The median anti PC and anti MDA levels

The median anti-PC and anti-MDA levels by group, comparing each disease group with the RHD−HIV− controls, are depicted in Figs. 2 and 3. We found that anti-PC IgM was lower in both HIV+ groups compared to the RHD−HIV− group, while for anti-MDA IgG there were no significant differences between the 3 disease groups and controls (all p>0.10). In further subgroup analysis of HIV positive individuals, those with CD4 count <200 (n=12) did not differ with respect to anti-PC IgM when compared to those with a CD4 count >500 (n=33) [median (Q25–Q75): 12 (8–40) U/mL vs. 19 (7–37) U/mL, p=0·91]. Similarly, there was no difference in anti-MDA IgG [16 (7–25)U/mL for CD4<200 vs. 11 (3–25)U/mL for CD4>500, p=0.64]. To further explore the effect of HIV and RHD on autoantibody levels, an adjusted analysis allowing for interaction was conducted (Table 2). In these models, HIV infection and RHD were each independently associated with lower anti-PC IgM (HIV: p<0.0001 and RHD: p=0.012). There was no evidence of effect modification interaction between RHD and HIV (p=0.50) for levels of anti-PC IgM, and thus it MLN 9708 was removed from the model. A significant HIV*RHD interaction was identified for IgG anti-MDA (p=0.045) such that in participants without RHD we found that HIV infection was associated with increased IgG anti-MDA, whereas it was associated with decreased IgG anti-MDA in participants with RHD.
Discussion These relationships between autoantibody responses and disease have been well characterized in patients with SLE, the archetypic systemic autoimmune disease (Gronwall et al., 2012); however, low IgM anti-PC has also been associated with atherosclerosis and increased risk of myocardial infarction and stroke in populations without known autoimmune disease (Fiskesund et al., 2010; Gronlund et al., 2009). In these latter studies, anti-PC IgM titer below the 30th percentile corresponded with a multivariable adjusted relative risk of 1.62 (CI 1.11–2.35) for stroke, while a level below the 25th percentile was associated with a relative risk of 1.69 (1.09–2.54) for myocardial infarction. In our study, half of participants with HIV and over two-thirds of those with both RHD and HIV had IgM anti-PC levels below the 25th percentile of the RHD and HIV negative group (Supplementary Figs. 1 and 2), suggesting that the degree to which these natural autoantibodies are altered in HIV infection may also be associated with a clinically significant increase in myocardial infarction and stroke. While we did not have statistical power to determine whether very low CD4 T-cell count in HIV patients was associated with altered levels of autoantibodies, given the associations in other cohorts between low nadir and proximal CD4+ T-cells counts and cardiovascular events (Longenecker and Triant, 2014), this should be further explored in future studies. Anti-MDA IgG has previously been associated with higher SLE disease activity (Gronwall et al., 2012). In addition, higher MDA-LDL levels in immune complexes have previously been associated with increased rates of myocardial infarction (Lopes-Virella et al., 2012). Higher levels of circulating IgG—especially the proinflammatory IgG1 and IgG3 subclasses that activate Fcγ receptors and complement—against oxidation-associated epitopes (on LDL or other macromolecules) may occur in the context of a higher burden of inflammatory atherosclerotic plaque (Mironova et al., 1996). Indeed we observed higher IgG against MDA in individuals with HIV, which we postulate may correspond to increased inflammation and formation of oxidation byproducts in these patients. Although these specific types of natural autoantibodies that were the focus of our investigations have not been previously studied in the context of HIV, in a recent study, levels of anti-MDA-LDL antibodies were evaluated in HIV-infected and uninfected subjects. It found lower levels of IgM natural autoantibody against MDA-LDL and higher levels of IgG against MDA-LDL, although further molecular characterizations were not performed (Yilmaz et al., 2014). Another study of IgG antibodies to oxidized LDL in HIV patients found a decrease in the levels of these antibodies after immune reconstitution following initiation of antiretroviral therapy (Ronchini et al., 2013). Our findings are therefore similar to patterns previously reported in HIV infected subjects.