Associations between perceived discrimination and immune cell composition in the Jackson Heart Study

Highlights

• Poor health outcomes among African American adults are well-documented.

• The impact of discriminatory experiences might be a contributing factor.

• Biological pathways incompletely understood, but might involve immune function.

• Associations were tested between perceived discrimination and leukocyte composition.

• Perceived discrimination burden predicted a higher neutrophil-to-lymphocyte ratio.

Abstract

African American adults suffer disproportionately from several non-communicable and infectious diseases. Among numerous contributing factors, perceived discrimination is considered a stressor for members of historically marginalized groups that contributes to health risk, although biological pathways are incompletely understood. Previous studies have reported associations between stress and both an up-regulation of non-specific (innate) inflammation and down-regulation of specific (adaptive) immunity. While associations between perceived discrimination and markers of inflammation have been explored, it is unclear if this is part of an overall shift that also includes down-regulated adaptive immunity. Relying on a large cross-section of African American adults (n = 3,319) from the Jackson Heart Study (JHS) in Jackson, Mississippi, we tested whether perceived everyday and lifetime discrimination as well as perceived burden from lifetime discrimination were associated with counts of neutrophils (innate), monocytes (innate), lymphocytes (adaptive), and the neutrophil-to-lymphocyte ratio (NLR), derived from complete white blood cell counts with differential. In addition, DNA methylation (DNAm) was measured on the EPIC array in a sub-sample (n = 1,023) of participants, allowing estimation of CD4T, CD8T and B lymphocyte proportions. Unexpectedly, high lifetime discrimination compared to low was significantly associated with lower neutrophils (b : -0.14, [95% CI: -0.24, -0.04]) and a lower NLR (b : -0.15, [95% CI: -0.25, -0.05]) after controlling for confounders. However, high perceived burden from lifetime discrimination was significantly associated with higher neutrophils (b : 0.17, [95% CI: 0.05, 0.30]) and a higher NLR (b : 0.16, [95% CI: 0.03, 0.29]). High perceived burden was also associated with lower lymphocytes among older men, which our analysis suggested might have been attributable to differences in CD4T cells. These findings highlight immune function as a potentially important pathway linking perceived discrimination to health outcomes.

Introduction

Black-White health disparities in the United States are well-documented across numerous health outcomes, particularly chronic non-communicable diseases such as cardiovascular disease (CVD) (Gravlee, 2009, Hunt and Whitman, 2015, Orsi et al., 2010). However, COVID-19 has also heightened awareness of disparities in infectious diseases, which have existed long before the pandemic (Evans, 2020, Feigenbaum et al., 2019, McLaren, 2021, Tirupathi et al., 2020). While there are numerous contributors to these health disparities, a growing body of evidence has indicated the importance of psychosocial stress experienced by members of historically marginalized groups (Boen, 2020, Cardel et al., 2021, Forde et al., 2020, Gravlee, 2009, McLaren, 2021, Sims et al., 2012, Sims et al., 2016). For example, reported experiences of discrimination predict morbidity and mortality risk independent of other life stressors such as socioeconomic status (SES) (Barnes et al., 2008, Boen, 2020, Cardel et al., 2021, Forde et al., 2020, Sims et al., 2012, Thoits, 2010). The biological pathways through which discrimination-related stress can become embedded and impact health are not well understood; however, research has increasingly highlighted the immune system (Baune et al., 2011, Black and Garbutt, 2002, Liu et al., 2017, Simons et al., 2017, Wirtz and von Känel, 2017).

Recent research on stress and immune function has focused primarily on chronic inflammation, which is linked to stress and implicated in a host of chronic non-communicable diseases, including CVD, type II diabetes and Alzheimer’s (Black and Garbutt, 2002, Liu et al., 2017, Wirtz and von Känel, 2017). Studies focusing specifically on discrimination-related stress have reported associations with elevated markers of chronic inflammation, such as C-reactive protein (CRP) and interleukin (IL)-6 (Brody et al., 2015, Cuevas et al., 2020, Lewis et al., 2010, McClendon et al., 2021, Saban et al., 2018, Sims et al., 2020). However, the recent pandemic has highlighted the importance of considering how discrimination-related stress might be related to immune function more broadly, potentially influencing vulnerability to infectious disease (Evans, 2020, Feigenbaum et al., 2019) .

In contrast to the up-regulated inflammatory activity that has been the recent focus in stress research, earlier studies focused on immunosuppressive effects (Herbert and Cohen, 1993, Liu et al., 2017, Segerstrom and Miller, 2004). Such seemingly contradictory findings of both suppression and heightened activity can be explained by considering the separate arms of the immune system, which include non-specific (often called innate) defense and specific (often called adaptive/acquired) defense. The innate arm is the faster acting first line of defense, responding to a host of bodily disturbances by initiating an inflammatory response (Kindt et al., 2007, McDade et al., 2016, Paul, 2013). Commonly used markers of innate inflammatory activity include CRP and IL-6, measured either in an unstimulated condition or following a laboratory-induced response (Cohen et al., 2012, Gouin et al., 2012, Kiecolt-Glaser et al., 2003, Miller et al., 2014, Saban et al., 2018). In contrast, the adaptive arm is the slower acting second line of defense, targeting specific pathogens and developing memory for more efficient future protection (Kindt et al., 2007, McDade et al., 2016, Paul, 2013). Measures of adaptive immune function include lymphocyte counts and proliferation following challenge (Herbert and Cohen, 1993, Segerstrom and Miller, 2004). Collectively, research findings suggest that stress is associated with an overall shift in immune function toward reduced adaptive and heightened innate activity, which is thought to increase morbidity and mortality risk across both non-communicable and infectious diseases (Fu et al., 2020, Herbert and Cohen, 1993, Liu et al., 2017, Segerstrom and Miller, 2004, Simons et al., 2017). While perceived discrimination has been associated with elevated markers of innate inflammation (Brody et al., 2015, Cuevas et al., 2020, Saban et al., 2018), it is unclear if this is also part of a larger shift in immune function that includes the down-regulation of adaptive immunity.

This study examines associations between perceived discrimination and measures of immune function across both innate and adaptive immunity among African American men and women in the Jackson Heart Study (JHS) (Sempos et al., 1999, Sims et al., 2009). Perceived everyday and lifetime discrimination, as well as perceived burden of lifetime discrimination, were measured along with the prevalence of innate and adaptive cells, including innate neutrophils and monocytes and adaptive lymphocytes. Further, DNA methylation (DNAm) was measured in peripheral blood mononuclear cells (PBMC’s) for a subsample of participants, which allowed estimation of proportions of different types of lymphocytes in circulation, including CD4T, CD8T, and B cells (Salas et al., 2018). DNAm also allowed estimation of accelerated aging of the immune system (Horvath, 2013). Up-regulation of the innate arm and down-regulation of the adaptive arm occurs during normal aging (Fülöp et al., 2018), while perceived discrimination has been associated with accelerated biological aging (Brody et al., 2016); Lee et al., 2017, Liu and Kawachi, 2017). Thus, we wanted to clarify this indirect pathway from perceived discrimination to immune function (Fig. 1). Using these data, we hypothesized that perceived discrimination and burden would be associated with a greater proportion of innate cells and lower proportion of adaptive cells in circulation. In addition, we hypothesized that perceived discrimination and burden would be associated with markers of accelerated immune system aging, and that accelerated aging would mediate the association between perceived discrimination and immune cell counts.