Vasculitis, Autoimmunity, and Cytokines: How the Immune System Can Harm the Brain

More and more findings suggest that neurological disorders could have an immunopathological cause. Thus, immune-targeted therapies are increasingly proposed in neurology (even if often controversial), as anakinra, inhibiting IL-1 for febrile inflammatory illnesses, and JAK inhibitors for anti-interferons treatment. Precision medicine in neurology could be fostered by a better understanding of the disease machinery, to develop a rational use of immuno-modulators in clinical trials. In this review, we focus on monogenic disorders with neurological hyper-inflammation/autoimmunity as simplified "models" to correlate immune pathology and targeted treatments. The study of monogenic models yields great advantages for the elucidation of the pathogenic mechanisms that can be reproduced in cellular/animal models, overcoming the limitations of biological samples to study. Moreover, monogenic disorders provide a unique tool to study the mechanisms of neuroinflammatory and autoimmune brain damage, in all their manifestations. The insight of clinical, pathological, and therapeutic aspects of the considered monogenic models can impact knowledge about brain inflammation and can provide useful hints to better understand and cure some neurologic multifactorial disorders

Impaired Recruitment of Grk6 and β-Arrestin2 Causes Delayed Internalization and Desensitization of a WHIM Syndrome-Associated CXCR4 Mutant Receptor

WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a rare immunodeficiency syndrome linked to heterozygous mutations of the chemokine receptor CXCR4 resulting in truncations of its cytoplasmic tail. Leukocytes from patients with WHIM syndrome display impaired CXCR4 internalization and enhanced chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely contribute to the clinical manifestations. Here, we investigated the biochemical mechanisms underlying CXCR4 deficiency in WHIM syndrome. We report that after ligand activation, WHIM-associated mutant CXCR4 receptors lacking the carboxy-terminal 19 residues internalize and activate Erk 1/2 slower than wild-type (WT) receptors, while utilizing the same trafficking endocytic pathway. Recruitment of β-Arrestin 2, but not β-Arrestin 1, to the active WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor. In addition, while both kinases Grk3 and Grk6 bind to WT CXCR4 and are critical to its trafficking to the lysosomes, Grk6 fails to associate with the WHIM-mutant receptor whereas Grk3 associates normally. Since β-Arrestins and Grks play critical roles in phosphorylation and internalization of agonist-activated G protein-coupled receptors, these results provide a molecular basis for CXCR4 dysfunction in WHIM syndrome

Hepatitis B And C In Hematopoietic Stem Cell Transplant

Although the risk of acquisition of hepatitis B or hepatitis C virus through blood products has considerably reduced since the last decade, some infected patients are candidates to stem cell transplantation. Others may have no alternative than an infected donor. In all these cases, recipients of transplant are prone to short and long term liver complications. The evolution of liver tests under chemotherapy before transplant may give useful information to anticipate on the risk of hepatitis reactivation after transplant, both for HBv and HCv. More than sixty percent of the patients who are HBsAg-positive before transplant reactivate after transplant, and 3% develop acute severe liver failure. Because both viral replication and immune reconstitution are the key factors for reactivation, it is crucial to closely follow liver function tests and viral load during the first months of transplant, and to pay a special attention in slowly tapering the immunosuppression in these patients. Lamivudine reduces HBv viremia, but favors the emergence of HBv polymerase gene mutants and should be individually discussed. Both in case of HBv or HCv hepatitis reactivation with ALT ≥ 10N concomitantly to an increase in viral load at time of immune reconstitution, steroids should be given. In case there is no alternative than a HBv or HCv positive geno-identical donor, the risk of viral hepatitis, including acute liver failure and late complications, should be balanced with the benefit of transplant in a given situation

La relación entre “lo grupal” y el Trabajo Social en la formación de la/os Trabajadoras/es Sociales en la provincia de Buenos Aires

El equipo de cátedra de la asignatura Trabajo Social IV y estudiantes y graduados de la licenciatura en Trabajo Social de la Universidad Nacional de José C. Paz se encuentran llevando adelante un proyecto de investigación denominado “El Trabajo Social con Grupos para el abordaje de problemáticas sociales complejas: procesos de enseñanza-aprendizaje e intervención en Trabajo Social”1. El problema en relación al cuál se han definido los objetivos de la investigación se configura alrededor de las maneras de conceptualizar en la actualidad la relación entre “lo grupal” y el Trabajo Social y cómo se expresan en la formación académica de los trabajadorxs sociales. Se ha propuesto indagar acerca de los procesos de formación en relación al Trabajo Social con Grupos (TSG) en las unidades académicas ubicadas en el área de influencia de la UNPaz a partir de identificar, describir y analizar los Planes de Estudio (PE) y, especialmente, los Contenidos Mínimos (CM) asociados a la relación entre “lo grupal” y el Trabajo Social.Eje temático 3: La educación superior como derecho: prácticas de enseñanza, investigación y extensión.Grupo de trabajo 24: Reflexiones acerca de la trayectoria del Trabajo Social en Argentina.Facultad de Trabajo Socia

La relación entre “lo grupal” y el Trabajo Social en la formación de la/os Trabajadoras/es Sociales en la provincia de Buenos Aires

