Reviews

IgG4-​related disease: an update on

pathophysiology and implications for
clinical care
Cory A. Perugino1,2 and John H. Stone1 ✉
Abstract | IgG4-​related disease (IgG4-​RD) has only existed as a unique disease entity
since 2003, yet remarkable progress has already been achieved in describing the essential
features of the disease. A framework for systematic clinical studies has been created by the
development of a quantitative disease activity tool (the IgG4-​RD Responder Index) and
the validation of classification criteria, both of which were the products of international,
multi-​centre investigations. In addition, substantial strides have been made in understanding
the pathophysiology of IgG4-​RD. In particular, the central role of B cells in the disease has been
demonstrated by both the robust clinical responsiveness of IgG4-​RD to B cell depletion and by
the identification of multiple self-​antigens that promote B cell expansion. CD4+ T cells have also
been investigated in detail; CD4+ cytotoxic T lymphocytes (suspected of promoting disease) and
a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been
defined by multiple groups. The mechanisms by which these immune cells converge on target
tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood
and will be an important research focus in the coming years.

Dacryoadenitis
Enlarged lacrimal glands that
are generally not tender.
1
Massachusetts General
Hospital, Division of
Rheumatology, Allergy
and Immunology, Boston,
MA, USA.
2
Ragon Institute of MGH,
MIT and Harvard, Cambridge,
MA, USA.
✉e-​mail: jhstone@
mgh.harvard.edu
https://doi.org/10.1038/
s41584-020-0500-7
IgG4-​related disease (IgG4-​RD) is an insidiously pro-
gressive, often highly destructive and sometimes fatal
condition that is typified by chronic activation of the
immune system and tissue fibrosis1–5. The chronicity
of the disease, responsiveness to immunosuppression
and association with autoantibodies provide support
for an autoimmune aetiology, but definitive evidence
is lacking. IgG4-​RD often presents with organ enlarge-
ment that mimics a tumour and can affect the lacri-
mal glands, orbits, major salivary glands, pancreas,
bile ducts, retroperitoneum, lungs, kidneys, aorta,
pachymeninges and thyroid gland (Fig. 1). This ten-
dency to cause mass lesions can occur as, for exam-
ple, dacryoadenitis (Fig. 2a), soft tissue expansion in the
retroperitoneum encasing the abdominal aorta (Fig. 2b)
or diffuse enlargement of the pancreas, leading to sus-
pected pancreatic adenocarcinoma (Fig. 2c). Concurrent
involvement of several of these organs in a manner
characteristic of IgG4-​RD is strongly suggestive of this
condition1–5.
Although IgG4-​RD was originally recognized as
a distinct systemic disease entity nearly two decades
ago1–3, the persistent lack of familiarity with this dis-
ease dictates that a large proportion of patients poten-
tially remain undiagnosed. Although Japan’s Ministry
of Health, Labour and Welfare has estimated an
incidence of IgG4-​RD of 0.28–1.08 per 100,000 peo-
ple and 336–1,300 newly diagnosed patients per year4,
rigorously conducted epidemiological studies of the
incidence and prevalence of IgG4-​RD are not avail-
able. Similarly, studies of the contribution of genetics
to IgG4-​R D remain in their infancy. Nevertheless,
advances in the study of IgG4-​R D include: con-
sensus on disease nomenclature5; consensus on the
histopathological features of the disease6; the devel-
opment and validation of an IgG4-​R D Responder
Index7; detailed phenotyping of the humoral immune
response in patients with IgG4-​RD8–10; the discovery of
potential causal autoantigens11–13; demonstration of the
T follicular helper (TFH) cell subset that is potentially
involved in IgG4 class-​switching14,15; identification of
a CD4+ effector T cell subset that probably promotes
the disease9,16,17; the elucidation of B cell depletion as
a highly effective therapy18; and the development of
IgG4-​RD classification criteria endorsed by both the
ACR and EULAR19. In this Review, we broadly discuss
the clinical nature of IgG4-​RD, examine advances in
our understanding of its pathophysiology and offer
an update on some of the knowledge deficits that
were identified around the roles of specific T cell
subsets in the most recent review of clinical practice
from 2018 (ref.20).

