Edoardo Fiorillo

@article{Ahuja2023-spb,

title = {Immune resilience despite inflammatory stress promotes longevity 

 and favorable health outcomes including resistance to infection},

author = {Sunil K Ähuja and Muthu Saravanan Manoharan and Grace C Lee and Lyle R McKinnon and Justin A Meunier and Maristella Steri and Nathan Harper and Edoardo Fiorillo and Alisha M Smith and Marcos I Restrepo and Anne P Branum and Matthew J Bottomley and Valeria Orr`u and Fabio Jimenez and Andrew Carrillo and Lavanya Pandranki and Caitlyn A Winter and Lauryn A Winter and Alvaro A Gaitan and Alvaro G Moreira and Elizabeth A Walter and Guido Silvestri and Christopher L King and Yong-Tang Zheng and Hong-Yi Zheng and Joshua Kimani and T Blake Ball and Francis A Plummer and Keith R Fowke and Paul N Harden and Kathryn J Wood and Martin T Ferris and Jennifer M Lund and Mark T Heise and Nigel Garrett and Kristen R Canady and Salim S Abdool Karim and Susan J Little and Sara Gianella and Davey M Smith and Scott Letendre and Douglas D Richman and Francesco Cucca and Hanh Trinh and Sandra Sanchez-Reilly and Joan M Hecht and Jose A Cadena Zuluaga and Antonio Anzueto and Jacqueline A Pugh and South Texas Veterans Health Care System COVID-19 team and Brian K Agan and Robert Root-Bernstein and Robert A Clark and Jason F Okulicz and Weijing" He},

year  = {2023},

date = {2023-06-01},

journal = {Nat. Commun.},

volume = {14},

number = {1},

pages = {3286},

abstract = {Some people remain healthier throughout life than others but the 

 underlying reasons are poorly understood. Here we hypothesize 

 this advantage is attributable in part to optimal immune 

 resilience (IR), defined as the capacity to preserve and/or 

 rapidly restore immune functions that promote disease resistance 

 (immunocompetence) and control inflammation in infectious 

 diseases as well as other causes of inflammatory stress. We gauge 

 IR levels with two distinct peripheral blood metrics that 

 quantify the balance between (i) CD8+ and CD4+ T-cell levels and 

 (ii) gene expression signatures tracking longevity-associated 

 immunocompetence and mortality-associated inflammation. Profiles 

 of IR metrics in ~48,500 individuals collectively indicate that 

 some persons resist degradation of IR both during aging and when 

 challenged with varied inflammatory stressors. With this 

 resistance, preservation of optimal IR tracked (i) a lower risk 

 of HIV acquisition, AIDS development, symptomatic influenza 

 infection, and recurrent skin cancer; (ii) survival during 

 COVID-19 and sepsis; and (iii) longevity. IR degradation is 

 potentially reversible by decreasing inflammatory stress. 

 Overall, we show that optimal IR is a trait observed across the 

 age spectrum, more common in females, and aligned with a specific 

 immunocompetence-inflammation balance linked to favorable 

 immunity-dependent health outcomes. IR metrics and mechanisms 

 have utility both as biomarkers for measuring immune health and 

 for improving health outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Fabre2022-znb,

title = {The longitudinal dynamics and natural history of clonal  haematopoiesis},

author = {Margarete A Fabre and José Guilherme Almeida and Edoardo Fiorillo and Emily Mitchell and Aristi Damaskou and Justyna Rak and Valeria Orr`u and Michele Marongiu and Michael Spencer Chapman and M S Vijayabaskar and Joanna Baxter and Claire Hardy and Federico Abascal and Nicholas Williams and Jyoti Nangalia and I nigo Martincorena and Peter J Campbell and Eoin F McKinney and Francesco Cucca and Moritz Gerstung and George S Vassiliou},

doi = {10.1038/s41586-022-04785-z},

year  = {2022},

date = {2022-06-01},

urldate = {2022-06-01},

journal = {Nature},

volume = {606},

number = {7913},

pages = {335--342},

publisher = {Springer Science and Business Media LLC},

abstract = {Clonal expansions driven by somatic mutations become pervasive 

 across human tissues with age, including in the haematopoietic 

 system, where the phenomenon is termed clonal haematopoiesis1-4. 

