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Human clinical phenotype associated with FOXN1 mutations.
No full textIn humans, a proper immune response relies on the innate immunity, characterized by a rapid and nonspecific initial response to infections, and later on the adaptive immunity, characterized by a specific response to a particular antigen. Disruption of any part of the orchestrated immune response results in the inability to control infections and, subsequently, in illness. An impairment of both effector arms of the specific immunity characterizes the clinical phenotype, known as severe combined immunodeficiency (SCID), which represents a heterogeneous group of inherited disorders due to abnormalities of T, B and NK cells.
The first congenital SCID was described as spontaneous immunodeficiency in 1966 in mice and referred as Nude/SCID, based on the association of athymia with complete hairless. In 1996, the human equivalent of the murine Nude/SCID phenotype (MIM #601705) was reported. As in mice, also in humans this form is characterized by an intrinsic defect of the thymus, congenital alopecia and nail dystrophy, and is due to mutations of the FOXN1 gene, as well. FOXN1 is mainly expressed in the thymus and skin epithelial cells, where it plays a critical role in differentiation and survival.
FOXN1 belongs to the forkhead box (FOX) gene family that comprises a diverse group of ‘winged helix’ transcription factors involved in development, metabolism, cancer and aging. These transcription factors share the common property of being developmentally regulated and of directing tissue specific transcription and cell fate decisions. In immune system, alterations of FOXN1 result in a thymus anlage that lacks the capacity to generate mature and functional thymocytes.
Because the significant expression levels of FOXN1 in skin elements, keratinocytes have been successfully used to support a full process of human T-cell development in vitro, resulting in the generation of mature T cells from hematopoietic precursor cells (HPCs). This finding would imply a role for skin as a primary lymphoid organ.
Thus, the present chapter will focus on the information that came out from the original description of the human Nude/SCID phenotype and on the role of FOXN1 and of the other members of FOX subfamilies in those immunological disorders characterized by abnormal T-cell development or abnormal T-cell regulatory homeostasis
L' apoptosi nella fisiologia della risposta immune e sue alterazioni nella patogenesi di quadri di patologia complessa.
No full textAnalisi della trasduzione del segnale via GHR in linee cellulari EBV di pazienti affetti da X-SCID e controlli.
No full textEvaluation of functional interaction between the common gamma chain and growth hormone receptor using a neutralization assay.
No full textAnalisi dell’ alterazione dei meccanismi di tolleranza periferica associata ad alta variabilità fenotipica.
No full text
La Sindrome Nude/SCID: dal modello murino al fenotipo umano
No full textA 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
GH-induced signaling and STAT5b nuclear translocation in control or X-SCID EBV cell lines.
No full textCharacterization of the T-cell ontogeny defect in the human athymic models of the Nude/SCID and DiGeorge syndromes.
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