Diagnóstico tardío de síndrome WHIM / Late diagnosis of WHIM sydrome

El síndrome WHIM es una inmunodeficiencia primaria de herencia autosómica dominante, debida a mutaciones en el gen CXCR4, que se caracteriza por verrugas cutáneo-mucosas, hipogammaglobulinemia, infecciones bacterianas recurrentes y mielocatesis. El tratamiento se basa en el uso de antibióticos profilácticos, gammaglobulina en dosis sustitutiva y factores estimulantes de colonias de granulocitos o de granulocitos y macrófagos, en forma crónica. Presentamos el caso de una mujer de 21 años que comenzó a los 10 meses de edad con leucopenia y al siguiente año múltiples infecciones con hipogammaglobulinemia requiriendo gammaglobulina endovenosa durante los episodios. Evolucionó con neutropenia crónica. Una punción aspiración de médula ósea mostró la serie mieloide aumentada con ligero predominio de elementos inmaduros. El cuadro fue interpretado como inmunodeficiencia común variable debido a la asociación de múltiples cuadros infecciosos, niveles disminuidos de IgG, IgM e IgA y linfopenia con disminución de linfocitos B de memoria, por lo que comenzó tratamiento sustitutivo con gammaglobulina endovenosa más antibióticos profilácticos. A los 20 años se registraron pequeñas verrugas en manos que progresaron hacia antebrazos, abdomen, cara y rodillas. Se realizaron estudios moleculares para la búsqueda de mutaciones en el gen CXCR4 donde se detectó la mutación p.Arg334STOP en estado heterocigota confirmando el diagnóstico de síndrome WHIM, que es una inmunodeficiencia infrecuente y de difícil diagnóstico.

WHIM syndrome is a primary autosomal dominant immuno deficiency due to CXCR4 mutations characterized by mucocutaneous warts, hypogammaglobulinemia, recurrent bacterial infections and myelokathesis. Treatment consists in prophylactic antibiotics, immunoglobulin replacement and granulocyte or granulocyte/monocyte colony stimulating factors. We present the case of a 21 year old woman who showed leukopenia at 10 months of age and one year later multiple infections with hypogammaglobulinemia requiring intravenous immunoglobulin. During follow up she developed chronic neutropenia. A bone marrow aspiration showed increased myeloid series with predominance of immature elements. On the basis of infections, low levels of IgG, IgA, IgM and lymphopenia with absent memory B cells, a diagnosis of common variable immunodeficiency was made. She started intravenous immunoglobulin replacement and prophylactic antibiotics. At age 20, small warts in hands that progressed to forearms, knees, abdomen and face were recorded. CXCR4 gene sequencing was done detecting a heterozygous p.Arg334STOP mutation, confirming WHIM syndrome. This disease is infrequent and difficult to diagnose.

Contralaterally transplanted human embryonic stem cell-derived neural precursor cells (ENStem-A) migrate and improve brain functions in stroke-damaged rats

The transplantation of neural precursor cells (NPCs) is known to be a promising approach to ameliorating behavioral deficits after stroke in a rodent model of middle cerebral artery occlusion (MCAo). Previous studies have shown that transplanted NPCs migrate toward the infarct region, survive and differentiate into mature neurons to some extent. However, the spatiotemporal dynamics of NPC migration following transplantation into stroke animals have yet to be elucidated. In this study, we investigated the fates of human embryonic stem cell (hESC)-derived NPCs (ENStem-A) for 8 weeks following transplantation into the side contralateral to the infarct region using 7.0T animal magnetic resonance imaging (MRI). T2- and T2*-weighted MRI analyses indicated that the migrating cells were clearly detectable at the infarct boundary zone by 1 week, and the intensity of the MRI signals robustly increased within 4 weeks after transplantation. Afterwards, the signals were slightly increased or unchanged. At 8 weeks, we performed Prussian blue staining and immunohistochemical staining using human-specific markers, and found that high percentages of transplanted cells migrated to the infarct boundary. Most of these cells were CXCR4-positive. We also observed that the migrating cells expressed markers for various stages of neural differentiation, including Nestin, Tuj1, NeuN, TH, DARPP-32 and SV38, indicating that the transplanted cells may partially contribute to the reconstruction of the damaged neural tissues after stroke. Interestingly, we found that the extent of gliosis (glial fibrillary acidic protein-positive cells) and apoptosis (TUNEL-positive cells) were significantly decreased in the cell-transplanted group, suggesting that hESC-NPCs have a positive role in reducing glia scar formation and cell death after stroke. No tumors formed in our study. We also performed various behavioral tests, including rotarod, stepping and modified neurological severity score tests, and found that the transplanted animals exhibited significant improvements in sensorimotor functions during the 8 weeks after transplantation. Taken together, these results strongly suggest that hESC-NPCs have the capacity to migrate to the infarct region, form neural tissues efficiently and contribute to behavioral recovery in a rodent model of ischemic stroke.

RANTES, MCP-1, CCR2, CCR5, CXCR1 and CXCR4 Gene Polymorphisms are not Associated with the Outcome of Hepatitis B Virus Infection: Results from a Large Scale Single Ethnic Population

Recovery from hepatitis B virus (HBV) infection depends on the cellular immune responses. Chemokines and their receptors play significant roles in immune defense. This study was undertaken to investigate the association between HBV infection and single nucleotide polymorphisms (SNPs) of genes for the chemokines and their receptors. Between March 2002 and February 2004, a total of 957 single ethnic Korean patients were enrolled into two different groups; "HBV clearance group" (n=350), who have recovered from HBV infection, and "HBV persistence group" (n=607), who were repeatedly HBsAg-positive. The HBV persistence group was subdivided into "inactive carrier" and "HBV progression group (chronic hepatitis and cirrhosis)". We assessed polymorphisms in regulated and normal T-cell expressed and secreted (RANTES) at position -403, monocyte chemoattractant protein-1 (MCP-1) at position -2518, CCR2 V64I, CCR5 -2459, CXCR1 S276T and CXCR4 I138I using single primer extension assay. Genotype distributions of the "HBV clearance versus persistence group" and "inactive carrier versus HBV progression group" were compared. On the basis of unconditional logistic regression analysis with adjustment for age and sex, no statistically significant association with susceptibility to persistent HBV infection was observed with RANTES -403, MCP-1 -2518, CCR2 V64I, CCR5 -2459, CXCR1 S276T, and CXCR4 I138I polymorphisms. In addition, no association of analyzed SNPs with HBV disease progression was found.