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2.
Genes Immun ; 25(2): 108-116, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38267542

RESUMO

Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti ß2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.


Assuntos
Síndrome Antifosfolipídica , Trombose , Humanos , Exoma , Síndrome Antifosfolipídica/complicações , Inibidor de Coagulação do Lúpus , Autoanticorpos , Trombose/complicações
3.
Z Rheumatol ; 82(8): 654-665, 2023 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-37782326

RESUMO

BACKGROUND: Ultrasound examination of the salivary glands (SG) is a quick and noninvasive method to detect and semiquantitatively estimate typical changes in the large SG in Sjögren's syndrome (SS). The differential diagnosis of SS is difficult because several diseases and adverse effects of treatment have a similar clinical picture as SS with sicca syndrome and can even induce alterations in the SG (mimic diseases). Hence, for a long time an SG biopsy was regarded as the diagnostic procedure of choice, especially in SS­A negative patients, whereas the significance of SD sonography is still controversially discussed. OBJECTIVE: Comparison of typical and atypical changes for SS in the salivary glands in ultrasound and associated histological sections. MATERIAL AND METHODS: This article describes six patient cases with antibody positive or negative SS with and without typical SS ultrasound patterns, SS-associated lymphoma, sarcoidosis and IgG4-associated disease. The findings of the sonographic examination of the parotid glands and the associated histology of the SD are explained and put into context. RESULTS: The SSA antibody positive patients with SS show a typical sonographic pattern with hypoechoic foci, especially if the disease has been present for a long time. This pattern can help support the diagnosis of SS. The ultrasound patterns of the mimic diseases sometimes differ significantly from the typical patterns of pSS. The histological examination of the SG helps to corroborate the diagnosis but low histological focus scores, in particular, require a critical synopsis of the clinical, serological and imaging findings. CONCLUSION: Both salivary gland ultrasound and the histological examination of SG biopsies are justified in the diagnostics and differential diagnosis of SS and sicca syndrome.


Assuntos
Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico por imagem , Glândulas Salivares/diagnóstico por imagem , Glândulas Salivares/patologia , Glândula Parótida , Ultrassonografia , Biópsia
4.
Z Rheumatol ; 79(10): 1057-1066, 2020 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-32040755

RESUMO

BACKGROUND: Raynaud's phenomenon and the frequently ensuing digital ulcerations represent an early and very distressing symptom in patients with systemic sclerosis (scleroderma, SSc) causing significant limitations in the ability to work and quality of life. The use of vasoactive drugs (especially intravenous prostacyclin derivatives) is recommended to reduce the risk of hypoxic tissue damage up to the loss of fingers. METHODS: In order to obtain information about the current state of treatment of patients with prostacyclin derivatives in routine clinical life in Germany, a survey was conducted among the centers affiliated to the German Network for Systemic Scleroderma (DNSS). In addition, a separate patient survey was conducted by the schleroderma self-help group (Sklerodermie Selbsthilfe e. V.), which only covered the symptoms Raynaud's syndrome, digital ulcers and the use of intravenous prostacyclin derivatives. RESULTS: Of the 433 patients surveyed 56% stated that they had already been treated with prostacyclin derivatives (iloprost/alprostadil) because of their illness and symptoms. A total of 61% received the treatment for severe Raynaud's phenomenon and 39% for digital ulcerations. Most respondents not only experienced an improvement in Raynaud's phenomenon and digital ulcers but also a significant improvement of limitations in everyday life. They also needed significantly less outside help and absenteeism from work was much lower. CONCLUSION: Patients consistently reported a positive effect of treatment with prostacyclin derivatives on Raynaud's phenomenon, acral ulcerations, pain and daily restrictions and felt well and safely cared for during inpatient treatment. These positive effects in the patients' perceptions provide crucial information supporting and confirming the current European and international treatment recommendations.


