Viewpoints

Atherosclerosis
A Chronic Inflammatory Disease With an Autoimmune Component
Kouji Kobiyama, Klaus Ley

A therosclerosis is a chronic inflammatory disease of

large and medium-sized arteries that causes isch-
emic heart disease, strokes, and peripheral vascular dis-
ease collectively called cardiovascular disease (CVD).
Atherosclerosis requires elevated LDL (low-density lipo-
protein) cholesterol, which can be controlled by statins
and PCSK9 (proprotein convertase subtilisin/kexin type
9) inhibitors. Both effectively control LDL cholesterol and
reduce major adverse cardiovascular events by ≈50%.1
When LDL cholesterol is under control, the remaining risk
for major adverse cardiovascular event is believed to be inflam-
matory in nature. The recent CANTOS trial (Canakinumab
Antiinflammatory Thrombosis Outcome Study) showed
that canakinumab, an antibody blocking IL-1β (interleukin-
1β), reduces major adverse cardiovascular event.2 However,
canakinumab treatment impacted host defense, leading to a
significant increase of lethal infections.2
Atherosclerosis is accompanied by an autoimmune re-
sponse to LDL and other antigens that can exacerbate or ame-
liorate the course of the disease. Recently, various approaches
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Initially, the innate immune response regulates the adap-
tive immune response.4 Antigen-presenting cells provide
MHC (major histocompatibility complex) molecules, costim-
ulatory molecules, and cytokines in response to molecules de-
rived from pathogens, microbes, and altered self5 and thereby
determine the polarization of the adaptive immune response.
Macrophages and dendritic cells are found in the arterial ad-
ventitia and neointima and are activated by TLR (Toll-like
receptor) ligands and scavenger receptors.6 Inflammatory cy-
tokines exacerbate and perpetuate atherosclerosis and attract
more immune cells. The inflammatory cytokine IL-1β is a
proven therapeutic target to treat atherosclerosis.2 In mature
atherosclerotic plaque, atherosclerosis antigen-specific T cells
secrete cytokines, perpetuate inflammation and shape the im-
mune cell infiltrate7 (Figure).
Atherosclerosis is always accompanied by an autoimmune
response. Antibodies against oxidized (oxLDL) are produced
by B cell-derived plasma cells and are detectable in the serum
of humans or animals with atherosclerosis. T cells against ath-
erosclerosis antigens are also found. Almost all the mecha-
nistic insight into the role of immune cells in atherosclerosis

