published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Lupus is a complex, poorly understood long-term disease in which the body's immune system mistakenly attacks healthy tissues of any part of the body. The disease mainly affects young women of childbearing age. Studies from developed countries show that the condition affects individuals physically, emotionally and socially. However, nothing is known about how having lupus has affected individuals living with the condition in the African continent. I explored how lupus had affected individuals living with the condition in Kenya from the time individuals began to feel unwell. I interviewed three groups of participants. 10 individuals who attended the public rheumatology clinic, 11 individuals who attended a private rheumatology clinic and 6 doctors who worked in the rheumatology clinics. The study found that some individuals delayed in getting medical help for their lupus. It appears to take a long time for individuals to get their lupus diagnosed due to organisation and staffing of the Kenyan health system. It was also perceived by individuals with lupus that treatment for the condition was difficult to access and it was also costly. Some individuals believed that their lupus had a supernatural cause. Often there appeared to be a lack of understanding of lupus by individuals who suffered from the condition; and also by others, some having experienced disapproval or negative feelings from others. Individuals with lupus reported lacking the financial resources and social support to manage their condition better. Lupus was affecting them physically, emotionally and had an impact on their social lives. There are a number of challenges in living with lupus in Kenya, including individuals' and others perception of the condition, but also how healthcare is provided to these individuals.

Introdução: A prolactina (PRL) exerce efeitos imunoestimulatórios in vitro e in vivo, porém a literatura é controversa quanto ao papel deste hormônio na atividade do Lúpus Eritematoso Sistêmico (LES). A macroprolactina possui menor atividade biológica in vivo e poderia explicar os resultados díspares. Objetivos: avaliar a prevalência de hiperprolactinemia e macroprolactinemia em pacientes lúpicas; analisar a correlação entre a atividade do LES e PRL, e interferência da macroprolactina nesta associação. Casuística e Métodos: Em 73 mulheres com LES ativo foi dosada a PRL pelo Immulite 2000®, e a macroprolactina pelo método do Polietilenoglicol (momento 1); em 62 destas pacientes foi colhida uma segunda amostra com a menor atividade do LES ao longo do tratamento (momento 2). Os controles foram 29 mulheres hígidas no menacme (grupo C) e 34 gestantes no terceiro trimestre (grupo G). Resultados: Houve 15 casos (20,55%) de hiperprolactinemia nas lúpicas, e nenhum entre as mulheres hígidas (p = 0,005). Todas as gestantes apresentaram hiperprolactinemia. A concentração de PRL foi maior (Med = 11,70 ng/ml) (p = 0,01) no LES do que no grupo C (Med = 8,81ng/ml), e correlacionou-se com a atividade da doença pelo SLEDAI (r = 0,41; p = 0,0003) no momento 1. No LES muito ativo os níveis de PRL foram maiores do que na doença inativa (Med = 17,10 ng/ml vs. Med = 8,36 ng/ml) (p< 0,01), e moderadamente ativa (Med = 7,75 ng/ml) (p < 0,05). Dentre as lúpicas hiperprolactinêmicas, 04 casos (26,7%) foram devidos à macroprolactina, e nas gestantes, 02 casos (5,9%). O LES foi tão ativo na macroprolactinemia quanto nos casos pela forma monomérica, porém a correlação entre PRL e SLEDAI foi maior para a PRL livre (r = 0,44; p = 0,0001). O tratamento das pacientes lúpicas hiperprolactinêmicas resultou em diminuição da concentração de PRL (Me momento 1 = 56,71 ± 43,87 ng/ml vs. Me momento 2 = 18,68 ± 24,20 ng/ml) (p = 0,015). Conclusões: pacientes lúpicas apresentam hiperprolactinemia mais frequentemente do que mulheres hígidas, e a PRL correlaciona-se com a atividade do LES. A macroprolactinemia não é marcador de doença inativa/pouco ativa. / Introduction: Prolactin (PRL) is a hormone with widespread influences in the cells of the immune system, which have been demonstrated by several in vitro and in vivo studies. However, the role of this hormone in the pathogenesis of Systemic Lupus Erythematosus (SLE) is controversial within the medical literature. The potentially lower biological activity of macroprolactin could explain the disparity of the results. Methods: PRL levels were determined by chemo luminescence method (Immulite 2000®) in 73 women with active SLE (group L), while the screening for macroprolactinemia was determined by the polyethylene glycol precipitation method (first moment). Sixty two of these patients had their PRL levels determined in a second occasion, when the disease was inactive or with the lowest activity observed after treatment (second moment). The control groups were 29 healthy women (group C) and 34 third-trimester healthy pregnant (group P). The levels of PRL were correlated with the SLE Disease Activity Index (SLEDAI). Results: In the study group there were 15 (20.55%) cases of hyperprolactinemia, while in the group C there were none (p = 0,005). All pregnant women presented hyperprolactinemia. Prolactin levels were higher in group L (Med = 11,70 ng/ml) then in group C (Med = 8,81ng/ml) (p = 0,01) and correlated with the SLEDAI in the first moment (r = 0,41; p = 0,0003). We also detected that PRL levels were higher at highly active SLE (SLEDAI ¡Ý 11) than when the disease was inactive (SLEDAI = 0) (Med = 17,10 ng/ml vs. Med = 8,36 ng/ml) (p< 0,01) or moderately active SLE (6 ¡Ü SLEDAI ¡Ü 10) (Med = 7,75 ng/ml) (p<0,05). In the 15 patients of group L with hyperprolactinemia, there were 04 cases of macroprolactinemia (26.7%), while 02 subjects in group P presented it (5.9%). SLE was as active in the patients with hyperprolactinemia caused by the monomeric form of the hormone, as in the ones with macroprolactinemia. The correlation of the PRL levels and the SLEDAI was, nevertheless, stronger for free PRL (r = 0,44; p = 0,0001). The SLE treatment in the hyperprolactinemic patients reduced PRL levels from 56,71 ng/ml (sd = 43,87) to 18,68 ng/ml (± 24,20) (p = 0,015). Discussion: the frequency of hyperprolactinemia is higher in SLE than in the general population, and the levels of PRL correlate with the activity of the disease. Macroprolactin is also associated to active SLE.

