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

Increased Fas and Bcl-2 Expression on Peripheral Blood T and B Lymphocytes from Juvenile-Onset Systemic Lupus Erythematosus, but not from Juvenile Rheumatoid Arthritis and Juvenile Dermatomyositis

Defective regulation of apoptosis may play a role in the development of autoimmune diseases. Fas and Bcl-2 proteins are involved in the control of apoptosis. The aims of this study were to determine the expression of Fas antigen and Bcl-2 protein on peripheral blood T and B lymphocytes from patients with juvenile-onset systemic lupus erythematosus (JSLE), juvenile rheumatoid arthritis (JRA) and juvenile dermatomyositis (JDM). Thirty-eight patients with JSLE, 19 patients with JRA, 10 patients with JDM and 25 healthy controls entered the study. Freshly isolated peripheral blood mononuclear cells (PBMC) were stained for lymphocyte markers CD3, CD4, CD8, CD19 and for Fas and Bcl-2 molecules. Expressions were measured by three-color flow cytometry. Statistical analysis was performed using Kruskal–Wallis test. Percentages of freshly isolated T lymphocytes positively stained for Fas protein from JSLE patients were significantly increased compared to healthy controls, patients with JRA and patients with JDM. Percentages of B lymphocytes positive for Fas from JSLE patients were higher than healthy controls and JRA patients. In addition, Fas expression on T cells from patients with JRA was increased compared to JDM patients. Otherwise, Fas expression on T and B cells from JRA and JDM patients were similar to healthy controls. MFI of Bcl-2 positive T lymphocytes from JSLE patients were significantly increased compared to healthy controls and JRA patients. MFI of Bcl-2 protein on B lymphocytes from JSLE patients was similar to healthy controls and patients with JRA and JDM. Bcl-2 expression did not differ between JRA and JDM patients and healthy controls. In conclusion, increased expression of Fas and Bcl-2 proteins observed in circulating T and B lymphocytes from patients with JSLE, but not from patients with JRA and JDM, suggests that abnormalities of apoptosis may be related to the pathogenesis of JSLE and probably are not a result of chronic inflammation

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

Increased IgE serum levels are unrelated to allergic and parasitic diseases in patients with juvenile systemic lupus erythematosus

OBJECTIVE: The aim of this study was to assess the IgE serum levels in juvenile systemic lupus erythematosus patients and to evaluate possible associations with clinical and laboratory features, disease activity and tissue damage. METHODS: The IgE serum concentrations in 69 consecutive juvenile systemic lupus erythematosus patients were determined by nephelometry. IgG, IgM and IgA concentrations were measured by immunoturbidimetry. All patients were negative for intestinal parasites. Statistical analysis methods included the Mann-Whitney, chi-square and Fisher's exact tests, as well as the Spearman rank correlation coefficient. RESULTS: Increased IgE concentrations above 100 IU/mL were observed in 31/69 (45%) juvenile systemic lupus erythematosus patients. The mean IgE concentration was 442.0 +/- 163.4 IU/ml (range 3.5- 9936.0 IU/ml). Fifteen of the 69 patients had atopic disease, nine patients had severe sepsis and 56 patients presented with nephritis. The mean IgE level in 54 juvenile systemic lupus erythematosus patients without atopic manifestations was 271.6 +/- 699.5 IU/ml, and only nine of the 31 (29%) patients with high IgE levels had atopic disease. The IgE levels did not statistically differ with respect to the presence of atopic disease, severe sepsis, nephritis, disease activity, or tissue damage. Interestingly, IgE concentrations were inversely correlated with C4 levels ( r = -0.25, p = 0.03) and with the SLICC/ACR-DI score (r = -0.34, p = 0.005). The IgE concentration was also found to be directly correlated with IgA levels (r = 0.52, p = 0.03). CONCLUSIONS: The present study demonstrated for the first time that juvenile systemic lupus erythematosus patients have increased IgE serum levels. This increase in IgE levels was not related to allergic or parasitic diseases. Our results are in line with the hypothesis that high IgE levels can be considered a marker of immune dysregulation.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) [08/58238

