Autoimmunity Reviews 19 (2020) 102646

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Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Update on IgG4-mediated autoimmune diseases: New insights and new T

family members
Inga Koneczny
Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Währingergürtel 18-20, 1090 Vienna, Austria

ARTICLE INFO ABSTRACT

Keywords: Antibodies of IgG4 subclass are exceptional players of the immune system, as they are considered to be im-
IgG4 munologically inert and functionally monovalent, and as such may be part of classical tolerance mechanisms.
Autoimmunity IgG4 antibodies are found in a range of different diseases, including IgG4-related diseases, allergy, cancer,
Autoantibodies rheumatoid arthritis, helminth infection and IgG4 autoimmune diseases, where they may be pathogenic or
Pathogenic mechanisms
protective. IgG4 autoimmune diseases are an emerging new group of diseases that are characterized by pa-
Classification
thogenic, antigen-specific autoantibodies of IgG4 subclass, such as MuSK myasthenia gravis, pemphigus vulgaris
and thrombotic thrombocytopenic purpura. The list of IgG4 autoantigens is rapidly growing and to date contains
29 candidate antigens. Interestingly, IgG4 autoimmune diseases are restricted to four distinct organs: 1) the
central and peripheral nervous system, 2) the kidney, 3) the skin and mucous membranes and 4) the vascular
system and soluble antigens in the blood circulation. The pathogenicity of IgG4 can be validated using our
classification system, and is usually excerted by functional blocking of protein-protein interaction.

1. Introduction mortality rate in pemphigus [3]).

IgG4 autoimmune diseases (IgG4-AID) are an emerging group of
autoimmune diseases that are characterized by the presence of auto-
antibodies of IgG4 subclass [1,2]. While the antigens in IgG4-AID are
located throughout the body, they are found accumulated in four major
organs (Fig. 1): 1) the predominant target organ with ten established
and proposed antigens is the central and peripheral nervous system
(including the neuromuscular synapse), 2) six antigens are located in
the skin, 3) three (six if we also count intracellular antigens) are tar-
geting the kidney and 4) two antigens are located in the blood circu-
lation (seven if we also count ANCAs and autoantigens in APECED),
extending the number of autoantigens in proposed IgG4-AID from
fourteen to up to 29. Examples for IgG4-AID are well-known diseases
such as pemphigus vulgaris and foliaceus, MuSK Myasthenia gravis or
thrombotic thrombocytopenic purpura. IgG4-AID are rare, with pre-
valence below 5 per 10,000 (Table 1), and severe, with many forms
being fatal if left untreated or even with treatment (e.g. 5–30%
Most pathogenic mechanisms of autoantibodies rely on the effector
function of the Fc region and can be called Fc-dependent (Fig. 2A).
These include the recruitment of C1q and activation of the classical
complement pathway and complement-dependent cytotoxicity (CDC),
as seen e.g. in myasthenia gravis with autoantibodies to the acet-
ylcholine receptor (AChR-MG, reviewed by [12]). By-products of the
complement cascade, C5a and C3a, may also recruit leukocytes that
further inflammation and tissue damage. Leukocytes may interact via
activating Fcγ receptors with the Fc region of bound IgG and may lead
to tissue damage via antibody-dependent cellular cytotoxicity (ADCC)
e.g. by release of reactive oxygen species, perforin, granzymes, lipid
mediators or proinflammatory cytokines, as seen e.g. in neuromyelitis
optica spectrum disorder (NMOSD) [13,14]. Soluble antigen may be
cross-linked by autoantibodies that bind multivalently, such as IgG or
IgM, forming immune complexes that may lead to microthrombosis or
further stimulate inflammation e.g. by activation of the complement
system, as seen in systemic lupus erythematosus (SLE) [15]. Cross-

Abbreviations: ADAMTS13, A disintegrin and metalloproteinase with thrombospondin motifs 13; APECED, Autoimmune poly-
endocrinopathy–candidiasis–ectodermal dystrophy; AR, Aldose reductase; BP, Bullous pemphigoid; CIDP, Chronic inflammatory demyelinating polyneuropathy;
CNTN1, Contactin 1; Caspr1,2, Contactin associated protein1,2; Dsg1,3, Desmoglein 1, 3; DPPX, Dipeptidyl-peptidase-like protein 6; FAE, Fab-arm exchange;
GPIHBP1, Glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1; GSH, Glutathione; IgLON5, IgLON family member 5; Lam332, Laminin
332; LGI1, Leucine-rich, glioma inactivated 1; Lrp4, Low density lipoprotein receptor-related protein 4; MBL, Mannose-binding lectin; MMP, Anti-laminin mucous
membrane pemphigoid; MuSK, Muscle-specific kinase; MG, Myasthenia gravis; MN, Membranous nephropathy; PLA2R, Phospholipase A2 receptor (PLA2R);
THSD7A, Thrombospondin type-1 domain- containing 7A; TTP, Thrombotic thrombocytopenic purpura; vWF, von Willebrand factor
E-mail address: inga.koneczny@meduniwien.ac.at.

