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
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Insigh Immunogene ics Un angling he immune basis o disease suscep ibili y