The role of apoptosis proteins and complement components in the etiopathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus is a prototypical autoimmune disease characterized by the deregulation of T and B cells, tissue infiltration by mononuclear cells, tissue damage and the production of autoantibodies. There is a consensus that accelerated apoptosis of circulating lymphocytes and/or impaired clearance of apoptotic bodies may increase the amount of nuclear antigens presented to T lymphocytes. This process is accompanied by autoimmune responses that can lead to the development of lupus. The dysfunction of apoptosis may be a direct consequence of alterations in proteins/genes such as Fas, Bcl-2 and C1q. Increased expression of Fas antigen could intensify the exposure of hidden antigens. The overexpression of Bcl-2 protein might inhibit the removal of auto-reactive cells, and the lack of C1q could impair the clearance of self-antigens. The complete knowledge of the role of apoptosis components in the etiopathogenesis of lupus could lead to the development of new therapies targeting the apoptotic threshold, which could result in a more specific and effective disease response compared to global immunosuppression. This review summarizes the role of each component of the apoptotic process in the pathogenesis of lupus

Anticorpos antifosfolípides em 57 crianças e adolescentes com lúpus eritematoso sistêmico

OBJECTIVE: To investigate the frequencies and behavior of antiphospholipid antibodies in 57 children and adolescents with systemic lupus erythematosus. METHODS: Anticardiolipin antibodies were investigated by ELISA and lupus anticoagulant antibodies by the international tests recommended. The antiphospholipid antibodies analyses were performed in frozen samples (mean of 5.3 samples per patient obtained during a mean follow-up period of 3 years and 7 months) and on blood samples collected between January 1997 and November 1998 (mean of 2.5 samples per patient during a 2-year follow-up period). RESULTS: The frequencies of antiphospholipid antibodies (anticardiolipin and lupus anticoagulant) were similar in the samples collected prospectively and in the frozen samples (retrospective study): 63.2% and 75.4% respectively. Positivity for these antibodies fluctuated during the follow-up period and was not associated with any clinical or laboratory parameters of lupus erythematosus, including autoantibodies and also including disease activity and/or severity scores. CONCLUSIONS: The frequencies of antiphospholipid antibodies in children and adolescents with lupus erythematosus were similar to those observed in adults. The positivity fluctuated during the follow-up and was not correlated with clinical and/or laboratory disease parameters.OBJETIVO: Investigara freqüência e o comportamento dos anticorpos antifosfolípides em 57 crianças e adolescentes com lúpus eritematoso sistêmico. MÉTODOS: A técnica laboratorial para a pesquisa do anticorpo anticardiolipina foi ELISA e para a pesquisa do anticorpo anticoagulante lúpico foram seguidas as recomendações internacionais. A pesquisa dos anticorpos antifosfolípides foi realizada em soros estocados (média de 5,3 amostras por paciente durante o período de seguimento de em média 3 anos e 7 meses) e em soros coletados no período de janeiro de 1997 à novembro de 1998 (média de 2,5 amostras por paciente em um período de dois anos). RESULTADOS: A freqüência dos anticorpos antifosfolípides (anticorpo anticardiolipina e anticoagulante lúpico) foi semelhante nos soros coletados prospectivamente e nos soros estocados (estudo retrospectivo): 63,2% e 75,4% respectivamente. A positividade destes anticorpos flutuou durante o seguimento e não esteve associado a nenhum parâmetro clínico e laboratorial do lúpus eritematoso sistêmico, incluindo auto-anticorpos e também atividade e/ou gravidade da doença. CONCLUSÕES: A freqüência dos anticorpos antifosfolípides em crianças e adolescentes com lúpus eritematoso sistêmico foi semelhante à observada em adultos. A positividade dos anticorpos flutuou durante o seguimento dos pacientes e não foi evidenciada associação com parâmetros clínicos e/ou laboratoriais da doença

Análise dos antígenos de histocompatibilidade leucocitária de classe II-DR em crianças e adolescentes brasileiros com lúpus eritematoso sistêmico

