Immunological Medicine

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Clinical use of anti-histone antibodies in idiopathic

and drug-induced lupus

Adrian Y. S. Lee

To cite this article: Adrian Y. S. Lee (2022) Clinical use of anti-histone antibodies in
idiopathic and drug-induced lupus, Immunological Medicine, 45:4, 180-185, DOI:
10.1080/25785826.2022.2060168

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IMMUNOLOGICAL MEDICINE
2022, VOL. 45, NO. 4, 180–185
https://doi.org/10.1080/25785826.2022.2060168

REVIEW ARTICLE

Clinical use of anti-histone antibodies in idiopathic and

drug-induced lupus
Adrian Y. S. Leea,b,c
a
Department of Immunology, Westmead Hospital, Westmead, Australia; bICPMR, NSW Health Pathology, Westmead, Australia;
c
Westmead Clinical School, University of Sydney, Westmead, Australia

ABSTRACT ARTICLE HISTORY

Anti-histone antibodies (AHAs) make their appearance in a number of systemic autoimmune Received 23 October 2021
diseases including systemic lupus erythematosus (SLE) and drug-induced lupus erythemato- Accepted 28 March 2022
sus (DILE). Although being known for over 50 years, they are poorly studied and understood.
KEYWORDS
There is emerging evidence for their use in predicting clinical features of SLE, diversifying
Anti-histone antibodies;
their clinical use. AHAs, however, are probably less prevalent in DILE than once thought autoantibodies; drug-
owing to a move away from older DILE drugs to modern biological agents which do not induced lupus; histone;
appear to elicit AHAs. This review examines the historical studies that have defined AHAs systemic lupus
and looks at some of the recent work with these autoantibodies. erythematosus

1. Basic histone biology
Histones are structural subunits that provide a core
in which chromatin can be wrapped around. The
core comprises of two H2A–H2B dimers and an
(H3–H4)2 tetramer (histone octamer) with an exter-
nal H1 histone, a conserved subunit that assists with
maintaining this ‘beads on a string’ structure
(Figure 1) [1]. The histone octamer coupled to
around 150 bp of DNA is known as the nucleosome
and forms the basic fundamental unit of chromatin
[2]. Histones not only form scaffolds for chromatin,
but they also play an important role in regulating
gene expression [3]. Histones themselves are
encoded by multiple genes spanning a number of
chromosomes including chromosomes 6, 11 and 12
in humans [4].
Histones may become ‘exposed’ through the for-
mation of apoptotic blebs or neutrophil extracellular
traps (NETs) [5]. Either through excess formation,
reduced clearance and/or post-translational modifi-
cation, histones may become immunogenic [6,7].
Furthermore, recent attention has turned to the role
of epigenetic modifications of these proteins in the
rendering of immunogenicity and hence, the forma-
tion of anti-histone antibodies (AHAs) [8,9].
Deliberate post-translational modification of histo-
nes may be done therapeutically in inflammatory
disorders. Murine systemic lupus erythematosus
(SLE) models injected with an inhibitor of histone
deacetylase attenuated renal pathology compared to
a vehicle control [10]. This may be through, in part,
the reduction of autoreactive plasma cells and auto-
antibodies [11].
Histone proteins are an example of a danger-
associated molecular pattern (DAMPs) and possess
the intrinsic ability to elicit inflammation. Notably,
mice administered histones elicited systemic inflam-
mation and suffer from multi-organ damage and
eventually death, in a dose-dependent manner [12].
In in vitro experiments, H1 and H2A histones were
able to induce specific T cell proliferation in SLE
patients. Moreover, they stimulated the production
of interferon-c, tumour necrosis factor and anti-
double stranded DNA (dsDNA) autoantibod-
ies [13,14].
2. Anti-histone antibodies (AHAs)
Amongst the antinuclear antibodies (ANAs), AHAs
represent a clinically important subset [15]. AHAs
are found in a variety of immunological and infec-
tious disorders. They may be directed against free
histones or histones bound to DNA [16]. Although
AHAs may be of any isotype, IgG is considered the
most clinically relevant and detected isotype. IgM
AHAs are less specific and may be found in a wide
range of other disorders such as rheumatoid arth-
ritis and mixed connective tissue disease. These anti-
bodies have been typed at the peptide level by
microarray analyses to define their precise