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Key points
• IgG4-​related disease (IgG4-​RD) is an insidiously progressive immune-​mediated
fibrotic disease typified by tumour-​like mass formation in many affected organs.
• High serum IgG4 concentrations or increased numbers of IgG4+ plasma cells in tissue
must be paired with appropriate clinical, histopathological and (often) radiological
information for a diagnosis of IgG4-​RD.
• B cell-​depletion therapy is a highly effective treatment for IgG4-​RD, confirming the
importance of B cells in the pathophysiology of this disease.
• CD4+ cytotoxic T lymphocytes (CTLs) dominate the immune cell infiltrate in IgG4-​RD
and decline after B cell-​targeted therapy, suggesting that B cells present antigen
to and thereby activate CD4+ CTLs.
• M2 macrophages, activated B cells, CD4+ CTLs and fibroblasts probably all contribute
to generating the inflammatory masses composed of immune cells and fibrotic tissue
that occur in IgG4-​RD.
• Novel therapeutic approaches to targeting B cells and/or CD4+ CTLs are being
evaluated for the treatment of IgG4-​RD.
Clinical features of IgG4-​RD
Clinical presentation
Certain clinical and histological features unify the
heterogeneous organ manifestations of IgG4-​R D
(Fig.  1) . Acute, fulminant or highly inflammatory
clinical presentations do not occur in IgG4-​RD. In
contrast to the rapidly progressive glomerulone-
phritis seen in anti-​neutrophil cytoplasmic antibody
(ANCA)-​associated vasculitis or the hypoxaemic res-
piratory failure of anti-​synthetase syndrome, IgG4-​RD
evolves insidiously, does not cause fever and seldom
leads swiftly to organ failure21. Patients can have sub-
clinical symptoms or signs of disease for months or
years before seeking medical evaluation, or can have
symptoms and signs of disease that go unrecognized
by medical practitioners for long periods22. Moreover,
many features of disease are detected only incidentally
by imaging (such as retroperitoneal fibrosis) or by
surgical pathology (such as IgG4-​related aortitis).
The slowly evolving nature of IgG4-​RD is one of
its characteristic features; it is also, unfortunately, one
of the traits most responsible for the potential of this
disease to cause harm. The long latency period preced-
ing clinical detection probably accounts for the fact that
~60% of all patients with IgG4-​RD have some degree of
irreversible organ dysfunction owing to damage at the
time of diagnosis22. The damage wrought by the insidi-
ous nature of IgG4-​RD is typified by the complications
associated with IgG4-​related autoimmune pancreatitis,
which include diabetes mellitus and exocrine pancre-
atic insufficiency. The dramatic weight loss that many
patients with IgG4-​RD experience before their diagno-
sis is often attributable to exocrine pancreatic insuffi-
ciency and the consequent inability to digest and absorb
nutrients, rather than to the constitutional effects of sys-
temic inflammation. Pancreatic failure often occurs in
these patients before the underlying diagnosis can be
established23,24.
IgG4-​RD is associated with transformations in the
gross appearance of affected organs. Some organs,
Obliterative phlebitis
such as the pancreas, lacrimal glands and major sal-
Targeted destruction of veins ivary glands, become diffusely enlarged25, whereas
as opposed to arteries. ductal organs (such as the bile duct and bronchus)
NaTure RevIews | RheumaToloGy
Reviews
assume the appearance of a pipe stem and have dif-
fuse wall-​thickening. Changes to the affected organs
are slow to detect via radiology. Some aspects of the
mass-​forming tendency of IgG4-​RD provide important
clues for diagnosis. For example, the capsule-​like rim of
oedema surrounding a diffusely enlarged pancreas — a
finding termed a ‘sausage-​shaped’ pancreas (Fig. 2c) — is
characteristic of IgG4-​RD. Another typical manifestation
is the soft tissue encasement of the anterolateral aspect
of the aorta in the setting of IgG4-​related retroperitoneal
fibrosis (Fig. 2b).
Histological features
Similarities in histopathology between affected organs
were the first indications that a single unique disease
process explained the clinical manifestations of IgG4-​RD
and the dysfunction across disparate organs2,3. An irreg-
ular, whorled pattern of fibrosis, termed ‘storiform’ from
the Latin for ‘woven mat’, is a highly distinctive feature of
IgG4-​RD, albeit non-​diagnostic6,19. Enmeshed within the
expanded extracellular matrix in storiform fibrosis is a
dense lymphoplasmacytic infiltrate rich in IgG4+ plasma
cells and CD4+ T cells (Fig. 2d and e). Eosinophils are
also encountered in immune cell infiltrates to a mod-
erate degree, but do not dominate the overall composi-
tion of immune cells6. Obliterative phlebitis resulting in
destruction of the walls and lumens of veins is another
characteristic lesion observed in some individuals with
IgG4-​RD. Staining for elastin is generally required
to visualize the remnants of the walls of blood vessels
histologically. Some organs, particularly the lung and
pancreas, can also demonstrate obliterative arteritis;
however, despite the vascular destruction that can occur
in IgG4-​RD, necrosis is seldom (if ever) a feature of this
disease6,19.
The accumulation of IgG4 class-​switched plasma
cells at sites of disease provides direct evidence for
the chronic activation of the adaptive immune sys-
tem in IgG4-​RD. Increased numbers of IgG4+ plasma
cells and high IgG4+:IgG+ plasma cell ratios provide
important information that is complementary to the
results from haematoxylin and eosin-​stained tissue
samples (Fig. 2e and f). For example, the findings of
≥50 IgG4+ plasma cells per high-​power field and an
IgG4+:IgG+ plasma cell ratio of >40% strongly support
a diagnosis of IgG4-​RD6,26. In patients with a confirmed
diagnosis of IgG4-​RD, abundant IgG4+ plasma cells are
generally expected to be observed at a site of disease,
but there are many caveats to such information in iso-
lation. The thresholds for the absolute number of IgG4+
plasma cells per high-​power field do vary to some degree
from organ to organ and between methods of obtain-
ing tissue samples6. The number of IgG4+ plasma cells
per high-​power field is usually high in tissue collected
from surgical biopsies of the major salivary glands,
lacrimal glands, pancreas, lungs and kidneys. By con-
trast, tissue gained from non-​surgical biopsies generally
yields fewer IgG4+ plasma cells than that from surgical
biopsies because of the limited quantities of tissue that
can be obtained from core or needle biopsies. Tissue
from biopsies of the retroperitoneum, unless obtained
by a surgical procedure (which is rarely done), is often
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Hypergammaglobulinaemia
Raised concentrations of
immunoglobulins in the blood.
704 | December 2020 | volume 16 www.nature.com/nrrheum
Pachymeninges
Diffuse thickening with
contrast enhancement
Lacrimal glands
Asymptomatic enlargement,
usually symmetric
Thyroid gland
Asymptomatic enlargement,
usually symmetric
Lungs
Masses, nodules,
bronchial wall thickening
Bile ducts
Intra-hepatic and
extra-hepatic strictures
Kidneys
Focal masses, usually
multiple
Fig. 1 | The manifestations of IgG4-related disease. Body schematic highlighting the 11 anatomical sites that are regarded
as typically involved in IgG4-​related disease according to the ACR–EULAR 2019 IgG4-​related disease classification criteria.
The most frequent manifestation for each organ is described. Colours indicate the relative frequency of involvement for
each organ.
overwhelmingly fibrotic and pauci-​cellular, limiting the
diagnostic utility of this tissue for IgG4 quantification.
In such retroperitoneal biopsies, as few as 10 IgG4+
plasma cells per high-​power field can be regarded as
supportive of the diagnosis of IgG4-​RD, particularly
if the IgG4+:IgG+ cell ratio is high and the remainder
of the clinical, radiological and pathological features
are consistent with a diagnosis of IgG4-​RD6.
The finding of increased concentrations of IgG4+
plasma cells in tissue must be interpreted with caution.
Abundant IgG4+ plasma cells in tissue are most relevant
to a diagnosis of IgG4-​RD when they affect one of the
organs typically involved in this disease (Fig. 1). Although
the nasal cavity, sinuses and lymph nodes can be involved
in IgG4-​RD, findings of increased IgG4+ plasma cells at
these sites were not considered sufficiently specific to
contribute to the classification criteria for IgG4-​RD19.
Immunostaining results from these sites must be inter-
preted in the context of the findings of haematoxylin
and eosin staining and ultimately, of course, the clinical
evaluation. A broad array of diseases are associated with
increased numbers of IgG4+ plasma cells within involved
tissues27. In fact, one of the most challenging mimick-
ers of IgG4-​RD — ANCA-​associated vasculitis — often
involves substantial accumulations of IgG4+ plasma cells
within the kidneys28, lungs, sinuses, meninges and other
organs that are also commonly affected by IgG4-​RD. In
short, the diagnosis of IgG4-​RD should never be pred-
icated on the results of immunostaining features alone.
Accurate diagnosis requires the synthesis of data from
the clinical, serological and radiological realms and
immunostaining results must be interpreted in the
context of the overall histopathological findings.
Orbits
Often symptomatic, masses,
extra-ocular muscle myositis
Major salivary glands
Asymptomatic enlargement,
usually symmetric
Pancreas
Diffuse enlargement, diabetes,
exocrine insufficiency
Aorta
Wall thickening sometimes
with aneurysm
Retroperitoneum
Soft tissue mass encasing the
anterolateral aorta
Frequent Occasional Infrequent
Response to glucocorticoids
Responsiveness to treatment is another clinical charac­
teristic of IgG4-​RD. The failure to respond to an ade-
quate course of glucocorticoids is an important exclusion
criterion in the ACR–EULAR IgG4-​RD classification
criteria19. The response of IgG4-​RD to treatment with
glucocorticoids highlights the dynamic nature of the
‘fibro-​inflammatory’ histological findings of this disease,
in which immune cell infiltrates are prominent and often
described as ‘dense’. The marked reversibility of fibrotic
lesions upon immunosuppressive treatment in IgG4-​RD
is uncommon among other immune-​mediated fibrotic
diseases such as systemic sclerosis (SSc).
Immunopathogenesis of IgG4-​RD
B cell and antibody responses
The pathogenic role of B cells. The humoral immune
system received the most attention after IgG4-​RD was
first recognized as a unique disease entity, principally
because of the hypergammaglobulinaemia and prominent
IgG4 class-​switching that is evident within both the
blood and affected tissues of patients with IgG4-​RD. In
six patients with IgG4-​related cholangitis, immunoglob-
ulin sequencing in peripheral blood mononuclear cells
revealed oligoclonal expansion of IgG4+ clones in all
patients29. The same IgG4+ clones identified in the blood
also dominated the tissue-​infiltrating IgG+ cells. In these
patients, the circulating clones declined in conjunction
with glucocorticoid-​induced remission, which suggested
a direct pathogenic role for oligoclonally expanded
B cells in patients with IgG4-​RD29.
A subsequent study validated the finding of oligo-
clonal expansion among circulating plasmablasts in

