Untangling the immune basis of disease susceptibility

IMMUNOGENETICS Un angling he immune basis o disease suscep ibili y In e ac ions be ween immune cell ecep o s and p o eins ha de e mine disease suscep ibili y shed ligh on how di e en a ms o he immune sys em a e in ol ed in h ee i al in ec ions and C ohn’s disease. RUY M RIBEIRO AND LUIS GRACA Why do people espond di e en ly o he same in ec ious agen ? A possi- ble answe is ha di e ences in he immune esponses o indi iduals, caused by gene ic a iabili y be ween hem, a e esponsi- ble. Indeed, many s udies ha e looked o asso- cia ions be ween genes in ol ed in immuni y and disease ou come (Buniello e al., 2019), and i has been ound ha a gene complex called he human leukocy e an igen (HLA) sys- em has a cen al ole (Ma za aki e al., 2017). The HLA genes encode he majo his ocom- pa ibili y complex (MHC). MHC p o eins a e ound on he su ace o cells and each one p esen s pep ides om p o eins wi hin he cell (ei he p o eins na i e o he cell o om o eign en i ies like bac e ia) o immune cells. Thus, MHC p o eins allow immune cells o ecognize i a gi en cell is dange ous o no . Fo example, immune cells called CD8+ T lymphocy es ecog- nize cells ha ha e been in ec ed wi h i uses because ecep o s on hese T cells bind speci ic MHC p o eins loaded wi h i al pep ides on he su ace o he in ec ed cells. Likewise, o he ypes o immune cells – such as na u al kille cells, mac ophages and dend i ic cells – ha e ecep o s ha bind o o he pa s o he MHC p o ein displayed by in ec ed cells (Augus o and Pe zl-E le , 2015;Hudson and Allen, 2016). The HLA is ex emely di e se among indi idu- als. I has been assumed ha he associa ion be ween some diseases and ce ain HLA alleles is e idence o a cen al ole o CD8+ T cells in ha disease. Howe e , gi en ha he HLA can also in e ac wi h ecep o s on o he immune cells, disen angling he con ibu ions o he di - e en a ms o he immune sys em emains a challenge. Now, in eLi e, Becca Asqui h o Impe- ial College and colleagues – including Bis a Debebe as i s au ho , esea che s om a ious ins i u es in he UK and US, and he IAVI P o o- col C In es iga o s – epo he esul s o a new app oach o disen angling hese con ibu ions (Debebe e al., 2020). Debebe e al. easoned ha i may be possi- ble o p edic which immune cells a e esponsi- ble o igh ing a speci ic disease since ecep o s om pa icula immune cells in e ac wi h di e - en egions o he MHC p o ein. Fo example, suscep ibili y o a disease may be associa ed wi h indi iduals ca ying MHC p o eins ha a e simila in he egion ha p esen s p o ein ag- men s o he T-cell ecep o (which can be hough o as being simila in ‘T-cell ecep o space’). I his is he case, hen CD8+ T cells a e likely in ol ed in igh ing he disease. The same easoning can be made o associa ions wi h he Copy igh Ribei o and G aca. This a icle is dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s un es ic ed use and edis ibu ion p o ided ha he o iginal au ho and sou ce a e c edi ed. Rela ed esea ch a icle Debebe BJ, Boe- len L, Lee JC, IAVI P o ocol C In es iga o s, Thio CL, As embo ski J, Ki k G, Khakoo SI, Don ield SM, Goede JJ, Asqui h B. 2020. Iden i ying he immune in e ac ions unde - lying HLA class I disease associa ions. eLi e 9:e54558. DOI: 10.7554/eLi e.54558 Ribei o and G aca. eLi e 2020;9:e56886. DOI: h ps://doi.o g/10.7554/eLi e.56886 1 o 3 INSIGHT o he ecep o s, such as he kille immunoglobu- lin-like ecep o (KIR) ecep o s in na u al kille cells and leukocy e immunoglobulin-like ecep o (LILR) in myeloid cells (Figu e 1). The challenge in his me hod is de ining MHC simila i y. Debebe e al. did so by aking an HLA known o associa e wi h a speci ic disease ou - come and p edic ing i s abili y o bind o di e - en immune cell ecep o s. Nex , hey compa ed his p edic ed binding abili y o ha o all o he HLAs, and ound he HLAs wi h he highes bind- ing simila i y. Finally, hey checked i hese HLAs a e also associa ed wi h disease suscep ibili y. Debebe e al. applied his me hod o h ee in ec ions (human T-cell leukemia i us ype one o HTLV-1; hepa i is C i us; and HIV-1) and one au oimmune disease (C ohn’s disease). They used well-cha ac e ized coho s whe e bo h he HLA and he ou come o he disease we e known o each indi idual. They s udied h ee known HLA-ou come associa ions o HTLV-1 and ound ha o he HLAs ha we e simila in T-cell ecep o space we e also associa ed wi h HTLV-1. Howe e , o he HLAs ha we e simila o hese h ee HLAs in LILR space o KIR space (see