IgG4 Related Disease

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IgG4-Related Disease

Article  in  Annual Review of Pathology Mechanisms of Disease · October 2013


DOI: 10.1146/annurev-pathol-012513-104708 · Source: PubMed

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PM09CH14-Stone ARI 24 September 2013 16:52

V I E W
E Review in Advance first posted online
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on October 2, 2013. (Changes may

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still occur before final publication
online and in print.)
C E
I N

A
D V A

IgG4-Related Disease
Vinay S. Mahajan,1 Hamid Mattoo,1
Vikram Deshpande,2 Shiv S. Pillai,1
and John H. Stone3
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

1
Cancer Center, 2 Department of Pathology, 3 Division of Rheumatology, Allergy, and
Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical
School, Boston, Massachusetts; email: pillai@helix.mgh.harvard.edu, jhstone@partners.org
by Harvard University on 12/03/13. For personal use only.

Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47 Keywords


The Annual Review of Pathology: Mechanisms of
Disease is online at pathol.annualreviews.org storiform fibrosis, IgG4-related disease, rituximab, obliterative
phlebitis, Fab arm exchange, autoimmune pancreatitis
This article’s doi:
10.1146/annurev-pathol-012513-104708
Abstract
Copyright  c 2014 by Annual Reviews.
All rights reserved Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-
mediated condition that can affect almost any organ and is now being
recognized with increasing frequency. IgG4-RD is characterized by a
lymphoplasmacytic infiltrate composed of IgG4+ plasma cells, stori-
form fibrosis, obliterative phlebitis, and mild to moderate eosinophilia.
The diagnosis of IgG4-RD unifies many eponymous fibroinflamma-
tory conditions that had previously been thought to be confined to
single organs. IgG4-RD lesions are infiltrated by T helper cells, which
likely cause progressive fibrosis and organ damage. IgG4 antibodies are
generally regarded as noninflammatory. Although autoreactive IgG4
antibodies are observed in IgG4-RD, there is no evidence that they are
directly pathogenic. Rituximab-induced B cell depletion in IgG4-RD
leads to rapid clinical and histological improvement accompanied by
swift declines in serum IgG4 concentrations. Although IgG autoanti-
bodies against various exocrine gland antigens have been described in
IgG4-RD, whether they are members of the IgG4 subclass is unknown.
The contribution of autoantibodies to IgG4-RD remains unclear.

315

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PM09CH14-Stone ARI 24 September 2013 16:52

INTRODUCTION IgG4-RD has also been observed in several


subjects formerly diagnosed with conditions
The concept of immunoglobulin G4 (IgG4)-
that were regarded as separate, organ-specific
Storiform fibrosis: related disease (IgG4-RD) as a novel clini-
a histological pattern entities. For instance, a subset of patients
cal entity emerged over the first 10 years of
characterized by previously considered to have primary scle-
the twenty-first century (1). Crucial to the
irregular, loosely rosing cholangitis are now considered to have
identification of this disease were the obser-
arranged whorls on IgG4-RD. This group of patients is much more
low-power light vations by Hamano, Kamisawa, and others (2–
likely to respond to immunosuppression (e.g.,
microscopy, akin to a 4) that several seemingly unrelated conditions
straw blanket glucocorticoid treatment) than are patients
encompassing a wide range of organs shared
with primary sclerosing cholangitis. Such
TIN: two characteristics: (a) elevations in serum
tubulointerstitial patients, now considered to have IgG4-related
IgG4 concentrations and (b) a set of unique
nephritis sclerosing cholangitis, also respond well to
histopathological features. The hallmark histo-
B cell depletion.
logic characteristics of IgG4-RD are a lympho-
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

In this review, we consider a number of


plasmacytic infiltrate, storiform fibrosis, oblit-
novel and intriguing issues regarding the
erative phlebitis, and mild to moderate tissue
pathogenesis of IgG4-RD. For now, we cate-
eosinophilia˜(Figure 1) (5, 6).
gorize this poorly understood syndrome as an
by Harvard University on 12/03/13. For personal use only.

IgG4-RD can involve almost any organ. The


autoimmune disease, given the evidence for au-
clinical, radiologic, and histopathologic fea-
toantibodies in IgG4-RD. The response of the
tures of the disorder in the pancreas, biliary
disorder to immunosuppressive therapy sup-
tree, salivary glands, periorbital tissues, kidneys,
ports an autoimmune or other chronic inflam-
lungs, lymph nodes, meninges, aorta, breast,
matory etiology. However, there is no evidence
prostate, thyroid, pericardium, and skin have
that the autoantibodies described so far in
been catalogued (7, 8). This diagnosis unifies
IgG4-RD contribute directly to pathogenesis.
many diverse conditions, previously thought to
IgG4-RD has a predilection for middle-aged
be unrelated to each other, as a part of the IgG4-
to elderly men, whereas most autoimmune
RD spectrum. These conditions include many
disorders develop in females who are younger
cases of orbital pseudotumor, Ormond’s disease
than the typical IgG4-RD patient (1). The
(retroperitoneal fibrosis), Riedel’s thyroiditis,
limited genetic studies performed to date have
Küttner’s tumor, Mikulicz’s disease, and mul-
indicated a major histocompatibility (MHC)
tifocal fibrosclerosis, as well as subsets of in-
class II bias in IgG4-RD patients of Asian
terstitial lung disease, tubulointerstitial nephri-
ancestry, but the numbers in these studies are
tis (TIN), hypertrophic pachymeningitis, and
small, leading to unreliable odds ratios (9).
other entities (Table 1). Understanding the
The possibility of a microbe-driven immune
pathogenesis of this disease could lead to novel
response underlying this disorder has not been
treatment approaches that would be applicable
formally excluded.
to this entire spectrum of disorders.

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→
Figure 1
Histopathological hallmarks of immunoglobulin G4–related disease (IgG4-RD). (a) The storiform pattern of fibrosis depicted in this
image from a patient with IgG4-RD involving the anterior neck adjacent to the thyroid is typical of IgG4-RD. (b) A high-power view of
the image in panel a, showing dense fibrosis within which lymphocytes, plasma cells, and occasionally eosinophils are embedded.
(c) Eosinophilic angiocentric fibrosis involving the orbital soft tissue. The concentric perivascular fibrosis is a characteristic feature of
this variant of IgG4-RD. Note the marked increase in eosinophils. (d ) A low-power view of IgG4-related pulmonary disease
demonstrates a diffuse and dense lymphoplasmacytic infiltrate with only rare residual air spaces (asterisk). Numerous lymphoid
aggregates are present. Note the obliterative phlebitis (arrowheads), which is typical of IgG4-RD. (e) An immunoperoxidase stain for
IgG4 (of the case shown in panel d ) shows a diffuse and marked increase in IgG4+ plasma cells, which is typical of IgG4-RD. ( f ) An
elastin stain performed on an obliterated venous channel. ( g) An immunoperoxidase stain for CD3 shows that the T cells are more
diffusely distributed. (h) An immunoperoxidase stain for CD20 highlights the B lymphoid aggregates.

316 Mahajan et al.

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PM09CH14-Stone ARI 24 September 2013 16:52

a b
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

c d *
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e f

g h

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Autoimmune disorders commonly involve investigators described several organ-specific


polarized T cells of the T helper 1 (Th1) or conditions that, until the twenty-first century,
Th17 subset (10). In contrast, IgG4-RD is were viewed as individual disease entities rather
Alternatively
activated characterized by an inflammatory and fibrotic than aspects of a larger systemic condition (15–
macrophages: process that appears to be driven by Th2 cells 17). Mikulicz’s disease, a dramatic enlargement
macrophages activated or a combination of Th2 cells and regulatory of the lacrimal, parotid, and submandibular
by Th2 cytokines that T cells (Treg cells) (11). Investigators have de- glands (15), was erroneously linked to Sjögren’s
bear a distinctive
duced the potential role of these categories of syndrome in the 1950s and was not clearly
phenotype and play a
role in tissue repair T helper cells in the pathogenesis of IgG4-RD, separated from that condition until 2005
but to date no direct evidence exists to support (18–20). Similarly, the links between Küttner’s
AIP: autoimmune
pancreatitis the notion that T cells drive inflammation in tumor, Riedel’s thyroiditis, and an underlying
this disease. Both Th2 cells and Treg cells can systemic condition were not established until
support the induction of alternatively activated more than 100 years after they were initially
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

macrophages (12, 13). However Th1 cells can described (21, 22).
also drive fibrosis, as seen in disorders such as Evidence of IgG4-RD comes from multiple
tuberculosis and Crohn’s disease. We consider case reports and case series published between
it likely that the storiform fibrosis in this disease the 1960s and the year 2000, particularly with
by Harvard University on 12/03/13. For personal use only.

results from the induction of an exaggerated, reference to “autonomous pancreatitis” (AIP)


aberrant repair process mediated either by (23), sclerosing pancreatitis (24–26), multifocal
Th1 cells or possibly by Th2-dependent, profi- systemic fibrosis (27, 28), Ormond’s disease
brotic, alternatively activated macrophages and (29), orbital pseudotumor (30), and others. In
myofibroblasts (14). the 1990s, Japanese investigators described
The role of IgG4 itself in the disease tumefactive lesions in the pancreas that mim-
process remains unclear. IgG4 antibodies are icked cancer in their clinical presentation and
generally believed to be noninflammatory gross pathology but defied ready categorization
immunoglobulins with a low affinity for Fc into known disease classifications (31, 32).
receptors (FcRs) and C1q. These low affinities Multiple descriptive names for this pancreatic
impair the ability of IgG4 antibodies to induce condition entered the literature before the cur-
phagocyte activation, antibody-dependent rently accepted term—type 1 (IgG4-related)
cellular cytotoxicity, or complement-mediated AIP—was established (7). In 2001, Hamano
damage. Thus, the actual role of IgG4 in the et al. (2) made the seminal observation that
disease process remains to be clarified: Does it sclerosing pancreatitis was associated with
have a primary or important secondary effect in elevated serum concentrations of IgG4.
the disease? Or do the increased concentrations Within 2 years of the report of elevated
of IgG4 in serum and IgG4-bearing plasma serum IgG4 concentrations, the cardinal
cells in tissue lack pathogenic significance? Are histopathologic and immunostaining charac-
they merely the result of other effector path- teristics in tissue had been identified, not only
ways that are more central to the inflammation in the pancreas but also in extrapancreatic
and damage of this disease (such as polarized organs of patients with AIP. Kamisawa et al.
T helper/Treg cytokines)? We consider such (3, 4) first proposed the existence of a systemic
questions in the course of this review. condition occurring in the context of AIP
in which pathological features identical to
those in the pancreas were also observed in
HISTORICAL CONTEXT extrapancreatic organs.
The roots of IgG4-RD in the medical litera- The first decade of the twenty-first cen-
ture can be tracked clearly to the nineteenth tury was remarkable for the identification of
century, but it is likely that the disease existed IgG4-RD in essentially every organ of the
far earlier. Nineteenth-century European body (8). Many disorders previously believed

