Biomedical subjects

Eleonora Gambineri

Publications and source records attributed to Eleonora Gambineri.

5 recordsLinked to original sources

PubMed2006

Immunodeficiencies with autoimmune consequences.

Far from being mutually exclusive, immunodeficiency and autoimmunity may occur simultaneously. During the last years, analysis of Autoimmune Polyendocrinopathy--Candidiasis--Ectodermal Dystrophy (APECED) and Immunodysregulation--Polyendocrinopathy--Enteropathy--X-linked (IPEX), two rare monogenic forms of immunodeficiency associated with autoimmunity, has led to the identification of Auto Immune Regulator (AIRE) and Forkhead Box P3 (FOXP3), essential transcriptional regulators, involved in central tolerance and peripheral immune homeostasis, respectively. Characterization of the molecular and cellular mechanisms involved in APECED, and recognition that AIRE expression is sustained by effective thymopoiesis, has recently allowed to define that the autoimmunity of Omenn syndrome, a combined immunodeficiency due to defects of V(D)J recombination, also results from defective expression of AIRE. The implications of identification of the basis of autoimmunity in these rare forms of immunodeficiency have important implications for a better understanding of more common autoimmune disorders, and for development of novel therapeutic approaches.

Animals↗

PubMed2006

Defective regulatory and effector T cell functions in patients with FOXP3 mutations.

The autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is caused by mutations in the forkhead box protein P3 (FOXP3) gene. In the mouse model of FOXP3 deficiency, the lack of CD4+ CD25+ Tregs is responsible for lethal autoimmunity, indicating that FOXP3 is required for the differentiation of this Treg subset. We show that the number and phenotype of CD4+ CD25+ T cells from IPEX patients are comparable to those of normal donors. CD4+ CD25high T cells from IPEX patients who express FOXP3 protein suppressed the in vitro proliferation of effector T cells from normal donors, when activated by "weak" TCR stimuli. In contrast, the suppressive function of CD4+ CD25high T cells from IPEX patients who do not express FOXP3 protein was profoundly impaired. Importantly, CD4+ CD25high T cells from either FOXP3+ or FOXP3- IPEX patients showed altered suppression toward autologous effector T cells. Interestingly, IL-2 and IFN-gamma production by PBMCs from IPEX patients was significantly decreased. These findings indicate that FOXP3 mutations in IPEX patients result in heterogeneous biological abnormalities, leading not necessarily to a lack of differentiation of CD4+ CD25high Tregs but rather to a dysfunction in these cells and in effector T cells.

Animals↗

PubMed2005

Safety and immunogenicity of measles-mumps-rubella vaccine in children with congenital immunodeficiency (DiGeorge syndrome).

Live attenuated vaccines are usually contraindicated in patients with congenital or acquired immunodeficiency. On the other hand, infections due to wild type virus may be particularly severe in patients with low levels of T cells. The aim of the present study was to evaluate safety and immunogenicity of measles-mumps-rubella (MMR) vaccine in children with congenital T cell defect (DiGeorge anomaly). Fourteen patients were included in the study. No severe adverse reaction was reported. No difference between patients and controls was found in frequency of seroconversion for both measles (92.9% versus 96.3%) and rubella (92.9% versus 100%). No difference in mean titres of anti-measles (1.62+/-0.54 versus 1.89+/-0.49 index) (p=0.13) or anti-rubella (78.1+/-48.0 versus 72.0+/-41.0 UI/ml, p=0.68) antibodies was found between patients and controls. No decrease in CD4 cells was detected after immunization. MMR vaccine is immunogenic and can be safely used in patients with DiGeorge anomaly, so preventing severe complication due to wild virus infection.

CD4 Lymphocyte Count↗

PubMed2003

Inducible CO-stimulator molecule, a candidate gene for defective isotype switching, is normal in patients with hyper-IgM syndrome of unknown molecular diagnosis.

BACKGROUND: Inducible CO-stimulatory molecule (ICOS), the third member of the CD28/CTLA4 family, is expressed by activated T cells and interacts with its ligand (ICOSL, B7-related protein-1 [B7RP-1]) that is constitutively expressed by B cells. The interaction of ICOS with its ligand leads to terminal differentiation of B cells to plasma cells. ICOS-deficient mice fail to undergo immunoglobulin-class switch recombination (CSR) and germinal center formation, suggesting that ICOS could be a candidate gene for phenotypic hyper-IgM (HIGM) syndromes characterized by recurrent infections, low serum IgG and IgA, and normal or elevated IgM. Genetically, at least 4 distinct molecular defects have been identified that result in defective CSR and present as HIGM syndromes: defects of the CD40 ligand gene (CD40L; HIGM1, X-linked), the activation-induced cytidine deaminase gene (AID; HIGM2, autosomal recessive), the CD40 gene (HIGM3, autosomal recessive), and the nuclear factor-kappaB (NF-kappaB) essential modulator gene (NEMO, or IKK-gamma, X-linked). In a substantial subgroup of HIGM patients, these 4 genes are normal, and the genetic defect is unknown. OBJECTIVE: We sought to investigate the possibility that mutations of ICOS could account for some patients' belonging to this HIGM subgroup. METHODS: The expression of ICOS protein by activated peripheral blood mononuclear cells and/or interleukin-2-dependent T cell lines derived from these patients was estimated by flow cytometery after incubation of the cells with the ICOS ligand fusion protein B7RP-1 Fc. The coding region and exon-intron boundaries of ICOS were assessed by sequence analysis. RESULTS: We studied 33 HIGM patients from 30 families, selected from an original cohort of 136 patients from 113 families, by excluding mutations of CD40L, AID, CD40, and NEMO. Activated T cells from all 33 patients expressed ICOS normally, and sequence analysis of the coding region and exon-intron boundaries revealed only wild-type ICOS, predicting that the protein structure is normal in this patient population. CONCLUSION: These findings strongly suggest that ICOS does not belong to the group of genes that, if mutated, present clinically as the HIGM syndrome.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2003

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis.

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) is one of a group of clinical syndromes that present with multisystem autoimmune disease suggesting a phenotype of immune dysregulation. Clinically, IPEX manifests most commonly with diarrhea, insulin-dependent diabetes mellitus, thyroid disorders, and eczema. FOXP3, the gene responsible for IPEX, maps to chromosome Xp11.23-Xq13.3 and encodes a putative DNA-binding protein of the forkhead family. Recent data indicate that FOXP3 is expressed primarily in the CD4+CD25+ regulatory T-cell subset, where it may function as a transcriptional repressor and key modulator of regulatory T-cell fate and function. This review describes the clinical features of IPEX and the structure, function, and known mutations of FOXP3 that provide important insights into its role in maintenance of immune homeostasis.

Animals↗