https://doi.org/10.1016/j.autrev.2020.102646
Received 29 February 2020; Accepted 8 March 2020
Available online 13 August 2020
1568-9972/ © 2020 The Author. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/BY/4.0/).
I. Koneczny
Fig. 1. IgG4 autoantigens have been identified in four distinct organs: 1) the
central and peripheral nervous system, 2) the skin and mucous membranes, 3)
the kidneys and 4) located in the blood circulation or associated with the
vascular system.
linking of transmembrane proteins may cause increased endocytosis
and degradation of antigen from the cell surface, thus depleting the
protein from the cell surface, which can also be seen with auto-
antibodies against the AChR but also with antibodies against the NMDA
receptor, glycine receptor and antibodies against other neurological
targets [16–20]. Phagocytes such as macrophages may also interact
with bound IgG via the FcγR and phagocytose the target cell, which can
be observed e.g. in autoimmune haemolytic anaemia [21]. A thorough
review on pathogenic mechanisms of autoantibodies can be found here:
[22].
Due to structural differences in the Fc region, IgG4 is incompatible
with these Fc-dependent effector mechanisms. Instead, IgG4 relies on
Fc-independent mechanisms, which is a block of protein-protein inter-
action with different consequences (Fig. 2B): direct blocking of receptor
or enzyme function, as seen in thrombotic thrombocytopenic purpura
[23] or AChR-MG, stimulation of the receptor by binding as seen with
anti-TSHR antibodies in Grave's disease [24,25], blocking of signal
transduction pathways as in MuSK-MG [26], and loss of cell-cell ad-
hesion that destabilizes the tissue architecture as seen in pemphigus
[27].
IgG4 is considered as immunologically inert and upregulated after
chronic or strong antigen stimulation [28–31]. Therefore it can be
present in addition to antibodies of other Ig classes and IgG subclasses,
where it has a protective (rather than a pathogenic) function. In con-
sequence it is essential for diseases associated with IgG4 to determine
whether IgG4 is pathogenic or protective. Our recently developed
classification system allows to determine IgG4 pathogenicity [1]. In this
study we will review the key characteristics of IgG4 and examine es-
tablished and proposed IgG4 autoimmune diseases for IgG4 patho-
genicity.
2. Structure and function of IgG4
2.1. IgG structure
IgG consists of two heavy chains (H) with 50 kDa and two light
chains (L) with 25 kDa that are connected via covalent and non-
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Autoimmunity Reviews 19 (2020) 102646
covalent interaction and that together form a heterotetramer (H2L2). At
the n-terminal end of the heavy and light chains, a variable region is
located (VH and VL), which recognizes and binds antigen. Specifically
the three hypervariable complementarity- determining regions
(CDR1–3) in the V-region ensure the high specificity and diversity of
the antibodies. Next to the V-region are one (light chain) or three
(heavy chain) constant domains, numbered from n-terminus to c-ter-
minus in ascending order (light chain: CL, heavy chain: CH1, CH2, CH3).
The constant regions mediate effector functions of the antibody. The
hinge region is located between the CH1 and the CH2, where the two
heavy chains are connected via disulphide bridges: two in IgG1 and
IgG4, four in IgG2 and eleven in IgG3 [32–34]. The hinge region allows
for structural flexibility of the antibody, which may assume different
conformations such as the Y-form, or the T-form that may grant in-
creased stability that withstands high pressure [35,36].
Functionally, IgG can also be divided in the “Fab” region which
consists of the CH1, VH, CL and VL, which binds the antigen, and the Fc
region, which consists of the CH2-CH3 and the hinge, and which med-
iates the antibody effector function. The term “Fab” and “Fc” derive
historically from the two products after IgG digestion with papain
(Fab= “Fragment, antigen binding”, Fc = Fragment, crystallized”, re-
viewed by [37]). There is over 90% sequence homology in the constant
domains of the four IgG subclasses, but single amino acid differences in
IgG4 (as compared to IgG1) have great impact on its structure and
function.
2.2. IgG4 is immunological inert
In the CH2 region, a serine instead of a proline at position 331
(“P331S”) changes the structure, which prevents binding of C1q and
leads to a loss of complement activation [38,39]. Complement activa-
tion can, however, not completely be dismissed as mechanism for IgG4,
as there are two notable exceptions to the rule: 1) mutations in the Fc
region of IgG4 led to the formation of artificial hexameric complexes
via non-covalent interactions, and these could bind C1q and activate
the classical complement pathway [40]. While this experimental setup
was quite artificial, another exception could be 2) IgG4 with hypoga-
lactosylated side chains that could recruit mannose-binding lectins
(MBL) and activate complement via the lectin pathway. This me-
chanism was suggested for PLA2R-IgG4 in membranous nephropathy
[41–46], rheumatoid arthritis [47] and IgA nephropathy [48].
Further single amino acid differences in the CH2 (L234F, P331S,
A327G) reduce the interaction with activating Fcγ receptors [49–54]).
As a consequence, IgG4 is not able to activate immune cells. Taken
together, IgG4 cannot induce inflammatory processes via complement
or immune cells and is therefore immunologically inert.
2.3. The IgG4 hinge region is flexible
The sequence differences between IgG1 and IgG4 have structural
consequences. Noncovalent interaction of the CH3 regions are strongly
reduced by a single amino acid change in the CH3 region (R409K)
[55,56] and another amino acid replacement in the hinge (P228S) leads
to greater stereometric flexibility. Indeed IgG4 is not only found in the
Y- and T-conformation but also occurs in a novel conformation termed
λ-shape. Here one of the Fab arms is located near the Fc region and the
other Fab arm is stretched out [57]. Moreover, this flexibility also al-
lows for the generation of intrachain disulphide bridges instead of the
interchain disulphide bridges that normally connect the two heavy
chains [58–60].
2.4. The mechanism of Fab-arm exchange
The loss of covalent connections between the heavy chains, together
with reduced binding of the CH3 regions leads to a dissociation of IgG4
into two half-molecules consisting each of a heavy and a light chain.
I. Koneczny Autoimmunity Reviews 19 (2020) 102646

Table 1
Prevalence of IgG4 autoimmune diseases.
Antigenic target of IgG4 Associated disease Prevalence (per 10,000) Reference/Source Orpha number

Class I disease: pathogenicity of IgG4 proven

MuSK MuSK Myasthenia gravis 0.02 [4,5] ORPHA:589
CNTN1 CIDP < 0.014 (less than 5% of CIDP which as a prevalence [6,7] ORPHA:2932
of 0.28)
NF155 Peripheral neuropathies, CIDP < 0.014 (less than 5% of CIDP which as a prevalence [6,7] ORPHA:2932
of 0.28)
Desmoglein 1 Pemphigus foliaceus 0.1–0.95 [8,9] ORPHA:79481
Desmoglein 3 Pemphigus vulgaris 1–5 Orpha.net ORPHA:704
ADAMTS13 Thrombotic thrombocytopenic purpura 1–5 Orpha.net ORPHA:93585

Class II disease: pathogenicity of IgG4 very likely

CASPR2 PNS and CNS diseases N/A N/A ORPHA:276402
LGI1 Limbic encephalitis N/A N/A ORPHA:163908
PLA2R Membranous nephropathy 0.1 Orpha.net ORPHA:97560
THSD7A Membranous nephropathy 0.003 Orpha.net ORPHA:97560
CASPR1 CIDP < 0.014 (less than 5% of CIDP which as a prevalence [6,7] ORPHA:2932
of 0,28)
GPIHBP1 GPIHBP1 autoantibody syndrome Only few patients described [10,11] Not yet registered
Lam 332 Mucous membrane pemphigoid < 0.246 [8] ORPHA:46486

