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Cisto Epidérmico , Herpes Simples , Pênfigo , Humanos , Pênfigo/complicações , Túnica Conjuntiva , Herpes Simples/complicaçõesRESUMO
Abstract Background: Bullous pemphigoid (BP) associated with milia lesions has been increasingly reported, but its prevalence has not been reported in a Brazilian BP population yet. Objectives: To describe the occurrence and clinical-laboratorial findings of BP-milia association in a southeastern Brazilian sample. Methods: A descriptive study based on the medical charts of 102 BP patients was accomplished. Clinical and laboratory data of BP-milia patients were compiled. Total serum IgE measurements, immunoblot assays based on basement membrane zone antigens, and HLA-DQ alleles typing were performed. Results: Milia was evident in 8 (7.8%) BP patients, five males, aged between 46 and 88 years. Increased total IgE levels were determined in 7 (87.5%) of the eight patients. In five of eight patients, immunoblotting showed IgG reactivity against the BP180-NC16a domain but not against collagen VII or laminin-332; it also revealed reactivity against the BP180 C-terminal domain or LAD-1, or both in four of them. The HLA-DQB1*03:01 and HLA-DQA1*05:05 alleles were identified in three of five BP-milia patients. Moreover, three of five cases presented the HLA-DQB1*06 allelic group. Study limitations: HLA determination was performed in five patients. Conclusions: Milia formation in BP patients seems to be less uncommon than previously admitted. Laboratory data revealed increased IgE; autoantibodies against the BP180 C-terminal domain or LAD-1, or both; and the HLA-DQB1*06 allelic group, described for the BP-milia association. Careful determination of antibodies against basement membrane zone molecules and HLA characterization in different populations may provide further insights into this association. © 2022 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).
RESUMO
BACKGROUND: Bullous pemphigoid (BP) associated with milia lesions has been increasingly reported, but its prevalence has not been reported in a Brazilian BP population yet. OBJECTIVES: To describe the occurrence and clinical-laboratorial findings of BP-milia association in a southeastern Brazilian sample. METHODS: A descriptive study based on the medical charts of 102 BP patients was accomplished. Clinical and laboratory data of BP-milia patients were compiled. Total serum IgE measurements, immunoblot assays based on basement membrane zone antigens, and HLA-DQ alleles typing were performed. RESULTS: Milia was evident in 8 (7.8%) BP patients, five males, aged between 46 and 88 years. Increased total IgE levels were determined in 7 (87.5%) of the eight patients. In five of eight patients, immunoblotting showed IgG reactivity against the BP180-NC16a domain but not against collagen VII or laminin-332; it also revealed reactivity against the BP180 C-terminal domain or LAD-1, or both in four of them. The HLA-DQB1*03:01 and HLA-DQA1*05:05 alleles were identified in three of five BP-milia patients. Moreover, three of five cases presented the HLA-DQB1*06 allelic group. STUDY LIMITATIONS: HLA determination was performed in five patients. CONCLUSIONS: Milia formation in BP patients seems to be less uncommon than previously admitted. Laboratory data revealed increased IgE; autoantibodies against the BP180 C-terminal domain or LAD-1, or both; and the HLA-DQB1*06 allelic group, described for the BP-milia association. Careful determination of antibodies against basement membrane zone molecules and HLA characterization in different populations may provide further insights into this association.