318 Mahajan et al.

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Table 1 Conditions once considered unrelated that are now recognized as part of the IgG4-RD
spectrum
Condition Affected organ(s) or tissue(s)
Eosinophilic angiocentric fibrosis Orbits, upper respiratory tract
Fibrosing mediastinitis Mediastinum
Hypertrophic pachymeningitis Dura mater
Idiopathic hypocomplementemic tubulointerstitial Kidney
nephritis with extensive tubulointerstitial deposits
Inflammatory aortic aneurysm Aorta
Inflammatory pseudotumor Orbits, lungs, kidneys, and other organs
Küttner’s tumor Submandibular glands
Mikulicz’s syndrome Salivary and lacrimal glands
Multifocal fibrosclerosis Orbits, thyroid gland, retroperitoneum,
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

mediastinum, and other tissues and organs


Periaortitis and periarteritis Aorta and large blood vessels
Retroperitoneal fibrosis (Ormond’s disease) Retroperitoneum
by Harvard University on 12/03/13. For personal use only.

Riedel’s thyroiditis Thyroid


Sclerosing mesenteritis Mesentery
Sclerosing pancreatitis Pancreas

Abbreviation: IgG4-RD, immunoglobulin G4–related disease.

to exclusively affect single organs were found in most organ systems is on the order of 3.5 to
to be linked by common histopathologic 1 (34). Some variability exists in the sex distri-
and immunohistochemical features. Several bution from organ to organ exists, however; if
conditions known by eponyms or acronyms one considers disease affecting the organs of the
have therefore been renamed over the past head and neck alone, for example, the male-to-
few years to reflect the new appreciation for female ratio is closer to 1 to 1 (5).
these relationships (Table 1) (33). A number The epidemiology of IgG4-RD remains
of different names have been employed to poorly described, partly because of the substan-
describe IgG4-RD during this time. In 2010, tial challenges in recognition and diagnosis,
a group of Japanese investigators chose the given that many practitioners are only now
consensus name IgG4-RD (7). This name was becoming aware of this condition. The only
adopted by the First International Symposium disease subset that has been studied in any
on IgG4-RD (33). detail with regard to epidemiology is AIP (34).
The incidence and prevalence of IgG4-RD are
probably substantially underestimated because
GENERAL CLINICAL, recognition of this condition has begun to
EPIDEMIOLOGIC, AND GENETIC increase only within the past decade.
CHARACTERISTICS IgG4-RD tends to form tumefactive lesions
The typical patient with IgG4-RD is a middle- (Figure 2). As a result, patients are often
aged to elderly male. This disease predilection suspected of having a malignancy. Many AIP
for males contrasts strikingly with classic au- patients have undergone Whipple procedures
toimmune diseases such as systemic lupus ery- because of presumed pancreatic cancer. IgG4-
thematosus and Sjögren’s syndrome, in which RD presents in a subacute fashion in most pa-
females usually outnumber males by 9 to 1. tients, without the rapid onset of constitutional
The overall male-to-female ratio in IgG4-RD symptoms such as fever. A minority of

www.annualreviews.org • IgG4-Related Disease 319

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PM09CH14-Stone ARI 24 September 2013 16:52

patients—probably fewer than 10%—have


a b weight loss, fevers, dramatic elevations of acute-
phase reactants, and other manifestations of
systemic inflammation. IgG4-RD typically
comes to medical attention because of single-
organ involvement, but more widespread
disease is often observed following a detailed
workup. Involvement by IgG4-RD of different
organs can occur either simultaneously or
metachronously, with the emergence of one
newly affected organ following another.
Spontaneous improvements are reported
c in a minority of patients, but the majority
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

appear to have slow, indolent progression.


The link between IgG4-RD and previous
tumefactive lesions in certain organs may not
be identified until the diagnosis is established
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through investigation of the index organ. By


the time the correct diagnosis is made, many
patients have already undergone biopsies of
other organs revealing reactive changes (e.g.,
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 2
d e Immunoglobulin G4–related disease (IgG4-RD)
tends to form tumefactive lesions. (a) Bilateral
enlargement of the parotid and submandibular
glands in a 48-year-old man with IgG4-RD. He also
had lacrimal gland disease; in another era, he would
have been diagnosed with Mikulicz’s disease.
(b) Lacrimal gland enlargement in a 56-year-old
man. (c) Proptosis and exotropia of the left eye in a
62-year-old man. The etiology of his eye lesion is an
orbital pseudotumor associated with IgG4-RD.
(d ) Coronal computed tomographic image of the
patient shown in panel c. In addition to his orbital
pseudotumor, he had left maxillary sinusitis (evident
in this image) and proteinuria caused by
f g tubulointerstitial nephritis. For these reasons, he was
suspected to have granulomatosis with polyangiitis
(formerly known as Wegener’s granulomatosis) for
many months. (e) IgG4-related thyroid disease,
formerly termed Riedel’s thyroiditis. The thyroid
gland has a hard, woody feel. The patient required
urgent surgery because of encroachment of the
pseudotumor on the structures of her anterior neck,
including her airway. ( f ) A gross image from a
surgical resection of IgG4-related thyroiditis. The
grayish white mass represents IgG4-RD. Note the
adjacent thyroid parenchymal tissue. (g) Low-power
image of a section from the case depicted in panel f,
showing that the inflammatory mass was located
adjacent to, and focally infiltrated, the thyroid gland.

320 Mahajan et al.

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PM09CH14-Stone ARI 24 September 2013 16:52

in lymph nodes) or nonspecific inflammation, ticularly characteristic of IgG4-RD (21).


typically a lymphoplasmacytic infiltrate. IgG4-related sialadenitis must be distinguished
To date, no clear genetic predisposition has from Sjögren’s syndrome, which has a predilec-
been identified. Potential genetic links to HLA tion for the parotid glands and does not involve
genes and the FcRL3, CTLA4, and KCNA3 the submandibular glands in isolation (39).
loci have been suggested in small studies Sjögren’s syndrome, a disorder that is clearly
from Japan (35–38). IgG4-RD has now been immunologically distinct from IgG4-RD, is
reported across the world, however, and more characterized by Th1/Th17 polarization (40,
extensive studies of patients from multiple 41). Biopsy of the minor salivary glands can be
ethnic backgrounds should be performed diagnostic of IgG4-RD even if the oral mucosa
before any conclusions regarding genetic has an unremarkable clinical appearance (42).
susceptibility can be drawn.
A proportion of patients have symptoms Orbital and periorbital lesions. Multiple
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

that overlap with allergic conditions. Whether presentations of IgG4-RD involve the orbits
this actually exceeds the frequency of allergic and orbital adnexa. The most common is
individuals in the population at large is un- lacrimal gland enlargement (dacryoadenitis)
clear. Some patients have longstanding histo- (Figure 2b), which often occurs in the context
by Harvard University on 12/03/13. For personal use only.

ries of allergy (rhinitis, nasal polyps, asthma, of submandibular or parotid gland enlarge-
mild eosinophilia) before the full IgG4-RD dis- ment (i.e., Mikulicz’s disease) but may occur in
ease phenotype emerges or is recognized. Mild isolation. Tumefactive lesions of the orbital or
to moderate peripheral eosinophilia, sometimes periorbital tissues (orbital pseudotumors) that
involving up to 20% or more of the circulating do not include the lacrimal gland also occur.
white blood cells, is occasionally observed. Ele- These usually lead to some degree of proptosis,
vations in serum IgE concentration, sometimes which is sometimes dramatic (Figure 2c,d ).
higher than 10 times the upper limit of nor- These mass lesions can extend into the
mal, are also observed. Whether there is a role pterygopalatine fossa and infiltrate along the
for allergens in the pathogenesis of IgG4-RD trigeminal nerve, mimicking malignancies on
remains unclear. radiologic studies (43). Mass lesions can also ex-
tend into the cavernous sinus or cause thicken-
INDIVIDUAL ORGAN SYSTEM ing of the palpebral fissure. Other ophthalmic
MANIFESTATIONS manifestations include orbital myositis, a pain-
less thickening of the extraocular muscles, and
The clinical features are discussed in the con- dacryocystitis.
text of the section of the body in which they oc-
cur: the head and neck, the chest, the abdomen, Thyroid gland. An association between
the retroperitoneum, and other sites of disease Riedel’s thyroiditis and multifocal systemic
presentation. fibrosis was first recognized in the 1960s (27).
Although IgG4-RD is now believed to account
Head and Neck for most cases of multifocal systemic fibrosis,
We describe below some of the manifestations the direct link between IgG4-RD and Riedel’s
of disease involving anatomically defined areas thyroiditis was not firmly established until 2009
of the head and neck. (22). The thyroid gland enlargement caused by
Riedel’s thyroiditis can lead to neck pain, dys-
Salivary gland involvement. The sub- pnea, dysphagia, and dysphonia. The thyroid
mandibular, parotid, and sublingual glands are becomes enlarged and sclerotic over time and
often involved, usually bilaterally (Figure 2a). can extend aggressively into adjacent tissues,
Prominent submandibular gland involvement, threatening vital organs in the anterior neck
formerly known as Küttner’s tumor, is par- region (Figure 2e). A disorder characterized

