IgG4-Related Disease
Emanuele Bozzalla Cassione, M.D. and John H. Stone, M.D., M.P.H.
Abstract
Purpose of review—Remarkable insights have been gleaned recently with regard to the
pathophysiology of IgG4-related disease (IgG4-RD). These findings have direct implications for
the development of targeted strategies for the treatment of this condition.
Recent findings—Oligoclonal expansions of cells of both the B and T lymphocyte lineages are
present in the blood of patients with IgG4-RD. Oligoclonal expansions of plasmablasts are a good
biomarker for disease activity. An oligoclonally-expanded population of CD4+ cytotoxic T
lymphocytes is found not only in the peripheral blood but also at tissue sites of active disease. This
cell elaborates cytokines that may drive the fibrosis characteristic of IgG4-RD. T follicular helper
cells (Tfhc), particularly the Tfhc2 subset, appear to play a major role in driving the class switch to
IgG4 that typifies this disease. The relationship between malignancy and IgG4-RD remains an
area of interest.
Summary—Advances in understanding the pathophysiology of IgG4-RD have proceeded swiftly,
leading to the identification of a number of potential targeted treatment strategies. The completion
of classification criteria for IgG4-RD, an effort supported jointly by the American College of
Rheumatology and the European League Against Rheumatism, will further facilitate studies in this
disease.
Keywords
IgG4-related disease; plasmablast; CD4+ cytotoxic T lymphocyte; T follicular helper cell
Introduction
IgG4-related disease (IgG4-RD) is a chronic fibroinflammatory condition characterized by
tumefactive lesions, dense lymphoplasmacytic infiltrates, and abundant IgG4-bearing plasma
cells in the affected tissues. Serum IgG4 concentrations in patients’ sera are often elevated
dramatically, yet are normal in approximately one third of patients with
clinicopathologically-confirmed disease. IgG4-RD was described first in the pancreas – the
condition once termed “lymphoplasmacytic sclerosing pancreatitis” or sometimes just
“sclerosing pancreatitis”, among other designations
1
.
Please direct correspondence to: Dr. John H. Stone, Rheumatology Clinic / Yawkey 2, Massachusetts General Hospital, 55 Fruit
Street, Boston, MA. 02114, jhstone@mgh.harvard.edu, 617-726-7938.
Conflicts of interest
None.
HHS Public Access
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Curr Opin Rheumatol
. Author manuscript; available in PMC 2018 August 13.
Published in final edited form as:
Curr Opin Rheumatol
. 2017 May ; 29(3): 223–227. doi:10.1097/BOR.0000000000000383.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Common histological features are now known to characterize IgG4-RD in essentially every
organ in the body
2
. Broader experience with this condition, however, has led to the
recognition that the diagnosis is critically dependent upon careful correlation between
clinical, pathological, and often radiological findings. American College of Rheumatology/
European League Against Rheumatism Classification Criteria are now being developed
based on this recognition.
The immunopathogenesis of IgG4-RD remains incompletely defined. B cells at first and
subsequently T cells have been recognized to be key players in disease pathogenesis, but
their full contributions to IgG4-RD remain to be elucidated. Moreover, other elements of the
immune system also likely play important roles. Treatment of IgG4-RD to date has been
predicated primarily on glucocorticoids, but the growing recognition of this approach’s
shortcomings has spawned earlier consideration of either non-specific “disease-modifying”
agents or targeted treatments, both of which are intended as steroid-sparing strategies.
Role of B cells
A first reliable advance into the pathophysiology of IgG4-RD was made when preliminary
studies with rituximab (RTX) showed that B cell depletion induced disease remission and
led to improvement in tissue fibrosis
3
. Clinical improvement was accompanied by a
reduction in serum IgG4 levels. Further studies in IgG4-RD patients with active, untreated
disease identified an oligoclonally-expanded population of circulating CD19+CD20-
CD27+CD38+bright plasmablasts, cells that are the precursors of tissue-resident, antibody-
producing plasma cells). Flow cytometry studies following treatment demonstrated that
clinical improvement correlated with selective depletion of this B cell subpopulation
4
. Many
patients achieved clinical remissions without normalizing their serum IgG4 concentrations,
even though substantial declines in serum IgG4 levels following treatment were the rule.
The B cell compartment of patients with IgG4-RD has been studied extensively because the
striking serum IgG4 elevation in many patients and the abundance of IgG4+ plasma cells at
sites of disease initially suggested the possibility of an underlying lymphoproliferative
condition. The latter hypothesis has then been excluded because of failure to identify
monoclonal plasma cells populations in the affected tissues
2
, but the issue of a potential
relationship between malignancy and IgG4-RD risk – and vice versa – remains an important
topic.
At least two lines of evidence from the humoral immune system have suggested that an
antigen-driven immune response is present in IgG4-RD. Studies on the cerebrospinal fluid
of subjects with IgG4-related pachymeningitis revealed the presence of oligoclonal IgG4
5
.
