Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease (AIBD) of the skin [1]. Usually, BP affects patients in their seventh or eighth decade of life and is elicited by circulating immunoglobulin (Ig) G autoantibodies targeting BP180 (Collagen XVII) and/or BP230, two components of the dermo-epidermal junction (DEJ) [1]. In recent years, some unclear evidence of rare sub-variants of BP triggered by pathogenic IgM directed against BP180, known as IgM pemphigoid, have been reported. However, the relevance of IgM in the pathogenesis of AIBD is still under debate [2]. Reported cases of IgM pemphigoid tend to have a more favourable and manageable disease course compared to classical BP. Yet, the question raised by the analysis of the more recent literature is whether IgM pemphigoid is rather triggered by barely detectable IgG (or IgA) antibodies. Here, we describe an otherwise healthy 51-year-old female patient who was admitted to our clinic showing tense blisters on erythematous skin on both elbows for 3 years (Figure 1A,B). The oral mucosa was not affected, and the patient complained of itch limited to the affected areas. A histological examination showed a dermo-epidermal cleft and sparse neutrophilic and eosinophilic infiltration (Figure 1C). Serological examination with a commercially available enzyme-linked immunosorbent assay (ELISA) kit (EUROIMMUN, Lübeck, Germany) did not detect circulating antibodies against components of the DEJ (BP180, BP230, collagen VII, laminin 332). Direct immunofluorescence analysis of perilesional skin showed the absence of IgG and IgA deposition, yet a strong linear tissue-bound IgM, together with a mild and discontinuous linear C3 deposition (Figure 1D−G). By indirect immunofluorescence on salt-split skin, we confirmed the absence of IgA and IgG and the presence of IgM binding to the epidermal side of the split (Figure 1H). A pattern typical for BP [1]. We repeated ELISA after 2 and 4 weeks, which confirmed the absence of IgG against BP180 and BP230. Furthermore, there was no evidence for a monoclonal IgM gammopathy, immunodeficiency, cryoglobulinemia or hyper IgM syndrome. According to the pathological and immunological findings, a diagnosis of IgM pemphigoid was done. We started a topical treatment with clobetasol propionate 0.05% cream twice a day, which rapidly led to improvement of skin lesions without scarring. To investigate the presence of specific IgM against BP180 better, we performed a western blot analysis (WB) with recombinant BP180 protein. WB results confirmed the presence of anti-BP180 IgM, but we also found a weaker presence of IgG and IgA (Figure 2). Exclusive detection of IgM has been reported in BP, epidermolysis bullosa acquisita and mucous membrane pemphigoid [2, 3]. The concomitant presence of tissue-bound IgM and C3 is plausible, given the described complement-fixing ability of IgM [4]. Boch et al. described three patients with IgM pemphigoid and provided mechanistic insights showing that anti-BP180 IgM cannot induce blistering but can internalize BP180 ex vivo [2]. Further cases of IgM pemphigoid have shown the presence of blisters and erosions, which is not compatible with the mechanistic results provided by Boch et al. [5, 6]. Based on the described immunological properties of IgM, we, therefore, propose that AIBDs presenting blisters might be caused by minimal or non-detectable circulating IgA or IgG since IgM cannot induce blistering. Another possible explanation could be the presence of prevalent IgG4 and minimal IgG1 levels. IgG4 has been shown to lead to false-negative DIF [7]. Our report highlights the relevance of performing additional investigations (i.e., WB or DIF with specific IgG subclasses) in patients with unusual clinical and serological findings to better characterize AIBD. D. Didona is involved in conceptualization and writing. R. Maglie and A. M. Sequeira Santos involved in writing. M. Hertl and F. Solimani involved in writing, supervision and conceptualization. All authors approved the final version of this manuscript. Dr. Farzan Solimani is a participant in the BIH Charité Clinician Scientist Program funded by the Charité–Universitätsmedizin Berlin, and the Berlin Institute of Health at Charité (BIH). This study was supported by a grant from the Deutsche Forschungsgemeinschaft (Pegasus, FOR 2497). The patient in this manuscript have given written informed consent for participation in the study and the use of her deidentified, anonymized, aggregated data and her case details (including photographs) for publication. The authors have nothing to report. The authors declare no conflicts of interest. Data is available on request from the authors.
BRCA1 is implicated in cellular responses to DNA damage, thereby substantially contributing to maintenance of the genome integrity. Mutations in the BRCA1 gene occur in breast and ovarian cancer and mutations that disable p53 are frequently found in human cancers, often accompanied by mutations in additional genes, contributing to tumor progression or high-grade malignancy. Therefore, the role of BRCA1 in the sensitivity to anticancer agents in p53-deficient cells was investigated using p53-deficient mouse knockout cell lines either deficient or proficient in Brca1 function. We report that Brca1-deficiency in p53-null cells was associated with increased sensitivity to the topoisomerase I poisons camptothecin and topotecan, the topoisomerase II poisons doxorubicin, mitoxantrone and etoposide, and to the platinum compounds carboplatin and oxaliplatin, but not to the antimetabolites 5-fluorouracil and gemcitabine and the taxanes docetaxel and paclitaxel. The increased growth inhibition to doxorubicin after loss of Brca1 correlated with increased cell killing caused by increased apoptosis. The data presented here indicate that Brca1 modulates p53-independent DNA damage response pathways and they support the case of a role of Brca1 to protect cells from apoptosis-mediated cell death in p53-deficient cells. These results suggest a higher chemotherapy susceptibility of cells disabled in both functions and they foster the concept that functional inhibition of BRCA1 may be a valuable adjunct to anticancer agents to increase the efficacy of chemotherapy in the treatment of p53-mutated cancers.
Chest wall recurrences are a frequent problem in patients treated by mastectomy for breast cancer. Surgery and ionizing radiation are established treatment modalities in these cases. Photodynamic therapy (PDT) provides an alternative treatment modality using a photosensitizer and laser light to induce selective tumor necrosis. PDT was performed as compassionate use in 7 patients aged 57.6 years (+/-12.6 SD). A total of 89 metastatic skin nodes were treated in 11 PDT sessions. As photosensitizer meta-tetra(hydroxyphenyl)chlorin (m-THPC) was applied intravenously. Patients (n = 3) photosensitized with a drug dose of 0.10 mg/kg bodyweight were irradiated 48 hr after drug application at a lightdose of 5 J/cm(2). Patients (n = 4) were illuminated by an optical dose of 10 J/cm(2) 96 hr after photosensitization with 0.15 mg/kg. Laser light at a wavelength of 652 nm was generated by a diode laser and applied by a front lens light diffuser using a fluence rate of 20--25 mW/cm(2). PDT using m-THPC resulted in complete response in all patients. Response to treatment did not differ when using the 2 different drugdose protocols. Healing time depended mainly on the size of the illumination field but not on the lightdose. Pain score usually raised 1 day after PDT and lasted at higher levels for about 10 days. Healing time usually ranged between 8--10 weeks. Photodynamic technique offers a minimal-invasive, outpatient treatment modality for recurrent breast cancer on the chest wall with few side effects, high patient's satisfaction and with possible repetitive application.