Class III disease: pathogenicity of IgG4 unclear

Type IV Collagen Goodpasture syndrome 0.001–0.009 Orpha.net ORPHA:375
IgLON5 IgLON5-parasomnia < 0.001 Orpha.net ORPHA:420789
DPPX DPPX-encephalitis < 0.001 Orpha.net ORPHA:329341
Neurofascin 140/186 CIDP < 0.014 (less than 5% of CIDP [6,7] ORPHA:2932
αenolase, SOD2, AR Membranous nephropathy N/A N/A ORPHA:97560
ANCA Granulomatosis with polyangiitis 0.1–0.9 Orpha.net ORPHA:900
Bulloid pemphigoid antigen 180/230 Bullous pemphigoid 1–5 Orpha.net ORPHA:703
IFN I, IL-17A, IL-17F and IL-22 APECED 0.01–0.09 Orpha.net ORPHA:3453
P200 (laminin γ1) Anti-laminin γ1/Anti-P200 < 0.01 Orpha.net ORPHA:454710
pemphigoid

The half-molecules can then recombine randomly to form chimeric, bi-
specific antibodies that may cross-link two different antigens and that
may also possess two different light chains. This process is termed “Fab-
arm exchange” and may occur continuously under reducing conditions
(Fig. 3), which may also have led to its comparison to “square-dancing”
of antibody half-molecules [61–68]. According to our calculations, we
estimate that up to 99% of IgG4 is bi-specific, and we could also observe
bi-specificity in IgG4 autoantibodies against MuSK [68,69]. The bi-
specificity has the consequence that IgG4 is not able to cross-link an-
tigen and therefore cannot induce antibody-induced endocytosis or
form antigen-antibody immune complexes [66,70,71]. IgG4 can instead
prevent immune precipitation by IgG1 antibodies [63,72].
2.5. Fc-Fc interactions
Interestingly, IgG4 has yet another unique function, as it was found
that a dissociation of the heavy chains of IgG4 was associated with the
binding to other IgG via Fc-Fc interactions if the binding partner is
immobilized on a solid phase [73–76]. This interaction with other IgG
may lead to the aggregation of IgG4, or the formation of IgG4-con-
taining immune complexes as observed in IgG4-RLD, rheumatoid ar-
thritis and membranous nephropathy [77–79], but it is unclear whether
this plays a role for IgG4 pathogenicity in IgG4-AID.
In parasitic infection, IgG4 was suspected to play a role in the
regulation of complement activation [80–83]. A recent study found that
the Fc of IgG4 interacts with other IgG FCs and reduces the affinity of
IgG1 and IgG2 (but not IgG3) for C1q binding, which was restored after
IgG4 depletion from the patient plasma [84]. Taken together with the
ability to break up immune complexes, this is another active me-
chanism for anti-inflammatory action, in addition to the passive me-
chanism of immunological inertness. The following excellent reviews
are suggested for a more in-depth understanding of the structure,
function and regulation of IgG4 [1,70,85–87].
3. IgG4 in health and disease
Due to its immunological inertness and inability to exert Fc-de-
pendent antibody effector mechanisms, it is thought that IgG4 plays a
role in anti-inflammatory tolerance mechanisms [87]. By competitive
binding and blocking of epitopes on autoantigens, IgG4 prevents
binding of other antibody classes or subclasses and thus neutralizes
their effector mechanism (Fig. 4) [30,31,72,88–93]. The protective role
of IgG4 has been demonstrated by passive transfer experiments with
purified IgG4, e.g. in the context of bee venom allergy and myasthenia
gravis [66,94,95].
Yet IgG4 has been associated with a range of diseases (Fig. 5). In
addition to the IgG4-AID, IgG4 may play a role in cancer, allergies,
rheumatoid arthritis, helminth infection, systemic lupus erythematosus
and rheumatoid arthritis and IgG4-related diseases (IgG4-RLD). The
loss of antibody effector function due to neutralization of antigen by
IgG4 is thought to be protective within the scope of allergy, as antigen-
specific IgG4 levels were increased in allergy patients [96] and IgG4
levels rise after allergen immunotherapy [97–99].
In the context of malignancies, stimulating a class switch towards
IgG4 of anti-tumour antibodies may be the tumour cell's way to escape
immune surveillance and survive and is associated with unfavourable
prognosis, e.g. in melanoma, extrahepatic cholangiocarcinoma, pan-
creatic cancer or glioblastoma [100].
Similarly, helminths are parasites that aim to evade the host im-
mune system, while the host organism tries to destroy the parasite,
which led to an arms race between parasite and host that shaped our
immune system [101,102]. To evade the host immune system, hel-
minths stimulate (among other things) the production of IL-10 and
Tregs [103], which inhibits T-cell immunity [104] and induce the class-
switch of anti-worm antibodies towards IgG4 [105,106]. As a “by-
stander effect”, the immune modulation by helminth parasites may
protect the host from allergies and autoimmune diseases. This is also
part of the “hygiene hypothesis” which sees causality between the rise
of autoinflammatory and allergy conditions in the Western world with

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I. Koneczny
the increase of hygienic standards and reduced parasite infections
[101,102,107,108]. Thus, whether anti-worm IgG4 is protective or not
in helminth infection depends on the perspective and circumstances,
since it certainly protects the worm. The study of helminth infection is
interesting also for the field of IgG4-AID, since in both conditions parts
4
Autoimmunity Reviews 19 (2020) 102646
Fig. 2. Effector mechanisms of antibodies. A) Fc-
dependent antibody effector mechanisms include
complement activation, formation of immune com-
plexes, leukocyte recruitment and activation of im-
mune cells via activating FcγR and phagocytosis,
leading to inflammation and tissue damage, and
cross-linking of transmembrane proteins leading to
increased turnover and antigen depletion, often
dramatically affecting functional tissue architecture.
B) Fc-independent mechanisms include receptor sti-
mulation, and mechanisms mediated by blocking of
protein-protein interaction in trans, e.g. interrupting
cell-cell interaction or block of ligand or substrate
binding to enzymes and receptors, or in cis, leading
to interruption of signal transduction pathways.
of the same machinery (Treg-IL10-IgG4) could be responsible for pa-
thogenicity, and may present similar targets for new therapies.
IgG4 subclass antibodies are present in rheumatoid arthritis, as they
comprise a large fraction of the anti-citrullinated protein antibodies
(ACPA) [109,110]. ACPA-IgG4 have also a different Fc-glycan profile
I. Koneczny Autoimmunity Reviews 19 (2020) 102646

