Seminar

IgG4- related diseases

M.Vishnu Vardhan Reddy

Clinical Immunology department
SGPGIMS,Lucknow,India
13 Jan 2011
 Format of Presentation

• Introduction
– History
– What is IgG4, special properties
• Clinical features
– Case report
– Clinical spectrum
– Prototype – AIP
– Extrapancreatic lesions
Introduction
 Timeline

• 1961 -Autoimmune pancreatitis was first described

• 2001- diagnostic value of serum IgG4 concentrations became

well known

• 2003- Kamisawa et al proposed a new concept of IgG4-related

autoimmune disease around autoimmune pancreatitis,
2003
 Ig G types

IgG4 subclass

•Least common in serum

•Expressed in conditions of chronic antigenic exposure
 IgG4 breaks rules

What we take for granted : But :

IgG antibodies have 2 identical Bispecific-functional

antigen binding sites- monovalency
monospecific

Antibodies are stable structures Posttranslational modification-

i.e they do not change after dynamic arm exchange
secretion by plasma cell
 Hinge region makes the difference

Hinge core of IgG1- CPPC:

Interchain disulphide bonds

IgG4- CPSC – Cannot form

interchain disulphide bonds
 Dynamic Exchange of IgG4 half molecules

Exchange fab arms by swapping a heavy chain and attached light chain
(half-molecule) with a heavy-light chain pair from another molecule

Bispecific but functionally monovalent

 IgG4 is anti-inflammatory :4 Mech
1. low affinity for C1q and Fc receptors

2. half antibody exchange
bi-specific’ and functionally monovalent

for a given antigen. IgG4 anti-bodies in the circulation cannot form
large immune complexes with antigen

3. much reduced binding to the low-affinity Fc-gamma receptors

4. IgG4 antibodies can displace the binding of those IgG1 or IgE

antibodies with related specificities
 This antiinflammatory property is
therapeutically exploited

IgG4 constant domain used in recombinant

antibodies where effector function is undesirable
 Eponyms -IgG4-related systemic disease
IgG4-RSD
• IgG4-related sclerosing disease

• IgG4-related disease

• IgG4 syndrome

• IgG-related systemic sclerosing disease

• IgG4-related autoimmune disease

• Hyper-IgG4 disease

• Systemic IgG4-related plasmacytic syndrome (SIPS)

• IgG4-postive Multiorgan Lymphoproliferative Syndrome

[MOLPS]
Japan leads in IgG4 RSD reports
Clinical Spectrum
 IgG4 -RSD presents as a mimic

IgG4 RSD Mimic

Autoimmune Pancreatitis
Igg4-associated Cholangitis
Isd-lung Involvement
Hepatopathy
Lymphadenopathy
Sialadenitis-mikulicz Disease,kuttners
Aortitis With Or Without Aneurysm
Retroperitoneal Fibrosis
Orbital Pseudotumor
Igg4 Thyroiditis/Reidels
Ca Pancreas
P S C/Cholangiocarcinoma
Interstitial Pneumonia/Lung Cancer
Autoimmunehepatitis
Lymphoproliferative Neoplasms
Sjogren Syndrome,sarcoid
Takayasu/Gaint Cell/Atherosclerosis
Ormonds Disease
Wegeners/Lymphoma
Hashimoto/Ca Thyroid
 Increasing list-not exhaustive

• Inflammatory masses-of Pituitary-prostate-breast-skin

• Constrictive pericarditis

• Cervical fibrosis

• Meninges -pachymeningitis

• Tubulointerstitial nephritis- increasingly reported

• Gallbladder- acalculous lymphoplasmacytic cholecystitis

Spectrum of IgG4-RSD
 4 histological hallmarks of IgG4 RSD

Lymphoplasmacytic infiltration
Storiform fibrosis

Phlebitis with unremarkable

IgG4 plasma staining on IHC
artery
 Clinical Spectrum

Autoimmune Pancreatitis
Prototype of IgG4 RSD
 Autoimmune pancreatitis
clinical presentation
• Pancreatic manifestations
• Acute
– painless obstructive jaundice (80%)
– [D/D panccreatic CA]
– Acute/recurrent pancreatitis –rare
• Subacute /late:
• Persistent pancreatic mass
• Atrophic pancreas +/- calcifications
• Unexplained steatorrhea
• Extrapancreatic manifestations
• -simultaneous; precede;years later
 AIP 2 types

AIP otherwise implies type 1 –IgG4 related

GCNA2008;37:439-60
Extrapancreatic lesions
Pathogenesis
 Autoimmune origin suggested but never proved
YES
• Autoantigen distribution matches disease distribution
• Response to immunosuppressive therapy
POSSIBLY
• Autoreactive immune response to defined autoantigens
• Production of disease by adoptive transfer of autoreactive cells
and/or antibody
• HLA association
• Induction of disease by sensitisation with autoantigen
• Spontaneous animal model with identical antigen specificity
NO
• Female predisposition
• Both children and adults affected
 Definitive Autoantigen not established

