Complex genetic signatures in immune cells underlie autoimmunity and inform therapy

Orrù, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Sergio; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Żołędziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; Abecasis, Gonçalo R.; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco

doi:10.1038/s41588-020-0684-4

Cited by 428 publications

(399 citation statements)

References 65 publications

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“…This emphasizes the urgent need to study genetics and functionality of γδ T cells in greater detail to better understand their ontogeny and trajectories in the context of life long exposure to pathogens. However, the here identified genetic influence on early differentiated T cells is in line with the data from Orrù et al [49] showing a decreasing heritability from naive via memory to terminally differentiated T cells, possibly because late differentiated subsets are more strongly influenced by environmental factors. So far, very little is known about genetic elements regulating the immune system under homeostatic conditions.…”

Section: Discussionsupporting

confidence: 92%

“…Moreover, one gene can control several immune traits and one immune trait can be influenced by multiple genes. Recently, several such associations between genetic loci and immune traits have been identified by genome-wide association studies (GWAS) [49,50], starting to uncover the complex mechanisms involved in genetic regulation of the immune system; further studies will elucidate genes controlling the γδ T cell population.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Influence on the Peripheral Differentiation Signature of Vδ2+ γδ and CD4+ αβ T Cells in Adults

Beucke

Wingerter

Hähnel

et al. 2021

Cells

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Adaptive as well as innate immune traits are variously affected by environmental and genetic influences, but little is known about the impact of genetics on the diversity, differentiation and functionality of γδ T cells in humans. Here, we analyzed a cohort of 95 middle-aged twins from the Danish Twin Registry. The differentiation status of peripheral αβ and γδ T cells was assessed by flow cytometry based on the surface expression of CD27, CD28 and CD45RA. Our data confirm the established associations of latent cytomegalovirus (CMV) infection with an accumulation of late differentiated memory T cells in the αβ compartment as well as in the Vδ1+ γδ T cell subset. A comparison of differentiation phenotypes of γδ and αβ T cells that were not affected by CMV seropositivity identified a significant correlation of early differentiated (ED) Vδ2+ and intermediate differentiated (ID) CD4+ T cells in monozygotic (MZ), but not in dizygotic (DZ) co-twins. Thus, our data suggest a genetic influence on the differentiation of γδ and αß T cell subsets.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Genetic Influence on the Peripheral Differentiation Signature of Vδ2+ γδ and CD4+ αβ T Cells in Adults

Beucke

Wingerter

Hähnel

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…The significant enrichment in cell lines and cell status coming from the hematopoietic lineages and the CNS-specific cell subsets corroborates data coming from recent reports such as the relevance of contextualizing and prioritizing the role of MS-associated GWAS signals. 31, 32, 45, 46 Our analysis supports the pivotal regulatory role of enhancer transcription (i.e., a main component of transient transcriptome) was recently reported as not dispensable for gene expression at the immunoglobulin locus and for antibody class switch recombination, 47 though more research is needed to unravel such topic at a finer grain.…”

Section: Discussionsupporting

confidence: 83%

GWAS associated Variants, Non-genetic Factors, and Transient Transcriptome in Multiple Sclerosis Etiopathogenesis: a Colocalization Analysis

Umeton

Bellucci

Bigi

et al. 2021

Preprint

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A clinically actionable understanding of multiple sclerosis (MS) etiology goes through GWAS interpretation, prompting research on new gene regulatory models. Our previous works on these topics suggested a stochastic etiologic model where small-scale random perturbations could eventually reach a threshold for MS onset and progression. A new sequencing technology has mapped the transient transcriptome (TT), including intergenic RNAs, and antisense intronic RNAs. Through a rigorous colocalization analysis, here we show that genomic regions coding for the TT were significantly enriched for both MS-associated GWAS variants, and DNA binding sites for molecular transducers mediating putative, non-genetic, etiopathogenetic factors for MS (e.g., vitamin D deficiency, Epstein Barr virus latent infection, B cell dysfunction). These results suggest a model whereby TT-coding regions are hotspots of convergence between genetic ad non-genetic factors of risk/protection for MS (and plausibly for other complex disorders). Our colocalization analysis also provided a freely available data web interface at www.mscoloc.com for future research on transcriptional regulation in MS.

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“…PNAS | 5 of 9 Natural resistance to worms exacerbates bovine tuberculosis severity independently of worm coinfection https://doi.org/10.1073/pnas.2015080118 ECOLOGY heterogeneities in immune cell populations and how this creates assymmetries in disease outcomes (e.g., ref. 42) is integral to identifying the range of plausible mechanisms that might account for the phenomenon we describe in this study.…”

Section: Ezenwa Et Almentioning

confidence: 99%

Natural resistance to worms exacerbates bovine tuberculosis severity independently of worm coinfection

Ezenwa

Budischak

Buss

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Pathogen interactions arising during coinfection can exacerbate disease severity, for example when the immune response mounted against one pathogen negatively affects defense of another. It is also possible that host immune responses to a pathogen, shaped by historical evolutionary interactions between host and pathogen, may modify host immune defenses in ways that have repercussions for other pathogens. In this case, negative interactions between two pathogens could emerge even in the absence of concurrent infection. Parasitic worms and tuberculosis (TB) are involved in one of the most geographically extensive of pathogen interactions, and during coinfection worms can exacerbate TB disease outcomes. Here, we show that in a wild mammal natural resistance to worms affects bovine tuberculosis (BTB) severity independently of active worm infection. We found that worm-resistant individuals were more likely to die of BTB than were nonresistant individuals, and their disease progressed more quickly. Anthelmintic treatment moderated, but did not eliminate, the resistance effect, and the effects of resistance and treatment were opposite and additive, with untreated, resistant individuals experiencing the highest mortality. Furthermore, resistance and anthelmintic treatment had nonoverlapping effects on BTB pathology. The effects of resistance manifested in the lungs (the primary site of BTB infection), while the effects of treatment manifested almost entirely in the lymph nodes (the site of disseminated disease), suggesting that resistance and active worm infection affect BTB progression via distinct mechanisms. Our findings reveal that interactions between pathogens can occur as a consequence of processes arising on very different timescales.

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Complex genetic signatures in immune cells underlie autoimmunity and inform therapy

Cited by 428 publications

References 65 publications

Genetic Influence on the Peripheral Differentiation Signature of Vδ2+ γδ and CD4+ αβ T Cells in Adults

Genetic Influence on the Peripheral Differentiation Signature of Vδ2+ γδ and CD4+ αβ T Cells in Adults

GWAS associated Variants, Non-genetic Factors, and Transient Transcriptome in Multiple Sclerosis Etiopathogenesis: a Colocalization Analysis

Natural resistance to worms exacerbates bovine tuberculosis severity independently of worm coinfection

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