 The understanding of how and when clonal haematopoiesis 

 develops, the factors that govern its behaviour, how it 

 interacts with ageing and how these variables relate to 

 malignant progression remains limited5,6. Here we track 697 

 clonal haematopoiesis clones from 385 individuals 55 years of 

 age or older over a median of 13 years. We find that 92.4% of 

 clones expanded at a stable exponential rate over the study 

 period, with different mutations driving substantially different 

 growth rates, ranging from 5% (DNMT3A and TP53) to more than 

 50% per year (SRSF2P95H). Growth rates of clones with the same 

 mutation differed by approximately $pm$5% per year, 

 proportionately affecting slow drivers more substantially. By 

 combining our time-series data with phylogenetic analysis of 

 1,731 whole-genome sequences of haematopoietic colonies from 7 

 individuals from an older age group, we reveal distinct patterns 

 of lifelong clonal behaviour. DNMT3A-mutant clones 

 preferentially expanded early in life and displayed slower 

 growth in old age, in the context of an increasingly competitive 

 oligoclonal landscape. By contrast, splicing gene mutations 

 drove expansion only later in life, whereas TET2-mutant clones 

 emerged across all ages. Finally, we show that mutations driving 

 faster clonal growth carry a higher risk of malignant 

 progression. Our findings characterize the lifelong natural 

 history of clonal haematopoiesis and give fundamental insights 

 into the interactions between somatic mutation, ageing and 

 clonal selection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Orru2020-vab,

title = {Complex genetic signatures in immune cells underlie autoimmunity  and inform therapy},

author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},

doi = {10.1038/s41588-020-0684-4},

year  = {2020},

date = {2020-10-01},

urldate = {2020-10-01},

journal = {Nat. Genet.},

volume = {52},

number = {10},

pages = {1036--1045},

publisher = {Springer Science and Business Media LLC},

abstract = {We report on the influence of ~22 million variants on 731 immune 

 cell traits in a cohort of 3,757 Sardinians. We detected 122 

 significant (P < 1.28 $times$ 10-11) independent association 

 signals for 459 cell traits at 70 loci (53 of them novel) 

 identifying several molecules and mechanisms involved in cell 

 regulation. Furthermore, 53 signals at 36 loci overlapped with 

 previously reported disease-associated signals, predominantly 

 for autoimmune disorders, highlighting intermediate phenotypes 

 in pathogenesis. Collectively, our findings illustrate complex 

 genetic regulation of immune cells with highly selective effects 

 on autoimmune disease risk at the cell-subtype level. These 

 results identify drug-targetable pathways informing the design 

 of more specific treatments for autoimmune diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Steri2017-qjb,

title = {Överexpression of the cytokine BAFF and autoimmunity risk},

author = {Maristella Steri and Valeria Orr`u and M Laura Idda and Maristella Pitzalis and Mauro Pala and Ilenia Zara and Carlo Sidore and Valeria Fa`a and Matteo Floris and Manila Deiana and Isadora Asunis and Eleonora Porcu and Antonella Mulas and Maria G Piras and Monia Lobina and Sandra Lai and Mara Marongiu and Valentina Serra and Michele Marongiu and Gabriella Sole and Fabio Busonero and Andrea Maschio and Roberto Cusano and Gianmauro Cuccuru and Francesca Deidda and Fausto Poddie and Gabriele Farina and Mariano Dei and Francesca Virdis and Stefania Olla and Maria A Satta and Mario Pani and Alessandro Delitala and Eleonora Cocco and Jessica Frau and Giancarlo Coghe and Lorena Lorefice and Giuseppe Fenu and Paola Ferrigno and Maria Ban and Nadia Barizzone and Maurizio Leone and Franca R Guerini and Matteo Piga and Davide Firinu and Ingrid Kockum and Izaura Lima Bomfim and Tomas Olsson and Lars Alfredsson and Ana Suarez and Patricia E Carreira and Maria J Castillo-Palma and Joseph H Marcus and Mauro Congia and Andrea Angius and Maurizio Melis and Antonio Gonzalez and Marta E Alarcón Riquelme and Berta M Silva and Maurizio Marchini and Maria G Danieli and Stefano Del Giacco and Alessandro Mathieu and Antonello Pani and Stephen B Montgomery and Giulio Rosati and Jan Hillert and Stephen Sawcer and Sandra DÁlfonso and John A Todd and John Novembre and Gonc calo R Abecasis and Michael B Whalen and Maria G Marrosu and Alessandra Meloni and Serena Sanna and Myriam Gorospe and David Schlessinger and Edoardo Fiorillo and Magdalena Zoledziewska and Francesco Cucca},

doi = {10.1056/NEJMoa1610528},

year  = {2017},

date = {2017-04-01},

urldate = {2017-04-01},

journal = {N. Engl. J. Med.},

volume = {376},

number = {17},

pages = {1615--1626},

abstract = {BACKGROUND: Genomewide association studies of autoimmune diseases 

 have mapped hundreds of susceptibility regions in the genome. 

