Autoimmune Diseases: The Role of Autoantibodies
Systemic Lupus Erythematosus (SLE)
SLE is a systemic autoimmune disease of multifactorial origin, in which genetic and environmental factors induce innate and acquired immunity derangement, with type I interferon (INF) production, Tand B-cell dysregulation, autoantibody production, and ﬁnally multiple organ damage. SLE is associated with accelerated atherosclerosis and markedly increased cardiovascular risk (CVR) (Shoenfeld et al. 2005). As in other autoimmune disorders, CVR cannot be fully explained by traditional risk factors, and various speciﬁc immune and inﬂammatory mechanisms have been demonstrated or proposed. The modiﬁcations of HDL level and function occurring in SLE have been indicated as possible factors contributing to cardiovascular damage.
Decreased circulating HDL-C levels have been often reported, although not unanimously, in SLE patients with active disease (de Carvalho et al. 2008; Hahn et al. 2008; Kiss et al. 2007), but the actual relevance of this ﬁnding with respect to CVR has not been clariﬁed so far. The most important pro-atherogenic modiﬁcations seem to be those relative to composition and function of HDL. HDLs in SLE have impaired anti-inﬂammatory and antioxidant properties. In SLE, the so-called proinﬂammatory HDL (piHDL) can be detected in as many as 45 % of patients, correlating with increased oxidized LDL formation, carotid plaque, and carotid intima-media thickness (cIMT) (McMahon et al. 2011). piHDL are characterized by decreased content in the protective proteins paraoxonase (PON1) and apoA-I and by markedly increased levels of the pro-oxidant SAA (Hahn et al. 2008). These HDLs can be deﬁned as proinﬂammatory because they actually enhance the oxidation of LDL and therefore monocyte attraction/activation, antioxLDL antibody production, and immune complex formation (Hahn et al. 2008; Teixeira et al. 2012; Carbone et al. 2013; Vuilleumier et al. 2014). It has been shown that the reduced activity of PON1 in some cases may be due also to the action of antiapoA-I and anti-HDL antibodies (O'Neill et al. 2010; Batuca et al. 2007). Anti-apoAI antibodies, ﬁrst described in SLE patients but detected also in patients with acute coronary syndrome, have shown independent association and predictive value with respect to cardiovascular events in various patient populations (Carbone et al. 2013). Proposed mechanisms for such association include the ability of anti-apoA-I antibodies to induce HDL dysfunction, scavenger receptor B1 (SR-BI) function impairment in endothelial cells, neutrophil inﬁltration and matrix-metalloproteinase 9 production in plaques, activation of NFkB via TLR2/CD14 complex interaction, and cytokine release (Carbone et al. 2013). Interestingly, anti-apoA-I and anti-HDL antibodies have been shown to correlate also with disease activity in SLE patients (O'Neill et al. 2010).
In addition, HDL dysfunction in SLE involves their capacity to promote cell cholesterol efﬂux (Ronda et al. 2014). In particular, in SLE patients HDL cholesterol efﬂux capacity (CEC) is reduced with respect to the ABCG1 and ABCA1 transporter pathways, while the SR-BI-mediated CEC is unchanged. In addition the correlation between SR-BI-mediated CEC and HDL-C levels was stronger in SLE plasmas as compared to control plasma. This pattern is consistent with a possible reduction/dysfunction of the small HDL populations (Favari et al. 2009) and a shift to larger HDL, typical acceptors of cholesterol efﬂuxed by SR-BI. Indeed, HDLs of SLE patients were found increased in size (Hua et al. 2009; Jua´rez-Rojas et al. 2008). The impaired ABCA1and ABCG1-mediated CEC in SLE patients may have a great impact because cholesterol efﬂux not only opposes lipid deposition in vessels but is also crucial for the modulation of macrophage, endothelial, and T-cell inﬂammatory functions (Prosser et al. 2012; Yvan-Charvet et al. 2010a, b).