El equipo de cátedra de la asignatura Trabajo Social IV y estudiantes y graduados de la licenciatura en Trabajo Social de la Universidad Nacional de José C. Paz se encuentran llevando adelante un proyecto de investigación denominado “El Trabajo Social con Grupos para el abordaje de problemáticas sociales complejas: procesos de enseñanza-aprendizaje e intervención en Trabajo Social”1. El problema en relación al cuál se han definido los objetivos de la investigación se configura alrededor de las maneras de conceptualizar en la actualidad la relación entre “lo grupal” y el Trabajo Social y cómo se expresan en la formación académica de los trabajadorxs sociales. Se ha propuesto indagar acerca de los procesos de formación en relación al Trabajo Social con Grupos (TSG) en las unidades académicas ubicadas en el área de influencia de la UNPaz a partir de identificar, describir y analizar los Planes de Estudio (PE) y, especialmente, los Contenidos Mínimos (CM) asociados a la relación entre “lo grupal” y el Trabajo Social.Eje temático 3: La educación superior como derecho: prácticas de enseñanza, investigación y extensión.Grupo de trabajo 24: Reflexiones acerca de la trayectoria del Trabajo Social en Argentina.Facultad de Trabajo Socia

La relación entre “lo grupal” y el Trabajo Social en la formación de la/os Trabajadoras/es Sociales en la provincia de Buenos Aires

El equipo de cátedra de la asignatura Trabajo Social IV y estudiantes y graduados de la licenciatura en Trabajo Social de la Universidad Nacional de José C. Paz se encuentran llevando adelante un proyecto de investigación denominado “El Trabajo Social con Grupos para el abordaje de problemáticas sociales complejas: procesos de enseñanza-aprendizaje e intervención en Trabajo Social”1. El problema en relación al cuál se han definido los objetivos de la investigación se configura alrededor de las maneras de conceptualizar en la actualidad la relación entre “lo grupal” y el Trabajo Social y cómo se expresan en la formación académica de los trabajadorxs sociales. Se ha propuesto indagar acerca de los procesos de formación en relación al Trabajo Social con Grupos (TSG) en las unidades académicas ubicadas en el área de influencia de la UNPaz a partir de identificar, describir y analizar los Planes de Estudio (PE) y, especialmente, los Contenidos Mínimos (CM) asociados a la relación entre “lo grupal” y el Trabajo Social.Eje temático 3: La educación superior como derecho: prácticas de enseñanza, investigación y extensión.Grupo de trabajo 24: Reflexiones acerca de la trayectoria del Trabajo Social en Argentina.Facultad de Trabajo Socia

G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells

CXCR4 receptor expression is required for the retention of granulocyte precursors and mature neutrophils within the bone marrow, and disruption of the SDF-1/CXCR4 axis in the bone marrow results in the mobilization of myeloid lineage cells to the peripheral circulation. We report that G-CSF down-regulates CXCR4 expression in bone marrow–derived murine and human myeloid lineage cells. When exposed to G-CSF, murine Gr1+ bone marrow myeloid cells display a time-dependent reduction of cell-surface CXCR4 and respond poorly to SDF-1 in attachment and migration assays. Bone marrow–derived cells of nonmyeloid lineage display no change in surface CXCR4 expression upon exposure to G-CSF. Compared with controls, mice treated with G-CSF for mobilization of hematopoietic progenitor cells display reduced levels of CXCR4 selectively in bone marrow Gr1+ myeloid cells. Since bone marrow myeloid cells express G-CSF receptors and G-CSF rapidly reduces CXCR4 expression in purified Gr1+ cells populations, these results provide evidence that G-CSF acts directly on myeloid lineage cells to reduce CXCR4 expression. By down-regulating CXCR4 expression in bone marrow myeloid cells and attenuating their responsiveness to SDF-1, G-CSF promotes their mobilization from the bone marrow to the peripheral blood

Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome

AbstractThe chemokine receptor CXCR4 and its functional ligand, CXCL12, are essential regulators of development and homeostasis of hematopoietic and lymphoid organs. Heterozygous truncating mutations in the CXCR4 intracellular tail cause a rare genetic disease known as WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis), whose pathophysiology remains unclear. We report CXCR4 function in 3 patients with WHIM syndrome carrying heterozygous truncating mutations of CXCR4. We show that CXCR4 gene mutations in WHIM patients do not affect cell surface expression of the chemokine receptor and its internalization upon stimulation with CXCL12. Moreover, no significant differences in calcium mobilization in response to CXCL12 are found. However, the chemotactic response of both polymorphonuclear cells and T lymphocytes in response to CXCL12 is increased. Furthermore, immunophenotypic analysis of circulating T and B lymphocytes reveals a decreased number of memory B cells and of naive T cells and an accumulation of effector memory T cells associated with a restricted T-cell repertoire. Based on our results, we suggest that the altered leukocyte response to CXCL12 may account for the pathologic retention of mature polymorphonuclear cells in the bone marrow (myelokathexis) and for an altered lymphocyte trafficking, which may cause the immunophenotyping abnormalities observed in WHIM patients. (Blood. 2004;104:444-452

The mutational spectrum of human malignant autosomal recessive osteopetrosis

Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogenous autosomal recessive disorder of bone metabolism, which, if untreated, has a fatal outcome. Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, are responsible for a subset of this condition. By sequencing the ATP6i gene in arOP patients from 44 unrelated families with a worldwide distribution we have now established that ATP6i mutations are responsible for ∼50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions, two insertions, 10 nonsense substitutions and 21 mutations in splice sites) are predicted to cause severe abnormalities in the protein product and are likely to represent null alleles. In addition, we have also analysed nine unrelated arOP patients from Costa Rica, where this disease is apparently much more frequent than elsewhere. All nine Costa Rican patients bore either or both of two missense mutations (G405R and R444L) in amino acid residues which are evolutionarily conserved from yeast to humans. The identification of ATP6i gene mutations in two families allowed us for the first time to perform prenatal diagnosis: both fetuses were predicted not to be affected and two healthy babies were born. This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe conditio