• Antilactoferrin (ALF)
• Anticarbonic anhydrase II or IV (ACA-II, IV)
• Antipancreatic Secretory Trypsin Inhibitor (PSTI) in 30–40%

Genetic factors
• DRB1*0405-DQB1*0401 in Japanese patients
• SNP in CTLA-4 gene in Taiwanese patients
 Tregs are increased in IgG4 RSD!
• number of Tregs increased – in both tissue and blood of
patients with IgG4-related disease

• Animal Models –Treg deficiency leads to spontaneous IgG4

RSD
1. WBN/Kob rats –congentially decreased peripheral Tregs
2. Treg-deficient NODmouse
3. CD28KOmice-closely resembles the human disease—
autoantigen-pancreatic amylase

• Hypothesis--Treg depletion may initiate AIP,while

progression of disease is mediated by Tregs and its
modulation of Th1/th2 balance towards Th2
 Link between IgG4 RSD and Allergic Diathesis-
Th2-dominant reaction

• IgG4-related disease commonly develops in people with a

predisposition to allergy

• serum eosinophilia and high serum IgE levels are frequently

seen

• histologically shows eosinophilic infiltration

• IgG4 class switching depends on interleukin-4 and/or
interleukin-13 mainly secreted by T-helper 2 cells
Biphasic model
Histology–Immunology correlation
 IgG4 elevation is a secondary response

• IgG4 type autoantibodies have not been detected in IgG4-

related disease!!
• whether IgG4 is an autoantibody in IgG4-related disease or is
overexpressed secondarily in response to an unknown
primary inflammatory stimulus??
 Molecular mimicry with H pylori

• Evidence 1:homology between human CA-II and a-CA of H

pylori--the homologous segments contain the binding motif of
DRB1*0405
• possession of the HLA DRB1*0405-DQB1*0401 genotype
confers a risk for AIP development

• Evidence 2: Antibodies to Plasminogen-binding Protein

Peptide
 AIP serology
• Serum IgG4
• >140mg/dl—sensitivity 76% ;specificity 93% PPV 36%
• > 280mg/dl—sensitivity 53% ;specificity 99% PPV 75%
• Elevated in 7-10 % of CA pancreas (usually mild) & 5% of
normal population
• unsuitable single marker for diagnosis but when combined
with other features of AIP, it is diagnostic
• Methods to detect IgG4 : Nephelometry & RID
• Other Autoantibodies-
• Lactoferrin & carbonic anhydrase2•
• disadv--sensitivity –only 50% and not widely available,
• Pancreatic Secretory Trypsin Inhibitor(PSTI),
• ANA, RF
Scatter plot for serum IgG4 in different groups

None 1%

5% 10%
 94%-AIP
5%- pancreatic cancer

PBP - Plasminogen-binding Protein-H.Pylori

UBR2-- Ubiquitin-protein Ligase E3 Component N-recognin 2— NEJM,2009
acinar cells of pancreas
 Diagnostic criteria

• Japan Pancreas Society (JPS I, JPS II)

• Mayo Clinic (HISORt criteria)

• South Korea criteria

• Asian consensus criteria-latest

 3 ways to establish AIP diagnosis
1.Typical imaging + serology or compatible histology
• If IgG4 levels not available ,then less specific
autoimmune serological markers, such as high titres of
ANAs and rheumatoid factor, may also be used

2.Diagnostic histology/immunostaining
• pancreatic histology showing all three features of LPSP-
but seen in only 20%
• IgG4 immunostaining, if there are >10 IgG4-positive
cells per high power field.
• Isolated IgG4 immunostaining is not diagnostic
3.Response to steroids
• Steroid trials are both diagnostic and reassuring
Diagnostic criteria
 Pancreatobiliary Imaging

• Enlargement of the pancreas, diffuse or focal

• Irregular narrowing of main pancreatic duct on ERCP

• Calcifications and cysts are rare

• Stenosis of the distal common bile duct

 Typical imaging features

•diffusely enlarged gland with loss of lobulation (‘‘sausage-shaped’’)

•rim-like enhancement (arrows)

pancreatic duct with multiple strictures BUT not associated with ductal dilatation
 serum IgG4 levels for monitoring therapy
and predicting relapse
• IgG4 levels failed to normalize in 115/182 (63%) of the
patients treated with steroids
• Only 30% of patients with persistent IgG4 elevation relapsed,
• relapse was also seen in 10% of patients who normalized IgG4
levels
• utility of serial IgG4 levels- not convincing at present