a d
b e
c
f
Fig. 2 | Clinical, radiological and histopathological characteristics of IgG4-related
disease. a | An enlarged right lacrimal gland (dacryoadenitis) is visible upon everting the
eyelid. IgG4-​related dacryoadenitis is usually bilateral. b | A CT scan shows a soft tissue
mass encasing the abdominal aorta (red arrow) consistent with retroperitoneal fibrosis.
IgG4-​related retroperitoneal fibrosis is typically over the anterolateral portion of the aorta.
c | A CT scan showing the diffusely enlarged ‘sausage-​shaped’ pancreas (red arrow) typical
of IgG4-​related autoimmune pancreatitis. d | Typical haematoxylin and eosin staining of
prostate gland showing a lymphoplasmacytic infiltrate enmeshed in storiform fibrosis.
e | Abundant IgG4+ plasma cells (brown) in a tissue sample from a biopsy of a submandibular
gland. f | IgG stains often have high amounts of background staining, as shown in this
image, which can complicate the calculation of precise IgG4+:IgG+ cell ratios.
patients with multi-​organ IgG4-​RD8. These cells had
the surface phenotype of mature and activated B cells
(high expression of HLA-​DR, SLAM family member 7
(SLAMF7) and IgG4) but comparatively little expression
of IgM. A separate microarray-​based study of circulating
plasmablasts in patients with IgG4-​RD later confirmed
this activated phenotype, which included upregula­
ted surface expression of HLA-​DR, CD95, CD86 and
CD62L, along with evidence of active proliferation
and secretion of IgG4 (ref.30). Additional immunoglob-
ulin sequencing of circulating plasmablasts has revealed
extensive somatic hypermutation involving both the
hypervariable and framework regions of immunoglob-
ulin genes8. This finding suggests that the IgG4+ plas-
mablasts that are found in patients with IgG4-​RD are
generated in a T cell-​dependent manner. Furthermore,
when paired heavy and light chains from dominant
plasmablasts were cloned, the recombinant monoclonal
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antibodies were autoreactive and could elicit a bright
cytosolic staining of Hep-2 cells8. The finding of dom-
inant, autoreactive B cell clones was the first evidence
that the humoral immune response in IgG4-​RD was
directed towards self-​antigens and provided clues about
how to identify those antigens (discussed in the section
on autoantibody responses in IgG4-​RD).
Importantly, the expansion of activated B cells in the
peripheral blood of untreated patients with IgG4-​RD
corresponds with disease activity8,26,30. This correlation
was initially suggested in a small study of 12 patients
treated with rituximab that compared patients who
relapsed within a year of achieving remission with
those who remained in remission8. A clear resurgence
of plasmablasts was noted in all six patients with relaps-
ing disease as early as 4 months after induction therapy.
However, no such resurgence was observed in the six
patients who did not experience disease relapse. Two
subsequent studies26,30 that used data from larger cohorts
of patients with IgG4-​RD (n = 37 and n = 42, respec-
tively) demonstrated correlations between circulating
plasmablast counts and the number of organs affected,
which were independent of serum IgG4 concentration.
Circulating plasmablast numbers decline in patients
with IgG4-​RD following remission induced by B cell
depletion 26. B cell subsets other than plasmablasts
have not been studied to the same degree; however,
some evidence suggests that the number of memory
B cells (CD19+CD20+CD27+CD38-) rises before dis-
ease relapses31. Moreover, the expansion of an activated
IgG4+ memory B cell subset characterized by the down-
regulation of the type 2 complement receptor, CD21,
has also been reported10. Overshadowing the extensive
descriptive and correlative data related to B cells in
IgG4-​RD, it is ultimately the established marked clinical
responsiveness to B cell-​depleting therapy that validates
the suggested pathogenicity of B cells in this disease18.
Additional molecular phenotyping, functional analy-
ses and immunoglobulin repertoire studies are needed
to understand the diversity and effector functions of
B cell subsets more completely, as well as to comprehend
the connectivity between plasmablasts and other types
of activated B cells in patients with IgG4-​RD. There
remains a paucity of data concerning the phenotype of
other B cell subpopulations in patients with IgG4-​RD,
such as transitional, naive and double-​negative B cells
(IgDloCD27lo B cells that have been described in the
context of systemic lupus erythematosus32).
The anti-​inflammatory role of IgG4. The precise patho-
physiological role of the IgG4 molecule remains an area
of investigation, but many clinical and epidemiological
observations have been made about its relationship to
disease activity. The degree to which IgG4 concentration
is raised at the time of diagnosis correlates with both the
extent of organ involvement and the risk of relapse26,33,34.
An increase in serum IgG4 has poor specificity for the
diagnosis of IgG4-​RD: similar to the finding of IgG4+
plasma cells within tissue, increases in the concentra-
tion of IgG4 in the blood are commonly found in mul-
tiple diseases marked by chronic immune activation35.
The serum IgG4 concentration does not correlate with
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Fab-​arm exchange
The swapping of half-​antibody
fragments between antibody
molecules, a property that is
unique to IgG4 among the
different IgG subclasses.
706 | December 2020 | volume 16 www.nature.com/nrrheum
indirect measures of fibrosis36, nor is it common for this
laboratory finding to entirely return to normal with
treatment-​induced remission. The preponderance of
literature on the effector functions of the IgG4 mole-
cule supports an anti-​inflammatory role for this IgG
isotype37. The potential for an anti-​inflammatory func-
tion is related to three unique features of IgG4 compared
with other IgG isotypes: Fab-​arm exchange; poor com-
plement protein C1q fixation; and a reduced capacity
to bind activating Fc receptors. Overall, the increase
in serum IgG4 in IgG4-​RD might represent a failing
counter-​regulatory response in which serum IgG4
concentrations rise higher and higher in an attempt to
(unsuccessfully) dampen the primary immune response.
Opinion on the role of IgG4 in this disease is not
unanimous. The pathogenic potential of IgG4 in the con-
text of IgG4-​RD has been evaluated through an adoptive
transfer model38. In this study, purified IgG subclasses
from patients with IgG4-​related autoimmune pancre-
atitis (IgGs 1–4) were administered subcutaneously to
neonatal Balb/c mice. Organs were subsequently ana-
lysed histopathologically to understand the pathogenic
capacity of each respective IgG isotype. Human IgG1
and IgG4 purified from patients with IgG4-​RD induced
disease in the pancreata and salivary glands of recipient
mice, whereas IgGs from healthy individuals did not38.
Although this model supports the hypothesis that IgG4
directly contributes to the pathophysiology of IgG4-​RD,
these provocative findings are a source of debate. The
affinity of human IgG4 to the only inhibitory Fcγ recep-
tor in mice (FcγRIIB) is markedly reduced compared
with that of mouse IgG1, which is the functional ana-
logue of human IgG4 (ref.39). In addition, human IgG4
binding to the activating mouse Fcγ receptor (FcγRI)
is markedly enhanced39. Thus, the degree to which this
adoptive transfer model in mice reflects the situation in
humans is not clear. A humanized mouse model that
recapitulates human Fcγ receptor structure and function
would be an appropriate model in which to validate the
findings from the neonatal Balb/c mouse model40.
Autoantibody responses in IgG4-​RD. Since the mid-
1990s, a plethora of autoantigens have been linked to
IgG4-​RD, primarily in the context of IgG4-​related auto-
immune pancreatitis. Autoantigens identified in these
cohorts of patients with organ-​limited disease include
carbonic anhydrase, plasminogen binding protein, lacto-
ferrin, pancreatic secretory trypsin inhibitor, amylase
alpha-2A, trypsinogen and annexin A11 (refs11,41–46).
However, most of these reports have suffered from a
lack of external validation, and the generalizability of the
results for patients with IgG4-​RD involving organs other
than the pancreas is unknown. Plasminogen-​binding
protein, initially reported to have high specificity for dif-
ferentiating IgG4-​related autoimmune pancreatitis from
other pathological pancreatic conditions, did not have
any diagnostic value in two external cohorts of patients
with IgG4-​related pancreatic disease47,48, highlighting the
importance of external validation.
The research group that described the pathogenic
potential of IgG4 in an adoptive transfer model 38
found that transferred human IgG colocalized with the
extracellular matrix of recipient mouse pancreata and
subsequently sought to identify the pancreatic protein
that was targeted12. Using an ELISA-​based screen of
proteins known to be abundant in the pancreatic extra-
cellular matrix, the investigators identified a truncated
form of laminin-511 as a culprit antigen12. Antibodies
to laminin-511-​E8 were then identified in approxi-
mately half of a cohort of 51 patients with autoimmune
pancreatitis. The immunization of mice with human
laminin-511-​E8 protein led to the development of anti-
body responses and pancreatic injury, providing sup-
port for the concept that autoantigens contribute to the
pathophysiology of IgG4-​RD.
Only two studies have reported the identification and
examination of autoantigens among clinically diverse
patients with multi-​organ IgG4-​RD13,49. In the first
of these studies49, which involved a cohort of Chinese
patients with IgG4-​RD, a series of cell lines were screened
for reactivity with patient plasma. The investigators
identified antibody responses against the nuclear pro-
tein prohibitin in 65 of the 89 patients (73%). However,
a 2019 study aimed at validating previously reported
B cell autoantigen responses in patients with IgG4-​RD
reported only a low frequency of anti-​prohibitin anti-
body responses in a cohort of patients from the USA50.
In this same report, autoantibody responses against
laminin-511-​E8 occurred at a very low frequency. One
possible explanation for these different observations
could lie in population-​level differences across geneti-
cally distinct cohorts, such as those related to the rela-
tive distribution of HLA alleles. HLA-​DRB1*04:05 was
reported to be a risk allele in a Japanese cohort of patients
with IgG4-​RD in a genome-​wide association study51, but
no such analysis has yet been performed in patients of
non-​Asian descent. Conceivably, HLA allele differences
across populations could determine the efficiency by
which different self-​antigens were presented to TFH cells
by germinal centre B cells. Such a restriction would pre-
determine the likelihood of a given patient developing
an IgG4 response against a particular antigen. However,
the possibility of HLA allelic differences across cohorts
of patients with IgG4-​RD requires further study.
The second investigation into autoantibody
responses was aimed at determining the antigenic
specificity of dominantly expanded plasmablast clones
from a patient with active, multi-​organ IgG4-​RD13. The
investigators identified galectin-3 as an autoantigen in
patients with IgG4-​RD via single-​cell immunoglobu-
lin sequencing, the cloning of paired immunoglobulin
heavy and light chains, and recombinant expression of
the dominant immunoglobulin protein. Anti-​galectin-3
autoantibodies were present in 28% of a diverse cohort of
121 patients with IgG4-​RD, most of whom had multi-​
organ involvement13. These autoantibodies were restricted
to IgG4 and IgE isotypes, consistent with the clinical
observation that both IgG4 and IgE are often increased
in the serum of patients with IgG4-​RD. Moreover, the
presence of anti-​galectin-3 antibodies correlated strongly
with increased plasma concentrations of galectin-3, com-
patible with a breach of tolerance promoted by the accu-
mulation of this self-​protein in IgG4-​RD. In the context
of chronic inflammatory diseases, autoreactive immune

