Clinical and Genetic Spectrum of Inborn Errors of Immunity in a Tertiary Care Center in Southern India

Objectives To study the incidence, clinical manifestations, and genetic spectrum of primary immunodefciency diseases (PID)/inborn errors of immunity (IEI) in a tertiary care hospital in Southern India. Methods A retrospective analysis of all patients with a clinical suspicion of PID/IEI seen at a tertiary care hospital was performed. All patients had at least one or more warning signs of PID. Serum immunoglobulin levels and other targeted investigations were performed as warranted by the clinical presentation. All families with suspected PID were counseled and ofered genetic testing. Results A total of 225 children were evaluated for PID during the study period of 6 y. Fifty-six of them did not meet the European Society of Immunodefciencies (ESID) criteria (working defnition of clinical diagnosis) and were excluded. An IEI was found in 30/49 (61.2%) patients. The most frequent reason for referral was recurrent/unusual or serious infections (28%), or cytopenia (16%). Group IV diseases of immune dysregulation was the most common category (19%), followed by group III predominant antibody defciencies in 23/163 (14%), as per the International Union of Immunological Societies (IUIS) classifcation. Conclusions This study highlights the heterogeneity of the present cohort, the underuse of genetic tests, and eforts to provide optimal care for children with possible IEI in this center.

Síndromes MonoMAC e Emberger em paciente com mutação no gene GATA2 / MonoMAC and Emberger syndromes in a patient with GATA2 mutation

As mutações que ocorrem no gene GATA2 podem ocasionar um amplo espectro de doenças genéticas. Os pacientes podem ter anormalidades na hematopoiese, na linfangiogenesis e na resposta imunológica. Os fenótipos incluem algumas síndromes caracterizadas por monocitopenia e infecção por micobactéria (síndrome MonoMac), síndrome mielodisplásica familiar, leucemia mieloide crônica ou aguda, síndrome de Emberger (linfedema primário), e mais raramente neutropenia, anemia aplástica e deficiência isolada de células NK. A idade da apresentação clínica pode variar desde a infância até a idade adulta. A deficiência autossômica dominante de GATA2 pode permanecer clinicamente silenciosa por décadas, ou mesmo durante toda a vida. Descrevemos o caso de uma jovem brasileira que apresentou a maioria dos problemas ligados à mutação no gene GATA2, observando-se as duas síndromes: MonoMAC e Emberger.

GATA2 mutations may cause a wide spectrum of genetic disorders. Patients may have several abnormalities in hematopoiesis, lymphangiogenesis and immune response. The phenotypes include monocytopenia and mycobacterial infection (MonoMAC) syndrome, familial myelodysplastic syndrome (MDS), chronic or acute myeloid leukemia (CML or AML), Emberger syndrome and, more rarely, neutropenia, aplastic anemia and isolated NKcell deficiency. Age at clinical onset ranges from early childhood to late adulthood. Autosomal dominant GATA2 deficiency may remain clinically silent for decades or even for life. We report a case of a Brazilian young patient who had most of the problems related to GATA2 mutation as well as MonoMAC and Emberger syndromes.

Papel do fator nuclear kappa B (NF-κB) na expressâo do gene NCF1 em leucócitos de indivíduos normais, e pacientes com doença granulomatosa crônica, displasia ectodérmica anidrótica, ou com defeitos no eixo IL-12/23-IFN-γ / Role of nuclear factor kappa B (NF-κB) on NCF1 gene expression in leukocytes from normal individuals, and patients with chronic granulomatous disease, anhidrotic ectodermal dysplasia, or with defects in the IL-12/23/IFN-γ axis