to immunotherapy and vaccination have shown promise in

comes from 2 mouse models, Apoe−/− mice and Ldlr−/− mice.
curbing atherosclerosis in animal models.3 Unlike antibodies
Regulatory CD4 T cells (Tregs) have long known to be athero-
to cytokines, immunotherapies and vaccinations are antigen-
protective in these mouse models.8
specific and thus spare host defense. This viewpoint focuses
Recently, we showed that CD4 T cells specific for an epit-
on the modulation of atherosclerosis by adaptive immune
ope in ApoB (apolipoprotein B), the core lipoprotein of LDL,
responses, especially CD4 T cells recognizing self-antigens,
very-LDL (VLDL), and chylomicron, are mostly Tregs in
which forms the basis for the development of a new type of
people without CVD, but assume mixed and effector pheno-
therapy targeting adaptive immune responses.
types in people with CVD.9 The exact mechanism of athero-
protection may involve other T- and B-cell subsets and is an
Immune Response in Atherosclerosis area of active investigation.
Atherosclerotic plaques can become unstable, rupture, or
erode, which leads to major adverse cardiovascular event. Chronic Inflammatory Diseases With a
Plaque stability is related to the level of inflammatory cells
Secondary Autoimmune Component
and the thickness of the cap: plaques with thin caps and
Autoimmune diseases are defined by autoantibodies, autore-
full of immune cells are called soft or vulnerable plaques.
active cells, identifiable autoantigen(s), and transmission by
Immune cell infiltration is initiated by chemokines and adhe-
immunization. Atherosclerosis is not a classic autoimmune
sion molecules.
disease. In atherosclerosis, autoantibodies, T cells, and B
cells have all been shown to exacerbate or ameliorate10 the
The opinions expressed in this article are not necessarily those of the disease. Similarly, Parkinson’s disease and emphysema are
editors or of the American Heart Association. not considered autoimmune diseases, but Parkinson’s and
From the Division of Inflammation Biology, La Jolla Institute emphysema patients harbor epitope-specific T and B cells.
for Allergy and Immunology, CA (K.K., K.L.); and Department of
Thus, we propose that these 3 diseases form a new class
Bioengineering, University of California San Diego, La Jolla (K.L.).
Correspondence to Klaus Ley, MD, Division of Inflammation Biology, of chronic inflammatory diseases with a secondary autoim-
La Jolla Institute for Allergy and Immunology, 9420 Athena Cir Dr, La mune component.
Jolla, CA 92037. Email klaus@lji.org
(Circ Res. 2018;123:1118-1120. Atherosclerosis and Autoreactive CD4 T cells
DOI: 10.1161/CIRCRESAHA.118.313816.)
© 2018 American Heart Association, Inc. Patients with atherosclerosis have anti-oxLDL and anti-HSP
(heat shock protein) 65 antibodies. However, anti-oxLDL an-
Circulation Research is available at https://www.ahajournals.org/
journal/res tibodies are also found in healthy individuals and might pro-
DOI: 10.1161/CIRCRESAHA.118.313816 tect against atherosclerosis and CVD. The majority of CD4+ T
1118
 Kobiyama and Ley   Autoimmunity in Atherosclerosis   1119
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cells in atherosclerotic lesions are memory T cells (CD45RO+)
and respond to oxLDL to produce inflammatory cytokines.
Many immunogenic epitopes derived from mouse ApoB have
been identified and used as vaccine antigens against athero-
sclerosis in animal models.
Until recently, there was no direct evidence that ApoB
epitope-specific CD4 T cells exist. To address this ques-
tion, we developed MHC-II tetramers to detect such cells in
both humans and mice. A tetramer consists of 4 molecules
of recombinant MHC-II loaded with the antigenic peptide
and held together by fluorochrome-conjugated streptavidin.
We focused on the ApoB epitope P18, which is sequence-
identical in mouse ApoB and human APOB. P18 binds the
mouse MHC-II allele I-Ab and DRB1*07:01 expressed by
≈8% of humans. To detect APOB-specific CD4+ T cells, we
Figure. Adaptive immune responses in
atherosclerosis. Top: In healthy individuals,
LDL (low-density lipoprotein) receptor on
antigen-presenting cells (APCs) recognizes
and takes up LDL, inducing production of
antiinflammatory cytokines. Self-reactive Tregs
recognize ApoB (apolipoprotein B) peptides
presented by MHC (major histocompatibility
complex)-II on APCs in the context of
costimulatory molecules that promote
Tregs, which also produce antiinflammatory
cytokines, thereby preventing or dampening
atherosclerosis. Bottom: Modified and oxidized
(ox)LDL accumulates in atherosclerotic lesions
and is recognized by receptors like TLR4
(toll-like receptor 4) and CD36 to induce
transcription of inflammatory cytokines like
IL (interleukin)-12 and IL-23. CD4 T cells
recognize ApoB peptides in the context
of proinflammatory cytokines and strong
costimulation, which induces Th1 (T-bet+)
and Th17 (RORγt+) T cells. Their production
of interferon (IFN)-γ and IL-17 exacerbates
atherosclerosis. Now, CD8 T cells also
recognize ApoB epitopes presented by MHC-I