In addition, next-generation sequencing analysis on tissue biopsy samples and on the
peripheral blood of IgG4-RD patients demonstrated oligoclonal expansions of somatically
hypermutated IgG4
+
B cell clones
4
.
The oligoclonally-expanded B cells were identified by flow cytometry as being
CD19
+
CD20
−
CD27
+
CD38
+
plasmablasts. Plasmablasts arise in germinal centres following
affinity maturation from naïve CD20+ precursors. Once in the bloodstream, plasmablasts
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differentiate into antibody-secreting short- or long-lived plasma cells, accounting for the
excess IgG4 production in this disease
6
. Plasmablast concentrations in the blood correlate
well with disease activity, decreasing sharply after RTX-induced remission and reemerging
during relapse. It is worth noting that the plasmablasts reemerging during disease relapses
express distinct V-J repertoires compared to samples from the same patients before their
initial treatment. This phenomenon, known as “clonal divergence”, further supports the
hypothesis of hypermutation driven by the selection of specific antigens.
Role of T cells
T cell responses have long been considered to be central to the pathophysiology of IgG4-
RD, but the focus of interest within the T cell population has shifted within recent years. Th2
immune responses were once believed critical to IgG4-RD pathways, partly because of the
high frequency of atopic symptoms observed in many patients with IgG4-RD
7
and partly
because of the detection of mRNA from cytokines frequently linked to Th2 responses, e.g.,
interleukin (IL)-4, IL-5, and IL-13
8
. More recent studies, however, have demonstrated
expansions of Th2 cells only in the circulation of IgG4-RD patients with an atopic history,
not in those without histories of atopy
9
. It seems, therefore, that despite initial appearances
the role of Th2 cells in IgG4-RD is marginal. Other subpopulations of T cells, however, are
involved more directly in IgG4-RD pathogenesis.
A novel population of effector memory CD4+ T cells with cytotoxic function (CD4+ CTLs)
has then been described in IgG4-RD patients
10
. Substantial evidence suggests that this
population of cells plays an important role in the pathophysiology of this disease. CD4+
CTLs are expanded in both the peripheral blood and in affected organs of IgG4-RD patients.
Moreover, together with circulating plasmablasts (though at a slower rate), these CD4+CTLs
decline following RTX treatment, supporting the concept that cells of the B and T cell
lineages cooperate closely in mediating this condition
10
.
Cytotoxicity associated with CD4+ T helper lymphocytes is a concept that has emerged
progressively in the past few years. The concept contrasts with the traditional view that
cytotoxic T cells arise only from MHC class I restricted CD8+ T lymphocytes. During
thymic development, lineage commitment towards CD4+ or CD8+ T cell fate is driven by
the action and counteraction of the key transcription factors ThPOK and Runx3,
respectively
11
. CD4+CTLs seem to represent highly differentiated, antigen-experienced
(memory) T cells with features of both CD4+ and CD8+ T lymphocytes (though there are
CD8-)
12
. It is likely that this cell population arises from chronic antigenic stimulation.
Indeed, in response to repeated antigenic stimulation, ThPOK is downregulated, resulting in
a cytolytic gene expression program in activated CD4+ T cells, with differentiation into
MHC class II-restricted CD4+ CTLs and an effector cell phenotype
11
.
The CD4+ CTLs identified express high levels of CD11a and CD11b integrins, and CD45
isoforms -RO and -RB. They lack the costimulatory receptors CD27, CD28, the chemokine
receptor CCR7, and CD45-RA. Small numbers of CD4+ CTLs can be detected in the blood
of healthy individuals
13
, and they significantly increase during chronic viral infections (such
as cytomegalovirus
14
, Epstein–Barr virus
15
, human immunodeficiency virus
13
),
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malignancies
16
, and autoimmune disorders
17
. CD4+ CTLs seem to bear protective functions
such as control of infected cells or elimination of transformed cells, thanks to their cytolytic
MHC class II restricted action. Nevertheless, the accumulation of CD4+ CTLs in the setting
of autoimmune conditions such as rheumatoid arthritis
18
and inflammatory bowel disease
19
suggests that these cells might also contribute to chronic inflammation. Indeed, CD4+ CTLs
numbers correlate with disease severity in rheumatoid arthritis and ankylosing spondylitis,
and decrease after treatment with anti-TNFalpha agents
20
.
In summary, the CD4+ CTLs identified in the context of IgG4-RD represent the most
carefully phenotyped such cell studied to date. The cell appears to have significant potential
to contribute to chronic inflammation of a variety of forms.
Role of T follicular helper cells
The powerful evidence of class-switching in IgG4-RD has led to substantial interest in the
role of T follicular helper (Tfh) cells in this condition. Tfh cells are known to be involved in
the differentiation of B cells during their development, and to contribute significantly to
class switching
21
. Akiyama et al.