Objetivo: Analisamos a relevância do NF-κB sobre a expressão do gene NCF1 em células mielóides U937 selvagens (U937) ou transfectadas com um repressor do NF-κB (IκBα-S32A/S36A - U937 IκBα-S32A/S36A) ou transfectadas com o vetor vazio (U937 pCMV3) e em células B imortalizadas pelo vírus Epstein-Barr (EBV) de pacientes com displasia ectodérmica anidrótica com imunodeficiência (EDA-ID) ou com doença granulomatosa crônica (CGD) devido a mutações no gene NCF1, ou de pacientes portadores de defeitos do eixo IL-12/ 23-IFN-γ. Métodos: O RNA celular total foi isolado pelo método TRI-zol®. Os cDNAs foram produzidos utilizando-se o SuperScript™ III e amplificados por Real-time PCR (SYBR® Green Master Mix). Resultados: Células U937 IKBα-S32A/S36A mostraram significante decréscimo na expressão do gene NCF1 comparadas com as células U937. A expressão do gene NCF1 em células EDA-ID S32I foi significativamente menor que em controles saudáveis, assim como em células EDA-ID NEMO/IKKγ X420W na mesma comparação. Estes resultados foram similares aos encontrados em células de pacientes CGD devido à mutação autossômica recessiva no gene NCF1 quando comparados com o controle normal. Defeitos nos receptores IFNGR1 e IFNGR2 levam à diminuição da expressão do gene NCF1 (p<0,05, Mann Whitney). Conclusões: Estes resultados mostram que o NF-κB é necessário para a expressão do gene NCF1, que possivelmente as subunidades p50 e/ou p65 do NF-κB ligam-se funcionalmente à região "upstream" do gene NCF1 e que defeitos no eixo IL-12/ 23-IFN-γ influenciam a expressão do gene NCF1.

Objective: We analyzed the relevance of NF-κB on NCF1 gene expression in regular myeloid U937 cells (U937), or transfected with a NF-κB repressor (IκBo-S32A/S36A - U937 IκBo-S32A/S36A), or transfected with the empty vector (U937 pCMV3), and in B cells immortalized by Epstein-Barr vírus (EBV) from patients with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), or with chronic granulomatous desease (CGD) due to mutations in NCF1 gene, or from patients with IL-12/23-IFN-γ axis defects. Methods: Total RNA was isolated by the TRIzol® method. The cDNAs were produced by Super Script™ III and amplified by Real-time PCR (SYBR Green Master Mix). Results: U937 IκBo-S32A/S36A cells showed significant decrease in the NCF1 gene expression compared with the U937 cells. The NCF1 gene expression was significantly lower in EDA-ID S32I cells compared to healthy controls as well as in EDA-ID NEMO/IKKy X420W cells. These results were similar to those obtained in the CGD patient cells due recessive mutations in the NCF1 gene compared to healthy controls. Cells form patients with defects in IFNGR1 e IFNGR2 receptors also presented decreased NCF1 gene expression (p<0,05, Mann Whitney). Conclusion: These results show that the NF-κB is necessary for NCF1 expression, possibly the p50 and/or p65 NF-κB subunits bind functionally to the upstream region of the NCF1 gene and that IL-12/23-IFN-γ axis defects also influence NCF1 gene expression.

Infección diseminada por BCG en la Región de Los Lagos, Chile: reporte de cinco casos clínicos / Disseminated infection by BCG in Región de Los Lagos, Chile: five cases report

The bacillus Calmette-Guerin (BCG) is the attenuated strain of Mycobacterium bovis used in developing countries for preventing serious forms of tuberculosis. The neonatal BCG vaccine is applied in countries with high prevalence of tuberculosis. Most of the vaccinated individuals develop no adverse reactions; although, some subjects show side effects due to a host altered immunity. These reactions range from a simple adenomegaly in the same side of BCG vaccine inoculation, to a spread infection, often fatal. A regional or systemic spread has been described in patients with secondary or primary immunodeficiencies and partial or total genetic defects of interleukin IL-12/23 and IFN-gamma called as a whole "Mendelian susceptibility to mycobacterial infections" (MSMD). We describe five patients infected with M. bovis BCG-diagnosed between 1995-2008, at the base hospital in the city of Puerto Montt, Region de Los Lagos, Chile. These patients have the clinical course of MSMD.

El bacilo Calmette-Guérin (BCG), es la cepa atenuada de Mycobacterium bovis utilizada en países en vías de desarrollo para la prevención de formas graves de tuberculosis. La vacuna BCG neonatal se administra en países con alta prevalencia de la enfermedad. La mayoría de los vacunados no presenta reacciones adversas, algunos evidencian reacciones secundarias a una inmunidad alterada del huésped. Dichas reacciones varían desde una simple adenomegalia ipsilateral a la inoculación de BCG, hasta una infección diseminada, a menudo mortal. La infección diseminada se ha descrito en pacientes inmuno deficientes secundarios, primarios y en pacientes con defectos genéticos del eje interleuquina 12-23 (IL12/23)-interferón gama (IFN-gamma ) denominados "Síndrome de predisposición mendeliana a infecciones micobacterianas" (PMIM). Describimos cinco pacientes con infección por M. bovis-BCG diagnosticados entre 1995-2008, en el Hospital Base de Puerto Montt, Región de Los Lagos, Chile que cumplen con los criterios del PMIM.