Figu e 1) we e no associa ed wi h HTLV-1. Thus, hey concluded ha HTLV-1 is mos likely con olled by CD8+ T cells. They also s udied h ee HLA- ou come associa ions o hepa i is C, eaching he same conclusion: disease ou come is mos ly con olled by CD8+ T cells. Fo HIV-1, Debebe e al. ound ha na u al kille cells and CD8+ T cells bo h ha e a ole, which is consis en wi h p e ious esul s (Bashi o a e al., 2011; McB ien e al., 2018). They also s udied wo known HLA-ou come associa ions o C ohn’s disease in a la ge sample (2650 indi iduals), bu o he HLAs ha we e simila in T-cell, LILR o KIR space did no ha e signi ican e ec on C ohn’s disease ou come. The app oach sugges ed by Debebe e al. gene a es insigh s in o which immune cells may be in ol ed in igh ing a disease. The e a e wo issues ha need o be explo ed u he . Fi s , while we know a g ea deal abou T-cell Figu e 1. Axes o simila i y in MHC p o eins. Debebe e al. showed ha simila i ies in egions o he MHC molecule ha in e ac wi h di e en immune cell ecep o s can be hough o in e ms o di e en ’spaces’ (which a e de ined by an axis o each ype o ecep o ). They ound ha MHCs ha a e simila in he T-cell ecep o (TCR) axis a e associa ed wi h disease ou comes o HLTV-1, hepa i is C i us (HCV) and HIV-1. Disease ou comes o HIV-1 a e also associa ed wi h MHCs ha show simila i y in he kille immunoglobulin-like ecep o (KIR) axis. Fo he diseases es ed, no MHCs we e ound o be simila in he egion ha in e ac s wi h he leukocy e immunoglobulin-like ecep o (LILR) ca ied by myeloid cells (MC). CD8: CD8+ T cells; NK: na u al kille cells; blue ci cle: pep ide. Ribei o and G aca. eLi e 2020;9:e56886. DOI: h ps://doi.o g/10.7554/eLi e.56886 2 o 3 Insigh Immunogene ics Un angling he immune basis o disease suscep ibili y ecep o s, we know less abou KIR, and e en less abou LILR binding (Hi ayasu and A ase, 2015). This knowledge (o lack he eo ) is pa o he de ini ion o simila i y used by Debebe e al., which can and should be upda ed as mo e da a becomes a ailable (Gwozdowicz e al., 2019). The second issue pe ains o he ac ha i may be possible o de ine simila i y in o he ways, leading o di e en esul s ha p o ide u he insigh s in o how gene ic a iabili y a ec s he immune esponse. Ruy M Ribei o is a he Labo a o´ io de Bioma ema´ ica, Ins i u o de Sau ´de Ambien al, Faculdade de Medicina, Uni e sidade de Lisboa, Lisboa, Po ugal [email p o ec ed]lisboa.p h ps://o cid.o g/0000-0002-3988-8241 Luis G aca is in he Ins i u o de Medicina Molecula , Faculdade de Medicina, Uni e sidade de Lisboa, Lisboa, Po ugal h ps://o cid.o g/0000-0001-6935-8500 Compe ing in e es s: The au ho s decla e ha no compe ing in e es s exis . Published 14 May 2020 Re e ences Augus o DG, Pe zl-E le ML. 2015. KIR and HLA unde p essu e: e idences o coe olu ion ac oss wo ldwide popula ions. Human Gene ics 134:929–940. DOI: h ps://doi.o g/10.1007/s00439-015-1579-9, PMID: 26099314 Bashi o a AA, Thomas R, Ca ing on M. 2011. HLA/ KIR es ain o HIV: su i ing he i es . Annual Re iew o Immunology 29:295–317. DOI: h ps://doi. o g/10.1146/annu e -immunol-031210-101332, PMID: 21219175 Buniello A, MacA hu JAL, Ce ezo M, Ha is LW, Hayhu s J, Malangone C, McMahon A, Mo ales J, Moun joy E, Sollis E, Su eges D, V ousgou O, Whe zel PL, Amode R, Guillen JA, Ria HS, T e anion SJ, Hall P, Junkins H, Flicek P, e al. 2019. The NHGRI-EBI GWAS ca alog o published genome-wide associa ion s udies, a ge ed a ays and summa y s a is ics 2019. Nucleic Acids Resea ch 47:D1005–D1012. DOI: h ps://doi. o g/10.1093/na /gky1120,PMID: 30445434 Debebe BJ, Boelen L, Lee JC, IAVI P o ocol C In es iga o s, Thio CL, As embo ski J, Ki k G, Khakoo SI, Don ield SM, Goede JJ, Asqui h B. 2020. Iden i ying he immune in e ac ions unde lying HLA class I disease associa ions. eLi e 9:e54558. DOI: h ps://doi.o g/10.7554/eLi e.54558,PMID: 3223 8263 Gwozdowicz S, Nes o owicz K, G aczyk-Pol E, Szlendak U, Roga ko-Ko os M, Mika-Wi kowska R, Pawliczak D, Zubala M, Malinowska A, Wi kowska A, Nowak J. 2019. 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DOI: h ps://doi.o g/10.1186/s13059-017-1207- 1,PMID: 28449694 McB ien JB, Kuma NA, Sil es i G. 2018. Mechanisms o CD8 + T cell-media ed supp ession o HIV/SIV eplica ion. Eu opean Jou nal o Immunology 48:898– 914. DOI: h ps://doi.o g/10.1002/eji.201747172, PMID: 29427516 Ribei o and G aca. eLi e 2020;9:e56886. DOI: h ps://doi.o g/10.7554/eLi e.56886 3 o 3 Insigh Immunogene ics Un angling he immune basis o disease suscep ibili y