Assuntos
Ceratose , Penfigoide Bolhoso , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos , Autoantígenos , Brasil , Humanos , Imunoglobulina E , Ceratose/patologia , Laboratórios Clínicos , Masculino , Pessoa de Meia-Idade , Colágenos não Fibrilares , Penfigoide Bolhoso/patologia , PrevalênciaRESUMO
BACKGROUND: Endemic pemphigus foliaceus (EPF), is also known as "fogo selvagem" or "wild fire," reflecting the intense burning sensation of the skin reported by patients with this disease. Based on this finding, we tested for neural autoreactivity in patients affected by a new variant of EPF (El Bagre-EPF). METHODS: We tested 20 El Bagre-EPF patients, 20 normal controls from the endemic area, and 20 age- and sex-matched normal controls from outside the endemic area. We tested for autoreactivity to several immunoglobulins and complement. Both human skin and bovine tail were used as antigens. RESULTS: We detected autoreactivity to neural structures, mechanoreceptors, nerves, perineural cell layers of the arachnoid envelope around the optic nerve, brain structures, and to neuromuscular spindles; these structures colocalized with several neural markers. The patient antibodies also colocalized with desmoplakins 1 and 2, with the armadillo repeat protein deleted in velo-cardio-facial syndrome and with p0071 antibodies. Autoreactivity was also found associated with neurovascular bundles innervating the skin, and immunoelectron microscopy using protein A gold against patient antibodies was positive against the nerve axons. Paucicellularity of the intraepidermal nerve endings and defragmentation of the neural plexus were seen in 70% of the cases and not in the controls from the endemic area (p<0.005). Neuropsychological and/or behavioral symptoms were detected in individuals from the endemic area, including sensorimotor axonal neuropathy. CONCLUSIONS: Our findings may explain for the first time the "pose of pemphigus," representing a dorsiflexural posture seen in EPF patients vis-a-vis the weakness of the extensor nerves, and furthermore, the autoreactivity to nerves in EPF could explain the "burning sensation" encountered in EPF disease.
Assuntos
Antígenos/imunologia , Autoanticorpos/imunologia , Plexo Corióideo/imunologia , Desmoplaquinas/metabolismo , Doenças Endêmicas , Nervo Óptico/imunologia , Corpúsculos de Pacini/imunologia , Pênfigo , Pele/imunologia , Adulto , Animais , Antígenos/análise , Antígenos/metabolismo , Autoanticorpos/análise , Autoanticorpos/metabolismo , Axônios/imunologia , Axônios/patologia , Antígenos CD57/genética , Antígenos CD57/imunologia , Antígenos CD57/metabolismo , Estudos de Casos e Controles , Bovinos , Plexo Corióideo/efeitos dos fármacos , Plexo Corióideo/patologia , Colômbia/epidemiologia , Desmoplaquinas/genética , Feminino , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imunoglobulinas/análise , Imunoglobulinas/imunologia , Imunoglobulinas/metabolismo , Imuno-Histoquímica , Masculino , Mercúrio/efeitos adversos , Microscopia Imunoeletrônica , Pessoa de Meia-Idade , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/patologia , Corpúsculos de Pacini/efeitos dos fármacos , Corpúsculos de Pacini/patologia , Pênfigo/epidemiologia , Pênfigo/imunologia , Pênfigo/patologia , Pênfigo/fisiopatologia , Postura , Pele/efeitos dos fármacos , Pele/metabolismoRESUMO
BACKGROUND: Previously, we described a new variant of endemic pemphigus foliaceus (EPF) in Colombia, South America (El Bagre-EPF). OBJECTIVE: Continuing our characterization of this variant of EPF, we now focus on one of our previously reported clinical findings: the presence of ocular lesions. These ocular lesions are seen in patients having extensive skin involvement, as measured by the Lund and Browder scale, which is generally used for patients with skin burns. METHODS: We specifically searched for evidence of autoreactivity to various eyelid structures in these patients and correlated our immunologic data with the clinical findings. We performed indirect immunofluorescence studies using normal-appearing human eyelid skin from routine blepharoplasties as substrate tissue. We tested sera from 12 patients with El Bagre-EPF and ocular lesions, 5 patients with sporadic (nonendemic) pemphigus foliaceus, and 20 healthy control subjects (10 from the El Bagre-EPF endemic area and 10 from nonendemic areas). We used fluorescein isothiocyanate conjugated goat antiserum to human total IgG/IgA/IgM as a secondary antibody. In addition, we used fluorescein isothiocyanate conjugated antibodies to human fibrinogen, albumin, IgG, IgE, C1q, and C3, Texas Red (Rockland Immunochemicals, Inc, Gilbertsville, PA), Alexa Fluor 555, or Alexa Fluor 594 (Invitrogen, Carlsbad, CA). Ki-67 (a cell proliferation marker) was used to determine the cell proliferation rate, and nuclear counterstaining was performed with either 4', 6-diamidino-2-phenylindole or Topro III (Invitrogen, Carlsbad, CA). RESULTS: We observed autoreactivity to multiple eyelid structures, including meibomian glands and tarsal muscle bundles at different levels, and some areas of the epidermis and the dermis close to the isthmus of the eyelids. Tarsal plate autoreactivity was seen in 10 of 12 of the El Bagre-EPF sera and in one control with pemphigus erythematosus. Furthermore, immunoprecipitation using an eyelid sample as a substrate with 1 mmol/L of sodium orthovanodate showed autoreactivity to several antigens, including some of possible lipid origin. LIMITATIONS: The main limitation of this study is the fact that the antigen or antigens remain unknown. CONCLUSION: We identified for the first time to our knowledge autoantibodies to meibomian glands and tarsal muscle in El Bagre-EPF. Our findings suggest that the autoantibodies to the ocular structures cause the clinical and histopathological findings in the ocular lesions in El Bagre-EPF.