Assuntos
Epoprostenol , Doença de Raynaud , Escleroderma Sistêmico , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Dedos/irrigação sanguínea , Alemanha , Humanos , Pacientes Internados , Qualidade de Vida , Doença de Raynaud/diagnóstico , Doença de Raynaud/tratamento farmacológico , Doença de Raynaud/epidemiologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/tratamento farmacológico , Pele/irrigação sanguínea
5.
Z Rheumatol ; 77(9): 789-798, 2018 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-30291433

RESUMO

The causes of diseases and disorders of the immune system, which lead to the development of systemic lupus erythematosus (SLE), are not yet completely understood; however, it is known that there are various mechanisms, which can lead to SLE. The development of the disease is based on an underlying genetic disposition but is first triggered by exposure to environmental factors, such as sunburn, viral infections or vitamin D deficiency. Disease flares can also be triggered by environmental factors. Many disease manifestations are caused by pathogenic autoantibodies; hence, B­cells and plasma cells play a critical role in the pathogenesis of SLE. This review provides an overview of the most frequent factors leading to the development of SLE and describes the key mechanisms of its pathogenesis.


Assuntos
Lúpus Eritematoso Sistêmico , Autoanticorpos , Linfócitos B , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia
6.
Z Rheumatol ; 77(2): 127-134, 2018 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-28752409

RESUMO

OBJECTIVE: To retrospectively assess and analyze the clinical efficacy and safety of off-label interleukin-1 (IL-1) blockade with anakinra during pregnancy of patients with familial Mediterranean fever (FMF). METHODS: Retrospective analysis of clinical and laboratory parameters making use of an electronic database system. Detailed descriptions of the genotype and phenotype of FMF are given and the course of the pregnancy and fetal development are reported. RESULTS: The data of three patients and a total of four pregnancies under treatedment with anakinra were analyzed. All patients were of Mediterranean origin, fulfilled the Tel Hashomer criteria for diagnosis of FMF and had a confirmed mutation in the MEFV gene. In all patients, treatment with anakinra was initiated due to an insufficient treatment response to colchicine. Anakinra led to a rapid response in all patients. In three pregnancies anakinra treatment was continued during the whole pregnancy, while in one pregnancy anakinra was started in the second trimester because of uncontrolled FMF activity. Fetal development was normal in all pregnancies. In two patients the fetuses were carried to term, while in one patient a primary cesarean section was carried out in week 33 because of an increased risk for complications. All children showed an unremarkable early childhood development without any signs of an existing disease. CONCLUSION: The data of our retrospective analysis suggest that IL-1-blockade by anakinra is an effective and safe treatment in pregnant women suffering from FMF, which can reliably prevent disease flares. In the four pregnancies presented the use of anakinra did not result in impaired fetal and (early) childhood development.


Assuntos
Febre Familiar do Mediterrâneo , Proteína Antagonista do Receptor de Interleucina 1 , Complicações Infecciosas na Gravidez , Cesárea , Criança , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1 , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Pirina , Estudos Retrospectivos
7.
Z Rheumatol ; 77(1): 21-27, 2018 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-28508096

RESUMO

OBJECTIVE: To evaluate the clinical efficacy and safety of off-label biological therapies in patients with ANCA-associated vasculitis (AAV) and non-ANCA-associated small-vessel vasculitis (nAAV) in clinical practice. METHODS: The German Registry in Autoimmune Diseases 2 (GRAID2) is a national, retrospective, non-interventional, multicentre observational study (August 2006 until December 2013) on patients with autoimmune diseases refractory to standard immunosuppressive therapy treated with off-label biologicals. RESULTS: Data from 64 patients (20.6% of all GRAID2 patients) were collected: 54 patients (84.4%) had ANCA-associated vasculitis (AAV) and 10 patients (15.6%) had non-ANCA-associated small-vessel vasculitis (nAAV). Of the AAV patients, 96.3% were treated off-label with rituximab (RTX) and 3.7% with tumor necrosis factor alpha (TNFα)-inhibitors. Of patients with nAAV, 30% were treated with RTX, 60% with TNFα-inhibitors, and 10% with tocilizumab. The main reasons for off-label biological treatment in AAV patients were pulmonary, renal, or ear, nose, and throat involvement. These manifestations clearly improved in most patients after off-label biological therapy was initiated. Daily glucocorticoid dosage could be reduced. The off-label biological therapy was generally well tolerated. In AAV patients, 4.18 severe infections per 100 patient years were observed. There was one death in the nAAV group caused by fungal infection and ileus. A correlation between this fatality and RTX treatment was regarded as possible. CONCLUSION: Safety and efficacy of off-label RTX-treatment in AAV-patients could be assessed in the GRAID2 data. Results point to good efficacy and safety of RTX in this special patient cohort and support the approval of RTX for AAV induction therapy.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Terapia Biológica , Uso Off-Label , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Humanos , Sistema de Registros , Estudos Retrospectivos , Rituximab
8.
Z Rheumatol ; 77(1): 28-39, 2018 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-28589389