CONTACT Adrian Y. S. Lee adrian.lee1@health.nsw.gov.au Department of Immunology, Westmead Hospital, Level 2 ICPMR, Hawkesbury Road,
Westmead 2145, Australia
ß 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the Japanese Society of Clinical Immunology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Figure 1. Basic subunit of DNA. A nucleosome comprises a
histone octamer core with DNA wrapped around, resembling
‘beads on a string’.
specificities [17]. Although classically attributed to
SLE and drug-induced lupus erythematosus (DILE),
AHAs have been studied since the 1970s and are
found in a large variety of pathologies including
Sj€
ogren’s syndrome, inflammatory myositides and
rheumatoid arthritis [18].[16]
The functional activity of AHAs is largely
unknown; although, they may possess proteolytic
activity towards histone proteins [19]. Whether this
directly contributes to disease pathogenesis is
unclear at this stage.
3. AHA detection in the laboratory
AHAs may refer to either total histones or histone
subunits; although the latter is more often seen in
the research laboratory. AHAs may be noted on
indirect immunofluorescence that screens for ANAs.
On the commonly-used HEp-2 substrate, AHAs
commonly appear as a homogenous pattern; but is
not specific for these autoantibodies [20]. Some false
positives have also been noted on the Crithidia luci-
liae immunofluorescence test (CLIFT) (which nor-
mally detects anti-dsDNA antibodies) in some
patients that produce AHA that can bind Chrithidia
luciliae kinetoplast [21].
One of the now-outdated AHA tests is the com-
plement fixation assay. These assays rely on the abil-
ity of complement to bind AHA and histone
antigen immune complexes, and therefore, do not
cause the haemolysis of added sensitised sheep red
blood cells. In contrast, the absence of AHA will
lead to unbound complement – due to lack of anti-
body-antigen immune complexes – and eventual
haemolysis of sensitised SRBCs. Haemolysis is meas-
ured spectrophotometrically [22].
A further historical test is the immunofluores-
cence assay on histone-reconstituted tissues [23].
Briefly, fixed mouse kidney cryostat sections are
treated with hydrochloric acid to elute histones. A
proportion of these is then reconstituted with calf
thymus histones. Comparison of acid-extracted and
IMMUNOLOGICAL MEDICINE 181
reconstituted tissues after incubation with diluted
patient sera allows the specific detection of histone
antibodies [23]. The advantage of this assay is the
specific detection of AHA; however, it is time-con-
suming and labour-intensive. The complement fix-
ation test and histone reconstitution assays have
good concordance [24].
Modern-day assays, such as the chemilumines-
cence assay, are based on an ELISA format with
various methods of antigen presentation and sec-
ondary antibody detection, which has the advantage
of being able to detect whole histone or histone sub-
units. These may be single- or multi-plex and afford
automaticity and quick turnaround times [25]. The
positivity may differ depending on assay use and if
there is contaminating DNA which acts as an anti-
genic source for patient antibodies [26].
Western blotting has been used to traditionally
detect antibodies against acid-extracted histone sub-
units. Sodium dodecyl sulphate-polyacrylamide gel
electrophoresis (SDS-PAGE) is used to separate his-
tones out into their constituents based on molecular
weights: H1 is around 23 kDa whilst the core histo-
nes (H2A, H2B, H3 and H4) range from 10–15 kDa
[27]. Detection against these components using IgG-
, IgA- or IgM-labelled secondary antibodies can be
performed. The line immunoassay works in a simi-
lar manner. The major drawback to these assays is
the histone antigens are denatured and therefore,
reduced sensitivity in detecting antibodies against
conformational epitopes [1].
4. AHAs in drug-induced lupus
erythematosus (DILE)
DILE is a syndrome that resembles some or most
pathological and clinical features of idiopathic SLE
but is temporally related to the commencement of a
particular drug. On cessation of the offending drug,
the syndrome abates [28]. Numerous drugs and bio-
logical agents are implicated. Although hydralazine
and procainamide are the most commonly impli-
cated agents [28]; infrequent drugs associated
include interferon-a, sulfasalazine and captopril
[29]. The risk of DILE is generally increased in the
older population and those that have been taking
implicated medications for a longer period of time
[30]. It is estimated to affect up to 30,000 people
each year in the United States [30].
DILE is characterised by the emergence of auto-
antibodies, including AHAs which appear at a much
higher frequency than idiopathic SLE [28,31]. In
contrast, biologic agents such as anti-tumour necro-
sis factor (TNF) do not appear to induce AHAs as
frequently, suggesting a different mechanism for the
pathogenesis [32,33]. Anti-TNF DILE tends to
182 A. Y. S. LEE

Table 1. Prevalence of IgG antibodies to total histones and histone subunits in selected disorders.
Histone component Disease Average prevalence, % (range) References
Total histone Rheumatoid arthritis 5 [50]
Various malignancies [50]
Inflammatory myositides 17 [20]
Systemic sclerosis 30 (29–33) [41,48]
Schizophrenia 23 [51]
Systemic lupus erythematosus (SLE) 53 (24–81) [24,39,43,50,52,53]
Drug-induced lupus erythematosus (DILE) 96 [36]
H1 Human immunodeficiency virus [54]
Inflammatory myositides 17 [20]
Mixed connective tissue disease (MCTD) [55]
SLE 32 (6–49) [36,39,42,53]
DILE 9 [36]
H2A SLE 34 [53]
DILE 67 [35]
Systemic sclerosis [56]
MCTD [55]
H2B SLE 63 [53]
Systemic sclerosis [56]
MCTD [55]
H2A-H2B complex SLE 9 [26]
DILE 91 [36]
H2A-H2B-DNA complex SLE 10 [26]
DILE 30 [57]
H3 SLE 42 (37–56) [42,53]
DILE 13 (H3–H4 complex) [36]
H4 SLE 1 (1–22) [39,53]