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as a subset of Hashimoto’s thyroiditis, known (Figure 3a), and destructive lesions in the
as fibrosing thyroiditis, also appears to be part middle ear and facial bones have been reported.
of the IgG4-RD spectrum in some cases (44).
Neck lesions adjacent to the thyroid gland have
Intracranial disease. The two principal
also been described (Figure 2f,g).
intracranial manifestations of IgG4-RD are
pachymeningitis and hypophysitis. IgG4-RD
generally does not affect the brain parenchyma.
Ear, nose, and throat. IgG4-RD can cause
Pachymeningitis may involve either the
diffuse inflammation in the pharynx, hypophar-
intracranial meninges or the intraspinal
ynx, and Waldeyer’s ring and is frequently
meninges; patients with this condition present
associated with mass lesions. Tracheal inflam-
with headache, radiculopathy, cranial nerve
mation and vocal cord involvement have also
palsies, or other symptoms resulting from spinal
been described. Further studies of the potential
cord compression. This disease also tends to
relationship between IgG4-RD and idiopathic
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

form mass lesions in the meninges, consistent


subglottic stenosis or isolated tracheal inflam-
with the term hypertrophic pachymeningitis
mation should be performed. The allergic
(45). Radiologic features of IgG4-related
phenomena that occur in a large subset of
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hypophysitis include a thickened pituitary stalk


patients with IgG4-RD—allergic rhinitis, nasal
or mass formation on the stalk, swelling of the
polyps, chronic sinusitis, nasal obstruction,
pituitary gland, or mass formation within the
and rhinorrhea—often manifest most promi-
pituitary (Figure 3b). The resulting clinical
nently in the ear, nose, and throat region.
manifestations depend on which hormonal axis
The pathophysiologic significance of this
is interrupted.
anatomic distribution is not well understood,
but a pathogenic trigger such as a microbial
infection may convert a preexisting allergic
response into IgG4-RD. Studies of the oral and Chest
gut microbiome that are designed to explore We describe below some of the manifestations
potential microbial triggers of IgG4-RD are of disease involving anatomically defined areas
warranted. Mass lesions can occur in the sinuses of the chest.

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→
Figure 3
Selected radiologic and pathologic features of immunoglobulin G4–related disease (IgG4-RD).
(a) Magnetic resonance imaging study demonstrating a large mass in the left maxillary sinus that enhances
with gadolinium. (b) Magnetic resonance imaging study of the brain showing enlargement and enhancement
of the pituitary gland and its stalk. The walls of the sphenoid sinus are also thickened and enhance with
contrast. (c) Bronchovascular bundle lesion in IgG4-RD involving the lung. IgG4-RD has a predilection for
the bronchovascular bundle regions within this organ. This figure illustrates hard, pearly nodules adjacent to
the large airways. The histopathology of these lesions is shown in panel d. (d ) Histopathology of IgG4-RD
involving the bronchovascular bundle within the lung. (e) Computed tomographic angiogram demonstrating a
dissection of the aortic arch. Examination of the resected aorta revealed IgG4-related aortitis. The patient also
had mediastinal lymphadenopathy and a serum IgG4 concentration of <1,500 mg dl−1 (normal is <121 mg
dl−1 ). ( f ) Lymphoplasmacytic aortitis. Shown is a section of the resected aorta stained with hematoxylin and
eosin and visualized at 25× magnification. Black arrowheads indicate lymphoid aggregates in the adventitia.
Yellow arrowheads indicate plasma cell infiltrates in the media. The dashed line indicates the intima–media
boundary. Reproduced with permission from Arthritis & Rheumatism. ( g) Type 1 (IgG4-related)
autoimmune pancreatitis. Computed tomography scan of the abdomen revealing diffuse pancreatic
enlargement, with loss of normal lobularity. (h) Retroperitoneal fibrosis. A 78-year-old man presented
with left hydronephrosis. A computed tomography scan revealed a large mass in the pelvis, near the bladder,
encompassing and compressing the left ureter. His serum IgG4 concentration was 200 mg dl−1 (normal is
<121 mg dl−1 ), and biopsy demonstrated classic histopathology and immunostaining findings of IgG4-RD.

322 Mahajan et al.

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a c

b
d
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* g
*

*
*

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Lung. The lungs are affected by IgG4-RD is typically present during the late phase of
in diverse ways (Figure 3c,d ). Four major contrast-enhanced computed tomography
clinical pulmonary syndromes have been (CT) scanning. This homogeneous enhance-
identified: inflammatory pseudotumor, central ment appears to correspond to sclerosing
airway disease, localized or diffuse interstitial inflammation that is located predominantly in
pneumonia, and pleuritis. These different the adventitia. Involvement of the abdominal
pulmonary syndromes are associated with a aorta by IgG4-RD is discussed below.
range of clinical symptoms, including cough,
hemoptysis, dyspnea, pleural effusion, and Fibrosing mediastinitis. Fibrosing medias-
chest discomfort. The radiologic features of tinitis is characterized by an aggressive fibroin-
disease are often striking even in the setting of flammatory process occurring within the medi-
mild clinical symptomatology. IgG4-RD in the astinum. Progressive fibrosis results from the
lung is often easily confused with other entities proliferation of invasive fibrous tissue within
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

in its radiologic manifestations, which include: the mediastinum. This process can compress vi-
(a) solid nodular lesions, sometimes with tal mediastinal structures, culminating in organ
spiculations; (b) round-shaped, ground-glass dysfunction that is difficult to treat. A review of
opacities; (c) alveolar interstitial disease, with 15 patients with fibrosing mediastinitis demon-
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honeycombing, bronchiectasis, and diffuse strated that 3 samples met predefined diagnos-
ground-glass opacities; and (d ) thickening of tic criteria for IgG4-RD on the basis of suf-
the bronchovascular bundle. The tendency of ficient numbers of IgG4-positive plasma cells
IgG4-RD to track along the bronchovascular within tissue (51). In addition, 11 cases were
bundle is particularly characteristic of this characterized by a cell-rich storiform fibrosis,
condition (Figure 3d ). often combined with other pathology features
The lung differs pathologically from other of IgG4-RD. Thus, a proportion of fibrosing
organs in two major ways. First, obliterative ar- mediastinitis appears to fall within the spectrum
teritis is more likely to be observed in the lung of IgG4-RD.
than in other organs. The more common vas-
cular lesion in IgG4-RD, obliterative phlebitis,
also occurs in the lung. Second, neutrophilic Abdomen
infiltrates are more common in the lung than We describe below some of the manifestations
in other organs affected by IgG4-RD, presum- of disease involving anatomically defined areas
ably because of the interface between the lung of the abdomen.
parenchyma and external environment through
the airways. Pancreas. Presentations of type 1 (IgG4-
related) AIP include mild abdominal pain;
Pleura and pericardium. Pleural lesions have weight loss; and acute, obstructive jaundice
severe, nodular thickening of the visceral or (known as painless jaundice). A significant mi-
parietal pleura with diffuse sclerosing inflam- nority of patients with type 1 AIP present with
mation, sometimes associated with pleural acute glucose intolerance. A small percentage
effusion. of patients present with either acute pancre-
atitis (severe upper abdominal pain, lipase el-
Thoracic aorta. The finding of inflammatory evation) or chronic pancreatitis with features of
aortitis often comes as a surprise at surgery, exocrine insufficiency and pancreatic calcifica-
when patients undergo repairs of thoracic tion, or pseudocysts. Pancreatic atrophy occurs
aortic aneurysms or dissections (Figure 3e, f ) as a complication of longstanding disease.
(46–50). Arterial wall thickening is de- Cross-sectional imaging or endoscopic
tected on cross-sectional imaging studies ultrasound examination of the pancreas
of the aorta. Homogeneous enhancement typically shows diffuse pancreatic enlargement

324 Mahajan et al.

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PM09CH14-Stone ARI 24 September 2013 16:52

(termed sausage-shaped pancreas) or segmental only in the context of AIP and identified
pancreatic enlargement, accompanied by loss upon examination of the pathology remnants
of normal lobularity. The tumefactive lesions of Whipple procedures. Whether patients
that occur in the pancreas often raise suspicions with the histopathological features of this
of adenocarcinoma of the pancreas (Figure 3g). disease have clinical symptoms is unclear.
A surrounding peripheral rim of low atten- The long-term consequences of IgG4-related
uation, caused by sclerosing inflammation gastropathy are unknown.
involving peripancreatic adipose tissue, may be
observed on contrast-enhanced imaging. The Mesentery. The mesentery can be involved
pancreatic duct is typically diffusely narrowed. in a devastating manner. The fibrosing process
can encase vital organ structures, often obviat-
Biliary tract. IgG4-related sclerosing cholan- ing any attempt at surgical resection. Sclerosing
gitis appears to account for the minority of pa- inflammation often originates from the root of
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

tients who had previously been considered to the mesentery and can be difficult to differenti-
have primary sclerosing cholangitis and who re- ate from retroperitoneal fibrosis.
spond well to glucocorticoids. Untreated IgG4-
related sclerosing cholangitis can progress to
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end-stage liver disease and is extremely difficult Retroperitoneum


to differentiate from primary sclerosing cholan- We describe below some of the manifestations
gitis on the basis of clinical and radiologic find- of disease involving anatomically defined areas
ings and sometimes even on the pathological of the retroperitoneal region.
material available for review.
Retroperitoneal fibrosis. Idiopathic retro-
Liver, gallbladder, and stomach. A form peritoneal fibrosis, known for decades as Or-
of IgG4-RD affecting the liver specifically mond’s disease, is known to exist within a larger
(as opposed to the more common bile duct disease spectrum now referred to as chronic
involvement plus AIP) has been described. periaortitis. The three major components of
Patients may present with mass hepatic le- chronic periaortitis are IgG4-related retroperi-
sions that sometimes give rise to obstructive toneal fibrosis, IgG4-related abdominal aorti-
jaundice. Solid-mass lesions may involve the tis, and IgG4-related perianeurysmal fibrosis
hilar and perihilar bile ducts and may resemble (Figure 3h) (53).
cholangiocarcinoma. The clinical features of Because presentations of IgG4-related
IgG4-RD in the gallbladder and stomach are chronic periaortitis are often subtle and non-
poorly described. A cholecystectomy is rou- specific, diagnostic delay may result. Common
tinely performed during Whipple resection, presentations are poorly localized pain in
and IgG4-related cholecystitis is generally the back, flanks, lower abdomen, or thighs;
detected incidentally during surgical resection lower-extremity edema; and hydronephrosis
for AIP. A severe transmural inflammatory in- from ureteral involvement. Radiologists some-
filtrate is typical of IgG4-related cholecystitis, times classify this condition into three subtypes
and a radiologically thickened gallbladder may defined by their location: (a) periaortic/arterial,
be observed (52). involving connective tissue around the abdom-
IgG4-related gastropathy represents a inal aorta or its first branches; (b) periureteral;
unique inflammatory disease of the stom- and (c) plaque-like, broadly involving the
ach that may be distinguishable from other retroperitoneal region.
causes of gastritis, such as Helicobacter pylori A major insight has been the link established
and the entity presently known as autoim- between IgG4-RD and vascular inflammation
mune gastritis. As with the gallbladder, the leading to aneurysms in both the abdominal
gastric manifestations have been described and thoracic aortas (46–50, 54–57). IgG4-RD

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PM09CH14-Stone ARI 24 September 2013 16:52

appears to cause a substantial proportion of


a cases that are often still referred to as idiopathic
inflammatory abdominal aortic aneurysms
(58).