RESUMO

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.


Assuntos
Doenças Autoimunes , Terapia Biológica , Uso Off-Label , Doenças Autoimunes/tratamento farmacológico , Feminino , Humanos , Masculino , Sistema de Registros , Estudos Retrospectivos , Padrão de Cuidado
9.
Z Rheumatol ; 75(4): 389-401, 2016 May.
Artigo em Alemão | MEDLINE | ID: mdl-27146405

RESUMO

Sarcoidosis is a rare granulomatous disease mainly affecting lymph nodes and the lungs but joints, bones, muscles and other organs can also be affected. Sarcoidosis therefore represents an important differential diagnosis to various rheumatic diseases. For the diagnosis and differential diagnostic clarification, bronchoscopy including endobronchial ultrasound-guided fine needle aspiration of mediastinal and hilar lymph nodes represent the main procedures. Because of the high spontaneous remission rate initiating a therapy requires a therapeutic goal defined by sarcoidosis-associated functional organ impairment, especially for acute sarcoidosis. Cortisone represents the most commonly administered medication whereas methotrexate and azathioprine are well-established second-line medications. Antibodies which neutralize tumor necrosis factors (TNF) are a potential third-line therapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Broncoscopia/métodos , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Imunossupressores/uso terapêutico , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/tratamento farmacológico , Cortisona/uso terapêutico , Diagnóstico Diferencial , Quimioterapia Combinada , Medicina Baseada em Evidências , Alemanha , Humanos , Resultado do Tratamento
10.
Z Rheumatol ; 74(1): 20-5, 2015 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-25616773

RESUMO

Plasma cells are specialized terminally differentiated B cells that synthesize and secrete antibodies to maintain humoral immunity. By the production of pathogenic antibodies, plasma cells contribute to the development of many conditions, such as autoimmune disorders, transplant rejection and allergies. Two different plasma cell compartments can independently generate different types of pathogenic antibodies: (1) short-lived plasmablasts (proliferating precursors of mature plasma cells) and plasma cells, which live only as long as B cells are activated. Consequently, these cells cause disease flares that respond to immunosuppressive drugs and B cell targeting therapies. (2) Long-lived non-proliferating memory plasma cells, which survive in niches in bone marrow and inflamed tissues for months, years or a lifetime independent of B or T cell help or antigen contact. Because they do not respond to immunosuppressants or treatment targeting B cells, they are responsible for refractory chronic conditions. Therefore, long-lived memory plasma cells in particular have emerged as important therapeutic targets and strategies to target these cells are discussed in this article. So far long-lived plasma cells can only be depleted by immunoablative therapy with antithymocyte globulin in the setting of stem cell transplantation or by treatment with proteasome inhibitors approved for multiple myeloma. These strategies provide options for treating refractory autoantibody-mediated diseases. One interesting approach aims at an antigen-specific elimination of target plasma cells without depleting the protective plasma cells responsible for maintaining humoral immunity.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Citocinas/imunologia , Imunidade Humoral/imunologia , Plasmócitos/imunologia , Plasmócitos/patologia , Humanos , Modelos Imunológicos
11.
Clin Exp Immunol ; 179(1): 39-49, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24673456