responses can occur secondary to the loss of normally
sequestered cytosolic or nuclear proteins. In IgG4-​RD,
it is the accumulation of immune cells and extracellular
matrix proteins to the extent of forming macroscopic
pseudo-​tumours that potentially causes an antigen to be
present in excess, which overcomes physiological toler-
ance mechanisms. Further investigation of the patho-
genic capacity and clinical importance of anti-​galectin-3
antibodies is ongoing.
Finally, patients with IgG4-​RD and autoantibody
responses against multiple self-​antigens have more
severe clinical phenotypes than patients who have lit-
tle evidence of reactivity against these same antigens50.
This finding provides further support for a pathogenic
role of some autoantibodies in IgG4-​RD. Alternatively,
consistent with the correlation between anti-​galectin-3
antibody responses and galectin-3 expression, it is pos-
sible that autoantibody responses against multiple anti-
gens might reflect the accumulation of non-​pathogenic
self-​reactive B cell responses as a consequence of chronic
tissue damage and the overexpression of these target
proteins within lesional tissues.
In summary, the expansion of activated B cells corre-
lates strongly with disease activity, and multiple studies
have suggested a pathogenic role for self-​reactive B cells
in IgG4-​RD. The most compelling data for a pathogenic
role for B cells in this disease are derived from the clin-
ical efficacy of targeted B cell-​depletion therapy (dis-
cussed in the section on B cell-​targeted therapy). Data
from the adoptive transfer model provides the strongest
evidence to date that autoantibody responses, including
those of the IgG4 isotype, are pathogenic and can induce
pathology in the pancreas and the salivary glands, an
organ distribution highly specific to IgG4-​RD38. Clearly,
the self-​antigens that are targeted by B cells in IgG4-​RD
are diverse, probably reflecting the considerable clinical
heterogeneity of this disease in terms of organ distribu-
tion. The diversity of self-​antigen targeting in IgG4-​RD
offers a parallel to a disease such as systemic lupus
erythematosus, in which a breach of B cell tolerance
results in diverse autoantibody responses, heterogene-
ity in organ manifestations and correlation between the
presence of specific autoantibodies and certain clinical
findings52. In IgG4-​RD, autoantigen discovery efforts
have made considerable strides over the past few years
through the conduction of rigorous studies, the use of
advanced techniques and initial findings from an adop-
tive transfer mouse model. Nevertheless, much work in
this area remains to be done, including pursuit of the
following goals: the expansion of autoantigen discov-
ery efforts; the identification of organ-​specific antigen
responses; confirmation or refutation that B cells and
T cells are responding to the same self-​antigen within
individual patients; and the development of broad col-
laborative efforts across patient cohorts to facilitate
external validation and international generalizability.
T cell responses
T follicular helper and T follicular regulatory cells.
The oligoclonal expansions of IgG4 + plasmablasts
that occur in patients with IgG4-​RD are marked by
enhanced somatic hypermutation within rearranged
NaTure RevIews | RheumaToloGy
Reviews
immunoglobulin heavy chain variable and framework
regions8. This observation is consistent with the hypoth-
esis that these B cell expansions take place via iterative
rounds of mutation and positive selection within germi-
nal centres in a process that is T cell-​dependent. Shortly
after the demonstration of plasmablast expansion in the
blood of patients with IgG4-​RD8, a similar expansion of
circulating TFH (cTFH) cells was reported53. Several sub-
sets of cTFH cells have been categorized according to the
expression of specific chemokine receptors, including
CXC-​chemokine receptor 3 (CXCR3), CC-​chemokine
receptor 6 (CCR6) and CCR4 (ref.54). In vitro experi-
ments have shown that some cTFH cell subsets — namely,
the cTFH2 and cTFH17 cell subsets — have the capacity
to collaborate with B cells and promote their differen-
tiation into antibody-​secreting cells54. Furthermore,
only cTFH cells that express the activation marker pro-
grammed cell death protein 1 (PD1) on their cell surface
are functionally capable of such B cell help55.
cT FH2 cells have been consistently linked with
IgG4-​RD, in particular as an expansion of PD1+ cTFH2
cells in the blood of patients with IgG4-​RD14,53,56–58. The
number of cTFH2 cells correlates with the number of
organs involved, circulating plasmablast numbers and
serum concentrations of both IgG4 and IL-4 (ref.53). IL-4,
long implicated in class-​switching of B cells to both IgG4
and IgE59, is produced by cTFH2 cells54. cTFH2 cells, but not
cTFH1 or cTFH17 cells, also induce IgG4 class-​switching
in B cells in co-​culture experiments14. Although IgG4
class-​switching is not specific to patients with IgG4-​RD,
a substantial expansion of cTFH2 cells seems to occur in
the context of IgG4-​RD. This expansion could result
from an, as yet undefined, cytokine milieu or, alterna-
tively, from a dendritic cell phenotype capable of guid-
ing such polarization in an antigen-​dependent manner.
Therefore, it is possible that the cTFH2 cells in patients
with IgG4-​RD represent post-​germinal centre TFH cells
involved in plasmablast differentiation and isotype
switching to IgG4.
In addition to expanded T FH  cells in the blood,
IL-4-​expressing TFH cells accumulate in tissues affected
by IgG4-​RD. In one study, quantitative multi-​colour
immunofluorescence revealed that IL-4 + T FH  cells
make up on average 50% of the total number of
tissue-​infiltrating TFH cells found within tertiary lym-
phoid structures in tissues affected by IgG4-​RD15. The
extent of tissue infiltration by IL-4+ TFH cells correlated
strongly with the number of IgG4+ B cells within the
same tissues and with serum concentrations of IgG4,
but not of other immunoglobulin isotypes. In addi-
tion, using a cytokine capture approach, IL-4-​secreting
T FH  cells purified from the blood of patients with
IgG4-​RD could be distinguished from IL-4-​secreting
CD4+ T helper cells by the expression of the transcription
factor BATF. The IL-4+ TFH cells from the circulation had
a distinctly activated phenotype with increased expres-
sion of CXCR5, PD1, inducible T cell costimulator and
CD40 ligand (CD40L), suggesting that these cells are
recently activated post-​germinal centre TFH cells. Within
the tissues, the vast majority of IL-4+CD4+ T cells were
CXCR5+ TFH cells. In this study15, IL4+BATF+ TFH cells
were abundant in both secondary and tertiary lymphoid
volume 16 | December 2020 | 707
Reviews