Fig. 3. Fab-arm exchange is a continuous process. Under reducing conditions

the two IgG half-molecules may lose the covalent connection via interchain
disulphide bridges in the hinge region, as intrachain and interchain disulphide
bridges exist in a dynamic equilibrium. The resulting IgG4 half-molecules dis-
sociate and may stochastically recombine to form intact bispecific IgG4, which
may again dissociate to half-molecules for the duration of reducing conditions.

than IgG1-ACPA [111], and it is possible that the differential glycosy-

lation and IgG subclass may affect effector- and regulatory function of
the antibodies. Interestingly, a positive treatment response in RA pa-
tients was associated with decreased levels of ACPA-IgG4 [112,113].
Furthermore, in RA and SLE, F(ab)2 fragments of IgG4 subclass anti-
bodies may become targets of anti-hinge antibodies (AHA), leading to
formation of large immune complexes that may induce inflammation
and tissue damage or reconstitution of complement activation by the Fc
of the AHA [114–116]. Nevertheless, the relevance of the IgG4 subclass
in RA is not understood yet.
Similarly, the role of IgG4 in IgG4-RLD is unclear [117]. IgG4-RLD
is a collective term for a group of diseases that may affect different
organs and are associated with IgG4, such as IgG4-related pancreatitis
[118,119], IgG4-related periaortitis/periarteritis [120], IgG4-related
lung disease [121] or IgG4-related hypophysitis [122]. Hallmark
characteristics are high levels of serum IgG4 [123], fibrosis and tume-
factive lesions in different target organs with IgG4+ plasma cell in-
Fig. 4. IgG4 is immunologically inert and may dampen immune reactions. IgG4
filtrates [124,125]. Notably, these characteristics are not observed in
competes for antigen binding with other antibody (sub-)classes that may exert
IgG4-AID, which is why we believe them to be two distinct groups of
Fc-dependent effector mechanisms, therefore effectively inhibiting antibody
diseases. There are also few known antigen-specific IgG4 auto- effector mechanisms. IgG4 is bispecific, which allows only for monovalent
antibodies in IgG4-RLD, with unclear evidence regarding the patho- antigen binding, thereby preventing the formation of antibody-antigen immune
genicity of IgG4, which is discussed in detail in this excellent review: complexes in solution, and the cross-linking and endocytosis of transmembrane
[117]. Indeed there is some evidence for a protective role of IgG4. proteins. Furthermore, IgG4 does not bind to C1q and has reduced affinity for
Shiokawa et al. showed that passive transfer of isolated IgG1 from activating FcγR, thereby preventing complement activation or immune cell
patients with a pancreatic form of IgG4-RLD (and to a degree also IgG4) mediated mechanisms such as antibody dependent cellular cytotoxicity
was pathogenic in neonatal male Balb/c mice, but that co-transfer of (ADCC).
IgG1 and IgG4 significantly inhibited the pathogenic damage [126].
Furthermore, autoantibodies of IgG1 and IgG4 subclass to annexin-A11, correlated with increased plasma galectin-3 levels and increase of IgG4
a calcium-dependent phospholipid-binding protein, were identified in levels [128] and it was hypothesized that these antibodies may be as-
patients with IgG4-RLD targeting the pancreas, bile duct and salivary sociated with tissue fibrosis [117]. There are further studies needed to
glands. Two binding epitopes were shared among patients and it was determine the role of IgG4 in IgG4-RLD. Recently a new animal model
suggested that IgG4 antibodies block the binding of IgG1 antibodies of IgG4-RLD was proposed, here a mutation of an adaptor protein in-
[127]. Still, annexin A11 is an intracellular protein, making it an un- volved in T-cell receptor signalling, Linker for activation of T cell (LAT),
likely target for pathogenic autoantibodies as a primary cause of dis- induced increased expression of the mouse-equivalent of human IgG4,
ease, and it is also found in a range of other autoimmune diseases such which is mouse IgG1, in combination with multiple organ tissue lesions
as SLE. A recent study identified another autoantibody target in IgG4- similar to those observed in patients with IgG4-RLD [129]. It would be
RLD, namely galectin-3, the autoantibodies were of IgG4 and IgE sub- interesting to study if autoantigen-specific antibodies are present in this
class and found in 28% of the patient cohort. Notably galectin-3-IgG4 mouse model, and whether passive transfer of IgG to wildtype animals

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I. Koneczny Autoimmunity Reviews 19 (2020) 102646

Fig. 5. Diseases associated with IgG4. IgG4 is found in a range of diseases, in

which it may have different roles. IgG4 has immune regulative properties and
by such is protective in the context of allergy, but may instead be harmful in the
context of cancer and helminth infection, where the host immune system is
prevented from attacking tumour cells or parasitic worms. In rheumatoid ar-
thritis, IgG4 may become a target of autoantibodies itself that target the IgG4
hinge region (so called anti-hinge antibodies, or AHAs). The role of IgG4 in
IgG4-related diseases is not understood. In IgG4 autoimmune diseases, antigen-
specific IgG4 are directly pathogenic by blocking mechanisms.

also induces IgG4-RLD-like symptoms. Taken together, it is not yet clear

what the role of IgG4 is in IgG4-RLD, but in many IgG4-AID there is
evidence (or at least a strong suspicion) that antigen-specific IgG4 is a
pathogenic entity [1].