RESUMO

Most cases of systemic lupus erythematosus (SLE) are characterized by an impaired clearance of apoptotic cells in various tissues. Non-cleared apoptotic waste is considered an immunogen driving the autoimmune response in patients with SLE. During the execution of apoptosis, membrane blebs are formed and filled with cellular components. Here, we evaluate the cytoskeletal pathway(s) responsible for the loading of SLE prototypic nuclear autoantigens into the apoptotic cell-derived membranous vesicles (ACMV) generated during late phases of apoptosis. HeLa cells expressing a fusion protein of histone H2B with green fluorescent protein (GFP) were irradiated with ultraviolet (UV)-B to induce apoptosis. The appearance and trafficking of chromatin-derived material was monitored by fluorescence microscopy. Specific inhibitors of cytoskeletal pathways were employed to identify the motile elements involved in translocation and trafficking of the nuclear components. We observed that immediately after their appearance the ACMV did not contain histone H2B(GFP) ; in this phase the fluorescence was contained in the nuclear remnants and the cytoplasm. Within consecutive minutes the ACMV were loaded with chromatin-derived material, whereas the loading of simultaneously created ACMV with histone H2B(GFP) was not uniform. Some ACMV were preferentially filled and, consequently, showed a remarkably higher histone H2B(GFP) accumulation. Inhibitors of the cytoskeleton revealed that functional microtubules and myosin light chain kinase are required for nuclear shrinkage and loading of nuclear material into the ACMV, respectively.


Assuntos
Apoptose/imunologia , Autoantígenos/imunologia , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Microtúbulos/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Apoptose/efeitos da radiação , Linhagem Celular , Tamanho do Núcleo Celular , Citoesqueleto/metabolismo , Humanos , Modelos Biológicos
12.
Clin Exp Immunol ; 174(2): 221-8, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23808414

RESUMO

Targeting autoreactive B lymphocytes at any stage of their differentiation could yield viable therapeutic strategies for treating autoimmunity. All currently used drugs, including the most recently introduced biological agents, lack target specificity. Selective silencing of double-stranded DNA-specific B cells in animals with spontaneous lupus has been achieved previously by the administration of a chimeric antibody molecule that cross-links their DNA-reactive B cell immunoglobulin receptors with inhibitory FcγIIb (CD32) receptors. However, long-lived plasmacytes are resistant to this chimeric antibody as well as to all conventional treatments. Bortezomib (a proteasome inhibitor) depletes most plasma cells and has been shown recently to suppress disease activity in lupus mice. We hypothesized that the co-administration of non-toxic doses of bortezomib, that partially purge long-lived plasma cells, together with an agent that selectively silences DNA-specific B cells, should have additive effects in an autoantibody-mediated disease. Indeed, our data show that the simultaneous treatment of lupus-prone MRL/lpr mice with suboptimal doses of bortezomib plus the chimeric antibody resulted in the prevention or the delayed appearance of the disease manifestations as well as in a prolonged survival. The effect of the combination therapy was significantly stronger than that of the respective monotherapies and was comparable to that observed after cyclophosphamide administration.


Assuntos
Anticorpos Monoclonais/metabolismo , Linfócitos B/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/terapia , Depleção Linfocítica , Fragmentos de Peptídeos/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Animais , Anticorpos Monoclonais/genética , Autoantígenos/imunologia , Linfócitos B/imunologia , Ácidos Borônicos/administração & dosagem , Bortezomib , Ciclofosfamida/administração & dosagem , DNA/química , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos MRL lpr , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Pirazinas/administração & dosagem , Receptores de IgG/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia
13.
J Intern Med ; 270(4): 309-18, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21793951