Kidneys. The most common renal manifesta-


tion of IgG4-RD is TIN (Figure 4). Although
this complication is indolent, the nephrotic
syndrome, advanced renal dysfunction, and
renal failure can develop (59–61). Even with the
prompt institution of glucocorticoid treatment,
renal fibrosis and renal atrophy may occur (62).
Membranous glomerulonephritis (GN) has
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

also been reported in a minority of IgG4-RD


patients who have renal disease (63). This form
b
of GN is distinct from idiopathic membranous
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GN, which is associated with antibodies to the


phospholipase A2 receptor (64, 65). However,
it is noteworthy that the predominant autoan-
tibody in idiopathic membranous GN is also a
member of the IgG4 subclass.
Patients with TIN generally present with
proteinuria, hematuria, decreased kidney func-
tion, hypocomplementemia, and radiologic
abnormalities. Nephrotic range proteinuria
occurs in a small minority of IgG4-RD patients
with renal disease and, when present, is asso-
ciated with membranous GN in addition to
TIN. Either subacute or progressive chronic
renal failure can occur. Asymptomatic tumoral
lesions, typically multiple and bilateral, are
sometimes detected on radiologic studies.
c Small, low-attenuation lesions on CT, usually
bilateral and multiple, or bilateral markedly

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 4
Tubulointerstitial nephritis in immunoglobulin
G4–related disease (IgG4-RD). (a) Both kidneys are
enlarged on computed tomography. Several large,
hypodense areas are present at the periphery of the
kidneys. (b) The disease is characterized by
aggressive tubulointerstitial nephritis. In addition to
the fibrosis, a dense lymphoplasmacytic infiltrate is
present. Note also the presence of numerous
eosinophils. A few residual tubules (arrow) are also
present. (c) An immunohistochemical stain for IgG4
reveals large numbers of IgG4+ plasma cells;
virtually all the plasma cells are positive for IgG4.

326 Mahajan et al.

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PM09CH14-Stone ARI 24 September 2013 16:52

enlarged kidneys (>14 cm) have also been are usually detected radiologically—typically
observed (Figure 4a). Approximately half of by magnetic resonance imaging—in the ab-
patients with IgG4-related renal disease are sence of symptoms. However, the predilection
GN:
hypocomplementemic (62). of IgG4-RD to involve nerves in the retroperi- glomerulonephritis
toneum may be an explanation for the pain as-
sociated with this condition.
Other (Diffuse or Miscellaneous
Disease Manifestations)
We describe below some of the manifestations SEROLOGICAL TESTING
of disease involving organs not described above. FOR IgG4
Most patients with IgG4-RD have elevated
Lymphadenopathy. Lymphadenopathy asso- serum IgG4 concentrations, but the range
ciated with IgG4-RD is either generalized or varies widely. Studies of type 1 AIP estimated
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

localized adjacent to a specific affected organ. the prevalence of serum IgG4 elevation to be
The lymph nodes involved are generally 1–3 cm on the order of 70% to 80% (69, 70). How-
in diameter and are nontender. Involvement ever, heterogeneity among other studies sug-
of the cervical, supraclavicular, submandibu- gests that further investigations are needed to
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lar, axillary, hilar, mediastinal, para-aortic, assess the test characteristics of serum IgG4
retroperitoneal, and inguinal nodes has been elevations in AIP. Some patients have nor-
described. Although lymphadenopathy is often mal serum IgG4 concentrations despite clas-
a prominent clinical feature of IgG4-RD, sic histopathologic and immunohistochemical
establishing the diagnosis through lymph node findings in tissue. Extremely limited data exist
biopsy is generally difficult because it is unusual regarding the test characteristics of serum IgG4
for lymph nodes to undergo the degree of concentrations in patients with extrapancreatic
fibrosis observed in other organs. IgG4-RD.
The prognostic implications pertaining to
Skin. The literature to date describes only a greater degrees of serum IgG4 elevation, if any,
small number of patients with cutaneous dis- remain to be thoroughly explored. A multicen-
ease associated with IgG4-RD (66). The typical ter study from Japan reported that IgG4 lev-
lesions are erythematous, flesh-colored papules els failed to normalize in 115 of 182 patients
with a predilection for the head and cheeks. (63%) treated with glucocorticoids (71). This
study also demonstrated that clinical remissions
Prostate. Symptoms of prostatism are as- could be maintained despite persistent IgG4 el-
cribed all too easily to benign prostatic hyper- evations and that disease relapse occurred in
trophy because the typical patient with IgG4- 10% of patients who had persistently normal
RD is a middle-aged to elderly man. Some IgG4 concentrations, yet the monitoring of se-
patients have dramatic improvements in their rial IgG4 concentrations appeared to be use-
urinary stream after treatment for IgG4-RD, ful in some patients for the identification of
however, and biopsy-proven prostatic disease early relapses. Studies with longer durations of
is a recognized complication of IgG4-RD (67). follow-up are required to understand the re-
lationship between serum IgG4 concentration
Peripheral nerves. IgG4-RD tends to cause and disease activity in greater detail.
perineural lesions at sites throughout the body. Anecdotal evidence suggests that the ratio of
It can affect the cranial nerves and other pe- IgG4 to total IgG in serum may be more useful
ripheral nerves in the head, such as the orbital, for diagnosis than IgG4 concentration alone.
optic, spinal, and greater auricular nerves (68). Some experts consider that a concentration
Peripheral nerve lesions consist of perineural of IgG4 that is greater than 8% of that of the
masses, often up to 3 cm in diameter, and total serum IgG concentration is suggestive of

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Table 2 Histopathologic hallmarks of IgG4-RD


Major
Lymphoplasmacytic infiltrate
High percentage of IgG4-positive plasma cells
Storiform fibrosis
Obliterative phlebitis
Mild to moderate tissue eosinophilia
Minor
Germinal centers
Lymphoid follicles
Nonobliterative phlebitis
Obliterative arteritis (usually found in lung)
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

Abbreviation: IgG4-RD, immunoglobulin G4–related disease.

IgG4-RD (72). As described below, an elevated The diagnosis of IgG4-RD relies primarily
by Harvard University on 12/03/13. For personal use only.

ratio of IgG4+ to IgG+ cells in tissue (>40%) is on the documentation of certain characteristic
supportive of the diagnosis in tissues with sub- histopathologic features and only secondarily
stantial degrees of fibrosis (6). on the presence of an elevated IgG4 concentra-
Serum IgG4 is frequently measured by tion in blood or tissue (74). This disease there-
nephelometry. However, nephelometric assays fore differs from many autoimmune conditions
are prone to error in the presence of large anti- (e.g., systemic lupus erythematosus, rheuma-
gen excess, which may give rise to gross un- toid arthritis, granulomatosis with polyangiitis)
derestimates of the serum IgG4 concentration in which strong presumptive diagnoses often
because flocculation fails to occur. This effect, rest on serological parameters such as the de-
known as the prozone phenomenon, can lead to tection of autoantibodies, even in the absence of
false reports of normal serum IgG4 concentra- histopathological confirmation. Although the
tions and has been frequently observed in pa- elevations of serum IgG4 concentrations are
tients with IgG4-RD whose serum IgG4 levels often striking in IgG4-RD, no compelling evi-
sometimes exceed 20 to 30 times the upper limit dence for a disease-specific autoantibody exists.
of normal (140 mg dl−1 ) (73). Thus, histopathology remains the cornerstone
of diagnosis in IgG4-RD and is particularly cru-
cial in differentiating this disorder from cancer.
PATHOLOGY Moreover, histopathology has played a critical
role in recognition of the multiorgan nature of
Histopathologic Features and the
IgG4-RD.
Mechanistic Implications
Granulomatosis with
polyangiitis: The four major pathological hallmarks of
a form of small- and IgG4-RD are a dense lymphoplasmacytic in-
medium-vessel filtrate with a high percentage of IgG4+ plasma The Inflammatory Infiltrate
vasculitis associated cells, storiform fibrosis, obliterative phlebitis, Although most investigations of IgG4-RD
with antineutrophil
and mild to moderate tissue eosinophilia have focused on the B cell lineage and IgG4,
cytoplasmic
antibodies; formerly (Table 2) (Figure 1) (5, 6, 74). Minor the dominant histopathologic feature is an
termed Wegener’s histopathological features, including germinal abundance of CD4+ T cells (Figure 1g) (6). In
granulomatosis centers, lymphoid follicles, obliterative arteri- most cases, the B cells are confined to small co-
tis, and nonobliterative phlebitis, are also found hesive lymphoid aggregates or, less commonly,
in many organs (74). germinal centers (Figure 1h) (6). The tissue