OBJECTIVE: To analyze the frequency of human leukocyte antigens class II-DR in children and adolescents with systemic lupus erythematosus. PATIENTS AND METHODS: Fifty-fiveBrazilian systemic lupus erythematosus children and adolescents and 308 healthy individuals were studied. Gender, race, and age of onset of systemic lupus erythematosus were recorded. The human leukocyte antigens typing of class II-DR was carried out by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP). Data were analyzed statistically using the chi square test with Yates' correction, Fisher's exact test, and Bonferroni's correction. RESULTS: Human leukocyte antigen-DR 15 was the most frequently detected antigen in this group of children and adolescents, and it also occurred more frequently in the female group, in children with onset of systemic lupus erythematosus between 0 and 9 years and between 10 to 14 years, and in the Black race group, but these associations were not statistically significants. CONCLUSION: In this group of children and adolescents with a high degree of racial admixture, we could not verify a significant association between human leukocyte antigens class II-DR and systemic lupus erythematosus.OBJETIVO: Analisar a freqüência dos antígenos de histocompatibilidade leucocitária de classe II-DR em crianças e adolescentes com o lúpus eritematoso sistêmico. PACIENTES E MÉTODOS: Cinqüenta e cinco crianças e adolescentes lúpicos brasileiros e 308 indivíduos sadios foram estudados. Os sexos, os grupos étnicos e as idades de início da doença foram anotados. A tipagem de histocompatibilidade leucocitária de classe II-DR foi realizada pela reação de polimerase em cadeia com amplificação de sondas de seqüência específica (PCR-SSP). Na análise estatística foram utilizados o teste de qui-quadrado com correção de Yates, o teste exato de Fisher e a correção de Bonferroni. RESULTADOS: A histocompatibilidade leucocitária-DR15 foi a mais freqüente neste grupo de crianças e adolescentes, sendo também mais freqüente nas mulheres, nas crianças com idade de início da doença entre zero e nove anos e entre 10 e 14 anos e nas crianças de raça negra, mas estas correlações não foram estatisticamente significativas. CONCLUSÃO: Neste grupo de crianças e adolescentes com alto grau de miscigenação não pudemos observar associação significativa entre os antígenos de histocompatibilidade leucocitária de classe II-DR e o lúpus eritematoso sistêmico

Arthrodiastasis for the treatment of stiffness of the hip in juvenile rheumatoid arthritis (JRA): preliminary results

OBJETIVO: Apresentar os resultados preliminares da utilização da artrodiastase do quadril em pacientes portadores de artrite reumatoide juvenil e com comprometimento da articulação coxofemoral. MÉTODOS: Estudo prospectivo de 12 pacientes (seis meninos e seis meninas) com idades entre oito e 18 anos (média de 10,5 anos). Foi utilizado um fixador externo monolateral que permite os movimentos de flexão e de extensão no quadril. O fixador externo foi mantido por um período que variou de 78 a 90 dias, com média de 86 dias. O controle radiográfico foi realizado durante o ato operatório e, semanalmente, durante o período de tração e a cada quatro semanas, quando terminado este período. Na avaliação clínica dos resultados, incluímos a graduação da dor e o grau de movimentação articular, com medidas e avaliações pré e pós-operatórias. O período de acompanhamento variou de 12 a 15 anos, com média de 13 anos. RESULTADOS: O valor médio da escala de dor foi de nove (9) antes da operação e de quatro (4) no período pós-operatório. Em dois pacientes não ocorreu melhora da dor. O arco de movimento do quadril aumentou em todos os pacientes, com exceção de dois. Na avaliação radiográfica evidenciamos um aumento no espaço articular de 2mm, em média, e que se manteve no pós-operatório. Não foram observadas complicações com a utilização da técnica. Apenas verificamos soltura dos pinos de Schanz da região do osso ilíaco em dois pacientes. A técnica operatória não ocasionou resultado satisfatório. CONCLUSÃO: O procedimento de artrodiastase está bem indicado para a recuperação da mobilidade em uma articulação coxofemoral comprometida e rígida, como ocorre em pacientes com artrite reumatoide juvenil.OBJECTIVE: To present the preliminary results of the use of hip arthrodiastasis in patients with juvenile rheumatoid arthritis and involvement of the hip joint. METHODS: A prospective study of 12 patients (six boys and six girls) aged between eight and 18 years (mean 10.5 years). We used a monolateral external fixator that allows flexion and extension at the hip. The external fixator was maintained for a period ranging from 78 to 90 days, with a mean of 86 days. Radiographic control was performed during surgery, weekly during the traction period, and every four weeks once this period was completed. The clinical evaluation of results included the degree of the pain and the degree of joint movement, measured and evaluatedpre-and post-operatively. The follow-up period ranged from 12 to 15 years, with a mean of 13 years. RESULTS: The average pain score was nine (9) before surgery and four (4) in the postoperative period. There was no improvement in pain in two patients. The range of motion of the hip increased in all patients except two. Radiographic evaluation evidenced a2 mm increase in joint space, on average,that has remained postoperatively. There were no complications with this technique. Only a loosening of the Schanz screws in the region of the iliac bone was observed in two patients. The surgical technique did not bring satisfactory results. CONCLUSION: The arthrodiastasis procedure is well suited for recovery of mobility in animpairedand rigid hip joint, as occurs in patients with juvenile rheumatoid arthritis