RESUMO

High-mobility group box 1 (HMGB1) protein is a nuclear DNA-binding protein, which functions as an alarmin when released from cells. Recent studies implicate extracellular HMGB1 in the pathogenesis of systemic lupus erythematosus (SLE), a prototypical autoimmune disease characterized by the formation of multiple autoantibodies, especially those directed against nucleosomes and double-stranded (ds)DNA. Elevated concentrations of HMGB1 are observed in sera as well as in skin lesions of patients with lupus. Of importance, serum HMGB1 and anti-HMGB1 autoantibody levels correlate with disease activity. In the blood of patients with SLE, HMGB1 is complexed with nucleosomes, at least partially. Moreover, HMGB1-nucleosome complexes from apoptotic cells activate antigen-presenting cells. Injection of HMGB1-nucleosome complexes into nonautoimmune mice results in the formation of autoantibodies against dsDNA and histones in a Toll-like receptor (TLR) 2-dependent manner. Additionally, HMGB1, as a part of DNA-anti-DNA immune complexes, can interact with receptor for advanced glycation end products (RAGE) on the surface of plasmacytoid dendritic cells and B cells leading to TLR9-dependent interferon (IFN)α release and activation of autoreactive B cells, respectively. HMGB1 attached to neutrophil extracellular traps may contribute to IFNα production by facilitating the recognition of self-nucleic acids. Furthermore, HMGB1, complexed with DNA and pathogenic anti-DNA autoantibodies, activates its receptors, TLR2, TLR4 and RAGE, and may thereby be involved in anti-DNA autoantibody-induced kidney damage in lupus nephritis. Collectively, these findings suggest that HMGB1 is a potential marker of disease activity and, because of its probable involvement in the pathogenesis, a novel therapeutic target in SLE.


Assuntos
Biomarcadores/metabolismo , Proteína HMGB1/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Animais , Proteína HMGB1/antagonistas & inibidores , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Camundongos , Modelos Biológicos , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/metabolismo
14.
Z Rheumatol ; 69(9): 803-12, 2010 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-21063829

RESUMO

Patients with autoimmune or rheumatic diseases are at increased risk for infectious complications due to immunosuppressive therapy and/or the underlying immunological disease itself. To date, the consistent use of vaccinations in this patient group has been limited due to concerns about flair-ups or lack of efficacy. In prospective studies neither an increased risk of disease flair-ups nor of initiation of autoimmune disorders was found as yet; however, the data is still considered insufficient (small studies including only patients in remission). Vaccination with non-live vaccines can generally be regarded as safe and relatively effective, even in patients on immunosuppressive therapy. Since the immune response to vaccination may be markedly impaired depending on the medication used and the underlying autoimmune disease, monitoring of both serum titers and of patients' vaccination schedules should form an integral part of rheumatological care.


Assuntos
Doenças Autoimunes/etiologia , Doenças Autoimunes/prevenção & controle , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológico , Reumatologia/tendências , Vacinação/efeitos adversos , Humanos
15.
Z Rheumatol ; 69(2): 152, 154-6, 2010 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-20107814

RESUMO

Systemic lupus erythematosus (SLE) is a complex prototypic autoimmune disease that is based on genetic factors (complement deficiencies) and is influenced by gender (female), environment (infections and UV irradiation), as well as random events (somatic mutations). The course of the disease is influenced by genes (e.g. FcgammaRIIA) and behaviour (sun-exposure). Inefficient clearance of dying cells and subsequent accumulation of apoptotic cell remnants is an intrinsic defect causing the permanent presence of cellular debris responsible for the initiation of autoimmunity. We favour the hypothesis that post-apoptotic debris accumulates in germinal centres, activates complement, and serves as a survival signal for B-cells that had stochastically become autoreactive in the process of somatic hypermutation (etiology). In the presence of autoantibodies against apoptotic cells or adaptor molecules the accumulation of post-apoptotic remnants (SNEC) causes immune complex formation and their pathological elimination, maintaining auto-inflammation. The SLE-type autoimmunity addresses nucleic acid-containing complex antigens (viromimetica). Autoantibody-protein-nucleic-acid complexes are likely to be mistaken for opsonised viruses. As a consequence, the immune system responds with the production of type-I interferons, a hallmark of SLE (pathogenesis). We conclude that the pathogenicity of autoantibodies is strongly increased if autoantigens are accessible and immune complexes are formed, which may be considered a binary pyrogen formed from less pro-inflammatory components. The accessibility of cognate autoantigens is likely to be related to impaired or delayed clearance of apoptotic cells.


