Biomedical subjects

Stefania Fontana

Publications and source records attributed to Stefania Fontana.

5 recordsLinked to original sources

PubMed2006

Combined decrease of defined B and T cell subsets in a group of common variable immunodeficiency patients.

Common variable immunodeficiency disease (CVID) is a primary immune disorder affecting B cells and characterized by hypogammaglobulinemia and recurrent infections. To elucidate the clinical and immunological heterogeneity of this condition, we have studied B and T cell subsets in 25 CVID patients. In eleven of them, we observed a remarkable relative expansion of a B cell subpopulation (CD19(hi)/CD21(lo) cells) characterized by the absence of CD23 and the reduced expression of the chemokine receptors CXCR5 and CCR7. Our analyses demonstrated in these patients that the expansion of CD19(hi)/CD21(lo) cells correlates with a selective decrease of circulating naïve and CD21(hi) memory B lymphocytes. The same group of patients displayed a simultaneous severe reduction of naïve CD4+ T cells associated with decreased levels of T cell receptor excision circles. These observations suggest that a combined defect in generation of B and T subpopulations may account for the abnormal immunophenotype characterizing this subgroup of CVID patients.

Adolescent↗

PubMed2006

Innate immunity defects in Hermansky-Pudlak type 2 syndrome.

Adaptor protein-3 (AP-3) is an ubiquitous cytoplasmic complex that shuttles cargo proteins from the trans-Golgi and a tubular-endosomal compartment to endosome-lysosome-related organelles. Lack of the beta3A subunit of this complex causes Hermansky-Pudlak syndrome type 2, an autosomal recessive disease characterized by partial albinism, prolonged bleeding tendency, and immunodeficiency. To investigate the pathogenesis of immunodeficiency, we studied natural killer (NK) cells and neutrophil functions in 2 previously unreported siblings affected by Hermansky-Pudlak type 2 syndrome. In both patients we observed a dramatic reduction of cytolytic activity of freshly isolated and of IL-2-activated NK cells. Levels of perforin were reduced in unstimulated NK cells, thereby accounting for the impairment of NK cytolitic activity. In addition, analysis of neutrophils in these patients demonstrated that intracellular elastase content was largely reduced while CD63 expression on plasma membrane was substantially increased. Taken together, these observations suggest that type 2 Hermansky-Pudlak syndrome is characterized by defects of innate immunity.

Adaptor Protein Complex 3↗

PubMed2005

AIRE deficiency in thymus of 2 patients with Omenn syndrome.

Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restricted receptor repertoire. Loss of central tolerance in genetically determined autoimmune diseases, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is associated with defective expression by medullary thymic epithelial cells of AIRE, the transcription activator that induces thymic expression of tissue-specific antigens. Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-beta receptor mRNAs, while mRNAs of the self-antigens insulin, cytochrome P450 1a2, and fatty acid-binding protein were undetectable in thymi from immunodeficiency patients. These results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development and suggest that in Omenn syndrome, the few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.

Animals↗

PubMed2004

Congenital neutropenia: advances in diagnosis and treatment.

PURPOSE OF REVIEW: A decade after the availability of hematopoietic growth factors, the long-term outcome of severe congenital neutropenia has dramatically changed. The prolonged survival of neutropenic patients receiving hematopoietic growth factors has drawn attention to the heterogeneity of this disease and to the complications of treatment. The dose of granulocyte colony stimulating factor that is required to obtain normal levels of circulating neutrophils and to prevent fever and infections is quite variable among patients, but is higher in children with severe congenital neutropenia than in those with other conditions of neutropenia. Moreover, leukemic transformation during treatment is not observed in all patients, but is more typical of severe congenital neutropenia and Shwachman-Diamond patients. RECENT FINDINGS: In recent years, the converging efforts of hematologists, immunologists and geneticists have led to the discovery of the genetic and biochemical basis of severe congenital neutropenia; cyclic neutropenia; warts, hypogammaglobulinemia, immunodeficiency, myelokathexis or WHIM syndrome and other rarer conditions associated to neutropenia. SUMMARY: Although the diagnosis of congenital neutropenia includes many disorders of distinct origin and variable prognosis, their treatment is still based on granulocyte colony stimulating factor administration. Understanding the pathogenesis of these forms of neutropenia and their evolution will focus future studies on the mechanisms of normal and pathological myelopoiesis and on the development of the most appropriate treatment for each type of neutropenia.

Chromosomes, Human, X↗

PubMed2003

Functional defects of dendritic cells in patients with CD40 deficiency.

We have recently identified 2 patients with a rare autosomal recessive form of hyper IgM disease, known as HIGM3, caused by mutations in the CD40 gene. These patients had opportunistic infections observed on X-linked hyper IgM syndrome (HIGM), suggesting that the CD40-CD40 ligand interaction is important for promoting T-cell-mediated immunity. To evaluate whether innate immunity signals may substitute CD154 for inducing the maturation of dendritic cells (DCs), we analyzed monocyte-derived DCs in these patients. Monocyte-derived DCs of HIGM3 subjects on ex vivo stimulation with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) combined with interferon-gamma (IFN-gamma) normally express all the markers of mature DCs, such as CD83 and DC-LAMP. However, cell surface levels of HLA-DR in mature DCs are reduced, as is costimulatory activity of these cells for allogeneic naive T cells. In addition, CD40-deficient DCs secrete lower amounts of interleukin-12 (IL-12) but larger quantities of IL-10 than control subjects. Finally, analysis of circulating plasmacytoid DCs demonstrates a normal percentage of this subset in CD40-deficient cells, but IFN-alpha secretion in response to herpes simplex virus 1 (HSV-1) infection is severely reduced in patients. These observations suggest that the severe impairment of DC maturation may contribute to the defect of T-cell-mediated immunity observed in HIGM3 patients.

CD40 Antigens↗