retrospectively that considers the relevant parameters.
The further establishment of our scoring system might be of great benefit in a prospective clinical setting in order to objectify disease activity. Moreover, it has to be investigated if regular ELISA analysis can show elevated BP180-ex- und BP180-N1-IgG reactivity indicating a relapse.