Assuntos
Apoptose/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Linfócitos B/imunologia , Estruturas Celulares/imunologia , Ativação do Complemento/imunologia , Feminino , Humanos , Interferon Tipo I/sangue , Masculino , Pirogênios/imunologia , Fatores de Risco , Hipermutação Somática de Imunoglobulina/imunologia
16.
Climacteric ; 13(2): 187-91, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19657787

RESUMO

Black cohosh is one of the most popular herbal therapies for premenstrual discomfort, hot flushes and other climacteric and menopausal symptoms. Most often, it is tolerated well. However, there are some recent reports on serious adverse events, probably associated with this complementary and alternative herbal medicine. We report a case of coagulation activation, fluid retention and transient autoimmune hepatitis most likely triggered by the use of black cohosh. Diagnostic procedures aimed to explain lower leg edema are not uncommon in the age group of women suffering from climacteric and menopausal symptoms. Therefore, black cohosh-induced fluid retention and coagulation activation should be considered in differential diagnosis, especially if thrombosis has been excluded.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Cimicifuga/efeitos adversos , Edema/induzido quimicamente , Fitoterapia , Extratos Vegetais/efeitos adversos , Síndrome Pré-Menstrual/tratamento farmacológico , Adulto , Cimicifuga/química , Edema/patologia , Feminino , Hepatite Autoimune/etiologia , Humanos , Fígado/enzimologia , Extratos Vegetais/uso terapêutico
17.
Ann Rheum Dis ; 67(11): 1626-32, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18165321

RESUMO

OBJECTIVE: Accumulation of dying and dead cells is thought to be involved in the etiopathogenesis of systemic lupus erythaematosus (SLE). Clearance has been described mainly for apoptotic cells; however, the knowledge of serum factors participating in the phagocytosis of necrotic cells is limited. PATIENTS AND METHODS: Sera from 18 patients with SLE and 10 normal healthy donors (NHD), and macrophages from 3 NHD were included. Autoantibodies and complement were measured by ELISA and phagocytosis by flow cytometry. Binding of serum IgG to necrotic cells was assessed by flow cytometry and confocal microscopy. RESULTS: Sera from patients with SLE and NHD generally promoted the phagocytosis of necrotic cells by macrophages isolated from NHD. Five independent experiments with macrophages from three different NHD led to similar results. The sera from healthy controls displayed a homogeneous activity, whereas sera from patients with SLE showed a dichotomic behaviour. Only sera containing autoantibodies binding to the surfaces of necrotic cells and sufficient complement showed increased phagocytosis promoting activities. In SLE sera, C4 turned out to be the critical complement component in this process. Sera de-complemented by heat treatment strongly reduced phagocytosis of necrotic cells. CONCLUSIONS: Serum components influence the uptake of necrotic cells by phagocytosis competent macrophages from NHD. Complement is required for this process and autoantibodies binding to the surfaces of necrotic cells additionally promote their phagocytosis.


Assuntos
Autoanticorpos/imunologia , Complemento C4/imunologia , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fagocitose/imunologia , Células Cultivadas , Feminino , Temperatura Alta , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino , Microscopia Confocal , Necrose/imunologia
18.
Cell Death Differ ; 15(3): 600-12, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18188168

RESUMO

The proteasome inhibitor bortezomib, which induces cell death in various cancer cell lines including lymphatic neoplasias, has recently been approved for the treatment of relapsed multiple myeloma. Important mechanisms of proteasome inhibitor-mediated tumor cell death are the inhibition of NF-kappaB activation and induction of the terminal unfolded protein response (UPR). However, little is known about effects of bortezomib on developing and mature lymphocytes. Therefore, Balb/C mice were injected with bortezomib and lymphocyte subsets were analyzed. This treatment resulted in dramatically decreased numbers of T and B lymphocyte precursors, while mature lymphocytes were only partially affected. Thymocytes were almost depleted 3 days after a single bortezomib injection, pro-B and pre-B cells already after 2 days. Thymocytes and B cell precursors recovered within 2 weeks. The decreased numbers of developing lymphocytes were due to apoptotic cell death accompanied by strongly increased caspase 3/7 activity. Within 8 h after bortezomib injection, there was a strong induction of heat shock protein 70 and C/EBP homologous protein in bone marrow B cells, indicating endoplasmic reticulum stress and activation of the terminal UPR, respectively. Hence, induction of apoptosis by proteasome inhibition can dramatically affect lymphocyte development, a fact which has important implications for the clinical use of bortezomib, especially in situations with ongoing lymphopoiesis.


