A proper normal immune response is initially based on the innate immunity, characterized by a rapid and nonspecific response to infections, and later on the adaptive immunity, characterized by a specific response to a particular pathogen. Disruption of any part of the orchestrated immune response can result in an inability to control infections and subsequent illness. Primary immunodeficiencies are congenital disorders of the immunological response, which can be divided into subgroups on the basis of the component of the immune system predominantly affected, including T, B, NK lymphocytes, phagocytic cells and complement proteins. The severe combined immunodeficiency (SCID), characterized by abnormalities of T, B and NK cells, consists of a group of distinct diseases associated with a severe clinical phenotype due to an impairment of both effector arms of the specific immunity. In the 1996, a novel form of SCID (MIM 601705; Pignata guarino syndrome) was described, and proposed as the human equivalent of the well known murine phenotype described by Flanagan in 1966. This murine model was defined as Nude/SCID. The hallmarks of the Nude/SCID phenotype are congenital alopecia, from which the term “Nude” for the spontaneous murine model, nail dystrophy and an intrinsic defect of the thymus, always associated with a profound T-cell defect. The affected mice described by Flanagan, also showed an inborn dysgenesis of the thymus resulting in a compromised immune system lacking T cells. Moreover, molecular studies on the nude murine model led to identify Foxn1 as the gene responsible of the Nude phenotype. Also in humans as in mice, the molecular analysis reveals alterations in FOXN1 gene. Of note, the immunological phenotype of these patients is characterized by a marked reduction of CD3+, CD4+ and CD8+ cells and by the absence of naïve CD4+CD45RA+ cells. It should be mentioned that studies performed in Nude/SCID mice gave a great contribution to the knowledge of cell-mediated immunity. In humans for a long time, the DiGeorge syndrome (DGS) was erroneously considered the human counterpart of the murine Nude/SCID phenotype. However, because of the profound differences among DGS and mouse Nude/SCID, the mouse model has been considered misleading to understand T-cell ontogeny in humans. The description of the human equivalent of the Nude/SCID syndrome unravelled many of the dilemmas of T-cell ontogeny in man. Novel knowledge in this field would be very helpful in the comprehension of the intimate mechanisms underlying the T-cell differentiation process in humans and in discovering novel clinical entities related to abnormalities of the process.

La Sindrome Nude/SCID: dal modello murino al fenotipo umano

PIGNATA, CLAUDIO;FUSCO, ANNA;AMOROSI, STEFANIA;VIGLIANO, ILARIA;
2009

Abstract

A proper normal immune response is initially based on the innate immunity, characterized by a rapid and nonspecific response to infections, and later on the adaptive immunity, characterized by a specific response to a particular pathogen. Disruption of any part of the orchestrated immune response can result in an inability to control infections and subsequent illness. Primary immunodeficiencies are congenital disorders of the immunological response, which can be divided into subgroups on the basis of the component of the immune system predominantly affected, including T, B, NK lymphocytes, phagocytic cells and complement proteins. The severe combined immunodeficiency (SCID), characterized by abnormalities of T, B and NK cells, consists of a group of distinct diseases associated with a severe clinical phenotype due to an impairment of both effector arms of the specific immunity. In the 1996, a novel form of SCID (MIM 601705; Pignata guarino syndrome) was described, and proposed as the human equivalent of the well known murine phenotype described by Flanagan in 1966. This murine model was defined as Nude/SCID. The hallmarks of the Nude/SCID phenotype are congenital alopecia, from which the term “Nude” for the spontaneous murine model, nail dystrophy and an intrinsic defect of the thymus, always associated with a profound T-cell defect. The affected mice described by Flanagan, also showed an inborn dysgenesis of the thymus resulting in a compromised immune system lacking T cells. Moreover, molecular studies on the nude murine model led to identify Foxn1 as the gene responsible of the Nude phenotype. Also in humans as in mice, the molecular analysis reveals alterations in FOXN1 gene. Of note, the immunological phenotype of these patients is characterized by a marked reduction of CD3+, CD4+ and CD8+ cells and by the absence of naïve CD4+CD45RA+ cells. It should be mentioned that studies performed in Nude/SCID mice gave a great contribution to the knowledge of cell-mediated immunity. In humans for a long time, the DiGeorge syndrome (DGS) was erroneously considered the human counterpart of the murine Nude/SCID phenotype. However, because of the profound differences among DGS and mouse Nude/SCID, the mouse model has been considered misleading to understand T-cell ontogeny in humans. The description of the human equivalent of the Nude/SCID syndrome unravelled many of the dilemmas of T-cell ontogeny in man. Novel knowledge in this field would be very helpful in the comprehension of the intimate mechanisms underlying the T-cell differentiation process in humans and in discovering novel clinical entities related to abnormalities of the process.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/364956
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