Our results provide the basis for a detailed prospective evaluation of autoimmunity and inflammation in the context of PIDs, with a view to accurately assessing these risks and describing the possible effect of medical intervention.

No abstract

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

The heparan sulfate proteoglycan agrin and adhesion molecules are key players in the formation of neuronal and immune synapses that evolved for efficient communication at the sites of cell-cell contact. Transcytosis of infectious virus across epithelial cells upon contact between HIV-1-infected cells and the mucosal pole of the epithelial cells is one mechanism for HIV-1 entry at mucosal sites. In contrast, transcytosis of cell-free HIV-1 is not efficient. A synapse between HIV-1-infected cells and the mucosal epithelial surface that resembles neuronal and immune synapses is visualized by electron microscopy. We have termed this the "viral synapse." Similarities of the viral synapse also extend to the functional level. HIV-1-infected cell-induced transcytosis depends on RGD-dependent integrins and efficient cell-free virus transcytosis is inducible upon RGD-dependent integrin cross-linking. Agrin appears differentially expressed at the apical epithelial surface and acts as an HIV-1 attachment receptor. Envelope glycoprotein subunit gp41 binds specifically to agrin, reinforcing the interaction of gp41 to its epithelial receptor galactosyl ceramide. INTRODUCTIONFor efficient transmission of information between adjacent cells, neuronal cells have evolved the synapse, the elaborate structure at the site of cell-cell contact in which pre-and postsynaptic membranes are tightly apposed (Bezakova and Ruegg, 2003). Immunological synapses, which have been described more recently Khan et al., 2001), share some of the molecules and processes involved in the formation and functions of the neurological synapse.Adhesion molecules play a critical role in the initial stages of synapse formation: they contribute to the recognition events between pre-and postsynaptic cells, resulting in turn, in tight apposition or locking of the pre-and postsynaptic surfaces. The adhesive clamp provides stability and aligns the presynaptic "active zones" and postsynaptic elements in relation to one another .Additionally, aggregation of pre-and postsynaptic surface molecules together with reorganization of membrane components at the synaptic zone is essential for synapse formation and for ensuring the rapid exchange of information between neurons. One such aggregating factor is agrin, a heparan sulfate proteoglycan of ϳ300 -400 kDa with two major conserved sites of glycanation (reviewed in Bezakova and Ruegg, 2003) that is active, glycosylated at the neuronal synapse, but only deglycosylated at the immunological synapse Khan et al., 2001;Yang et al., 2001). Different isoforms of agrin arise from alternative mRNA splicing. These include a transmembrane form and an isoform bound to the basement membrane (Hilgenberg et al., 1999;Neumann et al., 2001;Hoover et al., 2003). Agrin contains one heparin-and one integrin-binding site. Integrins, including the beta-1 integrin, have been shown to modulate agrin activities (Martin and Sanes, 1997;Burkin et al., 1998;Martin, 2002). In immune cells, agrin aggregating activity, in synergy with integrins, has been...

Autoimmune diseases develop in approximately 5% of humans. They can arise when self-tolerance checkpoints of the immune system are bypassed as a consequence of inherited mutations of key genes involved in lymphocyte activation, survival, or death. For example, autoimmune lymphoproliferative syndrome (ALPS) results from defects in self-tolerance checkpoints as a consequence of mutations in the death receptor-encoding gene TNF receptor superfamily, member 6 (TNFRSF6; also known as FAS). However, some mutation carriers remain asymptomatic throughout life. We have now demonstrated in 7 ALPS patients that the disease develops as a consequence of an inherited TNFRSF6 heterozygous mutation combined with a somatic genetic event in the second TNFRSF6 allele. Analysis of the patients' CD4 -CD8 -(double negative) T cells -accumulation of which is a hallmark of ALPS -revealed that in these cells, 3 patients had somatic mutations in their second TNFRSF6 allele, while 4 patients had loss of heterozygosity by telomeric uniparental disomy of chromosome 10. This observation provides the molecular bases of a nonmalignant autoimmune disease development in humans and may shed light on the mechanism underlying the occurrence of other autoimmune diseases.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobu-linemia, accumulation of double-negative TCR CD4 CD8 T cells (DNT cells), and autoimmunity. Previously, DNT cell detection and a functional defect of T cells in a FAS-induced apoptosis test in vitro had been used for ALPS diagnosis. However, a functional defect can also be detected in mutation-positive relatives (MPRs) who remain free of any ALPS-related disease. In contrast, lymphocytes from patients carrying a somatic mutation of FAS exhibit normal sensitivity to FAS-induced apoptosis in vitro. We assessed the soluble FAS-L concentration in the plasma of ALPS patients carrying FAS mutations. Overall, we showed that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS. (Blood. 2009;113: 3027-3030)

Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.

Mucosa, comprising epithelial and dendritic cells, are the major sites for Human Immunodeficiency Virus type 1 (HIV-1) transmission. There, DCs can capture incoming HIV-1 and in turn transfer virus to CD4(+) T lymphocytes in a two-phase process, thereby initiating HIV-1 dissemination. We show that the glycosphingolipid Galactosyl Ceramide (GalCer), acting as mucosal epithelial receptor for HIV-1, was expressed by human monocyte derived immature DCs (iDCs), human primary DCs isolated from blood and mucosal tissue and in situ on mucosal tissue and acts as HIV-1-gp41 receptor. Blocking both GalCer and CD4 with specific mAbs results in a >95% transfer inhibition of HIV-1 from human monocyte-derived iDCs to autologous resting T cells. GalCer interaction with HIV-1 controls the early infection-independent phase of HIV-1 transfer to T cells. Thus, GalCer appears as an initial receptor for HIV-1, common to both mucosal epithelial cells and iDCs.