328 Mahajan et al.

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PM09CH14-Stone ARI 24 September 2013 16:52

between these germinal centers is dominated A preponderance of IgG4+ plasma cells in tis-
by T lymphocytes, most of which are small, sue is not specific for IgG4-RD because other
mature-appearing CD4+ T cells. Although inflammatory, infectious, and malignant condi-
plasma cells predominate in some cases, tions occasionally exceed this threshold. For in-
they generally appear mature. Binucleate stance, granulomatosis with polyangiitis, as well
plasma cells and Mott cells are observed only as rheumatoid arthritis, is also associated with
occasionally. moderately elevated numbers of IgG4+ plasma
The inflammatory process in IgG4-RD cells in tissue (83, 84). In addition, plasma
tends to respect tissue planes in some organs cells bearing other immunoglobulin classes and
but not in others. As an example, the disease subclasses—IgE, IgG1, IgG2, and IgG3—are
does not extend beyond the confines of the identified within IgG4-RD lesions. However,
submandibular gland. In contrast, in type 1 IgG4-bearing plasma cells predominate.
(IgG4-related) AIP, the inflammatory process
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

frequently extends into retroperitoneal soft tis-


sue. Although overt necrosis is not a feature Fibrosis
of IgG4-RD pathology, the inflammatory pro- The storiform type of fibrosis that character-
cess can undermine the structural integrity of izes IgG4-RD represents an unusual pattern of
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involved organs. Destruction of the aorta and collagen deposition (Figure 1a). Storiform fi-
bones of the skull has been reported in a mi- brosis, observed in numerous neoplastic entities
nority of cases (50, 75). (85), is seldom observed in other inflammatory
Immunohistochemical and immunoglob- and rheumatologic diseases. In the active phase
ulin gene-rearrangement studies confirm that of IgG4-RD, the collagen deposition is accom-
both the plasma cell population and T cells are panied by an admixture of fibroblasts and my-
polyclonal (21, 76, 77). However, a recent pub- ofibroblasts. In cases presumed to be of long
lication suggests that IgG4-RD is associated duration, such fibroblastic cells dominate the
with lymphoid proliferation that is oligoclonal histological picture, creating a resemblance to
in nature, composed of a handful of dominant a mesenchymal neoplasm. These spindle cells
IgG4+ lymphoid cell clones, and compatible are generally positive for smooth muscle actin
with an immune response (78). Isolated reports and negative for desmin.
have raised concern about the potential for Immunostaining studies for IgG4- and
an increased risk of transformation into lym- IgG-positive plasma cells are less useful
phoproliferative disease in patients with long- for diagnosing cases in which the principal
standing IgG4-RD, but this concern remains histopathological finding is fibrosis. The ratio
unsubstantiated (79–82). Nevertheless, chronic of IgG4 to total IgG is helpful in such cases.
inflammation has a well-known link to in- Although the total number of plasma cells
creased incidence of malignant transformation, within any high-power field may be small, the
and more extensive studies may demonstrate finding of an increased ratio of IgG4 to total
such a link to IgG4-RD in the future. IgG is nevertheless suggestive of the diagnosis.
The key to diagnosis under such circumstances
may be the storiform morphology of the
IgG4-Bearing Cells fibrosis. However, the “burnt out” phase of
The histopathologic diagnosis is predicated IgG4-RD can be dominated by relatively
on the documentation of elevated numbers of acellular and patternless fibrosis.
IgG4+ plasma cells (Figures 1e and 4c) (74).
In attempts to codify the histopathologic diag-
nosis of IgG4-RD, investigators have proposed Obliterative Vascular Disease
diagnostic cutoffs for the frequency of IgG4+ A unique feature of IgG4-RD is the presence of
plasma cells (>40% of all plasma cells) (74). obliterated venous and, less commonly, arterial

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PM09CH14-Stone ARI 24 September 2013 16:52

channels (Figure 1d, f ). The lumina of these Macrophages are usually detectable within
small and medium-sized veins are partially or the fibroinflammatory infiltrate if immunohis-
completely occluded by an inflammatory infil- tochemical stains for antigens such as CD68
ANAs: antinuclear
antibodies trate composed of lymphocytes and plasma cells are performed (88). However, the finding of
that is consistent with features found elsewhere diffuse sheets of macrophages, particularly
in the lesion. Vessel wall necrosis and fibrin de- foamy macrophages and multinucleated giant
position are not observed in IgG4-RD, in con- cells, argues strongly against the diagnosis
trast to forms of vasculitis such as polyarteritis of IgG4-RD. The presence of granulomas,
nodosa, granulomatosis with polyangiitis, and particularly necrotizing granulomatous in-
microscopic polyangiitis. Although there is a flammation, similarly excludes IgG4-RD.
strong predilection for venous as opposed to Further studies of the role of macrophages
arterial involvement by the inflammatory infil- in IgG4-RD, particularly with regard to
trate in IgG4-RD, obliterative arteritis is ob- their potential contribution to the process of
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

served particularly in the lung. When the ar- storiform fibrosis, should be performed.
terial circulation is affected, there is a prefer-
ence for small- and medium-sized arteries, but
the disease can also affect large vessels, includ- PATHOPHYSIOLOGY OF
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ing the aorta. Rapid destruction of the blood IgG4-RELATED DISEASE


vessel wall is unusual and has been described
T Helper Cell Polarization and the
in the aorta and other medium- to large-sized
vessels (53, 75). The finding of obliterative le-
Pathogenesis of IgG4-Related Disease
sions of blood vessels is of immense diagnos- The immune response has the capability of
tic value because this histologic appearance ap- polarization toward one of many alternative
pears to be unique to IgG4-RD. The biology differentiation pathways. Each of these inflam-
underlying this pattern of vasculitis is currently matory pathways is characterized by a specific
unknown. set of effector molecules and cytokines that can
be tailored to meet specific challenges posed
by classes of pathogens or other environmental
Eosinophils, Germinal Centers, factors. This concept of immune response
and Macrophages polarization is exemplified by the Th1–Th2
Eosinophils are absent only in a minority paradigm (89). The molecules and cytokines
of cases. In some examples of IgG4-RD, that polarize T cell pathways form self-
such as eosinophilic angiocentric fibrosis, the amplifying autocrine loops and cross-inhibitory
eosinophils dominate the histological picture signaling networks (90). Over the past decade,
(Figure 1c) (86). Some examples of IgG4-RD, the discovery of the Th17 pathway has helped
such as eosinophilic cholangitis, had previously clarify inconsistencies in our understanding
been mistaken for an allergic process. of the Th1–Th2 paradigm and has cemented
Lymphoid aggregates composed of small this concept of T cell polarization as a general
B lymphocytes are ubiquitous in IgG4-RD organizational principle of the immune system.
(Figure 1g), but germinal centers are observed Autoantibodies such as antinuclear antibod-
in only a minority of cases (6, 87). These extran- ies (ANAs) and rheumatoid factor are detected
odal germinal centers resemble nodal germinal in many T cell–driven autoimmune disorders,
centers morphologically and are composed of but such antibodies are not always responsi-
centrocytes and centroblasts as well as a mesh- ble for the tissue damage observed in a given
work of CD21+ follicular dendritic cells. Some disease. IgG4-RD may represent the proto-
of these germinal centers are composed entirely type of a T cell–mediated autoimmune disease,
of IgG4-bearing lymphocytes (V. Deshpande, wherein the role of autoantibodies is not central
unpublished observations). to pathogenesis.

330 Mahajan et al.

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Class-switching to IgG4 and IgE is charac- eosinophils, fibroblasts, and myofibroblasts.


teristic of Th2 immune responses. IgG4-RD The immunologic characteristics of IgG4-RD
lesions exhibit significantly higher expression lesions have been described to only a limited ex-
IL: interleukin
of Th2 cytokines [interleukin (IL)-4, IL-5, tent, mostly through the use of histopathologic
TGF-β: transforming
and IL-13] than interferon (IFN)-γ (91–93). approaches and measurements of cytokine
growth factor β
Foxp3+ Treg cells are seen in IgG4-RD lesions levels. On the basis of studies with other
Tfh cell: follicular
and may account for the increased levels of IL- fibroinflammatory disorders and experimental
helper T cell
10 and transforming growth factor (TGF)-β models of fibrosis, we have presented a model
(91, 93, 94). Expression levels of IL-4 and IL-10 of how the coordinated actions of a range of cell
correlate with the ratio of IgG4 to IgG within types and cytokines in the fibroinflammatory
the labial salivary gland lesions of patients with infiltrate may cause the characteristic storiform
Mikulicz’s disease (IgG4-related dacryoadeni- fibrosis of IgG4-RD (Figure 5) (14, 103). Th2-
tis and sialadenitis) (93). An increase in the derived IL-4 and IL-13, as well as Treg-derived
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

circulating number of both Th2 and Treg cells IL-10, may result in the generation of alterna-
is observed in IgG4-RD (95, 96). In at least tively activated macrophages, which enhance
one case report, glucocorticoid therapy was fibrogenesis by providing additional profib-
associated with amelioration of the Th2 bias in rinogenic factors, such as TGF-β1 and platelet-
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IgG4-RD (97). IL-21 production by follicular derived growth factor (PDGF) (104). IL-5 pro-
helper T cells (Tfh cells) may explain the duced by these T cells may also promote fibrosis
generation of ectopic germinal centers within by recruiting eosinophils that, in turn, produce
disease lesions (87, 98). Although Th2 cy- TGF-β1, PDGF, and IL-13 (105–107). These
tokines are detectable in vivo, other researchers profibrotic cytokines can recruit and activate
have found a predominance of Th1 cytokines macrophages, fibroblasts, and myofibroblasts
following restimulation of T cells in vitro (99, and promote the characteristic fibrosis of
100). Whether Th1 or Th2 cytokines drive the IgG4-RD (14). However, we recognize that
disease process remains to be established. IgG4-RD may well be caused by Th1 cells,
The tissue damage associated with IgG4- and this model is not supported by any direct
RD results from a striking expansion of evidence.
fibroblasts. In the advanced stages, IgG4-RD The role of Foxp3+ Treg cells in IgG4-RD
is characterized by severe fibrosis (101, 102). is probably complex and remains to be fully
This fibrosis may be caused by the prolonged elucidated. Foxp3+ Treg cells have been de-
induction of IL-13, which is a strong inducer tected at tissue sites in subjects with IgG4-RD
of fibrosis and a central cytokine in the Th2 (91) and may represent a central factor in dis-
differentiation pathway. Although IFN-γ, the ease pathophysiology. If so, IgG4-RD would
key cytokine associated with Th1 responses, be unique among autoimmune diseases because
inhibits fibrosis (103) in certain contexts, it may the typical role of Foxp3+ Treg cells is to at-
well be linked to fibrosis in tuberculosis and tenuate the inflammatory process. IL-10 has
Crohn’s disease. Whether IgG4-RD results been detected in the involved tissues in IgG4-
from the pathological activation of the Th1 or RD, but the cellular sources of this cytokine
Th2 arm of the immune system remains to be have not yet been defined (91, 92). IL-10 can
established. be produced by innate immune cells, including
macrophages, dendritic cells, and neutrophils
(108, 109). Regulatory B cells also produce IL-
Fibroinflammatory Infiltrate in 10, but these cells have yet to be observed in
IgG4-Related Disease the context of IgG4-RD (110). IL-10 potenti-
The inflammatory lesions of IgG4-RD are ates the IL-4-mediated class-switching to IgG4
packed not only with IgG4+ plasma cells and suppresses switching to IgE (111). Under
but also with CD4+ T cells, macrophages, these circumstances, the antibody class-switch

