High-density lipoproteins neutralize C-reactive protein proinflammatory activity

BACKGROUND: C-reactive protein (CRP), a well-recognized marker of atherosclerosis, has recently been suggested to have a direct proinflammatory effect. The constitutive expression of low levels of CRP in normal plasma suggests the likelihood that a natural factor exists to neutralize the effect of CRP. This factor(s) has not yet been identified. Method and Results- The proinflammatory effect of CRP was measured by the induction of inflammatory adhesion molecules in human umbilical vein endothelial cells (HUVECs). We show that CRP significantly induced upregulation of adhesion molecules in both protein and mRNA levels. The CRP-induced expression of these inflammatory adhesion molecules was completely suppressed when the cells were preincubated with a physiological concentration (1 mg/mL apolipoprotein A-I) of HDLs derived from human plasma (native HDL) or reconstituted HDL (rHDL) at a very low concentration (0.01 mg/mL apolipoprotein A-I). A novel mechanism of HDL inhibition is likely to operate, because (1) rHDL was 100 times more potent than native HDL, (2) preincubation with HDL and its sustained presence were obligatory, and (3) oxidized 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine was the fundamental active component. CONCLUSIONS: The CRP-induced upregulation of inflammatory adhesion molecules in HUVECs was completely prevented by HDL via their oxidized phospholipid components.     

The polymorphism p.G219R of CD40L does not cause immunological alterations in vivo: conclusions from a X-linked hyper IgM syndrome kindred

Hyper-IgM syndromes (HIGM) are characterized by low levels of IgG, IgA and IgE and normal to high levels of IgM. Patients with these syndromes present recurrent infections due to an impaired immunoglobulin maturation. The most prevalent form of HIGM, X-linked hyper IgM syndrome (XHIM), is caused by mutations in the gene encoding the CD40 ligand (CD40LG). We present two siblings with XHIM caused by a large CD40LG deletion affecting more than half of the gene, and extended from the end of intron 3 to far upstream of the promoter regions. Genetic analysis in the maternal family discovered the CD40L(G219R) polymorphism in several members. Segregation of this polymorphism in the kindred indicated that the deletion of CD40LG was a de novo mutation in the mother. Although half of her CD4+ T cells did not express CD40L and the other half expressed the CD40L(G219R) variant, the mother was healthy. This suggests that this polymorphism is not pathogenic by itself although it has been recently related to X-linked lymphoproliferative syndrome.