Genome-wide association studies performed in COVID-19 patients have uncovered various loci significantly associated with susceptibility to SARS-CoV-2 infection and disease severity. However, the underlying cis-regulatory genetic factors contributing to heterogeneity in the response to SARS-CoV-2 infection and their impact on clinical phenotypes remain enigmatic. Here, we use single-cell RNA-sequencing to quantify genetic contributions to cis-regulatory variation in 361,119 peripheral blood mononuclear cells of 63 acute COVID-19 patients, 39 convalescent samples, and 106 healthy controls. Expression quantitative trait loci mapping across cell types within each disease state group reveals thousands of cis-associated variants, of which hundreds are detected exclusively in immune cells derived from acute patients. Patient-specific genetic effects dissipate as infection resolves, suggesting that distinct gene regulatory networks are at play in the active infection state. Further, 20.3% of tested loci demonstrate significant cell state interactions with genotype, with pathways related to interferon responses and oxidative phosphorylation showing pronounced cell state-dependent variation, predominantly in CD14+ monocytes. Overall, we estimate that 16.8% of tested genes exhibit gene-environment interaction effects, highlighting the importance of environmental modifiers in the transcriptional regulation of the immune response to SARS-CoV-2. Our findings argue for the existence of extensive gene-environment effects among patients responding to an infection.

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, in support of two proposed mechanisms5,6 for the regulation of aRMAE. We tested peripheral blood mononuclear cells from individuals with IEIs with shared genetic lesions but discordant clinical phenotypes for aRMAE. Among two relatives who were heterozygous for a mutation in PLCG2 (delEx19), an antibody deficiency phenotype corresponds to selective mutant allele expression in B cells. By contrast, among relatives who were heterozygous for a mutation in JAK1 (c.2099G>A; p.S700N), the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, whereas the affected carrier T cells exhibited biallelic expression. Allelic expression bias was also documented in phenotypically discordant family members with mutations in STAT1 and CARD11. This study highlights the importance of considering both the genotype and the 'transcriptotype' in analyses of the penetrance and expressivity of monogenic disorders.

Only one-third of immune-associated genome-wide association study (GWAS) loci colocalize with expression quantitative trait loci (eQTLs), leaving most mechanisms unresolved. To address this, we created a unified single-cell chromatin accessibility (scATAC) map of ∼280,000 peripheral immune cells from 48 individuals, including 20 COVID-19 patients. Topic modeling of scATAC data identified continuous cell states and revealed disease-relevant cellular contexts. We identified 37,390 chromatin accessibility QTLs (caQTLs) at 10% false discovery rate and observed extensive sharing of caQTLs, with <20% confined to a single context. Notably, caQTLs explained ∼50% more GWAS loci compared to eQTLs, nominating putative causal genes for some unexplained loci. Yet most GWAS-colocalizing caQTLs lacked eQTL support, limiting causal inference from chromatin data alone. Thus, while caQTLs can improve GWAS interpretation, robust mechanistic insights require integration with gene expression and other functional evidence. Our work underscores that cellular context is critical for regulatory variant interpretation and emphasizes the need to map genetic effects in disease-relevant cell states.

Humans exhibit considerable variability in their immune responses to the same immune challenges. Such variation is widespread and affects individual and population-level susceptibility to infectious diseases and immune disorders. Although the factors influencing immune response diversity are partially understood, what mechanisms lead to the wide range of immune traits in healthy individuals remain largely unexplained. Here, we discuss the role that natural selection has played in driving phenotypic differences in immune responses across populations and present-day susceptibility to immune-related disorders. Further, we touch on future directions in the field of immunogenomics, highlighting the value of expanding this work to human populations globally, the utility of modeling the immune response as a dynamic process, and the importance of considering the potential polygenic nature of natural selection. Identifying loci acted upon by evolution may further pinpoint variants critically involved in disease etiology, and designing studies to capture these effects will enrich our understanding of the genetic contributions to immunity and immune dysregulation.

Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the "Interferon paradox" previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity. The role of IFN signaling in SARS-CoV-2 infection and outcome is still debated. Here, the authors longitudinally profiled plasma samples from hospitalized patients and show that a persistent inflammatory response is linked to delayed generation of adaptive immunity and increased risk of death when coupled with severe infection.

