During acute or chronic inflammation, several changes occur in HDLs, as summarized in Table 1. As part of the acute-phase response, several plasma proteins carried in HDLs are decreased, including PON, LCAT, CETP, PLTP, hepatic lipase, and apoA-I. Acute-phase HDLs are depleted in cholesterol ester but enriched in free cholesterol, triglyceride, and free fatty acids – none of which can participate in reverse cholesterol transport or antioxidation [40, 41]. In these HDLs, levels of the pro-oxidant serum amyloid A (SAA) increase several-fold, as do levels of apoJ (also called clusterin) . In fact, apoA-I is displaced from HDLs by SAA, which is associated not only with disabling HDLs as anti-inflammatory mediators, but with creating piHDLs. These HDLs can be defined as proinflammatory because they actually enhance the oxidation of LDLs and therefore attract monocytes to engulf those oxLDLs . In fact, regulation of SAA, apoA-I, and PON1 is coordinated in murine hepatocytes; as SAA increases, the other two molecules decrease. These changes are promoted by nuclear factor-kappa-B and suppressed by the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-α) . Acute-phase HDLs (including piHDLs) are much less effective than normal HDLs in removing cholesterol from macrophages  and delivering cholesterol esters to hepatocytes . Lipids in the altered HDLs are themselves oxidized .
We can thus envision the piHDLs as pictured in Figure 2b. In the spherical particles, apoA-I and antioxidative enzymes are partially replaced by the products of oxidation, including oxidized lipids and serum amyloid protein. Such changes have been shown to occur in acute infection, in acute 'trauma' of surgical interventions, and in chronic inflammation. If one measures total HDLs by standard service clinical laboratory methods, they are usually low during periods of acute infection as well as in chronic inflammatory states such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [47–50]. A population study of monocytes from individuals from the general population with low plasma concentrations of HDLs showed increased expression of a cluster of inflammatory genes (IL-1β, IL-8, and TNF-α) and decreased PPAR-γ and antioxidant metallothionein genes compared with controls . It seems likely that there are at least two major factors determining whether an individual at any given time point has normal anti-inflammatory HDLs or nonprotective piHDLs, whether inflammation is present, and genetic background. Furthermore, it is likely that the measurement of HDL function shows a 'majority' activity. That is, HDLs consist of numerous particles of different sizes, contents, and activities. In assays for anti-inflammatory versus proinflammatory function of HDLs obtained from test serum, one detects a dominant activity that does not describe the exact distribution of these HDLs. These data would predict that the ratio of normal to proinflammatory HDLs would vary over time. In fact, as discussed below, in our data in patients with SLE, that was not true. piHDL activity in an individual was stable over time without relation to disease activity; normal HDLs were also found repeatedly in some individuals with SLE even during periods of marked disease activity. It is our idea that HDL functions are rooted in genetic susceptibility and influenced by the presence of chronic inflammation in rheumatic diseases.
What are the processes that account for modification of normal HDLs into piHDLs? These are probably complex and include (a) oxidation of lipids and lipoproteins in the HDL particle (by increased activities of peroxidases that occur during inflammation, for example), (b) decreased synthesis of the proteins that populate HDL particles (for example, apoA-I), (c) addition of proteins that may participate in inflammation, and (d) replacement of cholesterol-transporting proteins and antioxidant enzymes by pro-oxidants SAA and ceruloplasmin. This is probably a dynamic situation in which lipids and proteins interact with other lipids and transfer from one particle or lipid-containing membrane to another. Thus, chronic autoimmune inflammation, even if low-grade, in a permissive genetic background may determine a chronic composition of HDLs which is proinflammatory. A study of the protein content of HDLs from patients with CAD compared with HDLs from healthy individuals showed enrichment of CAD HDLs in complement regulatory proteins, serpins, and apoE . It is not clear how this work relates to the piHDLs that are discussed in this review.