organs from patients with IgG4-​RD, but were rarely seen
in analogous tissues from healthy individuals or from
patients with primary Sjögren syndrome, and the major-
ity of the cells in IgG4-​RD were found just outside of
germinal centres. This observation regarding disease
specificity, when paired with the strong correlative data
on IgG4+ B cells and serum IgG4 concentrations, sug-
gests that this unique subset of IL-4+BATF+ TFH cells
is uniquely related to IgG4 class-​switching (Fig.  3) .
Although TFH cells and other CD4+ T cell populations
involved in providing B cell help have been reported in
the context of other immune-​mediated diseases60–64, this
approach of examining TFH cell subsets on the basis of
specific cytokine secretion has not yet been studied more
broadly and requires confirmation.
IL-10-​s ecreting T cells might also contribute to
the pathogenesis of IgG4-​R D. T follicular regula-
tory (TFR) cells, originating from natural regulatory
T cells, are CXCR5-​expressing counterparts to TFH cells
that are widely regarded as inhibitors of germinal
centre reactions65,66. However, the results of one study
have suggested that TFR cells promote germinal centres
through the production of IL-10 (ref.67). A peripheral
blood analogue of TFR cells has also been character-
ized and is reduced in number in various autoimmune
diseases60,61,68. IL-10, which is overexpressed in tissues
affected by IgG4-​RD, potentially has a role in direct-
ing IgG4 class-​switching59,69, raising the possibility that
IL-10-​expressing TFR cells are germane to the IgG4
class-​switching mechanism in IgG4-​RD. A 2019 study
showed TFR cells to be expanded in peripheral blood as
well as in tissues affected by IgG4-​RD70. In that study,
circulating TFR cell numbers correlated with serum
IgG4 concentrations and with the number of organs
involved, but only a small fraction of these circulating
cells expressed IL-10.
An alternative theory is that a specific subset of
TFH cells is solely responsible for the IgG4 class-​switching
phenomenon by secreting both IL-4 and IL-10. Along
these lines, transcriptional profiling of the aforemen-
tioned IL-4+ TFH cell population suggested some degree
of overexpression of IL10 mRNA in comparison to
TFH cells that did not secrete IL-4 (ref.15). Although
reports suggest that IL-4 promotes isotype switching
from IgM to both IgG4 and IgE, the addition of IL-10
in the presence of IL-4 in vitro preferentially promotes
class-​switching to IgG4 rather than IgE59. Moreover, a
FOXP3−CXCR5+ IL-10-​producing TFH cell subset capa-
ble of suppressing IgE class-​switching has been described
in human tonsils71. Thus, it is possible that the relative
abundance of IL-4-​producing, IL-10-​producing or dual
IL-4–IL-10-​producing T cells determines whether a
given B cell class-​switches to IgG4 or IgE. Although IgE
is often increased in the serum of patients with IgG4-​RD,
and autoantibodies of the IgE isotype have been reported
in this disease context13, the exact role of IgE remains

Lymph nodes and tissues Tissues and blood Bone marrow

IL-4
IgG4+ plasmablast IgG4+ LLPC

PD1 PDL1
TCR MHC
LLPCs compete
ICOS ICOSL for bone marrow
CD40L CD40 niche

BATF+ TFH cell Activated IgM+ B cell ? IgG4+ memory B cell ?

IL-10
?

IgE+ plasmablast IgE+ LLPC

Clinical manifestations
Clinical manifestations Clinical manifestations
TFH cell and B cell expansion
contributes to lymphadenopathy (SLOs) • Raised serum IgG4 and IgE Incomplete decline in
and organ enlargement (TLOs) • IgG4 and IgE autoantibodies serum IgG4 post-RTX

Fig. 3 | T cell–B cell collaboration and immunoglobulin class switching in IgG4-related disease. Following germinal
centre reactions, affinity-​matured B cells leave the follicle and interact with IL-4-​secreting BATF+ T follicular helper (TFH)
cells. In conjunction with IL-10, which might be secreted by the same TFH cell subset, IgM+ B cells class-​switch to become
IgG4+ memory B cells and plasmablasts. IgE+ plasmablasts can develop directly from IgM+ B cells or indirectly from IgG4+
memory B cells. Short-​lived IgG4+ and IgE+ plasmablasts secrete self-​reactive IgG4 and IgE, respectively, circulate and
compete for survival niches within the bone marrow as long-​lived plasma cells (LLPCs). Both plasmablasts and LLPCs
contribute to the marked increases in serum IgG4 and IgE that are often found in IgG4-​RD. Question marks indicate
unproven areas of ongoing research. CD40L, CD40 ligand; ICOS, inducible T cell costimulator; ICOSL, ICOS ligand;
PD1, programmed cell death protein 1; PDL1, PD1 ligand 1; RTX, rituximab; SLOs, secondary lymphoid organs; TCR, T cell
receptor; TLOs, tertiary lymphoid organs.

