Interleucina-2 no tratamento adjuvante de paciente com linfocitopenia CD4 idiopática e tuberculose disseminada / Interleukin 2 as adjuvant treatment in a patient with idiopathic CD4 lymphocytopenia and disseminated tuberculosis

Linfocitopenia CD4 idiopática (LCI) é uma imunodeficiência rara e grave caracterizada por uma diminuição inexplicável da contagem absoluta de linfócitos T CD4, a qual está associada a infecções oportunistas. Existem poucos relatos de casos na literatura que descrevem a IL2 como uma opção terapêutica em infecções oportunistas associadas à LCI. Relatamos os benefícios da adição de IL2 ao tratamento padrão em um paciente com ICL e infecções oportunistas. Um homem de 38 anos de idade foi internado por acidente vascular cerebral isquêmico devido à vasculite infecciosa. A análise do líquido cefalorraquidiano mostrou meningite neutrofílica. Cultura e PCR foram positivos para Mycobacterium tuberculosis. A tomografia de tórax foi compatível com tuberculose pulmonar. O paciente também apresentava candidíase oral, onicomicose e dermatite seborreica. A contagem de células sanguíneas mostrou linfocitopenia. O tratamento padronizado para tuberculose disseminada (RIPE) e fluconazol foram iniciados e mantidos em casa após a alta do paciente. Após cinco meses de seguimento, o paciente foi encaminhado ao imunologista clínico, pois não apresentava melhora clínica significativa, tendo sido hospitalizado diversas vezes. A avaliação imunológica mostrou uma contagem sanguínea de CD4 T consistentemente inferior a 100 células/mm3 e o diagnóstico de LCI foi confirmado (linfocitopenia inexplicável com menos de 300 células/mm3 ou menos de 20% de células T CD4+ em mais de uma ocasião com pelo menos 2 meses de intervalo). O paciente também apresentava episódios raros de linfocitopenia de células B e hipogamaglobulinemia, tendo recebido gamaglobulina. Como tratamento adjuvante, a IL2 subcutânea foi associada ao tratamento padronizado. Até agora, o paciente recebeu cinco ciclos consecutivos de IL2, mostrando melhora clínica e aumento da contagem de células T CD4 no sangue, atingindo um valor máximo de 401 células/mm3. As células CD8, B e natural killer também aumentaram. Novas análises do líquido cefalorraquidiano foram normais, e a cultura de Mycobacterium tuberculosis e a PCR foram negativas. Nosso paciente com infecções oportunistas associadas à LCI apresentou evolução laboratorial e clínica favoráveis após a adição de IL2 ao tratamento padrão. Este relato de caso apoia o uso de IL2 como um coadjuvante seguro e potencialmente eficaz para infecções oportunistas associadas à LCI. O caso destaca a importância da avaliação e acompanhamento de pacientes com suspeita de imunodeficiência por imunoalergologistas.

Idiopathic CD4 T lymphocytopenia (ICL) is a rare and severe immunodeficiency disorder characterized by an unexplained decrease of absolute CD4 T-lymphocyte cell counts, which is associated with opportunistic infections. There are few case reports in the literature describing the use of interleukin 2 (IL2) as a therapeutic option in ICL-associated opportunistic infections. We report the benefits of adding IL2 to the standard treatment in a patient with ICL and opportunistic infections. A 38-year-old male patient was admitted with ischemic stroke due to infectious vasculitis. Cerebrospinal fluid analysis revealed neutrophilic meningitis. Culture and PCR were positive for Mycobacterium tuberculosis. Chest CT was compatible with pulmonary tuberculosis. The patient also presented oral candidiasis, onychomycosis, and seborrheic dermatitis. Blood cell count revealed lymphocytopenia. Standardized treatment for disseminated tuberculosis (RIPE therapy) and fluconazole were initiated and maintained at home after the patient's discharge. After five months of follow-up, the patient was referred to a clinical immunologist, due to the absence of significant clinical improvement, with multiple hospitalizations over the follow-up period. Immunological assessment showed CD4 T cell counts consistently below 100 cells/mm3, and the diagnosis of ICL was confirmed (unexplained lymphocytopenia with less than 300 cells/mm3 or less than 20% of CD4+ T cells on more than one occasion at least 2 months apart). The patient also presented rare episodes of B cell lymphocytopenia and hypogammaglobulinemia, treated with gammaglobulin. As an adjuvant treatment, subcutaneous IL2 was added to the standard treatment. So far the patient underwent five consecutive cycles of IL2, showing clinical improvement and increased CD4 T cell counts, reaching a maximum value of 401 cells/mm3. CD8, B and natural killer cells also increased. New cerebrospinal fluid analyses were normal, and new Mycobacterium tuberculosis culture and PCR were negative. Our patient had opportunistic infections associated with ICL and presented favorable laboratory and clinical outcomes after the association of IL2 to the standard treatment. This case report supports the use of IL2 as a safe and potentially effective adjuvant treatment for ICL-associated opportunistic infections. The case highlights the importance of immunological assessment and follow-up of patients with suspected immunodeficiency.

Inversion of the Vδ1 to Vδ2 γδ T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion.

