key: cord-1050446-ikaffba9
authors: Tal, Yuval; Adini, Avner; Eran, Alal; Adini, Irit
title: Racial disparity in Covid-19 mortality rates - A plausible explanation
date: 2020-05-28
journal: Clin Immunol
DOI: 10.1016/j.clim.2020.108481
sha: 898b201428557c1972048f2fe764f96d8150845b
doc_id: 1050446
cord_uid: ikaffba9

nan

As the Covid-19 pandemic rages on, black Americans seem to be at a greater risk of adverse outcome. While comorbidities and socioeconomic circumstances certainly have an impact on these perceived discrepancies, we hypothesize that additional contributing factors underlie the divergence in morbidity and mortality between ethnic groups. Given the significance of immunopathology in Covid-19 mortality, we pondered whether specific immune disparities might directly contribute to sensitizing patients of certain ethnicities. Indeed, we found evidence of inherent differences in the immune system, which may increase the predisposition of black Americans to a severe cytokine storm. We hope that these observations may contribute to the prognosis of this population and prompt the utilization of anti-cytokine biologics to treat patients in the immune phase of Covid-19.

Using RNAseq gene analysis data from the Genotype-Tissue Expression (GTEx) project, 1 we compared the expression of cytokines and other central immune modulators between healthy black and white Americans. We found that inflammasome-derived interleukin 1 beta (IL1 and Similarly, DCs also secrete IL6 and INF, which play a significant and well documented role in immune response against pathogens. Finally, TLR7 and TLR9, which are pertinent DCs receptors, present another route for DC activation by binding to pathogenic nucleic acids.

Notably, DC activation is also implicated in prompting eosinophil and mast cell migration, proliferation and activation. Mast cell and eosinophil activation further contribute to end-organ damage, with the latter secreting eosinophil-derived neurotoxin (EDN) which acts as a positive feedback DC activator. Elevation of type 2 cytokine (Th2) levels was reported in severe SARS cases. 3 The hallmark of a Th2 response is manifested by IL4 and IL13, directly linked to inflammation and resultant skin rashes. Atopic dermatitis and prurigo nodularis are classic Th2mediated diseases, both of which are more severe in black Americans. Interestingly, a rash was recently suggested as a possible symptom of COVID-19 ( Figure 1 ).

We thus postulated that DCs are likely to be a central player in the enhanced immune response in black Americans. While the mechanisms leading to racial disparities in cytokine expression levels seen in Covid-19 remain to be established, our experimentations in mice models suggest that in some cases, melanogenesis can directly impact the immune system through DC activation. Melanocytes are antigen-presenting cells and plays a dynamic role in the immune system. We previously described that fibromodulin (FMOD), a pigment-dependent angiogenic factor secreted by melanocytes, leads to proliferation of endothelial cells, followed by an increase in TGF1 levels. 4 Recent results have led us to hypothesize that melanocytes use FMOD/ TGF1 signaling to substantially modulate the immune system and more specifically, J o u r n a l P r e -p r o o f Journal Pre-proof DC maturation and activity. By inoculating mice with CpG (oligodeoxynucleotides containing nonmethylated CpG) or lipopolysaccharide (major membrane components express on Gramnegative bacteria), we were able to provoke inflammation and promote DCs migration to the spleen. Strikingly, induced DCs in the spleen were more numerous and mature (as revealed by their increased expression of MHCII and CD86) in pigmented Black-C57 mice than in their under-melaninated congenic Yellow-C57 mice counterparts. Knockdown of FMOD in lightly pigmented mice recapitulated the phenotype, supporting causality. Finally, as T-cell activation is directly associated with an elevated level of mature DCs, the dark-pigmented mice may be predisposed to a more severe cytokine storm.

In conclusion, our findings suggest that black individuals may have the tendency to develop a harsher pro-inflammatory cytokine response. Accordingly, we posit that when confronted with SARS-cov-2, black Americans would be more prone to develop a rapid and more aggressive cytokine storm. This may necessitate earlier administration of biologics to block the ensuing overwhelming immune response in an attempt to improve their prognosis. Figure 1 

Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans

High mortality due to sepsis in Native Hawaiians and African Americans: The Multiethnic Cohort

T cell responses to whole SARS coronavirus in humans

Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment

This study was supported in part by a grant from the NIH R01EY024046