708 | December 2020 | volume 16 www.nature.com/nrrheum


inadequately studied. Additional studies to characterize
the phenotype of the tissue-​infiltrating cells that are
responsible for IL-10 production are warranted.
In summary, TFH cells seem to be central to the
affinity-​maturation and oligoclonal expansion of IgG4
isotype-​s witched B cell responses in patients with
IgG4-​RD. In particular, the IL-4+BATF+ TFH cell subset,
which is abundantly present at the site of disease, has
been associated with IgG4+ B cell responses (Fig. 3). Both
IL-4 and IL-10 potentially have roles in directing IgG4
isotype switching; however, although evidence supports
a subset of TFH cells as the dominant source of IL-4 in
IgG4-​RD, research into the precise cellular source of
IL-10 within diseased tissues is ongoing.
Cytotoxic T cells. CD4+ T cells comprise a substantial
proportion of the immune cell infiltrate in IgG4-​RD,
being present in high numbers and distributed through-
out lesional tissues72. Early studies that interrogated
the T cell response in IgG4-​RD implicated T helper 2
(TH2) cell-​mediated inflammation as the central patho­
genic process. However, such conclusions were drawn
from the indirect evidence of overexpression of TH2
cell-​associated cytokines such as IL-4, IL-5 and IL-13
within affected tissues73,74. The same cytokines are
also expressed by cTFH2 cells54, and the cellular source
could not be distinguished by bulk tissue analyses in
these studies73,74. Subsequently, CD4+ effector memory
T cells — defined by the down-​regulation of CD27 and
CD62L — were investigated using population-​level gene
expression analysis9. Surprisingly, this study revealed a
dominant gene signature for CD4+ cytotoxic T lympho-
cytes (CTLs) rather than for TH2 cells. This gene sig-
nature included the upregulation of genes associated
with cytotoxicity, including granzymes, perforin and
granulysin, and lacked any features of TH2 cells. CD4+
CTLs were markedly expanded in the blood of patients
with IgG4-​RD and were shown to be highly clonally
expanded using T cell receptor (TCR) sequencing. In
stark contrast, the TH2 cells had a widely diverse TCR
repertoire suggestive of a lifetime of allergen exposure9.
A separate analysis demonstrated expansion of TH2 cells
in the blood exclusively in patients with IgG4-​RD who
had concurrent atopic disease75. These observations pro-
vided substantial evidence against a central role for TH2
cells in the pathogenesis of IgG4-​RD and brought CD4+
CTLs into focus. The authors of the initial studies that
suggested the importance of TH2 cell-​mediated immu-
nity in IgG4-​RD might have been misled by the impre-
cise methodology of whole-​tissue cytokine profiling
and by the potential confounding factor of concurrent
atopic disease. In fact, an association between allergic
disease and IgG4-​RD involving the salivary and lacri-
mal glands, rather than any other organ, was reported in
2020 (ref.76). However, the precise quantification of the
number of infiltrating TH2 cells within tissues affected
by IgG4-​RD has objectively demonstrated this cell type
to account for, on average, only 5–10% of all infiltrat-
ing CD4+ T cells, including those in salivary glands and
in patients with atopic disease9, making it unlikely that
TH2 cell-​mediated immunity has a major role in the
pathogenesis of IgG4-​RD.
NaTure RevIews | RheumaToloGy
Reviews
By contrast, the detailed quantification of tissue-​
infiltrating CD4+ T cells from tissues affected by IgG4-​
RD showed CD4+ CTLs to be the dominant CD4+ T cell
subset9. Subsequent work by another group of investiga-
tors confirmed the finding of CD4+ CTL expansion in
the blood of patients with IgG4-​RD and demonstrated
that the dominant CD4+ CTL clone in blood is also the
most abundant clone within the affected tissue of an
individual patient16. Circulating CD4+ CTLs in IgG4-​RD
decline in response to treatment-​induced remission,
and the number of tissue-​infiltrating CD4+ CTLs cor-
relates with the extent of organ involvement9,16,77. In the
context of chronic viral infection, an effector subset
of CD4+ CTLs has been defined by the upregulation of
CX3C-​chemokine receptor 1 (CX3CR1) and G protein
coupled receptor 56 (GPR56) and the downregulation of
CD127 (refs78–80). In IgG4-​RD, additional phenotyping
of CD4+ CTLs has revealed a CD27loCD28loCD57hi
sub­set of CD4+SLAMF7+ T cells to be the effector sub-
set with the most prominent signatures of cytotoxicity,
activation and metabolic activity17. This subset correlated
with a more severe clinical phenotype of IgG4-​RD and,
consistent with the effector phenotype in an anti-​viral
context, expressed CX3CR1 and GPR56 and had downreg-
ulated CD127 in patients with IgG4-​RD. The same study
also reported a novel role for CD8+ T cells17. Quantitation
of the tissue infiltrate of CD3+ T cells revealed that both
CD4+ T cells and CD8+ T cells abundantly infiltrate
tissues affected by IgG4-​RD. CD8+ T cells with an acti-
vated and cytotoxic phenotype were also expanded in the
blood of patients with IgG4-​RD and corresponded with
both disease severity and effector CD4+ CTL expansion.
The authors of the study propose an additive effect of
CD8+ CTLs in IgG4-​RD, in which naive CD8+ T cells are
activated by presentation of self-​peptides on MHC class I
molecules that would normally have been sequestered
but had not been because of the cytotoxic effect of CD4+
CTLs17. Additional studies are required to validate this
hypothesis.
Overall, the marked degree of clonal expansion of
CD4+ CTLs in patients with IgG4-​RD suggests that these
cells have undergone serial rounds of proliferation follow-
ing antigen presentation by MHC class II molecules. The
identification of the antigens that promote CD4+ CTL
expansion in patients with IgG4-​RD and the determina-
tion of whether different epitopes derived from the same
antigen are responsible for both CD4+ CTL and B cell
expansions remain important unanswered questions.
Fibrosis in IgG4-​RD
The mechanism by which CD4+ CTLs contribute to
fibrosis in tissues affected by IgG4-​RD currently remains
unproven. CD4+ CTLs express proteins known to acti-
vate fibroblasts, such as transforming growth factor-​β,
IFNγ and IL-1β, suggesting that these cells might directly
contribute to the excessive deposition of extracellular
matrix proteins by activating resident fibroblasts9. CD4+
CTL-​mediated cell death, directed by the presentation of
self-​antigen by MHC class II molecules on target cells,
has also been suggested as a mechanism leading to tissue
remodelling and fibrosis in the context of SSc81. CD4+
CTLs isolated from the blood of patients with IgG4-​RD
volume 16 | December 2020 | 709
Reviews
have the functional capacity to induce target cell cyto-
toxicity following TCR activation, and HLA-​DR-​positive
cells undergoing apoptotic cell death accumulate in tis-
sues affected by IgG4-​RD, suggesting that cell death is
promoted in an MHC class II-​restricted manner by CD4+
CTLs in IgG4-​RD17. In contrast to the study on SSc81, in
which endothelial cells accounted for a substantial pro-
portion of apoptotic cells, the target cells in IgG4-​RD
tissues were rarely of endothelial origin but rather of mes-
enchymal origin17. A potential mechanism of fibrosis in
IgG4-​RD could entail the antigen-​directed MHC class II-​
restricted killing of target cells by CD4+ CTLs paired
with the activation of fibroblasts to fill the space left by
the cytotoxic process82. In addition, given their relative
abundance in the affected tissues, it is possible that CD8+
CTLs contribute to apoptotic cell death in lesional tissue
in IgG4-​RD17. Additional studies are required to deter-
mine the antigen specificity of clonally expanded CD4+
CTLs and CD8+ CTLs and whether such antigens are
overexpressed by cells undergoing apoptotic cell death.
Activated B cells might also contribute to fibrogen-
esis in IgG4-​RD by exerting a direct pro-​fibrotic effect
through their expression of platelet-​derived growth fac-
tor (PDGF), a potent activator of fibroblasts83. In this
study, expression of PDGF by tissue-​infiltrating B cells
from patients with IgG4-​RD was confirmed by multi-
colour immunofluorescence, and B cell-​dependent,
PDGF-​mediated induction of collagen secretion by
fibroblasts was demonstrated by co-​culture experiments.
IgG4+ B cells also expressed lysyl oxidase homologue 2
(LOXL2), an enzyme known to crosslink type IV colla-
gens. These findings83 suggest a potential direct role for
activated B cells in tissue remodelling.
Polarized anti-​inflammatory ‘M2’ macrophages also
probably contribute to the tissue fibrosis associated
with IgG4-​RD84–86. A quantitative study84 of tissue from
salivary glands affected by IgG4-​RD demonstrated the
presence of abundant M2 macrophages that expressed
the pro-​fibrotic molecules IL-10 and CC-​chemokine
18. These cells preferentially accumulated within more
fibrotic portions of the diseased tissues and corre-
lated strongly with the degree of tissue fibrosis84. The
same investigators subsequently implicated another
pro-​fibrotic cytokine, IL-33, in IgG4-​RD tissue fibro-
sis and demonstrated abundant IL-33 expression by
M2 macrophages in tissues affected by IgG4-​RD85. M2
macrophages might also have a role in promoting
the survival of tissue-​infiltrating plasma cells by the
overexpression of the plasma cell survival factor APRIL86.
In summary, the fibrotic lesions in IgG4-​RD are
probably the result of complex interactions between
multiple cell types. In the current model, activated B cell
subsets, CD4+ CTLs and M2 macrophages produce
various pro-​fibrotic cytokines that activate fibroblasts,
thereby promoting the accumulation of collagens and
other extracellular matrix proteins in the tissue as
fibrotic lesions (Fig. 4).
Current treatment strategies for IgG4-​RD
Treatment strategies for IgG4-​RD are evolving quickly,
and a number of therapies that are based upon mecha­
nistic understanding of the disease are now under
710 | December 2020 | volume 16 www.nature.com/nrrheum
evaluation. In the following section, we discuss conven-
tional approaches to treating IgG4-​RD, before moving
onto some of the more promising targeted strategies.
Glucocorticoids
In 2015, a group of 42 experts on the clinical manage-
ment of IgG4-​RD from ten different countries who
represented eight different medicine subspecialties
published a consensus statement on the treatment of
this condition87. Glucocorticoids are typically viewed as
the first-​line treatment for IgG4-​RD, even though treat-
ment failures are common once these drugs are tapered
to low doses, and long-​term glucocorticoid treatment
leads to substantial toxicity. The numbers of activated
TFH cells, plasmablasts and CD4+ CTLs in the blood all
decline in response to treatment with glucocorticoids14,16.
Whereas the deleterious effects of glucocorticoids
on antigen presentation and T cell activation are well
established, knowledge regarding their direct effect on
B cells is much more limited88. Thus, the reduction in
circulating plasmablasts and serum IgG4 concentrations
following treatment with glucocorticoids is potentially
secondary to the decline in activated TFH cells and loss
of T cell-​dependent B cell responses. Although nearly
all patients with IgG4-​RD respond to glucocorticoids,
~40% either fail to achieve complete remission or
relapse within 1 year, even if glucocorticoids are con-
tinued at a minimum dose of 5 mg/day89–93. The issue
of glucocorticoid-​induced toxicity is compounded by
the high average age of patients with IgG4-​RD and
by the common complication of diabetes mellitus due
to pancreatic fibrosis secondary to the disease.
Conventional steroid-​sparing medications
Since the international consensus statement on the
management of IgG4-​RD was published in 2015, two
additional trials have been conducted exploring the
efficacy of the traditional disease-​modifying agents
low-​d ose cyclophosphamide and mycophenolate
mofetil (MMF)92,93. In the low-​dose cyclophosphamide
trial92, 102 patients with IgG4-​RD were allocated in a
non-​randomized fashion to receive either glucocorti-
coid monotherapy or combination therapy with gluco-
corticoids plus 50–100 mg/day of cyclophosphamide.
At 1-​year follow-​up, the investigators observed a 38.5%
relapse rate in the group that received glucocorticoids
alone, compared with a 12% relapse rate in those who
also received cyclophosphamide. Although the gluco-
corticoid regimen resulted in a new diagnosis of type II
diabetes mellitus in approximately 10% of the partici-
pants, low-​dose cyclophosphamide was reported to be
relatively well-​tolerated without any events of bone mar-
row suppression92. Two points from the study are worth
noting. First, the failure rate in the glucocorticoid treat-
ment arm was nearly 39%, despite the fact that patients
received up to 10 mg/day of prednisone for 1 year. This
finding strongly supports efforts to identify alternatives
to continuous glucocorticoid therapy. Second, the use of
cyclophosphamide in clinical practice must be weighed
against the potential long-​term consequences related to
this therapy, which have been well-​established in other
diseases94.
 Reviews