Risk factors associated with calcinosis of juvenile dermatomyositis

OBJETIVO: Identificar fatores de risco associados à calcinose em crianças e adolescentes com dermatomiosite juvenil. MÉTODOS: Prontuários de 54 pacientes com dermatomiosite juvenil foram estudados. Foram avaliados dados demográficos; características clínicas: grau de força muscular (I a V do Medical Research Council), presença de comprometimentos pulmonar (distúrbio ventilatório restritivo com presença ou ausência do anticorpo anti-Jo-1), gastrointestinal (refluxo gastroesofágico) e cardíaco (pericardite e/ou miocardite); exames laboratoriais: elevação de enzimas musculares (creatinoquinase, aspartato aminotransferase, alanina aminotransferase e desidrogenase lática) e terapias utilizadas: corticoterapia isolada ou associada à cloroquina e/ou imunossupressor. Os pacientes foram divididos em dois grupos de acordo com a presença ou ausência de calcinose e foram avaliados através de análise univariada e multivariada. RESULTADOS: Calcinose foi evidenciada em 23 (43%) pacientes, sendo em seis (26%) antes do diagnóstico e em 17 (74%) após. A análise univariada revelou que comprometimentos cardíaco (p = 0,01) e pulmonar (p = 0,02) e necessidade da utilização de um ou mais imunossupressores (metotrexato, ciclosporina A e/ou pulsoterapia com ciclofosfamida endovenosa) no tratamento da dermatomiosite juvenil (p = 0,03) foram associados com uma maior incidência de calcinose. A análise multivariada mostrou que comprometimento cardíaco (OR = 15,56; IC95% 1,59-152,2) e uso de um ou mais imunossupressores (OR = 4,01; IC95% 1,08-14,87) foram as únicas variáveis independentes associadas à presença de calcinose. CONCLUSÕES: O aparecimento da calcinose foi freqüente na dermatomiosite juvenil, habitualmente na evolução da doença. A calcinose foi associada aos casos mais graves, que apresentaram envolvimento cardíaco e necessitaram da utilização de imunossupressores no seu tratamento.OBJECTIVE: To identify risk factors associated with calcinosis in children and adolescents with juvenile dermatomyositis. METHODS: A review was carried out of the medical records of 54 patients with juvenile dermatomyositis. Data were collected on demographic characteristics, clinical features: muscle strength (stages I to V of the Medical Research Council scale), pulmonary involvement (restrictive pulmonary disease with presence or absence of anti-Jo1 antibodies), gastrointestinal problems (gastroesophageal reflux) and/or heart disease (pericarditis and/or myocarditis); laboratory tests: elevated muscle enzyme levels in serum (creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase and/or lactate dehydrogenase); and on the treatments given: corticoid therapy in isolation or associated with hydroxychloroquine and/or immunosuppressants. The patients were divided into two groups, depending on presence or absence of calcinosis and data were evaluated by both univariate and multivariate analyses. RESULTS: Calcinosis was identified in 23 (43%) patients, and in six (26%) patients it had emerged prior to diagnosis while in 17 (74%) it was post diagnosis. The univariate analysis revealed that cardiac (p = 0.01) and pulmonary (p = 0.02) involvement and the need for one or more immunosuppressor (methotrexate, cyclosporine A and/or pulse therapy with intravenous cyclophosphamide) to treat juvenile dermatomyositis (p = 0.03) were all associated with an increased incidence of calcinosis. The multivariate analysis then demonstrated that only cardiac involvement (OR = 15.56; 95%CI 1.59-152.2) and the use of one or more immunosuppressor (OR = 4.01; 95%CI 1.08-14.87) were independently associated with the presence of calcinosis. CONCLUSIONS: Calcinosis was a frequent development among these juvenile dermatomyositis cases, generally emerging as the disease progressed. Calcinosis was associated with the more severe cases that also had cardiac involvement and where immunosuppressors had to be included in the treatment

Increased IgE serum levels are unrelated to allergic and parasitic diseases in patients with juvenile systemic lupus erythematosus

OBJECTIVE: The aim of this study was to assess the IgE serum levels in juvenile systemic lupus erythematosus patients and to evaluate possible associations with clinical and laboratory features, disease activity and tissue damage. METHODS: The IgE serum concentrations in 69 consecutive juvenile systemic lupus erythematosus patients were determined by nephelometry. IgG, IgM and IgA concentrations were measured by immunoturbidimetry. All patients were negative for intestinal parasites. Statistical analysis methods included the Mann-Whitney, chi-square and Fisher's exact tests, as well as the Spearman rank correlation coefficient. RESULTS: Increased IgE concentrations above 100 IU/mL were observed in 31/69 (45%) juvenile systemic lupus erythematosus patients. The mean IgE concentration was 442.0 ± 163.4 IU/ml (range 3.5-9936.0 IU/ml). Fifteen of the 69 patients had atopic disease, nine patients had severe sepsis and 56 patients presented with nephritis. The mean IgE level in 54 juvenile systemic lupus erythematosus patients without atopic manifestations was 271.6 ± 699.5 IU/ml, and only nine of the 31 (29%) patients with high IgE levels had atopic disease. The IgE levels did not statistically differ with respect to the presence of atopic disease, severe sepsis, nephritis, disease activity, or tissue damage. Interestingly, IgE concentrations were inversely correlated with C4 levels (r = -0.25, p = 0.03) and with the SLICC/ACR-DI score (r = -0.34, p = 0.005). The IgE concentration was also found to be directly correlated with IgA levels (r = 0.52, p = 0.03). CONCLUSIONS: The present study demonstrated for the first time that juvenile systemic lupus erythematosus patients have increased IgE serum levels. This increase in IgE levels was not related to allergic or parasitic diseases. Our results are in line with the hypothesis that high IgE levels can be considered a marker of immune dysregulation