Assuntos
Apoptose , Ácidos Borônicos/farmacologia , Células Precursoras de Linfócitos B/efeitos dos fármacos , Células Precursoras de Linfócitos T/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Inibidores de Proteassoma , Pirazinas/farmacologia , Animais , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Bortezomib , Células Cultivadas , Feminino , Contagem de Linfócitos , Tecido Linfoide/citologia , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/imunologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos T/citologia , Dobramento de Proteína , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Timo/citologia , Timo/efeitos dos fármacos , Timo/imunologia
19.
Cell Death Differ ; 14(4): 733-42, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17170754

RESUMO

Apoptosis and phagocytosis of apoptotic cells are crucial processes. At best the phagocytic machinery detects and swallows all apoptotic cells in a way that progression to secondary necrosis is avoided. Otherwise, inflammation and autoimmune diseases may occur. Most apoptotic cells are phagocytosed instantaneously in a silent fashion; however, some dying cells escape their clearance. If the cells are not cleared early, they lose membranes due to extensive shedding of membrane surrounded vesicles (blebbing) and shrink. It is unclear how apoptotic cells compensate their massive loss of plasma membrane. Here, we demonstrate that endoplasmic reticulum- (ER) resident proteins (calnexin, the KDEL receptor and a dysfunctional immunoglobulin heavy chain) were exposed at the surfaces of shrunken late apoptotic cells. Additionally, these cells showed an increased binding of lectins, which recognize sugar structures predominantly found as moieties of incompletely processed proteins in ER and Golgi. In addition the ER resident lipophilic ER-Tracker Blue-White DPX, and internal GM1 were observed to translocate to the cell surfaces during late apoptosis. We conclude that during blebbing of apoptotic cells the surface membrane loss is substituted by immature membranes from internal stores. This mechanism explains the simultaneous appearance of preformed recognition structures for several adaptor proteins known to be involved in clearance of dead cells.


Assuntos
Apoptose/fisiologia , Membrana Celular/fisiologia , Epitopos/fisiologia , Membranas Intracelulares/fisiologia , Lipídeos de Membrana/fisiologia , Fosfatidilserinas/fisiologia , Animais , Apoptose/efeitos da radiação , Tamanho Celular , Células Cultivadas , Retículo Endoplasmático/fisiologia , Citometria de Fluxo , Humanos , Células Jurkat/patologia , Células Jurkat/fisiologia , Camundongos , Microscopia de Fluorescência , Neutrófilos/patologia , Neutrófilos/fisiologia , Coloração e Rotulagem
20.
Curr Top Microbiol Immunol ; 305: 161-76, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16724805

RESUMO

Dying cells were basically unnoticed by scientists for a long time and only came back into the spotlight roughly 10 years ago. The process of recognition and uptake of apoptotic and necrotic cells is complex and failures in this process can contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we discuss the recognition and uptake molecules which are involved in an efficient clearance of dying cells in early and late phases of cell death. The exposure of phosphatidylserine (PS) is an early surface change of apoptosing cells recognized by several receptors and adaptor molecules. We demonstrated that dying cells have cell membranes with high lateral mobility of PS, which contribute to their efficient clearance. Changes of the glycoprotein composition of apoptotic cells occur later than the exposure of PS. We further observed that complement binding is an early event in necrosis and a rather late event in apoptosis. Complement, C-reactive protein (CRP), and serum DNase I act as back-up molecules in the clearance process. Finally, we discuss how the accumulation of secondary necrotic cells and cellular debris in the germinal centers of secondary lymph organs can lead to autoimmunity. It is reasonable to argue that clearance defects are major players in the development of autoimmune diseases such as SLE.


Assuntos
Apoptose , Doenças Autoimunes/etiologia , Animais , Autoimunidade , Proteína C-Reativa/fisiologia , Proteínas do Sistema Complemento/fisiologia , Desoxirribonuclease I/fisiologia , Humanos , Glicoproteínas de Membrana/fisiologia , Fosfatidilserinas/fisiologia , Componente Amiloide P Sérico/fisiologia
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