The presence of autoantibodies in systemic lupus erythematosus (SLE) suggests a breach of tolerance. Recently, the IgM-IgD+ naïve B cell population has been shown to be enriched for self-reactive cells that are anergic in healthy subjects. Therefore, to determine whether there is altered selection of self-reactive cells in SLE, this population was examined using multiparameter flow cytometry. SLE patients had increased proportions of IgM-IgD+ cells in mature and transitional B cell compartments that were activated as compared to controls. Comparison of mature and transitional IgM-IgD+ B cell proportions suggested altered selection between the transitional to mature stages in SLE. There was no correlation between altered B cell function or genetic polymorphisms in B cell signalling molecules and the expansion or activation of IgM-IgD+ cells. Thus, selection of self-reactive B cells appears to be abnormal in SLE, but this does not appear to result from altered responses to Ig crosslinking.

The presence of autoantibodies in systemic lupus erythematosus (SLE) suggests a breach of tolerance. Recently, the IgM-IgD+ naïve B cell population has been shown to be enriched for self-reactive cells that are anergic in healthy subjects. Therefore, to determine whether there is altered selection of self-reactive cells in SLE, this population was examined using multiparameter flow cytometry. SLE patients had increased proportions of IgM-IgD+ cells in mature and transitional B cell compartments that were activated as compared to controls. Comparison of mature and transitional IgM-IgD+ B cell proportions suggested altered selection between the transitional to mature stages in SLE. There was no correlation between altered B cell function or genetic polymorphisms in B cell signalling molecules and the expansion or activation of IgM-IgD+ cells. Thus, selection of self-reactive B cells appears to be abnormal in SLE, but this does not appear to result from altered responses to Ig crosslinking.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Genetic factors playing an important role in disease susceptibility have long been suggested. Transforming growth factor-beta (TGF-beta) regulates differentiation and proliferation of T cells. Therefore, it could be a candidate gene for the development of systemic lupus erythematosus. Allelic polymorphisms in TGF-beta promoter region (-988, -800, -509) and in exon 1 (codon 10 and codon 25) have been suggested to associate with SLE susceptibility. Allelic polymorphisms at positions -988, -800, -509, codon 10 and codon 25 on TGF-beta gene in 138 SLE patients and 182 healthy controls were analyzed in this study. TGF-beta polymorphisms were determined by PCR amplification and sequencing. With the previous polymorphic data of interleukin-4 (IL-4) -590 and interleukin-10 (IL-10) -819, associations of cytokine genotyoe and allele frequencies were analyzed. Results showed that there were differences in the genotype distribution of TGF-beta promoter region at position -509 and in the signal sequence at codon 10 (Leu¡÷Pro) between case and control groups in this study. However, no significant differences were found for all the TGF-beta polymorphisms. Allele frequency of IL-10 -819 was significantly associated with the susceptibility of SLE (p = 0.011). No significant associations were found between lupus nephritis with all the cytokine polymorphisms, but CNS involvement and lung involvement were associated with the polymorphisms studied in this research.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成5年9月14日 水谷大裕氏の博士論文として提出された

published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Research in Medicine