4. IgG4 classification system

In order to determine the pathogenicity of IgG4 in IgG4-AID, we

have recently proposed a new classification system (Box 1, [1]). The
classification system is based on the Witebsky postulates and observa-
tions from Naparstek and Plotz [130–132].
Box 1: Specific indicators for IgG4 pathogenicity [1]

1. Autoantibodies of IgG4 subclass against extracellular antigen are

present.
2. A pathogenic mechanism for IgG4 can be demonstrated in vitro.
IgG4 could be purified from patient serum, and the purity of isolated
IgG4 should be validated. Alternatively, cloned patient antibodies
from IgG4+ B-cells could be used.
3. Reproduction of disease in animals by passive transfer of purified
IgG4 from patients, monoclonal IgG or scFv (single chain variable
region fragments) cloned from IgG4+ B-cells of patients.
4.1. IgG4 autoantibodies with validated pathogenicity (class I)
In these diseases, IgG4 is proven to be pathogenic by fulfilling the
three classification criteria. Importantly, a passive transfer of purified
IgG4 could reproduce the disease in experimental animals. This means
that these diseases are definitely caused by pathogenic IgG4 auto-
antibodies.
4.1.1. MuSK
Patients with autoantibodies against the muscle-specific kinase
(MuSK), a protein at the neuromuscular junction, develop MuSK
-myasthenia gravis [133]. MuSK is a key organizer of neuromuscular
junction development and maintenance. Upon release of the protein
agrin from the motoneuron, it binds to the agrin co-receptor Lrp4,
which in turn binds and activates MuSK, which is a receptor tyrosine
kinase that then becomes activated, phosphorylates downstream targets
and regulates the clustering of AChRs at the synapse via the scaffolding
Fig. 6. Pathogenic mechanisms of MuSK autoantibodies of IgG4 subclass in
Myasthenia gravis. A) The neuromuscular junction. During neuromuscular
transmission, the neurotransmitter acetylcholine (ACh) is released into the sy-
naptic cleft, where it binds to the acetylcholine receptor (AChR) at the post-
synaptic muscle membrane, causing the AChR to open, which leads to influx of
Na + ions and depolarisation of the membrane. The dense aggregation of
AChRs at the postsynaptic membrane is developed and maintained by the
function of the muscle-specific kinase (MuSK). The motoneuron releases neural
agrin into the synaptic cleft, which binds to the agrin co-receptor, low-density
lipoprotein receptor-related protein 4 (Lrp4), causing an increased binding of
Lrp4 to MuSK. This leads to autophosphorylation of MuSK, binding of the
adapter protein Dok-7 and to full activation of MuSK. MuSK then phosphor-
ylates further down-stream proteins which leads to the clustering of AChR via
the scaffolding protein rapsyn. B) MuSK autoantibodies of IgG4 subclass bind to
MuSk and prevent Lrp4-MuSK interaction, therefore interrupting the agrin-
Lrp4-MuSK-Dok-7 pathway, and leading to reduced densities of AChRs at the
neuromuscular junction and impaired neuromuscular transmission.
protein rapsyn [12] (Fig. 6A). MuSK antibodies are predominantly IgG4
[26,134] and are able to undergo Fab-arm exchange in vitro [69]. In-
deed calculations suggest that up to 99% of MuSK antibodies are bis-
pecific in vivo. The MuSK antibodies recognize several domains of