 However, only for a few association signals has the causal gene 

 been identified, and for even fewer have the causal variant and 

 underlying mechanism been defined. Coincident associations of DNA 

 variants affecting both the risk of autoimmune disease and 

 quantitative immune variables provide an informative route to 

 explore disease mechanisms and drug-targetable pathways. METHODS: 

 Using case-control samples from Sardinia, Italy, we performed a 

 genomewide association study in multiple sclerosis followed by 

 TNFSF13B locus-specific association testing in systemic lupus 

 erythematosus (SLE). Extensive phenotyping of quantitative immune 

 variables, sequence-based fine mapping, cross-population and 

 cross-phenotype analyses, and gene-expression studies were used 

 to identify the causal variant and elucidate its mechanism of 

 action. Signatures of positive selection were also investigated. 

 RESULTS: A variant in TNFSF13B, encoding the cytokine and drug 

 target B-cell activating factor (BAFF), was associated with 

 multiple sclerosis as well as SLE. The disease-risk allele was 

 also associated with up-regulated humoral immunity through 

 increased levels of soluble BAFF, B lymphocytes, and 

 immunoglobulins. The causal variant was identified: an 

 insertion-deletion variant, GCTGT$rightarrow$A (in which A is 

 the risk allele), yielded a shorter transcript that escaped 

 microRNA inhibition and increased production of soluble BAFF, 

 which in turn up-regulated humoral immunity. Population genetic 

 signatures indicated that this autoimmunity variant has been 

 evolutionarily advantageous, most likely by augmenting resistance 

 to malaria. CONCLUSIONS: A TNFSF13B variant was associated with 

 multiple sclerosis and SLE, and its effects were clarified at the 

 population, cellular, and molecular levels. (Funded by the 

 Italian Foundation for Multiple Sclerosis and others.).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Orru2013-epb,

title = {Genetic variants regulating immune cell levels in health and  disease},

author = {Valeria Örr`u and Maristella Steri and Gabriella Sole and Carlo Sidore and Francesca Virdis and Mariano Dei and Sandra Lai and Magdalena Zoledziewska and Fabio Busonero and Antonella Mulas and Matteo Floris and Wieslawa I Mentzen and Silvana A M Urru and Stefania Olla and Michele Marongiu and Maria G Piras and Monia Lobina and Andrea Maschio and Maristella Pitzalis and Maria F Urru and Marco Marcelli and Roberto Cusano and Francesca Deidda and Valentina Serra and Manuela Oppo and Rosella Pilu and Frederic Reinier and Riccardo Berutti and Luca Pireddu and Ilenia Zara and Eleonora Porcu and Alan Kwong and Christine Brennan and Brendan Tarrier and Robert Lyons and Hyun M Kang and Sergio Uzzau and Rossano Atzeni and Maria Valentini and Davide Firinu and Lidia Leoni and Gianluca Rotta and Silvia Naitza and Andrea Angius and Mauro Congia and Michael B Whalen and Chris M Jones and David Schlessinger and Gonc calo R Abecasis and Edoardo Fiorillo and Serena Sanna and Francesco" Cucca},

doi = {10.1016/j.cell.2013.08.041},

year  = {2013},

date = {2013-09-01},

urldate = {2013-09-01},

journal = {Cell},

volume = {155},

number = {1},

pages = {242--256},

abstract = {The complex network of specialized cells and molecules in the 

 immune system has evolved to defend against pathogens, but 

 inadvertent immune system attacks on ``self'' result in 

 autoimmune disease. Both genetic regulation of immune cell levels 

 and their relationships with autoimmunity are largely 

 undetermined. Here, we report genetic contributions to 

 quantitative levels of 95 cell types encompassing 272 immune 

 traits, in a cohort of 1,629 individuals from four clustered 

 Sardinian villages. We first estimated trait heritability, 

 showing that it can be substantial, accounting for up to 87% of 

 the variance (mean 41%). Next, by assessing ∼8.2 million 

 variants that we identified and confirmed in an extended set of 

 2,870 individuals, 23 independent variants at 13 loci associated 

 with at least one trait. Notably, variants at three loci (HLA, 

 IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease 

 associations. These results connect specific cellular phenotypes 

 to specific genetic variants, helping to explicate their 

 involvement in disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}