IFN-I inducible targets ADAR1 isoforms and fine tunes innate immune activation.

Regulation of innate immune responses is essential for maintenance of immune homeostasis and development of an appropriate immunity against microbial infection. We show here that , product of the host gene, is induced by type I interferon (IFN-I) in several human non-immune and immune cell types, in particular in primary myeloid cells. Studies in HeLa cells showed that represses both p110 and p150 ADAR1 and reduces constitutive and IFN-induced A-to-I RNA editing.

A partial form of inherited human USP18 deficiency underlies infection and inflammation.

Human USP18 is an interferon (IFN)-stimulated gene product and a negative regulator of type I IFN (IFN-I) signaling. It also removes covalently linked ISG15 from proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome.

USP18 and ISG15 coordinately impact on SKP2 and cell cycle progression.

USP18 is an isopeptidase that cleaves the ubiquitin-like ISG15 from conjugates and is also an essential negative feedback regulator of type I interferon signaling. We and others reported that USP18 protein is stabilized by ISG15 and targeted for degradation by SKP2 (S-phase kinase associated protein 2), the substrate-recognition subunit of the SCF ubiquitin E3 ligase complex, which operates in cell cycle progression. Here, we have analyzed how, under non stimulated conditions, USP18, ISG15 and SKP2 communicate with each other, by enforcing or silencing their expression.

Loss of the HPV-infection resistance EVER2 protein impairs NF-κB signaling pathways in keratinocytes.

Homozygous mutations in EVER genes cause epidermodysplasia verruciformis (EV), characterized by an immune defect and the development of skin cancers associated with β-human papillomavirus (HPV) infections. The effects of EVER protein loss on the keratinocyte immune response remain unknown. We show here that EVER2 plays a critical role in the interplay between the NF-κB and JNK/AP-1 signaling pathways.

EVER proteins, key elements of the natural anti-human papillomavirus barrier, are regulated upon T-cell activation.

Human papillomaviruses (HPV) cause a variety of mucosal and skin lesions ranging from benign proliferations to invasive carcinomas. The clinical manifestations of infection are determined by host-related factors that define the natural anti-HPV barrier. Key elements of this barrier are the EVER1 and EVER2 proteins, as deficiency in either one of the EVER proteins leads to Epidermodysplasia Verruciformis (EV), a genodermatosis associated with HPV-induced skin carcinoma.

Lower levels of surface B-cell-receptor expression in chronic lymphocytic leukemia are associated with glycosylation and folding defects of the mu and CD79a chains.

Low levels of B-cell-receptor (BCR) expression are the hallmark of tumoral B lymphocytes in B-cell chronic lymphocytic leukemia (B-CLL). These cells also respond inadequately to stimulation through the BCR. This receptor consists of a surface immunoglobulin associated with a CD79a/CD79b heterodimer.

Different isoforms of BSAP regulate expression of AID in normal and chronic lymphocytic leukemia B cells.

Activation-induced cytidine deaminase (AID) is key to initiating somatic hypermutation (SHM) and class switch recombination (CSR), but its mode of action and regulation remains unclear. Since Pax-5 and Id-2 transcription factors play an opposing role in AID regulation, we have studied the expression of Pax-5, Id-2, and prdm-1 genes in 54 chronic lymphocytic leukemia (CLL) B cells. In 21 cases, presence of AID is constantly associated with high expression of the complete form of the Pax-5 gene (Pax-5a) and lower expression of the Id-2 and prdm-1 transcripts.

DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination.

Base substitutions, deletions, and duplications are observed at the immunoglobulin locus in DNA sequences involved in class switch recombination (CSR). These mutations are dependent upon activation-induced cytidine deaminase (AID) and present all the characteristics of the ones observed during V gene somatic hypermutation, implying that they could be generated by the same mutational complex. It has been proposed, based on the V gene mutation pattern of patients with the cancer-prone xeroderma pigmentosum variant (XP-V) syndrome who are deficient in DNA polymerase eta (pol eta), that this enzyme could be responsible for a large part of the mutations occurring on A/T bases.

[Cell therapy by dendritic cells in chronic lymphoid leukemia: state of the art].

Chronic lymphocytic leukemia (CLL) results from the accumulation of small mature, slowly dividing, monoclonal B lymphocytes. The clinical course of this disease is heterogeneous, with some patients progressing rapidly with early death whilst others exhibit a more stable, possibly, non-progressing disease lasting many years. Despite progress in therapy, relapse invariably occurs and the disease remains uncurable.

Monocyte-derived dendritic cells in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) results from the accumulation of small mature, slowly dividing, monoclonal B lymphocytes. The clinical course of this disease is heterogeneous, with some patients progressing rapidly with early death whilst others exhibit a more stable, possibly, non-progressing disease lasting many years. Despite progress in therapy, relapse invariably occurs and the disease remains incurable.

Idiotype-pulsed dendritic cells are able to induce antitumoral cytotoxic CD8 cells in chronic lymphocytic leukaemia.

Idiotypic structures of immunoglobulins from malignant B cells constitute tumour-specific antigens, though the function of immunoglobulin-specific CD8+ T cells in disease control and rejection remains unclear. We have studied five cases of B chronic lymphocytic leukaemia patients affected with indolent (three patients) or aggressive (two patients) disease. We showed that CD8+ T cells with major histocompatibility complex class I-restricted cytotoxicity against autologous tumour B cells could be generated following repeated stimulations with idiotype-pulsed dendritic cells in vitro.

Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation.

In B cells, somatic hypermutation (SHM) and class switch recombination (CSR) depend on the activation-induced cytidine deaminase (AID) gene product, although the precise mode of action of AID remains unknown. Because some chronic lymphocytic leukemia (CLL) B cells can undergo CSR without SHM, it constitutes a useful model to dissect AID function. In this work, we have studied AID expression, the presence of mutations in the preswitch mu DNA region, CSR, and the SHM in 65 CLL patients.