• Perforin Efferocytosis
• Granzyme
2 3
1

MHC TCR

Apoptotic target cell

Activated B cell Activated CD4+ T cell CD4+ CTLs M2 macrophage

• IL-1β
• TGFβ
4 5 • IFNγ TGFβ 6
PDGF

• IL-10
• CCL18
• IL-33
Fibroblast

Tissue fibrosis

Clinical manifestations Histopathology

• Tumor-like soft tissue mass • Lymphoplasmacytic infiltrate
• Organ enlargement • Storiform fibrosis

Fig. 4 | Potential mechanism of immune-mediated fibrosis in
IgG4-related disease. The fibrotic lesions in IgG4-​related disease are
probably the result of an interchange between activated B cells, CD4+
cytotoxic T lymphocytes (CTLs), M2 macrophages and fibroblasts. Activated
B cells migrate to inflamed tissues and present antigen to activated CD4+
T cells, promoting the expansion of the T cells and their differentiation into
CD4+ CTLs (1). Clonally expanded CD4+ CTLs target cells within the inflam-
matory milieu of lesions that have upregulated MHC class II molecules and
induce apoptotic cell death by releasing perforin and granzyme (2).
Transforming growth factor-​β (TGFβ)-​activated M2 macrophages clear
apoptotic cells by efferocytosis (3). Activated immune cells converge on
fibroblasts, promoting their activation via the release of platelet-​derived
growth factor (PDGF) from B cells (4), IL-1β, TGFβ and IFNγ from CD4+
CTLs (5) and IL-10, CC-​chemokine 18 (CCL18) and IL-33 from M2 macro­
phages (6). Secretion of extracellular matrix proteins by fibroblasts fills the
potential space generated by apoptotic cell death, resulting in tissue
remodelling and fibrosis. Clinically, cell proliferation and extracellular space
expansion result in tumour-​like masses and organ enlargement. Histo­
pathologically, these changes are seen as a lymphoplasmacytic infiltrate
and storiform fibrosis. TCR, T cell receptor.