BACKGROUND:Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes.OBJECTIVE:We hypothesized that CD4+ T-cell lymphopenia could be associated with a state of T-cell exhaustion in previously transplanted SCID patients.METHODS:We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT.RESULTS:Compared to post-HCT SCID patients with normal CD4+ T-cell counts, those with poor T-cell reconstitution showed lower frequency of naive CD45RA+/CCR7+ T cells, recent thymic emigrants, and TCR excision circles. They also had a restricted TCR repertoire, increased expression of inhibitory receptors (PD-1, 2B4, CD160, BTLA, CTLA-4), and increased activation markers (HLA-DR, perforin) on their total and naive CD8+ T cells, suggesting T-cell exhaustion and aberrant activation, respectively. The exhaustion score of CD8+ T cells was inversely correlated with CD4+ T-cell count, recent thymic emigrants, TCR excision circles, and TCR diversity. Exhaustion scores were higher among recipients of unconditioned HCT, especially when further in time from HCT. Patients with fewer CD4+ T cells showed a transcriptional signature of exhaustion.CONCLUSIONS:Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution.

Severity of pulmonary viral infections, including influenza A virus (IAV), is linked to excessive immunopathology, which impairs lung function. Thus, the same immune responses that limit viral replication can concomitantly cause lung damage that must be countered by largely uncharacterized disease tolerance mechanisms. Here, we show that mitochondrial cyclophilin D (CypD) protects against IAV via disease tolerance. CypD-/- mice are significantly more susceptible to IAV infection despite comparable antiviral immunity. This susceptibility results from damage to the lung epithelial barrier caused by a reduction in interleukin-22 (IL-22)-producing natural killer (NK) cells. Transcriptomic and functional data reveal that CypD-/- NK cells are immature and have altered cellular metabolism and impaired IL-22 production, correlating with dysregulated bone marrow lymphopoiesis. Administration of recombinant IL-22 or transfer of wild-type (WT) NK cells abrogates pulmonary damage and protects CypD-/- mice after IAV infection. Collectively, these results demonstrate a key role for CypD in NK cell-mediated disease tolerance.

Humans differ in their susceptibility to infectious disease, partly owing to variation in the immune response after infection. We used single-cell RNA sequencing to quantify variation in the response to influenza infection in peripheral blood mononuclear cells from European- and African-ancestry males. Genetic ancestry effects are common but highly cell type specific. Higher levels of European ancestry are associated with increased type I interferon pathway activity in early infection, which predicts reduced viral titers at later time points. Substantial population-associated variation is explained by cis-expression quantitative trait loci that are differentiated by genetic ancestry. Furthermore, genetic ancestry–associated genes are enriched among genes correlated with COVID-19 disease severity, suggesting that the early immune response contributes to ancestry-associated differences for multiple viral infection outcomes.

Humans vary in their susceptibility to infectious disease, partly due to variation in the immune response following infection. Here, we used single-cell RNA-sequencing to quantify genetic contributions to this variation in peripheral blood mononuclear cells, focusing specifically on the transcriptional response to influenza infection. We find that monocytes are the most responsive to influenza infection, but that all cell types mount a conserved interferon response, which is stronger in individuals with increased European ancestry. By comparing European American and African American individuals, we show that genetic ancestry effects on expression are common, influencing 29% of genes, but highly cell type-specific. Further, we demonstrate that much of this population-associated expression variation is explained by cis expression quantitative trait loci, which are enriched for signatures of recent positive selection. Our findings establish common cis -regulatory variants—including those that are differentiated by genetic ancestry—as important determinants of the antiviral immune response.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated disease, COVID-19, has demonstrated the devastating impact of a novel, infectious pathogen on a susceptible population. Here, we explain the basic concepts of herd immunity and discuss its implications in the context of COVID-19.

DNA methylation is considered to be a relatively stable epigenetic mark. However, a growing body of evidence indicates that DNA methylation levels can change rapidly; for example, in innate immune cells facing an infectious agent. Nevertheless, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we generated time-course data on DNA methylation, gene expression, and chromatin accessibility patterns during infection of human dendritic cells with Mycobacterium tuberculosis . We found that the immune response to infection is accompanied by active demethylation of thousands of CpG sites overlapping distal enhancer elements. However, virtually all changes in gene expression in response to infection occur before detectable changes in DNA methylation, indicating that the observed losses in methylation are a downstream consequence of transcriptional activation. Footprinting analysis revealed that immune-related transcription factors (TFs), such as NF-κB/Rel, are recruited to enhancer elements before the observed losses in methylation, suggesting that DNA demethylation is mediated by TF binding to cis-acting elements. Collectively, our results show that DNA demethylation plays a limited role to the establishment of the core regulatory program engaged upon infection.

