Proatherogenic and Proinflammatory Properties of Immune Complexes Prepared with Purified Human oxLDL Antibodies and Human oxLDL

Atherogenesis and the humoral immune response to modified lipoproteins

“…Insoluble IC prepared with human LDL and rabbit LDL antibody also promote the transformation of macrophages into foam cells [56] and deliver activating signals as a consequence of their interaction with FcγRI [57] resulting in the release of pro-inflammatory cytokines, such as IL-1 and TNF, oxygen active radicals, and metalloproteinases [55,56,58,59]. LDL-IC prepared with human oxLDL and oxLDL antibodies isolated from patients with type 1 diabetes can also induce cholesterol and cholesterol ester accumulation in a variety of macrophage-like cell lines, including THP-1, U937, and MonoMac-6, which are also activated as reflected by the release of pro-inflammatory cytokines, including IL-1., Il-6, IL-12, and TNF [12,13], as well as of metalloproteinases [ MMP-1] [59]. Indeed, human LDL-IC were shown to induce CE accumulation in those cell lines to a much higher degree than oxLDL, even when oxLDL concentrations were about ten times greater than the amount of oxLDL contained in the oxLDL-IC was used as control [13].…”

“…LDL-IC prepared with human oxLDL and oxLDL antibodies isolated from patients with type 1 diabetes can also induce cholesterol and cholesterol ester accumulation in a variety of macrophage-like cell lines, including THP-1, U937, and MonoMac-6, which are also activated as reflected by the release of pro-inflammatory cytokines, including IL-1., Il-6, IL-12, and TNF [12,13], as well as of metalloproteinases [ MMP-1] [59]. Indeed, human LDL-IC were shown to induce CE accumulation in those cell lines to a much higher degree than oxLDL, even when oxLDL concentrations were about ten times greater than the amount of oxLDL contained in the oxLDL-IC was used as control [13]. The accumulation of cholesteryl esters by macrophages incubated with LDL-IC is dependent on IC uptake through Fcγ receptors, primarily the high affinity FcγRI [60] and appears to be a consequence of the delayed degradation of ingested LDL [61].…”

“…At the vessel wall level, both types of response are likely to play a significant role. Immune complexes formed by modified LDL and corresponding antibodies (mLDL-IC) are potent macrophage activators [12,13] and macrophage activation leads to the overexpression of MHC-II molecules, cytokine and chemokine release, and expression of costimulatory molecules. This will create ideal conditions for cross-activation between macrophages and Th1 lymphocytes [14].…”

Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells

“…On the other hand, oxLDL is immunogenic and elicits the production of antibodies, predominantly of the proinflammatory IgG1 and IgG3 isotypes (3,4). These antibodies form circulating immune complexes containing oxLDL (oxLDL-IC), and those immune complexes have pro-inflammatory properties (5)(6)(7) and are considerably more efficient than oxLDL in the induction of foam cell formation (8)(9)(10). While the uptake of both oxLDL and oxLDL-IC produce cells morphologically defined as foam cells, there is evidence for distinct molecular differences.…”

“…The basis for this difference in not known. Macrophages exposed to oxLDL-IC have higher levels of CE and display an increased release of cytokines as compared to cells exposed to oxLDL (5,7). These findings have led to the hypothesis that although foam cells generated by exposure to oxLDL and oxLDL-IC appear morphologically similar, they differ in the profile of genes that regulate survival and inflammatory response.…”