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From immune phenotype to clinical manifestations in CVID
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Introdução: A Imunodeficiência Comum Variável (IDCV) constitui a causa mais frequente de imunodeficiência primária sintomática, caracterizada por hipogamaglobulinemia resultante de defeitos na diferenciação das células B periféricas e alterações das subpopulações de células T. A sua diversidade imunológica e clínica dificultam a investigação da fisiopatologia subjacente e a identificação de factores de prognóstico.
Material e métodos: Foram consultados os processos clínicos e os dados imunológicos de 60 doentes adultos (idade média 45 ± 13anos; duração média de follow-up de 8.5 anos, máximo 24 anos) em 2015. Focou-se posteriormente a análise num subgrupo de 29 doentes com avaliação clínica e imunológica detalhada em 2008. Além das subpopulações de células B, quantificou-se por citometria de fluxo o grau de activação das células T e a diminuição das células CD4 naïve e comparou-se com controlos saudáveis com idades semelhantes. Compararam-se ainda estes parâmetros em grupos IDCV divididos consoante as suas manifestações clínicas. Correlacionaram-se as manifestações clínicas e as alterações das subpopulações linfocitárias B e T e avaliou-se a estabilidade do fenótipo clínico durante o follow-up.
Resultados: A prevalência actual de manifestações clínicas não-infecciosas é muito elevada, sendo que unicamente 3 doentes apresentam apenas infecções. Não obstante, em 63% dos casos, as manifestações iniciais da IDCV foram infecções respiratórias recorrentes. Citopénias autoimunes, esplenomegália, adenopatias e proliferação linfóide estão associadas a níveis mais elevados de marcadores de activação de células T, perda de células T CD4 naïve e expansão de células B CD21lowCD38low. Demonstrou-se que o espectro das manifestações clínicas evolui apesar do tratamento de substituição com IgG.
Conclusões: São necessárias terapêuticas adicionais para limitar a progressão de complicações não-infecciosas. Actuar sobre as alterações das células T poderá ser uma estratégia a ser explorada na terapêutica destes doentes.
Introduction: Common Variable Immunodeficiency (CVID) represents the most frequent cause of symptomatic primary immunodeficiency, defined by hypogammaglobulinemia due to defects in peripheral B-cell differentiation and disturbances in T-cell subsets. The immunologic and clinical diversity of CVID hampers the discovery of underlying disease-causing mechanisms and clinical or laboratorial relevant prognostic factors. Material and methods: We reviewed medical records and immunological data of 60 adult patients, (mean age 45 ± 13years; mean length of follow-up 8.5 years, up to 24). We further focused our analysis in a subgroup of 29 patients from whom we have detailed clinical and immunological evaluations performed 7 years before. In addition to the standard B-cell populations, we extended flow-cytometric analysis to quantify the loss of naïve CD4 T-cells and degree of T-cell activation. We compared these parameters in CVID groups split according to the presence of a given clinical manifestation and evaluated the stability of the clinical phenotype, through the analysis of the largest adult cohort under follow-up in a portuguese Centre. Results: The current prevalence of non-infectious manifestations was remarkably high, and an infection-only profile was confined to 3 patients. Nevertheless, in 63% of the cases, the initial manifestations were recurrent respiratory infections. Autoimmune cytopenias, splenomegaly, adenopathies and lymphoid proliferation were associated with significantly higher levels of T-cell activation markers, naïve CD4 T-cell loss and expansion of CD21lowCD38low B-cells. We were able to show that throughout follow-up the spectrum of clinical manifestations expands despite IgG replacement treatment. Conclusions: Additional therapies are required to contain the emergence of non-infectious complications that are main determinants of morbidity in CVID patients. Our data support that the targeting of T-cell imbalances may be a therapeutic strategy to be explored in the management of these patients.
Introduction: Common Variable Immunodeficiency (CVID) represents the most frequent cause of symptomatic primary immunodeficiency, defined by hypogammaglobulinemia due to defects in peripheral B-cell differentiation and disturbances in T-cell subsets. The immunologic and clinical diversity of CVID hampers the discovery of underlying disease-causing mechanisms and clinical or laboratorial relevant prognostic factors. Material and methods: We reviewed medical records and immunological data of 60 adult patients, (mean age 45 ± 13years; mean length of follow-up 8.5 years, up to 24). We further focused our analysis in a subgroup of 29 patients from whom we have detailed clinical and immunological evaluations performed 7 years before. In addition to the standard B-cell populations, we extended flow-cytometric analysis to quantify the loss of naïve CD4 T-cells and degree of T-cell activation. We compared these parameters in CVID groups split according to the presence of a given clinical manifestation and evaluated the stability of the clinical phenotype, through the analysis of the largest adult cohort under follow-up in a portuguese Centre. Results: The current prevalence of non-infectious manifestations was remarkably high, and an infection-only profile was confined to 3 patients. Nevertheless, in 63% of the cases, the initial manifestations were recurrent respiratory infections. Autoimmune cytopenias, splenomegaly, adenopathies and lymphoid proliferation were associated with significantly higher levels of T-cell activation markers, naïve CD4 T-cell loss and expansion of CD21lowCD38low B-cells. We were able to show that throughout follow-up the spectrum of clinical manifestations expands despite IgG replacement treatment. Conclusions: Additional therapies are required to contain the emergence of non-infectious complications that are main determinants of morbidity in CVID patients. Our data support that the targeting of T-cell imbalances may be a therapeutic strategy to be explored in the management of these patients.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2016
Palavras-chave
Fenótipo Imunodeficiência de variável comum Imunologia