Gut 2009,Kamisawa
 Treatment
• Natural history -less known
• Steroid responsive only before dense sclerosis sets in
• Aim of Rx- to prevent organ damage and to prevent the
involvement of other organ systems
• Indications for steroids: Obstructive jaundice, abdominal
pain, and back pain, and the presence of symptomatic
extrapancreatic lesions
• Symptomatic improvement in AIP occurs within 2 weeks
• Benefit of GCs
 higher remission rate
 Less time to remission
 improve pancreatic exocrine function
 2 GC regimens
Japanese
• initially with prednisolone,
0.6mg/kg/day for 2–4 weeks
• taper over a period of 3–6
months to a dose of 5mg/day,
• continue at a dose between
2.5–5mg/day for up to 3 years
• 25% -disease flares despite
receiving maintenance GCs
Mayo clinic
• Start with prednisone
40mg/day -4 weeks
• 7-week prednisone taper -
5mg/week, --stops by the end
of 11 weeks
• more than 50% of AIP patients
relapsed within a median of 3
months (range: 0–14 months)
after discontinuing GCs
 Other treatment options

• MMF and AZA-

• Rituximab
• Bortezomib
IgG4 Related Sialadenitis
 Mikulicz’s disease-IgG4-related plasmacytic
exocrinopathy
• 1888-- Johann von Mikulicz–Radecki reported a case exhibiting
bilateral, painless and symmetrical swellings of the lacrimal, parotid
and submandibular gland

• 1953- Morgan and Castleman - 18 cases diagnosed as having MD--

found both MD and SS were histologically similar;
• Concluded that most cases reported as MD could be included in
SS.– thus MD became a part of SS

• Present Criterion- persistent (>3 months) symmetrical swelling of

atleast two glands:lacrimal /parotid/SM glands
• Less female predominance[2.5:1]
• Persistent but not intermittent swelling of lacrimal and
salivary glands
• 50% lack KCS, &Sialogrphy was normal
• no anti-SS-A or SS-B antibodies
• All had elevated igg4
• Abundant plasmacytes with IgG4 are detected in the lacrimal
glands, salivary glands and lymph nodes
• frequency of apoptosis in glands of MD patients is lower
• Excellent response to steroids and rituximab
Serum IgG4 levels were significantly higher and serum IgG1 levels
were significantly lower in Mikulicz’s disease than in Sjogren’s
syndrome
Anti-IgG4 antibody staining:minor salivary glands

MD- abundant IgG4-bearing

SS- no infiltrating cell
plasmacytes infiltrating around
with IgG4
acinar and ductal cells
IgG4-associated
chronic sclerosing sialadenitis,
Küttner’s tumor
 Chronic sclerosing sialadentis (Kuttner tumor)

• middle-aged to elderly patients (mean 61 years) with a slight male

predominance
• a unilateral or bilateral, largely symmetrical hard enlargement of
the submandibular salivary glands
• One fourth have other manifestations of IgG4-RSD
• Salivary functions are normal
• serum IgG4 variably elevated
 Summary of Immune Mediated Sialadenitis

IgG4 related:
1. IgG4-associated sialadenitis-(Mikulicz’s disease) –
lacrimal/parotid/SM glands-symmetrical-atleast 2 , for >3
months
2. Chronic sclerosing sialadenitis[Kuttner tumor]-hard u/l or b/l
SM gland swelling

Non IgG4
1. Sjogren
2. Lymphoma
3. Sarcoidosis
• Compared with 31 typical SS patients
• the numbers of patients with symptoms of xerostomia, xerophthalmia and
arthralgia were significantly lower
• Allergic rhinitis and autoimmune pancreatitis were significantly more
common
• Interstitial pneumonitis was significantly rarer
• Not only IgG4 but also total IgG, IgG2 and IgE levels were significantly
higher
• IgG1, IgG3, IgA and IgMlevels were significantly lower
• Lymphocytic infiltration into the ducts (formation of lymphoepithelial
lesions) was rare
• good response to glucocorticoid treatment

• Suspect -IgG4+MOLPS should therefore be suspected in

patients with symptoms of SS but without auto antibodies,
and IgG subclasses should be examined in such patients
Effect of glucocorticoid therapy on swollen lacrimal glands.