Common variable immunodeficiency (CVID) is defined by low levels of IgG and IgA, but perturbations in T cells are also commonly found. However, there is limited information on γδ T cells in CVID patients. Newly diagnosed CVID patients (n = 15) were enrolled before and after intravenous IgG (IVIg) replacement therapy. Cryopreserved peripheral blood mononuclear cells were then used to study γδ T cells and CVID patients were compared to healthy controls (n = 22). The frequency and absolute count of Vδ1 γδ T cells was found to be increased in CVID (median 0.60% vs 2.64%, P <0.01 and 7.5 vs 39, P <0.01 respectively), while they were decreased for Vδ2 γδ T cells (median, 2.36% vs 0.74%, P <0.01 and 37.8 vs 13.9, P <0.01 respectively) resulting in an inversion of the Vδ1 to Vδ2 ratio (0.24 vs 1.4, P <0.001). Markers of immune activation were elevated on all subsets of γδ T cells, and HLA-DR expression was associated with an expansion of Vδ1 γδ T cells (r = 0.73, P = 0.003). Elevated PD-1 expression was found only on Vδ2 γδ T cells (median 1.15% vs 3.08%, P <0.001) and was associated with the decrease of Vδ2 γδ T cells (r = -0.67, P = 0.007). IVIg had no effect on the frequency of Vδ1 and Vδ2 γδ T cells or HLA-DR expression, but alleviated CD38 expression on Vδ1 γδ T cells (median MFI 965 vs 736, P <0.05). These findings suggest that immunological perturbations of γδ T cells are a general feature associated with CVID and are only partially reversed by IVIg therapy.

IL-10-Producing Regulatory B Cells Are Decreased in Patients with Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults. CVID patients often present changes in the frequency and function of B lymphocytes, reduced number of Treg cells, chronic immune activation, recurrent infections, high incidence of autoimmunity and increased risk for malignancies. We hypothesized that the frequency of B10 cells would be diminished in CVID patients because these cells play an important role in the development of Treg cells and in the control of T cell activation and autoimmunity. Therefore, we evaluated the frequency of B10 cells in CVID patients and correlated it with different clinical and immunological characteristics of this disease. Forty-two CVID patients and 17 healthy controls were recruited for this study. Cryopreserved PBMCs were used for analysis of T cell activation, frequency of Treg cells and characterization of B10 cells by flow cytometry. IL-10 production by sorted B cells culture and plasma sCD14 were determined by ELISA. We found that CVID patients presented decreased frequency of IL-10-producing CD24hiCD38hi B cells in different cell culture conditions and decreased frequency of IL-10-producing CD24hiCD27+ B cells stimulated with CpG+PIB. Moreover, we found that CVID patients presented lower secretion of IL-10 by sorting-purified B cells when compared to healthy controls. The frequency of B10 cells had no correlation with autoimmunity, immune activation and Treg cells in CVID patients. This work suggests that CVID patients have a compromised regulatory B cell compartment which is not correlated with clinical and immunological characteristics presented by these individuals.

Avaliação da frequência de linfócitos B reguladores produtores de IL-10 (B10) em pacientes com Imunodeficiência Comum Variável (ICV) / Evaluation of IL-10-producing regulatory B cells in patients with Common Variable Immunodeficiency (CVID)

A Imunodeficiência Comum Variável (ICV) é a imunodeficiência primária sintomática mais comum em adultos. Pacientes ICV frequentemente apresentam diversas alterações de linfócitos B, número reduzido de células Treg e ativação imune crônica, bem como infecções recorrentes, alta incidência de doenças autoimunes e um risco aumentado de doenças malignas. Testamos a hipótese de que a frequência de células B10 estaria diminuída nos pacientes ICV, já que elas desempenham um importante papel no desenvolvimento de células Treg, no controle da ativação de células T e na autoimunidade. Para tanto, nós avaliamos a frequência de células B10 em pacientes ICV buscando correlacioná-la com as diferentes manifestações clínicas e imunológicas associadas à doença. Quarenta e dois (42) pacientes com diagnóstico de ICV e 17 indivíduos saudáveis foram convidados a participar do estudo. A partir das CMSP criopreservadas foram realizados testes de perfil de ativação celular, presença de células T reguladoras (Treg) e caracterização das células B10. Os níveis de sCD14 no plasma foram determinados por ELISA. A produção de IL-10 foi determinada por ELISA em sobrenadante de cultura de células B. Pacientes ICV apresentam frequência diminuída de células B CD24hiCD38hi produtoras de IL-10 em diferentes condições de cultura celular e frequência diminuída de células B CD24hiCD27+ em cultura celular estimulada por CpG+PIB. No entanto, a produção de IL-10 por células B não demonstrou diferença significativa entre pacientes ICV e controles. A frequência de células B10 não teve correlação com a presença de autoimunidade, ativação celular ou frequência de células Treg em pacientes ICV. Este trabalho sugere que pacientes ICV têm um comprometimento na subpopulação de células B reguladoras, mas que não está correlacionado com as características clínicas e imunológicas apresentadas por esses indivíduos.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults. CVID patients often present changes in the frequency and function of B lymphocytes, reduced number of Treg cells, chronic immune activation, recurrent infections, high incidence of autoimmunity and increased risk for malignancies. We hypothesized that the frequency of B10 cells would be diminished in CVID patients because these cells play an important role in the development of Treg cells and in the control of T cell activation and autoimmunity. Therefore, we evaluated the frequency of B10 cells in CVID patients and correlated it with the different clinical and immunological characteristics of this disease. Forty-two CVID patients and 17 healthy controls were recruited for this study. Cryopreserved PBMCs were used for analysis of T cell activation, frequency of Treg cells and characterization of B10 cells by flow cytometry. Plasma sCD14 levels were determined by ELISA. IL-10 production was determined in supernatant by ELISA after culture of B cells. We found that CVID patients presented a decreased frequency of IL-10-producing CD24hiCD38hi B cells in different cell culture conditions and decreased frequency of IL-10-producing CD24hiCD27+ B cells stimulated with CpG+PIB. However, the B cells secretion of IL-10 was similar between CVID patients and healthy controls. The frequency of B10 cells had no correlation with autoimmunity, immune activation and Treg cells in CVID patients. This work suggests that CVID patients have a compromised regulatory B cell compartment which is not correlated with clinical and immunological characteristics presented by these individuals.