In the randomized MMF trial, in which glucocorti- B cell-​targeted therapy

coid monotherapy was compared with combination ther-
apy of glucocorticoids plus MMF (1,000–1,500 mg/day),
the investigators reported an increased likelihood of
inducing remission and a reduced likelihood of experi-
encing disease relapse at 1-​year follow-​up in the MMF
group93. Although this study was limited in terms of the
investigators and patients not being blinded to treat­
ment group designation, 20% of the patients in the MMF
group experienced disease relapse, despite receiving
low-​dose prednisone (5–10 mg/day) as maintenance
therapy. This study93 also underscores the high failure
rate of treatment regimens that focus on glucocorticoids
and conventional synthetic DMARDs.
Data regarding other conventional steroid-​sparing
medications such as azathioprine, methotrexate, hydroxy­
chloroquine and tacrolimus are limited to retrospective
analyses, case series or case reports and are insuffi-
cient to guide clinical decision-​making. Although the
two prospective clinical trials discussed here92,93 have
contributed to our understanding of the efficacy of
conven­tional steroid-​sparing medications, the ability
to maintain durable, steroid-​free remission in IgG4-​RD
with these agents is limited.
B cell depletion with rituximab (which targets CD20)
was studied in IgG4-​RD following the early observations
of hypergammaglobulinaemia and plasmablast expan-
sion in patients with this disease18,95,96. The clinical effects
of this treatment are frequently dramatic and often pro-
duce a reduction in size, if not complete resolution,
of the tumour-​like masses characteristic of IgG4-​RD.
Masses that change little in size following rituximab
therapy probably reflect highly fibrotic, damaged organs,
yet even small changes (as can occur in the case of retro-
peritoneal fibrosis) can lead to substantial improvement
in symptoms. The durability of clinical remission fol-
lowing initial induction with rituximab varies between
patients, but in most patients, remission persists for at
least 6 months and can extend beyond 18 months97. This
therapy has also been studied for remission maintenance
and showed similarly outstanding efficacy98.
In addition to the excellent treatment responses with
regard to remission induction and maintenance18,98,
rituximab therapy also reduces serum IgG4 concentra-
tions, plasmablast numbers, CD4+ CTL numbers in the
blood and tissue, serum markers of fibrosis and tissue
myofibroblast activation9,26,95,99. Multiple mechanisms

NaTure RevIews | RheumaToloGy volume 16 | December 2020 | 711

Reviews

could account for these remarkable effects of B cell
depletion on fibrotic lesions in IgG4-​RD: depletion of
the activated subset of B cells that express PDGF and
LOXL2; reduced secretion of CCL4 (originating from
B cells), thereby limiting the recruitment of monocytes
to inflamed tissues83; reduced secretion of CCL5 (origi-
nating from B cells), thereby limiting the recruitment of
CD4+ CTLs to inflamed tissues83; or depletion of a major
source of antigen presentation to CD4+ CTLs at the site
of disease (Fig. 4). These clinical observations following
rituximab treatment confirm the central role of B cells
in the pathogenesis of IgG4-​RD.
Two other therapeutic approaches that target B cells
have been studied in the past few years. First, XmAb5871,
a monoclonal anti-​CD19 antibody engineered to have
markedly enhanced binding to the Fc portion of the inhib-
itory Fc receptor (FcγRIIB), results in the downregula-
tion of CD19+ B cells and has shown promise in IgG4-​RD
in a phase II trial100. Further studies validating the ther-
apeutic effect of XmAb5871 are warranted. Second, a
pilot trial of abatacept (a cytotoxic T lymphocyte protein
4 (CTLA4)–Fc fusion protein) has now completed enrol-
ment and is underway101. As can occur with glucocorti-
coid treatment, it is possible that the interference with
costimulation by abatacept would inhibit the differen-
tiation of naive CD4+ T cells into activated TFH cells and
thereby limit ongoing B cell activation, as has been sug-
gested in the context of rheumatoid arthritis102. Results
from this trial101 are anticipated by the end of 2020. Other
agents that target T cell-​dependent B cell responses,
such as anti-​CD40L or anti-​IL-4 antibodies, have not yet
been studied in IgG4-​RD. The efficacy of B cell deple-
tion and the extensive somatic hypermutation shown by
immunoglobulin sequencing of expanded plasmablast
clones provides a strong rationale for therapeutically
targeting T cell–B cell interactions in this disease.
In addition to the aforementioned studies, at least
three other clinical trials in IgG4-​RD that have adopted
different therapeutic approaches will shortly begin.
These include a worldwide trial of inebilizumab, a mono­
clonal anti-​CD19 antibody that has previously shown
substantial efficacy in neuromyelitis optica103. The
international, multi-​centre trial in IgG4-​RD will enrol
160 patients from dozens of countries across several con-
tinents, making it the first such trial in IgG4-​RD104. The
second study is a phase II trial of the Bruton’s tyrosine
kinase (BTK) inhibitor PRN1008, a promising thera-
peutic approach currently in advanced stages of testing
in pemphigus vulgaris105. The BTK inhibitor trial in
IgG4-​RD will be a 20-​patient phase II proof-​of-​concept
trial106. The investigational agent in this trial offers the
considerable advantages of being an oral agent that
does not deplete B cells. Finally, a US National Institutes
for Health-​f unded trial of elotuzumab, a monoclo-
nal anti-​SLAMF7 antibody, will also begin shortly107.
Elotuzumab was the first medication granted break-
through designation by the FDA for the treatment of
refractory multiple myeloma108. Elotuzumab will target
the crucial cellular interactions perceived to be respon-
sible for the pathogenesis of IgG4-​RD: namely, the
interactions between activated B cells and CD4+ CTLs.
Activated B cell subsets, plasmablasts and CD4+ CTLs all
express SLAMF7 on their surfaces, making elotuzumab
a rational therapeutic approach for this disease. Overall,
the rapid evolution from conventional treatment
approaches to mechanism-​based targeted potential new
therapies underscores how quickly insights into the
pathophysiology of IgG4-​RD have emerged.
Conclusions
IgG4-​R D is an immune-​mediated fibrotic disease
marked by an insidious tempo, the development of
tumour-​like masses, the accumulation of B cells, T cells
and macrophages enmeshed in fibrotic material within
lesions and a marked responsiveness to both glucocorti-
coids and B cell depletion. Investigations have described
oligoclonal expansions of both activated B cells and a
cytotoxic subset of CD4+ T cells, which are both consid-
ered to be central to the underlying disease process. A
specific IL-4-​secreting subset of CD4+ TFH cells is thought
to sculpt the maturation of B cells, possibly in conjunc-
tion with IL-10, leading to IgG4 class-​switching. A com-
pendium of experimental data describing self-​reactive
B cell responses is beginning to form and shed light on
the nature of IgG4-​RD. The role macrophages have in the
generation of fibrosis through interactions with adaptive
immune cells and fibroblasts is also a promising area
for further investigations. The expanding knowledge of
the pathophysiology of IgG4-​RD offers the possibility
of new therapeutic approaches in the near future.
Published online 16 September 2020

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Acknowledgements
The work of C.A.P. is supported by a Scientist Development
Award from the Rheumatology Research Foundation and a
New Investigator Award from the Scleroderma Foundation.
The work of J.H.S. is supported by an Autoimmunity Center
of Excellence award from the National Institute of Allergy and
Infectious Diseases (UM1 AI-144295).
Author contributions
The authors contributed equally to all aspects of the article.
Competing interests
C.A.P. declares no competing interests. J.H.S. declares that
he has received grants and consultation fees related to
IgG4-​related disease from Principia Biopharma, Roche and
Viela Bio.
Peer review information
Nature Reviews Rheumatology thanks H. Umehara, W. Zhang
and J. van Laar for their contribution to the peer review of
this work.
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