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I. Koneczny
MuSK, but they predominantly bind to the first Ig-like domain
[133–137]. This is interesting, because the first Ig-like domain also
contains two regions that are functionally important, one that is re-
quired for MuSK dimerization and a second one around Ile96 that is
required for the interaction between Lrp4 and MuSK [138], suggesting
functional consequences of MuSK antibody binding. Indeed we could
demonstrate that MuSK antibodies block the binding between Lrp4 and
MuSK (Fig. 6B) [26,137,139], which also led to a decreased MuSK ac-
tivation and phosphorylation [139] and reduced AChR clustering at the
neuromuscular synapse. While the blocking mechanism was exclusive
for IgG4 subclass antibodies, IgG1–3 was also able to reduce agrin-in-
duced AChR clustering in vitro [26]. There may be another signalling
pathway that is blocked by MuSK antibodies, but we don't understand
the exact mechanism yet. We induced AChR clusters by overexpressing
Dok-7, independent of agrin, and therefore independent of agrin-Lrp4-
MuSK interaction, and found that MuSK MG IgG and Fab fragments
were able to disrupt these AChR clusters [26,140]. Perhaps the anti-
bodies induced conformational changes in MuSK that affected binding
of MuSK to Dok-7 or another protein.
Interestingly, antibody valency also plays a role in pathogenicity of
MuSK autoantibodies. MuSK IgG4 is bispecific and binds monovalently,
and monovalent binding by Fab Fragments also blocked Lrp4-MuSK
interaction and reduced agrin- induced AChR clusters [26]. Divalent
recombinant MuSK antibodies cloned from MuSK MG B-cells had a
different mechanism, they cross-linked MuSK and induced MuSK
phosphorylation and agrin-independent AChR clustering [141]. This
may present another pathogenic mechanism, perhaps for MuSK IgG1–3
that may by this mechanism deplete AChRs from the NMJs and instead
form ectopic AChR clusters.
Another puzzling finding is that MuSK antibodies may affect a ret-
rograde signal to the motoneuron, since presynaptic effects have been
observed in MuSK MG patients and animal models. These include a
reduction of the quantal release of acetylcholine and structural ab-
normalities in the NMJ architecture [142–146]. Lrp4 was found to
contribute to a retrograde signalling to the motor neuron [147,148],
therefore it is possible that MuSK binding to Lrp4 is also involved in the
retrograde signalling pathway, perhaps by anchoring Lrp4 at the NMJ.
MuSK antibodies may potentially also affect MuSK located in the brain.
One study suggests that passive transfer of patient animals to mice led
to reduced exploring time in the novel object recognition test. This
could have been caused by cognitive defects, though it cannot entirely
be excluded that it was caused by muscle weakness [149]. It would
certainly be interesting to investigate potential effects of MuSK anti-
bodies on the brain.
4.1.2. CNTN1
Contactin-1 (CNTN1) is an adhesion molecule that are expressed on
the surface of axons at the axoglial junction (Fig. 7). CNTN1 binds to-
gether with CNTN1-associated protein 1 (Caspr1) to the protein Neu-
rofascin-155 (NF155) on the surface of oligodendroglia [150–153], and
all three proteins have been suggested as targets for IgG4 auto-
antibodies. The CNTN1-Caspr1-NF155 complex is required to maintain
paranode architecture and to maintain myelin insulation of the axon for
nerve impulse propagation along myelinated axons. In patients with
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP),
autoantibodies of IgG1 and IgG4 subclass target CNTN1 that may alter
the paranode structure [154–157], and there is evidence that the IgG4
antibodies have a blocking mechanism that leads to a block of NF155-
CNTN1 interaction [158]. Some CNTN1 antibody positive patients (as
well as NF186 positive patients) may also present with nephrotic syn-
drome, or a “neuro-renal syndrome”. This may be explained by the
expression of CNTN1 and NF186 on podocytes [159,160], where au-
toantibodies might affect the structure and function of the glomeruli in
the kidney [161].
IgG4 may also not be the sole contributor to pathogenicity, as
passive transfer of serum with predominant IgG3 subclass antibodies
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against CNTN1 to rats caused a conduction block in the absence of
abnormal paranodal structure [162]. Notably IgG3 was not the only
subclass present in the patients, also IgG1 and IgG4 were present at
reduced levels, but IgG3 and C1q deposits were colocalized at the
paranode. This suggests that complement-fixing IgG3 may play a role in
early disease stages, while non-complement fixing IgG4 may be re-
levant in the chronic phase by blocking.
Interestingly a subclass switch from complement fixing IgG sub-
classes to IgG4 was also observed in patients with anti- PLA2R anti-
bodies [43,163]. Perhaps a class switch from IgG1/3 to IgG4 is at work
in other IgG4-AID, but this will be challenging to prove, since many of
these diseases are difficult to diagnose. By the time the autoantibodies
are tested, the subclass switch may already have happened.
Last, but not least, the disease could be reproduced by passive
transfer of purified IgG4 to Lewis rats, leading to a loss of paranodal
clusters and reduced motor nerve conduction [164], which makes it a
class I IgG4-AID.
4.1.3. Neurofascin 155
The binding partner of CNTN1 in the axo-glial complex, Neurofascin
155 (NF155, Fig. 7), is also targeted by IgG4 autoantibodies. NF155 is
an adhesion protein expressed on the glia cells in the paranodal septate-
like junctions of myelinated axons [165,166,167]. Autoantibodies to
NF155 (as to CNTN1 and perhaps also Caspr1) are thought to cause
changes in the axo-glial complex that lead to peripheral neuropathies
[158,168–170], including chronic inflammatory demyelinating poly-
neuropathy (CIDP). There are some differences though, as patients with
NF155 antibody positive CIDP have a distinct clinical phenotype that is
defined by a low-frequency and high-amplitude tremor with cerebellar
features and IVIG unresponsiveness [171–174]. To date, at least two
pathogenic mechanisms have been proposed for NF155-IgG4: 1) a
blocking mechanism that prevents the interaction between CNTN1-/
Caspr1 and NF155 and disrupts the paranodal structure [158] and 2)
induction of NF155 clustering and depletion from the cell surface by yet
unidentified mechanisms, with a clear absence of any blocking function
[175].
In the latter study, IgG4 was isolated from plasmapheresis material
from three CIDP patients and used for studies in vitro in different cell
lines, as well as in vivo by passive transfer to postnatal and adult Lewis
rats.
The in vitro experiments showed no block of interaction between
NF155 and CNTN1/Caspr1 in transfected HEK293 cells, but instead
induction of NF155 clustering. This is interesting, as it suggest a mul-
tivalent binding and cross-linking mechanism. In cell culture experi-
ments with Schwann cells, oligodendrocytes or transfected HEK293
cells, it was shown that NF155-IgG4 did not induce internalization of
antigen as it would be found in cross-linking and endocytosis. And yet,
in the Lewis rats, NF155 was found to be depleted, and in the postnatal
rats this was accompanied by impaired paranode formation and loss of
Caspr1 positive septate-like junctions. It is puzzling how NF155 could
be depleted if cross-linking and internalization is not a likely me-
chanism of action, due to the results of the in vitro experiments and the