Correlação entre as alterações osteocondrais evidenciadas à ressonância magnética e a progressão da doença

PURPOSE: To determine the consequences of the chronic use of systemic corticosteroids in children with juvenile rheumatoid arthritis by means of evaluating osteochondral effects depicted by magnetic resonance imaging. PATIENTS AND METHODS: We reviewed clinical and magnetic resonance imaging findings in 69 children (72 knees) with juvenile rheumatoid arthritis. Two groups were studied. Group I: 34 (49.3%) children had previous or current use of systemic corticotherapy (22 girls; 12 boys; mean age: 11.3 years; mean disease duration: 5.9 years; mean corticotherapy duration: 2.9 years; mean cumulative dose of previous corticosteroids: 5000 mg); Group II: 35 (50.7%) children had no previous use of corticosteroids (27 girls; 8 boys; mean age: 11.7 years; mean disease duration: 5.3 years). The groups were compared statistically. RESULTS: In the group that had received corticotherapy (Group I), osteochondral abnormalities were significantly correlated to long-standing disease (>;3.5 years; pOBJETIVO: Determinar as conseqüências do uso crônico de corticosteróides sistêmicos em crianças com artrite reumatóide juvenil através da avaliação dos efeitos osteocondrais à ressonância magnética. PACIENTES E MÉTODOS: Achados clínicos e imaginológicos (ressonância magnética) de 72 joelhos em 69 crianças com artrite reumatóide juvenil foram revisados. Trinta e quatro (49.3%) pacientes fizeram uso prévio de corticoterapia sistêmica (22 pacientes do sexo feminino; 12 pacientes do sexo masculino; idade média: 11.3 anos; duração média da doença: 5.9 anos; duração média da corticoterapia: 2.9 anos; dose média cumulativa de corticosteróides: 5000 mg); 35 (50.7%) pacientes não haviam feito uso prévio de corticoterapia sistêmica (27 pacientes do sexo feminino; 8 pacientes do sexo masculino; idade média: 11.7 anos; duração média da doença: 5.3 anos). RESULTADOS: No grupo que recebeu corticoterapia sistêmica prévia (Grupo I) a presença de alterações osteocondrais à ressonância magnética relacionou-se de uma forma estatisticamente significativa com longo tempo de duração da doença (>;3.5 years;