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PM09CH14-Stone ARI 24 September 2013 16:52

Pathogens
a Allergens

Tissue damage
Commensals

Th1 Th2 Treg

b (i)

reg
Treg
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

h1
Th1 h2
Th2
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IFN-γ IL-13 IL-5 IL-4 IL-10 TGF-β

(ii) (v)
Fibroblast Eosinophils B cells
Macrophage Vicious cycle of antigen
Plasma cells
presentation by
autoreactive B cells

IgE IgG4

(iii) (iv) Cross-reactivity


Fibrosis to self-antigen

Epithelial cells

Figure 5
A model for the pathogenesis of immunoglobulin G4–related disease (IgG4-RD). (a) Potential triggers of
IgG4-RD. Although the initiating events in IgG4-RD are unknown, the disease may be triggered by an
aberrant immune response to commensal microbes, food and environmental allergens, infectious pathogens,
or tissue damage. (b) (i ) Signals from the innate immune system may determine the state of T helper cell
polarization in IgG4-RD. When the inflammation turns chronic, Treg cells may also be induced to dampen
it. (ii ) Activated T helper cells and Treg cells may produce an inflammatory cytokine milieu that includes
IFN-γ, IL-4, IL-10, IL-5, and IL-13. IL-4 and IL-10, possibly produced by T follicular helper cells, may
drive preferential class-switching of autoreactive B cells to IgG4 and IgE and induce the differentiation and
expansion of IgG4+ plasma cells. IL-5, IL-13, and TGF-β could lead to the recruitment of eosinophils and
the activation of fibroblasts. This cytokine milieu may also generate profibrotic, alternatively activated
macrophages that produce additional fibrogenic cytokines. Alternatively, IFN-γ may contribute to the
activation of inflammatory macrophages that drive the process of fibrosis. (iii ) Activated fibroblasts and
macrophages create a dense storiform pattern of fibrosis. (iv) Some IgG4 antibodies, and potentially some
IgE antibodies, may be cross-reactive to self-antigen. (v) B cells that recognize self-antigen are capable of
efficient antigen presentation of the cognate self-antigens to autoreactive T cells, thereby setting up a vicious
cycle of collaboration between T and B lymphocytes. These activated self-reactive T cells may facilitate
germinal center formation and recruit increasing numbers of high-affinity autoreactive B cell clones that
have undergone somatic mutation into the fibroinflammatory immune response. Abbreviations: IFN,
interferon; IL, interleukin; TGF, transforming growth factor; Th, T helper cell; Treg, regulatory T cell.

332 Mahajan et al.

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PM09CH14-Stone ARI 24 September 2013 16:52

to IgG4 in IgG4-RD may reflect the failed at- and possibly IgG4 immunoglobulins, are crit-
tempt of Treg cells to dampen Th2 inflam- ical for antigen presentation to Th2 effec-
mation. It is also possible that the fibrosis so tor cells or CD4+ effector memory cells.
ICOS: inducible
characteristic of the advanced stages of IgG4- B cells are required for the maintenance of T cell costimulator
RD results from the combined effects of Th2 CD4+ memory T cells: They provide addi-
FcγRI: Fcγ receptor I
and Treg cells. However, the disease itself may tional specialized antigen-presenting capacity
be caused by Th1 cells rather than Th2 cells. over and above that of dendritic cells (116, 117).
More studies should be performed to better un- B cells may also provide antigen-independent
derstand the role of T cell subsets in disease factors, such as IL-6, that promote the pro-
pathogenesis. liferation of pathogenic T cells (118). A po-
Increased tissue concentrations of IgG4+ tential mechanism for the sustained response
plasma cells are a diagnostic hallmark of IgG4- to B cell depletion by rituximab in IgG4-
RD (6). B cell follicles composed of IgG4+ RD is through interference with the mainte-
nance of CD4+ T cell memory (Figure 6).
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

B cells and extrafollicular plasma cells are


generally observed within the lymphoplasma- Following rituximab-mediated B cell depletion,
cytic infiltrate, as are T cells. Expanded clones the CD4+ T effector or memory cells that drive
of IgG4-bearing cells that had undergone the disease process are lost.
by Harvard University on 12/03/13. For personal use only.

somatic hypermutation were demonstrated by IgG4 bound to FcγRI on the surface


next-generation sequencing in the inflamed of innate immune cells, including dendritic
tissues of subjects with IgG4-related cholangi- cells, alternatively activated macrophages,
tis (78). Extranodal germinal center formation and eosinophils, may help in the sampling
and expansion of somatically mutated clones and presentation of extracellular antigens to
suggest that the elevated IgG4 serum levels and T cells. Theoretically, this process could oc-
IgG4 class-switch are caused by an antigen- cur within the fibroinflammatory infiltrate as
driven, T cell–dependent B cell response. well as within the lymphoid organs, thereby sus-
Substantial evidence from other autoimmune taining the inflammation. Activated eosinophils
diseases attributes autoantibody responses to upregulate class II MHC and costimulatory
dysregulated Tfh cells (112). The involvement molecules. Indeed, studies of parasite infection
of Tfh cells in autoantibody production has suggest that activated eosinophils within lesions
been established in various mouse strains that present antigens to CD4+ T cells (119, 120).
show altered expression of several molecules Thus, the decline in IgG4 levels after ritux-
associated with Tfh cells: CD40L, ICOS (in- imab therapy may also contribute indirectly to
ducible T cell costimulator), and IL-21 (113). the clinical response. The specificity of the au-
This observation is consistent with the elevated toreactive T cells in IgG4-RD is not known.
IL-21 messenger RNA expression reported in Unless it is established that the autoreactive
the affected tissues of IgG4-RD patients with T cells and B cells in IgG4-RD recognize epi-
lacrimal and salivary gland involvement (87). topes from the same antigen, the role of antigen
So far, there is no evidence to suggest that the or autoantibodies in establishing and sustaining
IgG4 autoantibodies are directly pathogenic in the T cell–B cell collaboration in IgG4-RD will
IgG4-RD. remain speculative.
The serum IgG4 concentration falls
dramatically within 2 weeks of rituximab ad-
Therapeutic Response of ministration (121), while the concentrations of
IgG4-Related Disease to Rituximab other immunoglobulin isotypes remain stable.
Patients with IgG4-RD dramatically respond This rapid and selective rituximab-induced
to B cell depletion with rituximab (114, 115). decline in IgG4 levels suggests that the bulk of
This observation is consistent with the idea IgG4 in this disease originates from short-lived
that IgG4+ B cells (or B cells in general), plasma cells. Whether long-lived autoreactive

www.annualreviews.org • IgG4-Related Disease 333

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PM09CH14-Stone ARI 24 September 2013 16:52

Plasma cell

a
T cell receptor

Class II pMHC antigen


B IL-4 Antigen presentation
IL-10
Cytokine production
pMHC

Autoantigen
CD4+/ Antigen-specific IgG4
Treg
C IFN-γ Profibrotic response FcγRI
pMH /IL-13
?
pMHC

? IL-4 IL-10
IFN-γ TGF-β Activated fibroblast
Eosinophil B
Antigen-specific B cell
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

(class-switched to IgG4)
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Activated
macrophage

b Plasma cell

1 2
B IL-4
IL-10
pMHC

3 CD4+/
Treg 4
C IFN-γ
p MH /IL13
?
pMHC

? IL-4 IL-10
IFN-γ TGF-β Fibroblast
Eosinophil

Resting
macrophage

Figure 6
Possible mechanism of the response of immunoglobulin G4–related disease (IgG4-RD) to rituximab. (a) T helper cells and Tregs may
act as critical mediators of fibrosis by secreting IFN-γ, IL-4, IL-13, and TGF-β. These cytokines induce the recruitment and
activation of fibroblasts and macrophages. T follicular helper cells (as well as Th2 cells and Tregs) may secrete IL-4 and IL-10, thereby
promoting class-switching to IgG4 and differentiation of B cells into IgG4+ plasma cells. The activated state of T cells may be
maintained by antigenic peptides presented in the context of class II MHC molecules by autoreactive B cells, and perhaps by activated
macrophages, dendritic cells, and eosinophils in an IgG4- and FcγRI-dependent manner. (b)  Rituximab-mediated B cell depletion
results in the loss of short-lived plasma cells by depleting their CD20+ precursors.  This leads, in turn, to a rapid decline in serum
IgG4 levels. B cell depletion may eliminate a major cell type required for antigen presentation to T cells, leading to  loss of activated
T cells and profibrotic cytokines and a reduction in the inflammatory cellular infiltrate.  In the absence of a profibrotic cytokine
milieu, the fibroblasts and macrophages may also acquire the potential to remodel fibrosis to some degree. Abbreviations: IL,
interleukin; MHC, major histocompatibility complex; TGF, transforming growth factor; Th, T helper cell; Treg, regulatory T cell.

