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    • We found evidence of similar

    2018-11-07

    We found evidence of similar alterations in levels of certain natural autoantibodies (low IgM anti-PC and high IgG anti-MDA) among patients with RHD, although the effect size was smaller than for HIV infection. As an autoimmune condition, RHD may be associated with global immune dysregulation that also affects levels of these natural autoantibodies, and further study with larger sample sizes are needed to more clearly reveal this association. For the reasons mentioned above, these findings may also provide insight into atherosclerotic vascular disease risk in patients with RHD. Compared to classical atherosclerotic cardiovascular disease, patients with RHD tend to be younger and their cardiovascular morbidity and mortality are driven more by complications of progressive valvular poly ic failure and the need for heart valve surgery. However, a national database study from Sweden reported that hospitalization for acute rheumatic fever was associated with a 4.7-fold increased risk of subsequent coronary heart disease (Zoller et al., 2012). While intriguing, this finding could potentially be confounded by ascertainment bias (i.e. RHD patients undergoing heart valve surgery are routinely evaluated for co-existing coronary artery disease). Another study found that carotid intima-media thickness and aortic stiffness were increased in children with a prior diagnosis of rheumatic fever (Ciftel et al., 2014). Therefore the relationships between natural autoantibodies to oxidation-associated antigens, subclinical vascular disease, ventricular-vascular interactions, and RHD disease susceptibility and progression should be evaluated in future studies. A central aim of our study was to examine the interaction between RHD and HIV status—two highly prevalent diseases in sub-Saharan Africa. Very little is known about this interaction, although there is a reason to believe that concurrent HIV infection may alter susceptibility to RHD or RHD disease progression in positive and negative ways (Longenecker et al., 2014). Our group has previously reported a decreased prevalence of latent rheumatic heart disease detected by echocardiography among HIV-infected children compared to other Ugandan school children (Gleason et al., 2014) but there are many health system factors (e.g. access to healthcare services, use of prophylactic antibiotics) that may confound this finding. Besides the finding that HIV infection may adversely affect the natural autoantibody responses, other findings from our study suggest that HIV-infected patients with RHD may be different from HIV-uninfected patients with RHD in ways that may protect against RHD progression. First, there was an interaction between RHD and HIV in our multivariable model, such that HIV infection was associated with lower anti-MDA IgG levels among subjects with RHD—this is opposite of the effect of HIV in the overall cohort. Second, HIV-infected subjects with and without RHD had lower ASO titers than HIV-uninfected controls. This may reflect a decreased burden of invasive GAS infection among subjects with HIV, possibly due to better engagement in care and access to antibiotics. Compared to uninfected subjects with RHD, HIV-infected subjects with RHD had lower levels of systemic inflammation as measured by hsCRP, again suggesting some protective confounder. Among the first reported immune abnormality in HIV infected individuals was the appearance of rheumatoid factors and anti-nuclear antibodies (Lane et al., 1985), and HIV infection also has been reported to impact risk for some autoimmune diseases (Zandman-Goddard and Shoenfeld, 2002). The immunosuppression caused by HIV at low CD4+ T-cell counts may protect against autoimmune disease; in fact, patients with SLE have been reported to symptomatically improve as HIV disease progresses and CD4 counts declines, but then may later symptomatically worsen after immune reconstitution with ART (Zandman-Goddard and Shoenfeld, 2002). In the era of effective ART, autoimmune disease may occur as an immune reconstitution inflammatory syndrome (IRIS), but overall the incidence of associated connective tissue diseases appears to be on the decline (Calabrese et al., 2005; Iordache et al., 2014). In our study, HIV infection was associated with perturbations in levels of natural autoantibodies to oxidation-associated determinants that have been previously associated with increased disease severity in SLE (Gronwall et al., 2012). HIV infection likely has a complex relationship with autoimmune predisposition to diseases such as SLE and to RHD — perturbations in these types of natural autoantibodies may also increase risk and disease severity while the immunosuppression and profound CD4 T cell depletion in untreated HIV may reduce risk and disease severity.