Fator reumatóide-imunoglobulina E na artrite reumatóide juvenil

OBJECTIVES: To determine the presence of immunoglobulin E-rheumatoid factor in patients with juvenile rheumatoid arthritis and to correlate it with clinical and laboratory parameters. METHODS: A multicenter prospective study was carried out from January 1993 to January 1999 with the enrollment of 3 centers of pediatric rheumatology. Ninety-one children with juvenile rheumatoid arthritis diagnosed according to the American College of Rheumatology criteria were studied: 38 (42%) with systemic, 28 (31%) with pauciarticular, and 25 (27%) with polyarticular onset. Ages ranged from 2.1 years to 22.6 years (mean 10.5 ± 4.7), with 59 (65%) girls. The control group consisted of 45 healthy children. The detection of immunoglobulin E-rheumatoid factor was carried out utilizing an enzyme-linked immunosorbent assay. Associations of immunoglobulin E-rheumatoid factor with immunoglobulin M-rheumatoid factor (latex agglutination test), total serum immunoglobulin E, erythrocyte sedimentation rate, antinuclear antibody, and functional and radiological classes III or IV were analyzed. RESULTS: Positive immunoglobulin E-rheumatoid factor was found in 15 (16.5%) of the 91 children with juvenile rheumatoid arthritis: 7 (18.5%) with systemic, 5 (18%) with pauciarticular, and 3 (12%) with polyarticular onset. A significant correlation was observed between immunoglobulin E-rheumatoid factor and total serum immunoglobulin E in the juvenile rheumatoid arthritis patients. No correlation was found between immunoglobulin E-rheumatoid factor and positive latex agglutination slide test, erythrocyte sedimentation rate, antinuclear antibody, or the functional and radiological classes III or IV in any disease onset group. In 4 out of 45 control children (8.9%), immunoglobulin E-rheumatoid factor was positive but with no correlation with total serum immunoglobulin E levels. CONCLUSIONS: Immunoglobulin E-rheumatoid factor could be detected in 16.5% of juvenile rheumatoid arthritis patients, particularly in those with high levels of total serum immunoglobulin E, and immunoglobulin E-rheumatoid factor appears not to be associated with disease activity or severity.OBJETIVOS: Determinar os níveis séricos do fator reumatóide-imunoglobulina E na artrite reumatóide juvenil e correlacioná-los com parâmetros clínicos e laboratoriais. MÉTODOS: Estudo multicêntrico prospectivo, realizado entre janeiro de 1993 a janeiro de 1999 com participação de três centros de reumatologia pediátrica. Estudaram-se 91 crianças com o diagnóstico de artrite reumatóide juvenil de acordo com os critérios do Colégio Americano de Reumatologia: 38 (42%) com a forma de início sistêmica, 28 (31%) pauciarticular e 25 (27%) poliarticular. A idade variou de 2,1 a 22,6 anos (média de 10,5 ± 4,7 anos) e 59 (65%) crianças eram do sexo feminino. O grupo controle constituiu-se de 45 crianças sadias. A detecção do fator reumatóide-imunoglobulina E foi realizada através de um ensaio imunoenzimático. Associações do fator reumatóide-imunoglobulina E com: fator reumatóide-imunoglobulina M (látex), imunoglobulina E sérica total, VHS, FAN, classe funcional e radiológica III ou IV foram analisadas. RESULTADOS: Das 91 crianças com artrite reumatóide juvenil, quinze (16,5%) apresentaram fator reumatóide-imunoglobulina E positivo. Destas, 7(18,5%) na forma sistêmica, 5 (18%) na pauciarticular e 3 (12%) na poliarticular. Observou-se correlação estatisticamente significativa entre o fator reumatóide-imunoglobulina E e a média geométrica da imunoglobulina E sérica total no total dos pacientes com artrite reumatóide juvenil; não foi observada correlação estatística entre o fator reumatóide-imunoglobulina E e positividade para o Látex, VHS, FAN e classe funcional e radiológica 3 ou 4 em nenhuma das formas de início da doença. Dos 45 controles, 4 (8,9%) também apresentaram fator reumatóide-imunoglobulina E positivo, mas não houve correlação com a imunoglobulina E sérica total. CONCLUSÕES: O fator reumatóide-imunoglobulina E pode ser detectado em 16,5% dos pacientes com artrite reumatóide juvenil, especialmente naqueles com níveis elevados de imunoglobulina E sérica total. O fator reumatóide-imunoglobulina E parece não se associar com atividade ou gravidade da artrite reumatóide juvenil

Therapeutic depletion of CCR8+ tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy.

BACKGROUND: Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker. METHODS: We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models. RESULTS: We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4+ and CD8+ T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs. CONCLUSIONS: Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy

DataSheet1_Riparian Zones—From Policy Neglected to Policy Integrated.pdf

Supplementary Material for Frontiers in Environmental Science 10: 868527 (2022)1. Riparian zones are vital areas of interaction between land and rivers and are often degraded by several pressures such as urbanisation, intensive agriculture and river engineering works. 2. This policy brief provides five key policy messages and recommendations to be considered by policy-makers, scientists, managers, and stakeholders to enhance riparian zone management. 3. Adopting an integrated socio-economic and environmentally dynamic view will ensure the sustainable management of riparian zones. 4. In light of climate change, it is critically important to conserve and/or restore the ecological integrity of riparian zones. 5. European Union Directives and national-scale legislation and regulations need updating to ensure coordinated implementation of riparian zone-related policies. 6. Stakeholder knowledge exchange, policy co-creation and adaptive management are key to enhancing riparian zone functions.Peer reviewe