produce more internal organ involvement and
rashes compared to classic DILE [34]. In addition,
AHAs are generally absent in drug-induced ANA
without symptoms [35].
Overall, AHAs (mainly IgG isotype) are present
in a substantial proportion of DILE patients (Table
1). In a cohort of patient samples submitted to a
diagnostic laboratory, AHA had a sensitivity of 67%
and specificity of 95% for the diagnosis of DILE
[18]. This is in contrast to the reported prevalence
of 96% in one study [36]; however, the latter was
derived from a cohort of DILE patients rather than
a general laboratory population. Furthermore, older
studies in DILE excluded newer biological agents
that cause DILE without AHA, so this may be
somewhat biased.
IgG and IgM antibodies to the H2A–H2B and
H2A–H2B–DNA histone complexes have been
noted in patients with procainamide DILE [37,38].
In contrast, patients with hydralazine and chlorpro-
mazine DILE had predominantly IgM directed
against DNA-free histone complexes, namely to
H2A–H2B, H1, (H3–H4)2 tetramers [37]. These
data reinforce the heterogeneous immune response
in DILEs, yet the specific reasons for targeting these
histone complexes are unclear.
5. AHAs in systemic lupus erythematosus
In contrast to DILE, SLE ANAs are more heteroge-
neous and include AHAs and non-histone antibod-
ies, perhaps reflecting the complex pathogenesis.
IgG, IgA and IgM to individual core histones are
primarily directed against H1, H2A, H2B and H3;
very little is directed against H2A–H2B complex or
H4 [39]. Antibodies to these histone subunits are
generally more diverse and reflect epitope spreading
than DILE AHAs [38], and may also be directed to
histone complexes (e.g., H2A–H2B) and histone
coupled to DNA [26].
Studies reveal the presence of antibodies against
total histone in approximately half of the patients
with SLE (Table 1). Compared to healthy controls
and non-SLE ANA-positive patients, total histone
autoantibody detection has a diagnostic sensitivity
of 55–92% and specificity of 69–82% for SLE
[40,41]. H4 antibodies are relatively rare in SLE but
when present, they have excellent diagnostic sensi-
tivity (95%) and specificity (90%) for SLE when
compared to healthy controls [25]. This is analogous
to H1 and H3 specific antibodies which also demon-
strate high specificity (94–96%) for the diagnosis
[42]. In general, AHA has lower sensitivity for SLE
than anti-nucleosomes and lower specificity than
anti-dsDNA for the diagnosis [40].
AHAs often co-exist with anti-dsDNA and anti-
nucleosome antibodies, particularly in lupus neph-
ritis (LN), and may reflect more severe renal
involvement than those LN patients negative for
these autoantibodies [43]. AHA quantitation appears
to correlate with LN severity and may be predictive
of flares [43–45]. Although total IgG AHA may fluc-
tuate with disease activity, levels do not reliably cor-
relate with overall disease activity [16]. Clinically,
studies show that AHA is associated with oral ulcer-
ation, neuropsychiatric symptoms, lymphopaenia
and fatigue [39,41,46]. There is no association with
arthritis or other cutaneous features [46]. As of yet,

there appears not to be clinical significance ascribed
to the differential expression of antibodies to histone
subunits [47].
6. Conclusions
Although AHAs were classically attributed to DILE
and SLE, there is an expanding spectrum of the
association of these autoantibodies to other auto-
immune and infectious disorders. The value of these
may be to help predict and prognosticate clinical
features in disorders such as SLE and systemic scler-
osis [48]. Subunit histone antibody analyses may
also help distinguish SLE from certain cases of DILE
but this is not routinely performed in the diagnostic
laboratory and probably does not add significant
diagnostic value. Moreover, the prevalence of AHAs
in DILE likely is much less than reported in older
literature since newer agents implicated in DILE do
not elicit AHAs as frequently as older agents such
as procainamide.
What can be done to further study AHAs?
Firstly, the factors that make histones immunogenic
are a matter of ongoing research, particularly in
terms of epigenetics in recent times. In addition,
there are only a handful of studies that examine iso-
type determination in various disorders and, apart
from a research perspective, there appears to be lit-
tle clinical relevance although further studies in this
area are warranted. Certainly, isotypes other than
IgG increase the sensitivity of picking up AHAs
[39]. Furthermore, emerging mass spectrometry
technology to type these autoantibodies at the
amino acid and peptide levels has afforded an
innovative way to study these autoantibodies at high
resolution [49], increasing our understanding of
their pathogenicity and the immunological epiphe-
nomena of systemic autoimmunity. It is possible
that with increasing observational studies, databases
of disease associations may be established to enable
clinicians and laboratorians to find value in the
molecular typing of these fascinating autoantibodies.
Disclosure statement
No potential conflict of interest was reported by
the author(s).
ORCID
Adrian Y. S. Lee http://orcid.org/0000-0002-5179-4803
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