and exacerbate inflammation by producing IFN-
γ. TCR indicates T-cell receptor; and TGF-β,
transforming growth factor-β.
created human APOB-peptide P18:DRB1*07:01 tetramers
and found that P18-recognizing CD4+ T cells exist in hu-
man PBMCs (peripheral blood mononuclear cells). These
P18-specific CD4+ T cells were found in subjects with and
without subclinical CVD. Interestingly, the majority of
P18-specific CD4+ T cells from individuals without CVD
expressed FoxP3 (forkhead box P3), the defining transcrip-
tion factor of Tregs. However, P18-specific CD4+ T cells
from subclinical CVD patients expressed the Th17-defining
transcription factor RORγτ (retinoic acid receptor-related
orphan receptor γτ) or the Th1-defining transcription factor
T-bet alone or together with FoxP3.9 This is the first evidence
that self-peptide recognizing CD4+ T cells exist in human
PBMCs. The phenotype of these cells seems to change dur-
ing atherosclerosis progression.
 1120  Circulation Research  October 26, 2018
Future Atherosclerosis Therapy
and Prevention
Vaccination is the most successful intervention in medicine.
At least 27 infectious diseases and several cancers are prevent-
able by vaccination. Now, the vaccine development field is
moving from vaccines against infectious diseases to vaccines
for noncommunicable diseases, such as cancer, atherosclero-
sis, hypertension, Alzheimer disease, and diabetes mellitus.
To develop an atherosclerosis vaccine, vaccine antigen(s)
must be identified. Possible atherosclerosis vaccine antigens
include PCSK9, HSP65, and ApoB. The concept of a vaccine
against PCSK9 is to induce a neutralizing antibody response.11
This is similar to the use of monoclonal antibodies (passive
immunization). Antibodies to PCSK9 are already in clinical
use. Targeting PCSK9 is known to be safe because humans
with null mutations in PCSK9 are asymptomatic except for
being resistant to atherosclerosis.12
Immunization with ApoB-derived MHC-II-restricted pep-
tides strongly induced peptide-specific antibody responses in
Apoe- or Ldlr-deficient mice, associated with reduced athero-
sclerotic lesions.13 This observation resulted in a clinical trial
(GLACIER [Study to Evaluate the Safety, Tolerability, and
Activity of Intravenous MLDL1278A in Patients on Standard-
of-Care Therapy for Stable Atherosclerotic Cardiovascular
Disease]), in which a monoclonal antibody to oxLDL was
administered.14 Atherosclerosis was assessed by positron
emission tomography imaging after injection of FDG (flude-
oxyglucose) glucose, a marker for myeloid cell accumulation.
This trial showed no evidence of efficacy of antibody treat-
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ment. In mouse models, it is known that vaccine-induced anti-
body responses are dispensable for atheroprotection.15
Several vaccines against ApoB induce antiinflammatory
responses, such as IL-10 production or Tregs. Immunization
with the APOB-derived peptide P210 elicited CD4 T cell
responses with IL-10 production. Immunization with other
ApoB-derived peptides also induced IL-10+ and FoxP3+CD4+
T cells. However, these studies did not demonstrate induction
of vaccine antigen-specific CD4 T cells.9 Interestingly, P18
immunization increased the number of P18-specific CD4 T
cells compared with the adjuvant-only group, and many vac-
cine-induced P18-specific CD4 T cells were Tregs. We also
found that P18-specific CD4 T cells produced IL-10 and P18
immunization significantly reduced atherosclerotic lesions in
Apoe−/− mice.9 Thus, vaccines inducing antigen-specific Tregs
might be a novel and viable approach for atherosclerosis ther-
apy. Important for clinical translation, Addavax, a squalene oil
similar to the clinically approved MF59, may be useful as an
adjuvant for a future atherosclerosis vaccine for humans.15
Conclusions
In spite of the success of statins and PCSK9 antibodies, athero-
sclerosis-triggered diseases are still the number 1 killer in the
world. Atherosclerosis is a chronic inflammatory disease with a
secondary autoimmune component. Self antigen-specific adap-
tive immune responses are found in both humans with atheroscle-
rosis and in animal models. These immune responses are strongly
involved in the progression of atherosclerosis and atheroprotec-
tion. The recent discovery of APOB-specific CD4 T cells in both
humans and mice and the induction of Tregs by vaccination with
an ApoB peptide suggests that vaccination to self-antigens could
be a viable approach to prevent atherosclerosis. It is currently un-
known how long the vaccination-induced atheroprotection lasts,
how often the vaccine would have to be administered, and what
the best dose, formulation, and route of administration would be.
Sources of Funding
This work was supported by grant from the National Institutes of
Health R01 HL121697, P01 HL088093, R01 HL126543, and P01
HL136275 to Dr Ley.
Disclosures
None.
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Key Words: atherosclerosis ◼ autoimmunity ◼ interleukin-1 ◼ peripheral
vascular disease ◼ stroke ◼ vaccination