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.

Bats are reservoir hosts of numerous viruses that cause severe pathology in humans. How bats cope with such pathogens remains elusive. In a recent issue of Cell, Pavlovich et al., 2018Pavlovich S.S. Lovett S.P. Koroleva G. Guito J.C. Arnold C.E. Nagle E.R. Kulcsar K. Lee A. Thibaud-Nissen F. Hume A.J. et al.The Egyptian Rousette Genome Reveals Unexpected Features of Bat Antiviral Immunity.Cell. 2018; 173: 1098-1110.e18Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar describe several key adaptations in innate immune-related genes that suggest that the Egyptian rousette fruit bat relies on immune tolerance mechanisms to manage viral infections. Bats are reservoir hosts of numerous viruses that cause severe pathology in humans. How bats cope with such pathogens remains elusive. In a recent issue of Cell, Pavlovich et al., 2018Pavlovich S.S. Lovett S.P. Koroleva G. Guito J.C. Arnold C.E. Nagle E.R. Kulcsar K. Lee A. Thibaud-Nissen F. Hume A.J. et al.The Egyptian Rousette Genome Reveals Unexpected Features of Bat Antiviral Immunity.Cell. 2018; 173: 1098-1110.e18Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar describe several key adaptations in innate immune-related genes that suggest that the Egyptian rousette fruit bat relies on immune tolerance mechanisms to manage viral infections. Throughout folklore, literature, and films, bats signify darkness and mystery, are often associated with the undead, and are portrayed as night creatures able to strike primal fear in the hearts of those that encounter them. Although the threat that bats pose to humans à la Count Dracula is an imaginary one, bats serve as asymptomatic carriers of many viruses known to cause highly virulent, often lethal human diseases, including but not limited to the Ebola and Marburg filoviruses, rabies virus, and SARS coronavirus (Smith and Wang, 2013Smith I. Wang L.F. Bats and their virome: an important source of emerging viruses capable of infecting humans.Curr. Opin. Virol. 2013; 3: 84-91Crossref PubMed Scopus (196) Google Scholar). The immunological means through which bats are able to harbor pathogens seemingly without any significant impact on host fitness remain elusive. However, two broad mechanisms have been proposed: immune tolerance and host resistance. Tolerance refers to the capacity of a host to limit the impact of damage caused by both infection-associated pathology, or the specific pathogen itself, and immune-related pathology, or the immune responses raised against it. On the other hand, resistance describes the ability of a host to mount especially potent innate and adaptive immune responses capable of efficiently controlling pathogen load, ultimately leading to infection clearance. A recent study from Pavlovich et al. proposes a mechanism of disease tolerance to explain why the Egyptian rousette fruit bat (Rousettus aegyptiacus), a natural host of the Marburg virus, is able to asymptomatically harbor a pathogen known to devastate humans (Pavlovich et al., 2018Pavlovich S.S. Lovett S.P. Koroleva G. Guito J.C. Arnold C.E. Nagle E.R. Kulcsar K. Lee A. Thibaud-Nissen F. Hume A.J. et al.The Egyptian Rousette Genome Reveals Unexpected Features of Bat Antiviral Immunity.Cell. 2018; 173: 1098-1110.e18Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). The authors utilize a comparative immunogenomic approach to gain insight into the evolution of gene families involved in innate immune responses and antiviral defense in R. aegyptiacus. The authors used a combination of both short- and long-read next-generation sequencing technology followed by whole-genome annotation to construct a highly contiguous and complete R. aegyptiacus genome, containing a total of 19,668 protein-coding genes. After genome assembly, the authors performed comparative analyses of homologous protein families among R. aegyptiacus and additional mammals to elucidate evolutionary relationships across various species. They found that many gene families were significantly expanded in the Egyptian rousette as compared to the ancestral megabat. Interestingly, the importance of natural selection in shaping the evolution of immune genes in R. aegyptiacus is evident in that multiple signatures of positive selection were detected among several interferon (IFN)-related genes. Three major findings are consistent with the hypothesis that the Egyptian rousette evolved toward a state of immune tolerance to successfully manage viral infections, as opposed to a reliance on mechanisms of host resistance to clear infections: (1) the expansion of the type I IFN gene family, (2) the