334 Mahajan et al.

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PM09CH14-Stone ARI 24 September 2013 16:52

IgG4+ plasma cells or IgG4+ memory B cells they have internalized IgG4 molecules from the
develop in IgG4-RD is unknown. plasma via FcRn in the presence of a reducing
Following rituximab therapy, we observed environment provided by chaperones, protein
dramatic resolution of the cellular infiltrate but disulfide isomerase, and/or reduced glutathione
also a partial reduction in the fibrosis itself (124, 125).
(V. Deshpande, J. Stone, unpublished observa- The properties of IgG4 antibodies lead
tions). These observations may be understood to the general perception that they are
in the context of the dual roles of macrophages noninflammatory. Their failure to bind effi-
as instigators of both fibrosis and the resolu- ciently to low-affinity FcRs and C1q renders
tion of fibrosis under differing conditions (14). them inefficient in phagocyte activation,
Given the right stimulus, macrophages can be antibody-dependent cellular cytotoxicity, and
induced to transform from a profibrotic pro- complement-mediated damage (126). IgG4
gram to an antifibrotic one. Thus, therapeutic antibodies can bind to FcγRI, the high-affinity
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

reversal, or at least partial reversal of fibrosis, receptor for IgG Fc, but less efficiently than
may be possible as long as the involved tissue IgG1 and IgG3 (127, 128).
has an extensive cellular infiltrate rather than IgG4 antibodies are typically produced in
simply “burnt out” scar tissue. This reversal of response to food and environmental allergens
by Harvard University on 12/03/13. For personal use only.

fibrosis emphasizes the need for early, accurate (129). Long-term exposure to antigens is
diagnosis and for prompt initiation of immuno- required before significant titers of IgG4 an-
suppressive therapy in IgG4-RD. The molecu- tibodies develop. The resolution of childhood
lar phenotypes of macrophages and other cells allergies is accompanied by a change in the
within the lymphoplasmacytic infiltrate follow- children’s anti-allergen antibody profiles from
ing the response to rituximab require further IgE to IgG4 (130). IgG4 antibodies are also
definition. induced by allergy treatments designed to in-
duce tolerance (131). In this context, the IgG4
antibodies are thought to protect the children
IgG4 Antibodies as Potential from allergens by acting as blocking antibodies,
Inhibitors of Inflammation sequestering the offending antigen from IgE
Antibodies of the IgG4 isotype are unusual in that is located on mast cell surfaces. One
many respects. These antibodies are considered function of IgG4 immunoglobulins, therefore,
to be functionally monovalent (122). A single– may be to serve as inhibitory antibodies whose
amino acid difference in the hinge region (a production is induced by IL-10, perhaps under
serine in lieu of the proline found in IgG1) the direction of Treg cells (132).
causes inefficient formation of disulfide bridges The possible role of IgG4 antibodies in driv-
between the heavy chains of the molecule (123). ing the pathology of IgG4-RD is a controversial
Many IgG4 heavy chains, therefore, have non- subject that has yet to be addressed satisfac-
covalent associations. As a result, these an- torily. Elevated serum IgG4 concentrations in
tibodies can undergo a phenomenon known this disease may represent an epiphenomenon
as Fab arm exchange, wherein hemi-IgG4 that has no direct pathogenic consequence.
molecules—one heavy chain covalently associ- This hypothesis is consistent with the pre-
ated with one light chain—associate with dis- vailing idea that IgG4 is a noninflammatory
tinct hemi-IgG4 molecules that have different antibody. However, the general correlation
antigen-binding specificities (Figure 7a). Fab between serum IgG4 concentration and both
arm exchange requires a reducing environment, disease severity and the response to treatment
but the precise location of the exchange in vivo is good, raising the possibility that IgG4 anti-
has not been determined. It is believed to oc- bodies contribute directly to the pathogenesis
cur within endosomes of endothelial cells after of this condition.

www.annualreviews.org • IgG4-Related Disease 335

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PM09CH14-Stone ARI 24 September 2013 16:52

a Interchain Intrachain
IgG1 IgG2 IgG3 IgG4
C C C C Complement fixation +++ + +++ –
P P P P Activating FcγR binding ++ + ++ +
S S S S Inhibitory FcγR binding ++ + ++ ++
C C C C

+ = +

IgG4 Fab arm exchange generates bispecific antibodies


Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

b
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i. Bispecific antibodies with ii. Bispecific antibodies without


functional monovalency: functional monovalency:
nonprecipitating immune complexes potentially large immune complexes

Figure 7
Unique characteristics of immunoglobulin 4 (IgG4) antibodies. (a) IgG4: a noninflammatory antibody. Fab
arm exchange, inability to fix complement, poor binding to activating FcγRI, and the capacity to engage the
inhibitory FcγR (FcγRIIB) are unique features of IgG4 that make it a noninflammatory immunoglobulin.
The heavy chains of IgG4 can switch between inter- and intrachain disulfide bonded configurations.
Intrachain disulfide bonded IgG4 is composed of noncovalently associated hemi-IgG4 molecules, which can
be exchanged in vitro, under reducing conditions, or in vivo, potentially aided by FcRn recycling. This
process, termed Fab arm exchange, can give rise to bispecific IgG4 antibodies. (b) Theoretical immune
complexes that can be formed by bispecific IgG4 antibodies. The nature of the immune complexes formed in
vivo in IgG4-related disease is unknown. There are two possibilities: (i ) Fab arm exchange of antigen-
specific IgG4 with antibodies of irrelevant specificity may result in functionally monovalent antibodies. Such
antibodies would give rise to small, nonprecipitating immune complexes. (ii ) Fab arm exchange between
IgG4 antibodies that react with different epitopes on the same antigen would result in functionally bivalent
antibodies, and may result in the formation of large immune complexes. Such immune complexes may be
inefficiently cleared due to lack of complement binding and may account for the IgG4 deposits seen in some
cases of IgG4-related disease.

Potential Inflammatory Role of IgG4 membranes has been described in type 1 (IgG4-
Antibodies in IgG4-Related Disease related) AIP and IgG4-related TIN (133, 134).
Hypocomplementemia is particularly common
Although IgG4 does not readily activate the
among patients with IgG4-related TIN; it
classical complement pathway, reductions in
occurs in 50% to 70% of patients with this
the circulating levels of C3 and C4 are com-
disease complication (62). These findings,
monly observed in IgG4-RD. In addition, the
typical of immune complex–mediated dis-
deposition of C3c and IgG4 along the basement
ease, indirectly support a role for IgG4 in

336 Mahajan et al.

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PM09CH14-Stone ARI 24 September 2013 16:52

complement-mediated pathology but appear remains unclear. Evidence for an in vivo reg-
contradictory to the known inability of IgG4 ulatory role of IgG4 Fab arm exchange was
to fix complement. suggested in a rhesus macaque antibody trans-
ANCAs:
Complement fixation may be induced by fer model of myasthenia gravis (124). Unlike antineutrophil
other IgG subclasses (e.g., IgG1) that can fix IgG1 antibodies, IgG4 antibodies against the cytoplasmic antibodies
complement. Serum concentrations of IgG1 acetylcholine receptor failed to cross-link the
are also elevated in IgG4-RD, albeit to a sub- acetylcholine receptor in vivo and failed to
stantially lower degree. Indeed, elevated levels induce signs of myasthenia. This failure was
of immune complexes containing C1q, poten- thought to arise from the functional mono-
tially containing IgG1, have been observed in valency of the IgG4 antibodies generated by
some cases of AIP with evidence for classical Fab arm exchange. However, the control an-
complement pathway activation (135). Depo- tibody used in these experiments was a mem-
sition of IgG4 immune complexes in the tis- ber of the IgG1 subclass, which would probably
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

sue may also activate complement through the also have been able to fix complement. Indeed,
alternative or lectin pathway, as observed in both complement-mediated damage to the neu-
membranous glomerulonephropathy (65, 136). romuscular junction and acetylcholine recep-
Complement fixation in IgG4-RD may also tor cross-linking contribute to pathogenesis in
by Harvard University on 12/03/13. For personal use only.

be triggered directly by oxidative tissue dam- myasthenia gravis patients (141). The protec-
age in an immunoglobulin-independent man- tive effect of IgG4 Fab arm exchange in this
ner through the lectin pathway, as observed in rhesus macaque model may have been overesti-
ischemia-reperfusion injury of the kidney (137, mated if the investigators failed to account for
138). differences in complement activation between
IgG4 antibodies can bind activating FcRs IgG4 and IgG1.
in vitro and may contribute to the pathogen- Studies in individuals with the K409 allo-
esis of certain antineutrophil cytoplasmic anti- type of IgG4 (142), which lacks the ability to
body (ANCA)-associated vasculitides that have undergo Fab arm exchange (143), may help
elevated ANCAs, including those of the IgG4 elucidate the role of Fab arm exchange not only
subclass (139). ANCAs may contribute to the in IgG4-RD but also in other human immune
pathophysiology of ANCA-associated vasculitis responses more generally (144). Functional
by, among other actions, triggering activating monovalency of IgG4, which arises from Fab
FcγRs on neutrophils. IgG4 ANCAs can induce arm exchange with antibodies of irrelevant
superoxide release and degranulation in neu- specificity, is thought to limit the generation of
trophils in vitro but cannot induce IL-8 secre- large immune complexes and allows only the
tion (139, 140). However, a pathogenic role for formation of small, nonprecipitating immune
IgG4 ANCAs in vivo has not been established. complexes (145). However, Fab arm exchange
In addition, ANCAs have not been detected between IgG4 molecules against different
in IgG4-RD. IgG4 also binds FcγRIIb, an in- epitopes on the same antigen would not give
hibitory receptor on myeloid cells and B cells rise to functionally monovalent antibodies and
(127). Therefore, it is possible that IgG4 has a may be able to form large immune complexes
limited inflammatory potential and that IgG4 (Figure 7b). Given the important role played
immune complexes contribute to the dampen- by complement in limiting the size of immune
ing of inflammation and B cell responses. complexes and maintaining their solubility
(146), one would expect IgG4-containing im-
mune complexes (if actually formed in vivo) to
Possible Immunoregulatory Role of be large and poorly solubilized and, therefore,
IgG4 Fab Arm Exchange potentially pathogenic. Currently, however,
The regulatory role of IgG4 Fab arm exchange, few data pertaining to IgG4 immune com-
if any, in various pathophysiological contexts plexes generated in vivo are available, in the