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Autoanticorpos/análise , Oftalmopatias/imunologia , Pálpebras/imunologia , Músculos Faciais/imunologia , Glândulas Tarsais/imunologia , Pênfigo/imunologia , Feminino , Imunofluorescência , Humanos , MasculinoRESUMO
We previously described a new variant of endemic pemphigus foliaceus in El Bagre, Colombia, South America (El Bagre-EPF). On physical examination, the palms and soles of El Bagre-EPF patients reveal an edematous texture and mild hyperkeratosis, in comparison with the non-glabrous skin of the patients where blisters, pustules or other lesions are commonly found. Based on the preceding observation, we tested the palms of 20 El Bagre-EPF cases and 20 controls from the endemic area for any pathological alterations in the samples by direct immunofluorescence (DIF). Our DIF demonstrated pathological deposits of fibrinogen and albumin, as well as IgG, IgA, IgM, IgD and C3c, at 1) the epidermal basement membrane zone; 2) around isolated areas in the epidermis, 3) within the dermal vessels and nerves, and 4) in areas surrounding dermal neurovascular structures and sweat glands. Specific markers for blood vessels, including 1) anti-intercellular adhesion molecule 1 (ICAM-1)/CD54, and 2) anti-junctional adhesion molecule (JAM-A); as well as specific markers for nerves, including 1) anti-glial fibrillary acidic protein (GFAP), and 2) anti-human neuron specific enolase (NSE) co-localized with the patients' autoantibodies. Although no blisters, ulcerations, pustules or erosions are clinically observed on the palms of El Bagre-EPF patients, our DIF detected distinct immunoreactivity in palm tissue. These alterations may contribute to the clinically edematous texture of the palms and the mild clinical hyperkeratosis found in most of these patients. We propose that normal glabrous skin and non-glabrous skin may be different with regard to the expression of selected molecules, which may vary in number, size or structural organization depending on their anatomical site. Our findings may also partially explain the hyperkeratotic palms that have been clinically well documented in the chronic phase of fogo selvagem i.e., endemic pemphigus foliaceus, in Brazil.
Assuntos
Autoanticorpos/análise , Doenças Endêmicas , Dermatoses da Mão/imunologia , Pênfigo/imunologia , Pele/imunologia , Albuminas/análise , Colômbia/epidemiologia , Fibrinogênio/análise , Técnica Direta de Fluorescência para Anticorpo , Mãos , Dermatoses da Mão/metabolismo , Dermatoses da Mão/patologia , Humanos , Imunoglobulinas/análise , Pênfigo/epidemiologia , Pênfigo/metabolismo , Pênfigo/patologia , Pele/metabolismoRESUMO
A prospective, controlled epidemiologic survey performed in El Bagre, Colombia revealed a new variant of endemic pemphigus disease, occurring in a gold mining region. The disease resembled Senear-Usher syndrome, and occurred in an endemic fashion. The aim of this study is to describe the most frequent histopathologic patterns in non-glabrous skin and in glabrous skin observed in these patients, and their clinical correlation. The study was performed on non-glabrous skin biopsies of 30 patients from the dominantly clinical affected areas (either on the chest, arms or face). Simultaneously, biopsies from the palms were obtained in 10 randomly chosen patients of the 30 total patients. The specimens were examined following hematoxylin and eosin (H&E) staining. The most common blisters observed were subcorneal, although in some cases intraspinous and subepidermal blisters were visualized. Our results showed a very heterogeneous pattern of histopathologic patterns in non-glabrous skin, which seemed to correlate with the clinical features. The most common pattern was typical pemphigus foliaceus-like, with some lupus erythematosus-like features. A non-specific, chronic dermatitis pattern prevailed in the clinically controlled patients taking daily corticosteroids. In the patients who have had the most severe and relapsing pemphigus, early sclerodermatous changes and scleredermoid alterations prevailed in their reticular dermis. In addition to the scleredermoid alterations, the reticular dermis showed a paucity of appendageal structures. On the contrary, in the palms, a similar pattern was seen in all cases, including thickening of the stratum corneum, hypergranulosis, edema in the papillary and reticular dermis and a dermal perivascular lymphocytic infiltrate. The direct immunofluorescence of the glabrous vs. the non-glabrous skin also showed some differences. We conclude that the histopathologic features of this new variant of endemic pemphigus are complex, therefore, classical histopathologic features previously described for superficial, endemic pemphigus cannot be used alone to diagnose this disease.