discovery of natural killer (NK) cell receptors with distinct signaling components, and (3) the presence of MHC class I genes dispersed throughout the genome (Figure 1). During early stages of viral infections, type I IFN responses are triggered and subsequently initiate an antiviral immune cascade that leads to the activation of hundreds of interferon-stimulated genes (ISGs). Strikingly, R. aegyptiacus harbors 46 type I IFN genes, more than twofold the number found in the megabat ancestor. The marked expansion of genes in the IFN-ω subfamily (22 in total) contributes the most to this increase. Although the type I IFN gene family is found to be expanded, only minimal basal expression of these genes is detected, whereas a previous study describes constitutive activation of IFN genes in the bat Pteropus alecto (Zhou et al., 2016Zhou P. Tachedjian M. Wynne J.W. Boyd V. Cui J. Smith I. Cowled C. Ng J.H. Mok L. Michalski W.P. et al.Contraction of the type I IFN locus and unusual constitutive expression of IFN-α in bats.Proc. Natl. Acad. Sci. USA. 2016; 113: 2696-2701Crossref PubMed Scopus (184) Google Scholar). This suggests that R. aegyptiacus harbors a baseline expression profile with reduced inflammatory capacity compared to that of other bats. Further, in an in vitro antiviral assay in which immortalized R. aegyptiacus cells were infected with vesicular stomatitis virus (VSV), Pavlovich et al. showed that IFN-ω4—one of the IFN-ω subfamily members—hindered VSV infection, although IFN-β induced a stronger antiviral effect. This indicates that certain Egyptian rousette IFNs are capable of inducing a less potent, more restrained response that might confer reduced immune-related pathology. Being able to quickly recognize and eliminate virus-infected cells, NK cells are a critical part of the innate immune system. NK cell responses are mediated by a balance of signals provided from activating receptors, which promote NK cell killing, and inhibitory receptors, which suppress NK cell responses. Although previous reports described an absence of NK cell receptors in numerous bat genomes (Zhang et al., 2013Zhang G. Cowled C. Shi Z. Huang Z. Bishop-Lilly K.A. Fang X. Wynne J.W. Xiong Z. Baker M.L. Zhao W. et al.Comparative analysis of bat genomes provides insight into the evolution of flight and immunity.Science. 2013; 339: 456-460Crossref PubMed Scopus (410) Google Scholar), Pavlovich et al. showed that this is not the case. They identified several putative NK cell receptor genes, namely those belonging to the killer lectin-like receptor (KLR) NKG2/CD94 family, in the R. aegyptiacus genome. Furthermore, upon re-examination of previously sequenced bat genomes, they were able to identify multiple NKG2-like genes in other bats. Interestingly, in R. aegyptiacus, all NKG2 genes except one encode receptors containing inhibitory interaction motifs. Notably, two of the inhibitory receptor genes identified, NKG2-13 and NKG2-14, are expressed at high levels in peripheral lymphoid tissue and blood mononuclear cells of uninfected bats, indicating that R. aegyptiacus might be primed to activate inhibitory signaling pathways. Of the receptors with activating domains, most seem to favor preferential recruitment of the adaptor molecule DAP10 instead of DAP12. Compared to DAP12 activation, activation of DAP10 is associated with less robust cytokine production (Lanier, 2009Lanier L.L. DAP10- and DAP12-associated receptors in innate immunity.Immunol. Rev. 2009; 227: 150-160Crossref PubMed Scopus (208) Google Scholar), suggesting that R. aegyptiacus activating receptors might elicit dampened proinflammatory responses. Surprisingly, the majority of NK receptors discovered concurrently encode both activating and inhibitory motifs. Such dual-function receptors are atypical among mammals, and it is unclear what would determine which function is engaged or whether one function is repeatedly utilized to a greater extent. The sole dual-function receptor in humans, KIR2DL4, has been shown to induce strong IFN-γ responses and limited cytotoxicity (Kikuchi-Maki et al., 2005Kikuchi-Maki A. Catina T.L. Campbell K.S. Cutting edge: KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein.J. Immunol. 