RESUMO
CD40 ligand deficiency (CD40L), currently classified as an inborn error of immunity affecting cellular and humoral immunity, prevalently emerges in boys within the first two years of life. It manifests itself as a decrease in serum IgG, IgA and IgE, with normal or high IgM, defects in T cell proliferation, and decrease in soluble CD40L. These accompany sinopulmonary and/or gastrointestinal infections, and there may be infections caused by pyogenic bacteria, opportunistic infections, autoimmune diseases, and neoplasms. Mild and moderate cases of this deficiency may respond well to prophylactic antibiotic therapy or to human immunoglobulin replacement therapy, in addition to the early treatment of infections. Severe cases can be treated with hematopoietic stem cell transplantation, which allows the healing of such patients, rather than sequelae and a poor progression. Thus, its differential diagnosis with other inborn errors of immunity is essential, especially CD40 deficiency and variable common immunodeficiency; the reason why we have proposed the present literature review.
Assuntos
Ligante de CD40/deficiência , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/diagnóstico , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/terapia , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/imunologia , MasculinoRESUMO
Following a fatal case of Cryptococcus neoformans meningitis in a child with X-linked hyper-immunoglobulin M syndrome (XHIGM), we evaluated the fungal isolate in an experimental infection in a mouse model with respect to microbiology, epidemiology, virulence and response to therapy. The minimum inhibitory concentrations for antifungals in the susceptibility test were 0.5mg/L for amphotericin B, 4.0mg/L for fluconazole and 0.12mg/L for voriconazole. Evaluation of pathogenicity by means of an experimental infection in BALB/c mice showed that fungus isolated from the blood and cerebrospinal fluid of the child was able to disseminate, reaching the spleen, lungs and brain, where it caused significant macroscopic alterations in the size and texture of each organ. Treatment of infected mice with amphotericin B reduced the fungal load in the spleen and lungs, but not in the brain.
Assuntos
Cryptococcus neoformans/isolamento & purificação , Cryptococcus neoformans/patogenicidade , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/complicações , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/microbiologia , Meningite Criptocócica/diagnóstico por imagem , Meningite Criptocócica/microbiologia , Anfotericina B/farmacologia , Animais , Antifúngicos/farmacologia , Pré-Escolar , Cryptococcus neoformans/efeitos dos fármacos , Modelos Animais de Doenças , Evolução Fatal , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/diagnóstico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Tomografia Computadorizada por Raios XRESUMO
CD40 ligand (CD40L) deficiency or X-linked hyper-IgM syndrome (X-HIGM) is a well-described primary immunodeficiency in which Pneumocystis jiroveci pneumonia is a common clinical feature. We have identified an unusual high incidence of fungal infections and other not yet described infections in a cohort of 11 X-HIGM patients from nine unrelated Brazilian families. Among these, we describe the first case of paracoccidioidomycosis (PCM) in X-HIGM. The molecular genetic analysis of CD40L was performed by gene sequencing and evaluation of CD40L protein expression. Nine of these 11 patients (82%) had fungal infections. These included fungal species common to CD40L deficiency (P. jiroveci and Candida albicans) as well as Paracoccidioides brasiliensis. One patient presented with PCM at age 11 years and is now doing well at 18 years of age. Additionally, one patient presented with a simultaneous infection with Klebsiella and Acinetobacter, and one with condyloma caused by human papilloma virus. Molecular analysis revealed four previously described CD40L mutations, two novel missense mutations (c.433 T > G and c.476 G > C) resulting in the absence of CD40L protein expression by activated CD4(+) cells and one novel insertion (c.484_485insAA) within the TNFH domain leading to a frame shift and premature stop codon. These observations demonstrated that the susceptibility to fungal infections in X-HIGM extends beyond those typically associated with X-HIGM (P. jiroveci and C. albicans) and that these patients need to be monitored for those pathogens.