bi-specific nature of IgG4. The authors hypothesize that antibody
binding to the thrombin cleavage site in the third fibronectin type III
domain could induce proteolysis [176], or a reduced interaction with
an unknown binding partner may cause reduced anchoring of NF155 to
the paranodal junction. Also it is possible that NGF155-IgG4 induces
conformational changes that may lead to NF155 clustering and sub-
sequent breakdown of NF155. It is also thinkable that immobilized
IgG4, via Fc-Fc interaction with other IgG4 or IgG1–3 could lead to
cross-linking after all.
Importantly, patient-like symptoms were induced by chronic in-
trathecal infusion with patient IgG4 to adult Lewis rats, including gait
abnormalities, slower motoneuron conduction velocity, paraparesis and
complete tail paralysis in the absence of demyelination.
Taken together there may be different mechanisms at hand that are
I. Koneczny
Fig. 7. The nodes of Ranvier in motoneuron axons are densely packed with IgG4 autoantigens. Schwann cells are providing electric insulation in motoneuron axons,
and together with the gaps, the nodes of Ranvier, allow for saltatory conduction, the propagation of action potentials, in the axon. To this end, the membranes of axon
and Schwann cell have to be tightly sealed. Many IgG4 autoantigens are, curiously, expressed at the juxtaparanodal junction, namely CNTN1, Caspr1, Caspr2, NF186,
NF140 (not shown), and NF155. It is unclear why this structure seems to be so susceptible to IgG4 autoantibodies.
not fully understood to date. Nevertheless, the Manso study clearly
proves the pathogenic status of NF155-IgG4, as the disease could be
reproduced by passive transfer experiments [175].
4.1.4. ADAMTS13
A disintegrin and metalloproteinase with thrombospondin motifs 13
(ADAMTS13) is the target of IgG4 autoantibodies in patients with
thrombotic thrombocytopenic purpura (TTP).
ADAMTS13 is located in the blood circulation, where it cleaves the
active, multimeric form of the von Willebrand factor (vWF, Fig. 8).
ADAMTS13 binds to the vWF via its spacer domain, which is also the
main epitope for the IgG4 autoantibodies, thus blocking the binding of
the protease to its target. This leads to the accumulation of multimeric
vWF which also binds to platelets, forming microthrombi that lead to
vascular occlusion [177,178]. The pathogenicity of the antibodies was
demonstrated in vitro, using IgG4 and IgG1 antibodies cloned from TTP
patient B-cells. Both IgG4 and IgG1 were able to block ADAMTS13
activity in vitro [179], and inhibition of ADAMTS13 was increased in
patients that had predominantly IgG4 subclass antibodies [180]. Fur-
ther evidence comes from an association of IgG4 levels with relapse,
and some patients have only IgG4 subclass antibodies, which adds
clinical evidence for the pathogenicity of IgG4 [181]. Disease could also
be reproduced by expression of patient derived (monovalent) scFv ex-
pressed in mice, though the subclass of the original patient antibodies is
unknown [182]. There is also an IgG subclass switch from IgG1 at the
first presentation of disease to IgG4 during (or shortly before) relapse,
with increased IgG levels in patients with the DR7-DQ2 and DR13-DQ6
haplotypes [180].
4.1.5. Dsg1 and Dsg3
Antibodies to desmoglein 1 or desmoglein 3 (Dsg1,3) of IgG4 sub-
class are present in patients with pemphigus [27]. Dsg1 and Dsg3 are
transmembrane cell-adhesion proteins expressed in keratinocytes
(Fig. 9). Dsg1 is expressed in the superficial layers of the epidermis,
while Dsg3 is expressed in the basal and parabasal layers of the skin.
Pemphigus foliaceus is induced by Dsg1 antibodies, while pemphigus
vulgaris is induced by antibodies against Dsg3, or both Dsg1 and Dsg3
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Autoimmunity Reviews 19 (2020) 102646
simultaneously [183,184]. The antibodies recognize epitopes in the
EC1 and EC2 domain of Dsg1 and Dsg3 [185,186], and binding of the
autoantibodies leads to a block of cell-cell adhesion and causes blis-
tering of the skin [187,188]. This pathogenic mechanism could be de-
monstrated in vitro, as antibodies induced the dissociation of cell sheets
of cultured human keratinocytes [189,190] and human skin explants
[191]. In an endemic form of pemphigus, fogo selvagem, the main
epitope was a 16-residue peptide in the EC1 domain of Dsg1
(A129LNSMGQDLERPLELR144), and binding of Fab fragments disrupted
the binding between Dsg1 and the desmosome protein desmocollin 1
(Dsc1) [192]. Blocking of cell-cell adhesion is not the only mechanism
at work, since the autoantibodies can also alter the signal transduction
pathways that affect cytoskeleton rearrangement and cell adhesion in
keratinocytes [191,193–199]. There is clinical evidence for the patho-
genicity of IgG4 since the depletion of IgG4 from patient serum reduced
the pathogenicity in vitro [200], and passive transfer of maternal anti-
bodies to the fetus induces a transient neonatal form of pemphigus
[201]. Importantly, passive transfer of IgG4 subclass antibodies could
reproduce the disease in animals [185,202].
4.2. IgG4 autoantibodies with non-validated pathogenicity (class II)
IgG4-AIDs where pathogenicity of IgG4 has not yet been proven but
is otherwise strongly suspected belong to the class II IgG4-AIDs. Usually
the antibodies have been demonstrated to be pathogenic by a blocking
mechanism in vitro, but in vivo evidence by passive transfer of patient
IgG4 is still lacking.
4.2.1. LGI1
Patients with LGI1- associated limbic encephalitis have auto-
antibodies to the neuronal antigen LGI1 and present with a range of
neurological dysfunction, specifically regarding memory and behaviour
which is also accompanied by seizures [203–206]. LGI1 antibody po-
sitive patients have very characteristic faciobrachial dystonic seizures
(short, unilateral seizures in the upper limb and face), subtle dyscog-
nitive or autonomic seizures, and generalized tonic–clonic seizures
[207].
I. Koneczny
Fig. 8. The pathogenic mechanism of ADAMTS13 autoantibodies in thrombotic thrombocytopenic purpura. ADAMTS13 is an enzyme located in the blood circu-
lation. It cleaves the active, multimeric form of the von Willebrand factor (vWF). IgG4 autoantibodies bind to the same region as vWF, block the binding of vWF to
ADAMTS13 and prevent cleavage of vWF. Multimeric vWF accumulates, binds platelets and forms microthrombi that and cause vascular occlusion.
LGI1 is a neuronal antigen, which is expressed at synapses in the
CNS as part of the voltage gated potassium channel complex (VGKC). It
is secreted by pre- and postsynaptic neurons and cross-links trans-
membrane proteins from both sides of the synaptic cleft. LGI1 binds
presynaptically to ADAM23 and postsynaptically to ADAM22. LGI1-
ADAM22 and -ADAM23 interaction is thought to regulate neuro-
transmitter receptor and ion channel levels at the synapse.
The binding to ADAM22 is mediated by a hydrophobic pocket of the
c-terminal epitempin-repeat (EPTP) domain of LGI1 which binds to the
metalloprotease-like domain of ADAM22 [208,209]. ADAM22 then
binds the scaffolding protein PSD-95, and taken together the complex is
thought to regulate AMPA receptor levels [210]. AMPAR are ionotropic
neurotransmitter receptors are required for excitatory synaptic trans-
mission in many parts of the brain and play a role in long-term po-
tentiation, synaptic plasticity and memory. LGI1 expression is high in
the CA3 region in the hippocampus, which is important for episodic
memory. In line of a neurotoxic effect of LGI1 autoantibodies, LGI1
