Prevalence and correlation of cytokine-specific autoantibodies with epidemiological factors and C-reactive protein in 8,972 healthy individuals: Results from the Danish Blood Donor Study

Abstract

Natural cytokine-specific autoantibodies (c-aAb) have been measured in healthy and diseased individuals, and have been considered as both endogenous immune-regulators and pathogenic factors. Overall, the etiology and potential pathology of c-aAb are still undefined. To further characterize the sero-prevalence, predictors and consequences of high c-aAb levels, we performed the largest population-based study of c-aAb to date, using participants and epidemiological data from the Danish Blood Donor Study. Using a validated bead-based multiplex assay we assessed plasma levels of IL-1α, IL-6, IL-10, IFNα and GM-CSF-specific c-aAb in 8,972 healthy blood donors. Trace levels of at least one of the investigated c-aAb could be measured in 86% of the participants. The presence of high levels of potentially inhibitory c-aAb was generally associated with increasing age and male or female sex, depending on the c-aAb in question. A negative correlation between high levels of IL-6-specific c-aAb and plasma levels of C-reactive protein was observed, indicating cytokine-neutralizing levels of c-aAb in healthy blood donors. There was no substantial correlation between high levels of the five individual c-aAb investigated in this study. These data suggest that autoimmunity against endogenous cytokines is a relatively common phenomenon in healthy individuals, and that predictive factors for high, potentially neutralizing c-aAb levels vary depending on the cytokine in question, and may differ from predictors of general c-aAb presence.

Cytokine Autoantibodies Are Associated with Infection Risk and Self-Perceived Health: Results from the Danish Blood Donor Study

“…In line with prior studies [16], we found c-aAb levels to be associated with sex and age, as well as a novel association of IL-6 c-aAb and oral contraceptives. As such, we observed a strong sex interaction for c-aAb and our investigated outcomes.…”

“…GM-CSF c-aAb have also been associated with multiple variants of opportunistic infections [30], and here we observed high levels of c-aAb to be associated with an increased risk of sulfonamide prescriptions in women. Interestingly, despite the previously observed association between IL-6 c-aAb and low levels of CRP [16], high levels of IL-6 c-aAb did not predict higher or lower risk of filing prescriptions in this study, which may reflect the pleiotropic roles of IL-6 as both a pro-and antiinflammatory cytokine [31]. Furthermore, c-aAb have in some reports been observed to act as agonists of their target cytokine function [32], adding further complexity to our findings.…”

“…High levels of c-aAb were defined as median fluorescence intensity (MFI) signals above the 99th percentile, to identify participants with c-aAb levels most likely to inhibit their target cytokines. Separate cutoff values were generated for men and women, due to differences in c-aAb signals between the groups, as previously described [16]. Low c-aAb levels were defined as MFI values below MFI + 4 standard deviations (SD) of the negative control, and intermediary c-aAb levels were defined as MFI values between the low and high MFI groups.…”

“…Due to previously described sex-specific variation regarding c-aAb distribution [16], descriptive data were stratified according to sex. Continuous normally distributed data were compared across sex by student's t-test (c-aAb MFI signals were log-transformed, to approximate normal distributions).…”

“…We have previously reported that detectable levels of c-aAb are common among healthy individuals, with high levels being associated with older age and male sex. Furthermore, in healthy individuals, high levels of IL-6 c-aAb are associated with low C-reactive protein (CRP) levels, indicating a possible functional effect of naturally occurring, high-titer c-aAb [16].…”