Masaki Y et al. Ann Rheum Dis 2009;68:1310-1315

Clinical Spectrum

Other diseases
 Systemic IgG4-related Lymphadenopathy
• CLINICAL PRESENTATION
• Systemic lymphadenopathy
• Lymph node are not very large (usually up to 2cm)
• Exocrine or extranodal lesions may precede,follow, or present
together with the lymph node swelling
• Absence of fever

• ABNORMAL LABORATORY FINDINGS:

• Polyclonal hyperimmunoglobulinemia
• Raised serum IgG and IgE levels
• Elevation of serum soluble interleukin-2 Receptor
• Presence of autoantibodies

• Normal laboratory findings-- IL-6 level,CRP,LDH

 IgG4-related lymphadenopathy
4 histologic patterns

Distribution pattern of
Pattern Histological subtype IgG4-positive cells
Castleman’s disease-like
1 morphology Interfollicular
2 Reactive follicular hyperplasia Interfollicular
Interfollicularplasmacytosis
3 and immunoblastosis Interfollicular
Progressive transformation of Intra-germinal
4 germinal center-like center
Inflammatory pseudotumor-like
5 morphology Interfollicular
Lung Disease- 4 patterns
Thyroid disease
 IgG4 thyroiditis

Organ specific Systemic

Hashimoto’s
Reidels
disease subtype-
thyroiditis
more common
 Hashimoto thyroiditis -IgG4 subtype
• 10% of all patients with Hashimoto’s thyroiditis
• gland is usually larger and more fibrotic
• a recent striking enlargement with severe neck
pressure symptoms –confused with malignant disease
• More males but still female predominant
• shorter disease duration of Hashimoto’s thyroiditis
before surgery
• higher doses of L-T4 needed
• Higher serum titers of the thyroid auto-antibodiesTgAb
and TPOAb
• Diffuse low echogenicity [c.f. diffuse coarse
echogenicity in non IgG4 thyroiditid]
Riedel’s Thyroiditis - Invasive fibrousThyroiditis
• Rare Incidence -0.06% only
• a nonpainful, rapidly growing thyroid mass
• fibroinflammatory mass extends beyond the thyroid capsule
into adjacent anatomic structures
• 1/3 rd have evidence of multifocal fibrosclerosis
Idiopathic Retroperitoneal Fibrosis
All reported till date are male
Pancreas –mc other organ > salivary
glans>lymph node

Middle aged to elderly male

Low back pain
Obstructive renal failure
ureteral colic-like pain,
constipation, deep vein thrombosis,
leg edema, and scrotal swelling due
to varicocele or hydrocele

May or may not be a/w chronic

periaortitis
 IgG4-related chronic periaortitis

• Abdominal > Thoracic

• 2 types
– Aneurysmal
– Nonaneurysmal–called IRPF
• Elderly > 60 years
• Rare
 Idiopathic Cervical Fibrosis—latest entry

• rare tumefactive inflammatory-sclerosing lesion involving the soft

tissues of the head and neck
• Also have inflammatory fibrosclerosing lesions in other anatomic
sites
• Presents with an infiltrative, firm cervical mass

American Journal of Surgical Pathology: Nov 2010,

IgG4- related Tubulo Interstitial Nephritis
• usually has tubular basement membrane (TBM) and interstitial
immune complex deposits
• Affects 20-30% of AIP patients
• When to suspect-
presence of a plasma cell rich TIN in a patient with :

• renal mass / enlarged kidneys on imaging studies

• hypergammaglobulinemia,
• hypocomplementemia,
• Eosinophilia
• an extrarenal inflammatory mass
• sialadenitis, lymphadenopathy,
• patchy lesion distribution
Anti-PLA2R autoantibodies in serum and
Immunoglobulin subclass in glomerular deposits– IgG4
 Myasthenia gravis-MuSK antibodies

• Nowadays ,2 clinicopathologic MG subsets recognised:

1. AChR-MG-IgG1 and IgG3 subclass antibodies
2. MuSK-MG-Antibodies of igg4 subclass to muscle-specific
tyrosine kinase (MuSK)
 Take home messages
• IgG4- monovalent, bispecific,antiinflammatory
• Most common presentation- AIP- mimics CA pancreas
• Knowledge of Full spectrum still evolving
• Suspect IgG4 rsd:
• All unexplained tumorous swelling –
• Any Fibrosclerosing lesion-
• Any steroid responsive mass lesion-
• All males with SS,negative autoantibodies
• Generalized lymphadenopathy without constitutional
symptoms
 Take home messages
• Once diagnosed in one organ Search actively for e/o other
organ involvement
• Take histories of asthma, eczema, or atopy
• Risk of Lymphoma transformation –only case reports-not
proved
• Elevated serum IgG4 concentrations are neither necessary nor
sufficient for the diagnosis of IgG4-RSDbut when present are
helpful in suggesting the diagnosis
• gold standard for the diagnosis-identification of typical
histopathological features, including the presence of
numerous IgG4þ plasma cells within affected tissue
Suggested readings
IgG4RSD-reminds of Elephant and 5
blind men
Thank you