RESUMEN
HAX1 was originally described as HS1-associated protein with a suggested function in receptor-mediated apoptotic and proliferative responses of lymphoid cells. Recent publications refer to a complex and multifunctional role of this protein. To investigate the in vivo function of HAX1 (HS1-associated protein X1) in B cells, we generated a Hax1-deficient mouse strain. Targeted deletion of Hax1 resulted in premature death around the age of 12 wk accompanied by a severe reduction of lymphocytes in spleen, thymus and bone marrow. In the bone marrow, all B-cell populations were lost comparably. In the spleen, B220(+) cells were reduced by almost 70%. However, as investigated by adoptive transfer experiments, this impairment is not exclusively B-cell intrinsic and we hypothesize that a HAX1-deficient environment cannot sufficiently provide the essential factors for proper lymphocyte development, trafficking and survival. Hax1(-/-) B cells show a significantly reduced expression of CXCR4, which might have an influence on the observed defects in B-cell development.
Asunto(s)
Linfocitos B/inmunología , Movimiento Celular/inmunología , Linfopoyesis/inmunología , Proteínas/inmunología , Animales , Linfocitos B/metabolismo , Médula Ósea/inmunología , Médula Ósea/metabolismo , Movimiento Celular/genética , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Péptidos y Proteínas de Señalización Intracelular , Antígenos Comunes de Leucocito/genética , Antígenos Comunes de Leucocito/inmunología , Antígenos Comunes de Leucocito/metabolismo , Linfopoyesis/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Proteínas/genética , Proteínas/metabolismo , Receptores CXCR4/biosíntesis , Receptores CXCR4/genética , Receptores CXCR4/inmunología , Bazo/inmunología , Bazo/metabolismo , Timo/inmunología , Timo/metabolismoRESUMEN
The classical allergic reaction starts seconds or minutes after Ag contact and is committed by Abs produced by a special subset of B lymphocytes. These Abs belong to the IgE subclass and are responsible for Type I hyperreactivity reactions. Treatment of allergic diseases with humanized anti-IgE Abs leads primarily to a decrease of serum IgE levels. As a consequence, the number of high-affinity IgE receptors on mast cells and basophils decreases, leading to a lower excitability of the effector cells. The biological mechanism behind anti-IgE therapy remains partly speculative; however, it is likely that these Abs also interact with membrane IgE (mIgE) on B cells and possibly interfere with IgE production. In the present work, we raised a mouse mAb directed exclusively against the extracellular membrane-proximal domain of mIgE. The interaction between the monoclonal anti-mIgE Ab and mIgE induces receptor-mediated apoptosis in vitro. Passive immunization experiments lead to a block of newly synthesized specific IgEs during a parallel application of recombinant Bet v1a, the major birch pollen allergen. The decrease of allergen-specific serum IgE might be related to tolerance-inducing mechanisms stopping mIgE-displaying B cells in their proliferation and differentiation.