22–23
have reported that among Tfh cells subsets, Tfh2 cells
induce the differentiation of naïve B cells into plasmablasts, subsequently promoting the
production of IgG4 in active, untreated IgG4-RD. Circulating Tfh2 cells are expanded IgG4-
RD and their concentrations are linked to disease activity, the concentrations of circulating
plasmablasts, and serum IgG4 levels.
In contrast, although circulating activated Tfh1 cells were also found to be expanded in
IgG4-RD, their levels correlated with disease activity but not with serum IgG4 levels. These
findings support the hypothesis of a greater role for Tfh2 cells in the class switch observed
in IgG4-RD. It is known that Tfh cells in germinal centers cooperate with B cells in the
formation and antibody production. Therapy with glucocorticoids did not affect Tfh2 cell
counts, but did result in a decrease in numbers of plasmablasts and levels of serum IgG4 and
IL-4. Because IL-4 is believed to be produced by Tfh2 cells and not by the other Tfh cell
subsets, it is possible that glucocorticoid treatment affects the function and not the number
of these cells.
Plasmacytoid dendritic cells
Plasmacytoid dendritic cells (pDCs) were shown to be important in the development of
pancreatic inflammation through production of IFN-alpha
24
. Autoimmune pancreatitis (AIP)
in IgG4-RD patients is associated with an infiltration of pDCs. Peripheral pDCs from IgG4-
RD patients were shown to enhance IgG4 antibody production by cells through IFN-alpha
mediated signaling. Demonstration of a role for IFN-alpha in this disease comes from
studies conducted on experimental AIP models in which regression of the inflammation was
seen to occur with depletion of IFN-alpha production or signaling.
Final proof of its relevance in AIP in humans requires studies with pDC-depleting antibodies
(Ab) or neutralizing IFN-alpha receptor antibodies. In addition to pDCs, inflamed pancreata
also harbor NETs. These structures have been seen to be involved in the activation of
pDCs
25–26
. In fact, co-cultures of pDCs and neutrophils, forced to express NETs by
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monosodium urate (MSU) crystals or anti-lacto-ferrin (LF) Ab (NET component protein)
showed increased production of IFN-alpha and the B lymphocyte activating factor known as
BAFF. Moreover, when these cells were co-cultured together with B cells, they led to
increases in IgG4 production.
Some data do support the notion that anti-LF Ab contribute to IgG4-RD. Serum anti-LF Ab
titers, especially those of the IgG4 subclass, were elevated in the serum of IgG4-RD patients.
In contrast, there has to date been no demonstration of MSU deposition in the IgG4-related
pancreatic lesion.
Therapy
A group of international experts published a Consensus Guidance Statement on the
Management of IgG4-RD
27
. This effort grew out of the Second International Symposium on
IgG4-RD and Associated Conditions, held in 2014. The Third such Symposium is scheduled
for 2017 and it is there that the ACR/EULAR Classification Criteria will be completed.
RTX was used initially in patients who did not respond to glucocorticoids, conventional
steroid-sparing agents, or both, under the assumption that B-cell depletion might ameliorate
the condition through decreasing serum IgG4 concentrations
28
. The fundamental assumption
underlying this approach now seems not entirely true. Indeed, careful mechanistic studies of
patients with IgG4- RD treated with RTX have led to novel insights about the
pathophysiology of this disorder. First, B-cell depletion targets the subset of plasma cells
that produce IgG4 in IgG4-RD
29
, by depleting all circulating CD20- positive B cells, the
precursors of short-lived plasma cells. Second, IgG4+ plasmablasts
(CD38+CD27+CD19+CD20-IgG4+ cells) seem to be a good biomarker for IgG4-RD and
are superior to serum IgG4 concentrations for diagnosis and monitoring of disease activity
30
.
Yamamoto et al.
31
described the use of abatacept (CTLA4-Ig) to treat one patient with IgG4-
RD whose condition had been refractory to RTX. Given the recognition of the importance of
T cells in this disease now emerging, greater attention to treatment strategies directly
targeting T cell function may be of value.
Tumor association
Discussions of a possible link between IgG4-RD and malignancy have emerged recently.
Evidence against such a relationship, however, came from a retrospective study showed that
history of malignancy was 2.5 times more likely in IgG4-RD patients compared to the
general US population
32
. Morever, a history of malignancy was three times more common
among IgG4-RD patients than among control patients in a case–control analysis performed
as part of the same study. Prostate cancer was the most common malignancy in both the
IgG4-RD patients and the controls, a point not surprising given the demographics of IgG4-
RD and its tendency to afflict middle-aged to elderly males. It is worth noting, however, that
lymphoma was responsible for 19% of the malignancies in the IgG4-RD cohort, compared
to only 4% in the control cohort. This data may suggest a possible interplay between the
immune dysregulation found in IgG4-RD and lymphomagenesis.
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