RESUMO
BACKGROUND: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. OBJECTIVE: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. METHODS: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. RESULTS: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. CONCLUSION: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
Assuntos
Antígeno CTLA-4/genética , Mutação em Linhagem Germinativa , Síndromes de Imunodeficiência/terapia , Adolescente , Adulto , Agamaglobulinemia/etiologia , Idoso , Doenças Autoimunes/etiologia , Antígeno CTLA-4/deficiência , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/genética , Lactente , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto JovemRESUMO
Patients with CTLA4 mutations present with autoimmune diseases, lymphoproliferation, and hypogammaglobulinemia, and a subset of patients developed Epstein-Barr virus (EBV)-associated malignancies, suggesting an impaired immune function against EBV. Here we investigated EBV infection in individuals with CTLA4 mutations. We measured EBV viral DNA in healthy individuals, individuals with autoimmune diseases, and individuals with CTLA4 mutations. In addition, we evaluated the numbers and function of EBV-specific T cells, invariant NKT cells, and NK cells. More than half of individuals with CTLA4 mutations including asymptomatic ones had detectable EBV DNA, which is a significantly higher frequency with higher viral loads compared with healthy and disease controls. However, individuals with CTLA4 mutations had almost normal immunity against EBV. Individuals with CTLA4 mutations have an increased susceptibility to Epstein-Barr virus infections. Asymptomatic viremia occurs at high frequencies, which can be persistent and can occur in unaffected individuals.
Assuntos
Doenças Autoimunes/genética , Antígeno CTLA-4/genética , DNA Viral/análise , Infecções por Vírus Epstein-Barr/genética , Predisposição Genética para Doença , Herpesvirus Humano 4/fisiologia , Viremia/genética , Adolescente , Doenças Assintomáticas , Células Cultivadas , Criança , Feminino , Estudos de Associação Genética , Humanos , Imunidade Celular/genética , Japão , Masculino , Mutação , PrevalênciaRESUMO
A 16-year-old boy was incidentally found to have hyperleukocytosis during a school physical examination. He was diagnosed with atypical chronic myeloid leukemia in chronic phase. Although treatment with hydoxyurea was started, his white blood cell count increased and he eventually developed lethal intracranial hemorrhage. Although very rare, intracranial hemorrhage should be considered as a possible complication in patients with atypical chronic myeloid leukemia, even in chronic phase, if they have hyperleukocytosis and thrombocytopenia.