2005; 174: 3859-3863Crossref PubMed Scopus (117) Google Scholar), although it is unknown if R. aegyptiacus receptors would follow this pattern. Finally, Pavlovich et al. reported the expansion of MHC class I genes in the Egyptian rousette genome. Many of the identified MHC-I genes mapped to non-classical genomic contexts, suggesting that MHC-I genes were the subject of genomic dispersion as well as expansion. It is possible that these expanded MHC-I genes can act as ligands for the similarly expanded KLRs and that specific NKG2 receptor/MHC-I ligand interactions exist in R. aegyptiacus. The authors hypothesize that the spread of MHC-I genes outside of the typical MHC locus serves to generate ligand redundancy which in turn might result in increased activation thresholds for NK cells, ultimately rendering them less reactive. The findings of Pavlovich et al. support other findings that suggest that certain bat species forego mounting highly proinflammatory immune responses in the face of viral infection, and instead rely on mechanisms of tolerance. Reports of prolonged incubation periods and viremia in bats along with the observation of only marginal inflammation in highly infected bat tissues suggests that augmented antiviral defenses are not the key mechanism driving the uniquely avirulent state characterized by these reservoir hosts (Jones et al., 2015Jones M.E. Schuh A.J. Amman B.R. Sealy T.K. Zaki S.R. Nichol S.T. Towner J.S. Experimental Inoculation of Egyptian Rousette Bats (Rousettus aegyptiacus) with Viruses of the Ebolavirus and Marburgvirus Genera.Viruses. 2015; 7: 3420-3442Crossref PubMed Scopus (91) Google Scholar). Yet, there is still a long road ahead to uncover the functional relevance of the genomic expansions described by Pavlovich et al. and to what extent they contribute to the basis of increased viral resilience in bats. The role of IFNs, especially the significantly expanded IFN-ω subfamily, is intriguing because different patterns of ISG activity have been shown to trigger responses of varying magnitude as well as antiviral effectiveness and thus lead to differential host immune outcomes (Hoffmann et al., 2015Hoffmann H.H. Schneider W.M. Rice C.M. Interferons and viruses: An evolutionary arms race of molecular interactions.Trends Immunol. 2015; 36: 124-138Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar). For example, SARS patients who exhibit constitutive type I IFN production coupled with high ISG expression frequently manifest poor outcomes, suggesting that heightened inflammation can be deleterious in certain viral-infection contexts (Totura and Baric, 2012Totura A.L. Baric R.S. SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon.Curr. Opin. Virol. 2012; 2: 264-275Crossref PubMed Scopus (313) Google Scholar). Furthermore, KLR signaling in murine T cells has been shown to restrict T cell activation and attenuate immunopathology during viral infection (Rapaport et al., 2015Rapaport A.S. Schriewer J. Gilfillan S. Hembrador E. Crump R. Plougastel B.F. Wang Y. Le Friec G. Gao J. Cella M. et al.The inhibitoryreceptor NKG2A sustains virus-specific CD8+ T cells in response to a lethal poxvirus infection.Immunity. 2015; 43: 1112-1124Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar), raising the question of whether KLR-dependent immune tolerance mechanisms significantly impact adaptive immune-cell responses, in addition to those of innate cells, by potentially repressing T cell activity in bats. The availability of high-quality genomes is the first step toward performing future comparative studies of immune responses to define the immunological parameters that are specific to bats. Other mammals, including mice, baboons, and rhesus macaques, are also particularly resilient to infection. It will be of great interest to assess whether other species share similar mechanisms of immune tolerance.

Bats are reservoir hosts of numerous viruses that cause severe pathology in humans. How bats cope with such pathogens remains elusive. In a recent issue of Cell, Pavlovich et al. (2018) describe several key adaptations in innate immune-related genes that suggest that the Egyptian rousette fruit bat relies on immune tolerance mechanisms to manage viral infections.

Humans display remarkable immune response variation when exposed to identical immune challenges. However, our understanding of the genetic, evolutionary, and environmental factors that impact this inter-individual and inter-population immune response heterogeneity is still in its early days. In this review, we discuss three fundamental questions concerning the recent evolution of the human immune system: the degree to which individuals from different populations vary in their innate immune responses, the genetic variants accounting for such differences, and the evolutionary mechanisms that led to the establishment of these variants in modern human populations. We also discuss how past selective events might have contributed to the uneven distribution of immune-related disorders across populations.