Insights into the cytokine april in b cell trafficking and in adipose-derived mesenchymal stem cells
- Autores: Manuela Zonca
- Directores de la Tesis: Lourdes Planelles Carazo (dir. tes.), Núria Gironés Pujol (codir. tes.)
- Lectura: En la Universidad Autónoma de Madrid ( España ) en 2013
- Idioma: español
- Tribunal Calificador de la Tesis: María Luisa Toribio García (presid.), Rebeca Pérez Diego (secret.), Belén de Andrés Muguruza (voc.), Manuel Fresno Escudero (voc.), José Mario Mellado García (voc.)
- Materias:
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- Resumen
1) in mice, the loss of function of bruton¿s tyrosine kinase (btk) gives rise to the x-linked immunodeficiency (xid). This consists of reduced mature b-1 and b-2 b cell compartments, and of alterations in several b cell functions, resulting in low levels of natural antibodies, hyporesponsive b cells to t-independent antigens (such as lps) and a high rate of spontaneous apoptosis. April-tg mice show an expanded peritoneal b-1 b cell population, increased natural antibody levels, and enhanced ti humoral responses. We generated xid/april mice as a model to study if april overexpression could ameliorate the b cell immunodeficiency of xid mice. Previous data of the laboratory demonstrated that april transgene does not rescue the b cell developmental defect of btk-deficient mice. In contrast, xid/april mice showed enhanced natural igm antibody levels and a restored lps igm antibody response. We analyzed some of the mechanisms underlying the rescued functions in xid mice, and found that april overexpression increases plasma cell survival. We then investigated whether april cytokine modulates b cell migration, because it is defective in btk-deficient b cells and it is needed to generate a full lps antibody response. We found that april-tg mice have enhanced b-1 b cell homing to the peritoneal cavity, a process mainly dependent on cxcl13/cxcr5. In fact, april ¿priming¿ enhances cxcr5/cxcl13-mediated b cell chemotaxis in vitro. We studied the molecular mechanisms behind and found that april upregulates cxcr5 expression in b cells, through the induction of the cxcr5 transcription, by the activation of nf¿b and klf2 factors. Similarly, in xid/april mice, we found that overexpression of april induces cxcr5 upregulation and enhances b cell egress from the peritoneum to the omentum, after lps stimulation. All these data indicate that april signaling partially restores the lpsactivated cascade impaired in a btk-deficient cell, by improving, among others, b cell survival and trafficking processes.
2) human adipose-derived stem cells (hascs) are mesenchymal stem cells with reduced immunogenicity and the ability to modulate immune responses. April and baff proteins are found in inflammatory diseases for which allogeneic hascs therapy is currently under clinical investigation. We found that hascs express both april and baff, as well as their receptors taci, bcma and the baff-specific receptor (baff-r). April and baff secretion was differentially enhanced by cxcl12 and ifn-¿, implicated in hascs-mediated migration and immunosuppression, respectively. In addition, april and baff induced rapid phosphorylation of erk1/2 and akt kinases and promoted an increase in hascs proliferation, without affecting the immunosuppressive capacity of these cells. The use of specific chemical inhibitors showed that the pi3k transduction pathway is involved in hascs basal growth and that april- and baff-mediated effects are erk-dependent. These results provide new information about the molecular mechanisms that underlie april and baff secretion and signaling in hascs, and are of special relevance for the use of allogeneic hascs as therapeutic tools.