Assuntos
Doenças Endêmicas , Pênfigo/epidemiologia , Pênfigo/patologia , Pele/patologia , Vesícula/epidemiologia , Vesícula/patologia , Colômbia/epidemiologia , Humanos , Seleção de PacientesRESUMO
Potential chemopreventive agents exist in foods. Artepillin C in Brazilian propolis was investigated for its effects on colon carcinogenesis. We had found that artepillin C was a bioavailable antioxidant, which could be incorporated into intestinal Caco-2 and hepatic HepG2 cells without any conjugation and inhibited the oxidation of intracellular DNA. Artepillin C was then added to human colon cancer WiDr cells. It dose-dependently inhibited cell growth, inducing G(0)/G(1) arrest. The events involved a decrease in the kinase activity of a complex of cyclin D/cyclin-dependent kinase 4 and in the levels of retinoblastoma protein phosphorylated at Ser 780 and 807/811. The inhibitors of the complex, Cip1/p21 and Kip1/p27, increased at the protein level. On the other hand, Northern blotting showed that artepillin C did not affect the expression of Kip1/p27 mRNA. According to the experiments using isogenic human colorectal carcinoma cell lines, artepillin C failed to induce G(0)/G(1) arrest in the Cip1/p21-deleted HCT116 cells, but not in the wild-type HCT116 cells. Artepillin C appears to prevent colon cancer through the induction of cell-cycle arrest by stimulating the expression of Cip1/p21 and to be a useful chemopreventing factor in colon carcinogenesis.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fase G1/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/farmacologia , Fenilpropionatos/farmacologia , Própole/química , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Northern Blotting , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ciclina D , Quinase 4 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Ciclinas/metabolismo , Citometria de Fluxo , Células HCT116 , Humanos , Imunoprecipitação , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína do Retinoblastoma/metabolismoRESUMO
BACKGROUND: Endemic forms of pemphigus are a unique group of autoimmune diseases that represent opportunities to study interactions of the environment and genetics with the immune system. The restriction to relatively well-defined regions of South and Central America and perhaps Africa characterizes these diseases. OBJECTIVES: The aims of this study were to confirm the endemic nature of a new type of autoimmune disease occurring in a mining town in northeastern Colombia in the El Bagre area, to characterize it, and to compare it with other forms of endemic pemphigus. METHODS: A 10-year prospective, controlled epidemiologic, humanitarian, and immunologic fieldwork case-control survey was performed in El Bagre, Colombia. RESULTS: Our work revealed that this disease is endemic in rural areas surrounding El Bagre. The disease appeared in 4.7% of middle-aged and older men and postmenopausal women from these rural areas. This disease differs from previously described forms of endemic pemphigus. It shares some heterogeneous immunoreactivity with paraneoplastic pemphigus but is not associated with malignant tumors. The disease resembles Senear-Usher syndrome (pemphigus and lupus) but occurs endemically either with a localized stable clinical course or in a systemic form. This systemic form may affect organs other than skin and is characterized by episodic relapses and poor prognosis in comparison with the localized form. CONCLUSION: We have confirmed endemic pemphigus foliaceus in El Bagre as an autoimmune disease that shares features with Senear-Usher syndrome but occurs in an endemic fashion. Heterogeneous antigenic reactivity is observed as in paraneoplastic pemphigus but with no evidence of association with neoplasia. In addition, constant exogenous antigenic stimulation and a genetic predisposition may be required in the pathogenesis of this disease.