www.annualreviews.org • IgG4-Related Disease 337

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PM09CH14-Stone ARI 24 September 2013 16:52

context of either infections or autoimmunity. were not determined, the serum levels of IgG4
Circulating IgG4 immune complexes have and anti-CA-II antibodies correlated with
been observed in IgG4-RD subjects, but their disease activity (150). Studies of autoantibodies
CA-II and CA-IV:
carbonic anhydrases II physical characteristics and size have yet to be against CA-II and CA-IV in AIP have generally
and IV ascertained (2). not distinguished between type 1 (IgG4-
related) AIP and type 2 AIP (a non-IgG4-
related condition), and antibodies against CA-II
Antigenic Specificity of IgG4 have also been found in systemic lupus erythe-
Antibodies in IgG4-Related Disease matosus, systemic sclerosis, dermatomyositis,
Identification of the target antigens in IgG4- polymyositis, endometriosis, autoimmune hep-
RD will be critical to obtain a detailed un- atitis, and viral hepatitis (149). Autoantibodies
derstanding of the pathogenesis of this dis- against other antigens expressed in the acinar
ease. ANAs are commonly found in IgG4- cells of pancreas and salivary glands, such as
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

RD, but the specificities of these ANAs and lactoferrin, amylase-α-2A, pancreatic trypsino-
the specific IgG subclasses that constitute this gens and pancreatic secretory trypsin inhibitor,
response are not known. Rheumatoid factor– have also been reported in IgG4-RD (151–
like activity is also common in IgG4-RD but 153). Although autoantibodies against secreted
by Harvard University on 12/03/13. For personal use only.

probably arises from the nonspecific inter- exocrine antigens are common in IgG4-RD,
actions between the Fc portions of different they lack specificity. So far, no disease-
IgG4 molecules. Therefore, this phenomenon specific autoantibodies have been identified in
is not classic rheumatoid factor activity (de- IgG4-RD.
fined as Fab binding of one immunoglobu-
lin to the Fc portion of another) and may
not reflect the presence of a true autoantibody Molecular Mimicry of Microbial
(147). Antigens in IgG4-Related Disease
Putative autoantibodies against pancreatic Several mouse models of AIP have been
and salivary antigens have been proposed in induced by immunization with bacterial
type 1 (IgG4-related) AIP and IgG4-related products (154). Antibodies against lactoferrin
sialadenitis. However, the autoantibodies de- and CA are found in these models following
scribed in these contexts thus far are not spe- the induction of pancreatitis and sialadenitis.
cific for IgG4-RD, and the expression pattern of However, these autoantibodies may simply
the potential autoantigens does not fully over- reflect an underlying inflammatory process,
lap with the disease involvement in the patients and their pathogenic role (if any) has yet to be
with IgG4-RD. An immunohistochemical proven. Although unknown bacterial proteins
study using sera from patients with IgG4-RD may either initiate or drive this disease due
with pancreatic and salivary gland involvement to molecular mimicry, it is also possible that
showed IgG4 autoreactivity against the epithe- microbial products induce polarization in a
lial tissue lining the pancreatic ducts, salivary Th2 direction, independently of molecular
gland ducts, intra- and extrahepatic bile ducts, mimicry. Such microbial products could
and gallbladder (148). IgG4 reactivity against stimulate specific combinations of pattern-
acinar cells in the pancreas or salivary glands, or recognition receptors on antigen-presenting
hepatocytes, was not investigated in this study. cells that drive the production of IL-4, leading
Autoantibodies against the antigens ex- to polarization of the T cells response in a Th2
pressed in the duct epithelia such as carbonic direction.
anhydrase II and IV (CA-II and CA-IV) have An association between H. pylori infection
been described in ∼30% to 50% of AIP cases and AIP has been proposed (155). Another
(99, 149). Although the IgG subclasses of the study, which used a random peptide display
anti-CA-II and anti-CA-IV autoantibodies library to identify target antigens in AIP,

338 Mahajan et al.

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PM09CH14-Stone ARI 24 September 2013 16:52

has led to further speculation that molecular from several commensal and environmental
mimicry between H. pylori and self-proteins microbes such as Bacteroides fragilis, Olsenella
is involved in AIP (156). Sera from more than uli, Entamoeba invadens, and Owenweeksia
90% of AIP patients specifically recognized hongkongensis. Many of these hits come from
the peptide SKDERRF. A homology search recently available bacterial whole-genome
in the H. pylori proteome yielded a similar sequences. Furthermore, a BLAST search
peptide sequence, AKEERRY, in the H. pylori also reveals that residues 48–54 of another
plasminogen binding protein. Patients’ sera human protein, TGF-β regulator 1, are 100%
recognized this protein both in SDS-PAGE identical to the putative H. pylori antigenic
(sodium dodecyl sulfate–polyacrylamide gel peptide AKEERRY. Even if microbial mimicry
electrophoresis) Western blots and in the form did play a causative role in AIP, these findings
of a synthetic peptide epitope. The authors illustrate the difficulties in finding the relevant
of this study note that a human E3 ubiquitin microbial antigens when the reactivity of the
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

ligase, UBR2, contains a homologous peptide autoimmune sera is known only in terms of
sequence, AKEQRRQ, similar to residues a short peptide sequence, especially in an era
298–304 of the H. pylori plasminogen-binding when protein sequence databases are expanding
protein, AKEERRY. UBR2 is also specifically exponentially.
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recognized by the autoimmune sera. This The same research group (157–159) has
report has led to further speculation that also reported independent associations between
molecular mimicry between H. pylori and H. pylori and Alzheimer’s disease, glau-
self-proteins is involved in AIP. coma, and acute inflammatory demyelinat-
However, a Basic Local Alignment ing polyradiculoneuropathy. In the absence
Search Tool (BLAST) search (Supplemental of a meta-analysis that adequately corrects
Table 1; follow the Supplemental Material for multiple-hypothesis testing, or independent
link from the Annual Reviews home page studies that can confirm the association be-
at http://www.annualreviews.org) that the tween H. pylori and AIP, one cannot be con-
original hit from the random peptide library, fident about the pathophysiologic significance
SKDERRF, is 100% identical to proteins of these associations.

SUMMARY POINTS
1. IgG4-RD is a systemic fibroinflammatory condition that can affect almost any organ
in the body. This disease tends to cause tumefactive lesions that are often mistaken for
malignancies.
2. The four cardinal histopathologic features of this condition are a dense lymphoplasma-
cytic infiltrate with IgG4+ plasma cells, storiform fibrosis, mild to moderate eosinophilia,
and obliterative phlebitis.
3. Minor pathology features that are also present in many patients include germinal centers,
lymphoid follicles, obliterative arteritis, and nonobliterative phlebitis.
4. T helper and Treg cells in IgG4-RD lesions induce an inflammatory cytokine milieu
that leads to the IgG4 class-switch and the recruitment of profibrotic macrophages and
fibroblasts.
5. IgG4-RD shows an excellent clinical response to rituximab, a selective B cell–depleting
agent. This finding is consistent with the idea that at least one major function of

www.annualreviews.org • IgG4-Related Disease 339

Changes may still occur before final publication online and in print
PM09CH14-Stone ARI 24 September 2013 16:52

B cells in IgG4-RD is to sustain T helper cells, principally through continuous antigen


presentation.
6. Immunoglobulins of the IgG4 subclass have some unique features. They can undergo Fab
arm exchange and become functionally monovalent. They are unable to fix complement,
weakly bind FcγRs, and are generally considered to be noninflammatory.
7. Autoantibodies against various self-antigens have been described in IgG4-RD, but their
contribution to this disease remains to be clarified. Although autoreactive IgG4 antibodies
have been detected in IgG4-RD, their antigenic targets have not been identified. The
precise role of IgG4 autoantibodies in the disease pathophysiology remains unclear.
Annu. Rev. Pathol. Mech. Dis. 2014.9. Downloaded from www.annualreviews.org

FUTURE ISSUES
1. We anticipate that genetic factors will play a role in the disease process, but the sub-
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jects studied to date are too few for meaningful genome-wide association studies or the
identification of rare genetic variants by sequence analyses. A sufficiently powered search
for genetic factors that are shared with known Th2 disorders or with other chronic
inflammatory diseases would be valuable.
2. Regarding the initiating events in the pathogenesis of IgG4-RD, little is known with
certainty. Clues about a possible role for microbes in the process of initiation and patho-
genesis of other disorders may be relevant to IgG4-RD. Studies of the human microbiome
may also be useful in this regard.
3. B cells clearly play an important role in this disease, but uncertainty remains about the
nature of IgG4 immune complexes and their ability to fix complement in IgG4-RD.
Autoreactive B cells and possibly IgG4 autoantibodies appear to play a crucial role in
maintaining pathogenic CD4+ T cells in what may actually be a T cell–mediated disease.
Identifying the target antigens of the IgG4 antibodies in IgG4-RD will probably be
critical in understanding the pathogenesis of this condition.
4. IgG4-RD appears to be driven by pathogenic Th1 or Th2 cells, possibly in conjunction
with Treg cells. These T cell subsets may drive the differentiation and activation of con-
ventional or alternatively activated macrophages and fibroblasts that cause the crippling
storiform fibrotic lesions in this disease. Further studies on the role of fibroblasts and
macrophages in the pathogenesis of fibrosis will be rewarding.

DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
2. Presents the first link
might be perceived as affecting the objectivity of this review.
of elevated serum IgG4
concentrations to an
organ manifestation,
now recognized as part
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3. Kamisawa T, Egawa N, Nakajima H. 2003. Autoimmune pancreatitis is a systemic autoimmune disease.


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