Reduced G protein signaling despite impaired internalization and ß-arrestin recruitment in patients carrying a CXCR4Leu317fsX3 mutation causing WHIM syndrome.

WHIM syndrome is an inherited immune disorder caused by an autosomal dominant heterozygous mutation in CXCR4. The disease is characterized by neutropenia/leukopenia (secondary to retention of mature neutrophils in bone marrow), recurrent bacterial infections, treatment-refractory warts, and hypogammaglobulinemia. All mutations reported in WHIM patients lead to the truncations in the C-terminal domain of CXCR4, R334X being the most frequent. This defect prevents receptor internalization and enhances both calcium mobilization and ERK phosphorylation, resulting in increased chemotaxis in response to the unique ligand CXCL12. Here, we describe 3 patients presenting neutropenia and myelokathexis, but normal lymphocyte count and immunoglobulin levels, carrying what we believe to be a novel Leu317fsX3 mutation in CXCR4, leading to a complete truncation of its intracellular tail. The analysis of the L317fsX3 mutation in cells derived from patients and in vitro cellular models reveals unique signaling features in comparison with R334X mutation. The L317fsX3 mutation impairs CXCR4 downregulation and ß-arrestin recruitment in response to CXCL12 and reduces other signaling events - including ERK1/2 phosphorylation, calcium mobilization, and chemotaxis - all processes that are typically enhanced in cells carrying the R334X mutation. Our findings suggest that, overall, the L317fsX3 mutation may be causative of a form of WHIM syndrome not associated with an augmented CXCR4 response to CXCL12.

[Hodgkin's Lymphoma and Autoimmunity: Is There a Relationship?]. / Linfoma de Hodgkin e Autoimunidade: Existirá uma Relação?

INTRODUCTION: The relationship between lymphomas and autoimmune diseases has been reported as bi-directional, however there is a few data in pediatric population. The aim of this work is to evaluate the prevalence of autoimmune diseases in children and adolescents with Hodgkin's lymphoma followed in a Pediatric Oncology Unit. MATERIAL AND METHODS: By reviewing Hodgkin's lymphomas data from the past 16 years (collected prospectively), an apparently large incidence of autoimmune diseases, mostly in female patients, was noted. We decided to do this retrospective study with an update on follow-up. Data analyzed: age, gender, autoimmune disease, temporal relation with lymphoma, lymphoma's stage, histologic subtype and treatment. RESULTS: Fifty-two cases were included, 7 (13.5%) of which, all female, had an autoimmune disease diagnosed previously, simultaneously or after lymphoma. Autoimmune diseases were: juvenile idiopathic arthritis, inflammatory bowel disease, Behçet's disease, autoimmune hepatitis, systemic erythematosus lupus, Hashimoto's thyroiditis and idiopathic thrombocytopenic purpura. The diagnosis was made after lymphoma in 4 patients, before in 2 and simultaneously in 1 patient. All cases, except the one with simultaneous diagnosis, are out of treatment and without oncologic disease relapse. No deaths were registered. DISCUSSION: There was an important prevalence of autoimmune diseases in girls with Hodgkin's lymphoma. We present data and discuss the possible causes based on a literature review. CONCLUSIONS: This relationship should be invoked, requiring more studies, especially in pediatric age.

Introdução: A relação entre linfomas e doenças autoimunes é descrita na literatura como bidirecional, existindo poucos dados em idade pediátrica. Este trabalho tem como objetivo avaliar a prevalência de doenças autoimunes em crianças e adolescentes com linfoma de Hodgkin seguidos num Serviço de Oncologia Pediátrica. Material e Métodos: Ao rever a casuística do Serviço de linfomas de Hodgkin nos últimos 16 anos (dados colhidos prospetivamente), constatou-se uma incidência aparentemente elevada de doenças autoimunes nas raparigas pelo que se realizou um estudo retrospetivo, com atualização do seguimento fora de tratamento, relativamente à existência de doenças autoimunes. Avaliaram-se: idade, sexo, tipo de doença autoimune, relação temporal com o linfoma, estádio e grupo histológico do linfoma e terapêutica efetuada. Resultados: Incluíram-se 52 casos de linfoma de Hodgkin, dos quais sete (13,5%), todos do sexo feminino, tiveram uma doença autoimune diagnosticada previamente, em simult'neo ou posteriormente ao linfoma. As doenças autoimunes encontradas foram: artrite idiopática juvenil, doença inflamatória intestinal, doença de Behçet, hepatite autoimune, lúpus eritematoso sistémico, tiroidite de Hashimoto e púrpura trombocitopénica idiopática. Em quatro doentes o diagnóstico foi posterior ao linfoma, em dois, prévio, e num simult'neo. Todos os casos, exceto o diagnóstico simult'neo, estão fora de tratamento e sem recidiva da doença oncológica. Não se verificaram óbitos. Discussão: Verificou-se uma importante prevalência de doenças autoimunes nas raparigas com linfoma de Hodgkin. Apresentamos os dados e discutimos possíveis causas desta relação com base numa revisão bibliográfica. Conclusões: Esta associação deve ser evocada, sendo necessário mais estudos, sobretudo em idade pediátrica.

Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential.

Fanconi anaemia (FA) is an inherited disorder characterized by chromosomal instability. The phenotype is variable, which raises the possibility that it may be affected by other factors, such as epigenetic modifications. These play an important role in oncogenesis and may be pharmacologically manipulated. Our aim was to explore whether the epigenetic profiles in FA differ from non-FA individuals and whether these could be manipulated to alter the disease phenotype. We compared expression of epigenetic genes and DNA methylation profile of tumour suppressor genes between FA and normal samples. FA samples exhibited decreased expression levels of genes involved in epigenetic regulation and hypomethylation in the promoter regions of tumour suppressor genes. Treatment of FA cells with histone deacetylase inhibitor Vorinostat increased the expression of DNM3Tß and reduced the levels of CIITA and HDAC9, PAK1, USP16, all involved in different aspects of epigenetic and immune regulation. Given the ability of Vorinostat to modulate epigenetic genes in FA patients, we investigated its functional effects on the FA phenotype. This was assessed by incubating FA cells with Vorinostat and quantifying chromosomal breaks induced by DNA cross-linking agents. Treatment of FA cells with Vorinostat resulted in a significant reduction of aberrant cells (81% on average). Our results suggest that epigenetic mechanisms may play a role in oncogenesis in FA. Epigenetic agents may be helpful in improving the phenotype of FA patients, potentially reducing tumour incidence in this population.

Isolated anaemia as a manifestation of Rh isoimmunisation.

Rh isoimmunisation leads to haemolytic anaemia and hyperbilirubinaemia in the first h of life. Isolated early onset neonatal anaemia has rarely been reported. The authors describe the case of a term infant, born to an 'A' negative, second gravida mother. On the second day of life, pallor was noticed. His haemoglobin (Hb) was 6.8 g/dl, he had reticulocytosis and a positive direct antiglobulin test. However, he did not have a high total serum bilirubin (TSB) (87.2 µmol/l). He was transfused with red blood cells and kept under phototherapy for 3 days. Three weeks later, he received another transfusion for severe anaemia (Hb 6 5 g/dl). During this period, he was never jaundiced and the maximum level of TSB was 122 µmol/l. On follow-up, his Hb stabilised and he had no further problems. This report highlights the possibility of early onset anaemia without jaundice as the sole manifestation of Rh isoimmunisation.