patients suffer from memory deficits with focal atrophy in the CA3
region [211]. The neurotoxic effect of LGI1 antibodies on hippocampal
neurons could be observed in a recent study, where LGI1-IgG incuba-
tion on hippocampal neurons in cell culture was associated with
apoptosis and reduced calcium currents [212].
At the postsynaptic site, the LGI1 antibodies cause a block between
LGI1 and ADAM22 binding. The antibodies bind to the same region as
ADAM22, which is the EPTP domain, thereby effectively blocking LGI1-
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Autoimmunity Reviews 19 (2020) 102646
ADAM22 interaction, which is associated with reduced AMPAR levels
[213]. There is some evidence that LGI1 antibodies may also cross-link
and endocytose LGI1, with one in vitro study showing internalization of
LGI1 in ADAM22-transfected HEK293T cells incubated with soluble
LGI1 [214]. A limit of the study is the use of whole serum. These had
either predominant LGI1-IgG1 or LGI1-IgG4, but the complete IgG
subclass profile was not provided, therefore it is not entirely clear
which antibody subclass was associated with this mechanism. A repeat
of the experiment with purified patient IgG4 and IgG1 would be ad-
visable.
At the presynaptic site, LGI1 is also involved in regulation of the
density of presynaptic Kv1.1 receptors at the axonal initial segment,
which regulates the action potential firing [215]. LGI1 binds ADAM23,
which in turn binds to and regulates expression levels of the presynaptic
Kv1.1 [216]. Kv1.1 are shaker related voltage-gated potassium ion
channels, that open during the repolarization phase and become se-
lective ion channels for potassium ions. Interestingly, Kv1.1 are also the
target of autoantibodies in autoimmune neuromyotonia (Isaac's syn-
drome). The interaction between LGI1 and ADAM23 is therefore also
important to maintain functionality of the presynaptic site, and as it
turns out, may also be targeted by LGI1 antibodies. Passive transfer of
purified IgG from LGI1 patient serum to mice led to a block of LGI1-
ADAM23 binding and reduced synaptic and overall expression levels of
Kv1.1 and AMPAR at the mouse hippocampus [217]. Reduced Kv1.1
levels may also have caused the observed hyperexcitability in
I. Koneczny
Fig. 9. Blocking is a key pathogenic mechanism of IgG4 autoantibodies in
pemphigus vulgaris. Desmosomes are cellular complexes that mediate cellular
adhesion. Desmogleins (Dsg) and desmocollins (Dsc) are part of this complex
that mediate the cell-cell interaction. Keratinocytes of the skin and mucous
membranes are targeted by IgG4 antibodies against Dsg1 or Dsg3, these have a
direct blocking function and lead to a loss of cellular adhesion. This leads to
blistering of the skin and mucous membranes.
hippocampus preparations from the mouse, which was also previously
shown with hippocampal CA3 pyramidal cells ex vivo [218]. The re-
duced AMPAR levels may have cause the defects in long-term po-
tentiation that were observed in the mice, as well as severe, but re-
versible, memory deficits. These are in line with the memory deficits of
LG1 patients. What was missing in the mouse model was the occurrence
of seizures, which are frequent in limbic encephalitis and in LGI1 null
mutant mice [219].
The passive transfer experiments underline pathogenicity of LGI1
autoantibodies, but what is still lacking is the evidence that IgG4 sub-
class antibodies mediate the pathogenic mechanisms.
4.2.2. CASPR2
Patients with antibodies against the neuronal antigen Contactin
associated protein 2 (CASPR2) are associated with a range of diseases
such as neuromyotonia, Morvan's syndrome and limbic encephalitis
[220–224]. CASPR2 antibodies are associated with many different
neurological symptoms, including neuropathic pain, sleep alterations,
seizures, memory impairment, cognitive deficits, and psychosis
[204,220,224–229]. The wide range of disorders and symptoms is due
to the different roles of CASPR2 in the peripheral and central nervous
system. CASPR2 is a neurexin-related cell-adhesion molecule and is
expressed in the peripheral and central nervous system, specifically in
the juxtaparanodal region of myelinated axons (Fig. 7), hippocampal
GABAergic interneurons and in excitatory synapses in the cortex
[230,231](Fernandes, Santos et al., 2019). CASPR2 forms a complex
with transient axonal glycoprotein-1 (TAG-1, also named Contactin-2)
and shaker-type voltage-gated potassium channels Kv1.1 and Kv1.2,
and may be relevant for different processes that are essential for neu-
ronal activity:
1) it is a scaffolding protein for VGKCs, 2) it regulates the synaptic
expression of AMPAR and thus synaptic plasticity in the visual cortex
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Autoimmunity Reviews 19 (2020) 102646
and 3) it plays a role in nociceptive pain, as it regulates the excitability
of dorsal root ganglion cells by regulating the trafficking of Kv1 chan-
nels to the membrane [232]. The patients may have predominantly
IgG1 and IgG4 antibodies, and due to the different sites of expression, it
is thought that CASPR2 antibodies may have different pathogenic ef-
fects.
CASPR2 antibodies block CASPR2- TAG-1 interaction [233,234].
This mechanism is associated with IgG4 since IgG4-enriched CASPR2
antibodies were found to be blocking. In addition, an internalization of
CASPR2 was excluded since the antibodies in this study did not affect
cell surface expression of CASPR2 in hippocampal neurons in vitro
[233]. A recent study also verified the block of Caspr2-TAG1 interac-
tion, and observed an upregulation of Kv1.2 in hippocampal neurons as
a consequence of incubation with CASPR2 autoantibodies [235].
Another mechanism is an increased turnover/internalization of
CASPR2. In a passive transfer animal model using CASPR2-IgG, reduced
dendritic levels of CASPR2 were observed, likely induced by inter-
nalization of CASPR2. Here IgG was used that contained both IgG4 and
IgG1 subclass antibodies, and it is thought that the internalization may
be induced by IgG1 [236]. In addition, AMPAR levels were reduced at
the synapses in cortical neurons, and the cortical excitatory transmis-
sion was decreased. This may be due to a role of CASPR2 for regulation
of AMPAR trafficking that may have been interrupted by CASPR2 an-
tibodies. In another study, IgG from a patient with CASPR2-encephalitis
was injected intraperitoneally, to reproduce the transport of serum IgG
via LPS-breached blood brain barrier to the CSF [237]. Successful
transport to the brain was verified, as IgG deposits were located in the
brain parenchyma, in addition to increased levels of activated microglia
and astrocytes. There was otherwise no sign of an inflammatory re-
sponse, and no reduction in CASPR2 expression. Importantly, the mice
displayed behavioural changes in social interactions and working-
memory defects. Unlike expectations of reduced CASPR2 levels as result
of increased internalization, an increase in cell surface expression of
CASPR2 was observed in these mice. An explanation could be that ex-
pression of CASPR2 was upregulated by a compensatory mechanism
after initial internalization. This was reproduced in further in vitro ex-
periments with hippocampal neurons and CASPR2-transfected HEK293
cells that showed internalization of patient IgG to a small degree, to-
gether with higher surface CASPR2 expression. The patient IgG was
comprised of IgG1, 2 and 4 (72% IgG4, 22% IgG1, 6%IgG2, < 1%
IgG3), therefore it may be that IgG1 and IgG2 were responsible for the
internalization.
The reduction of CASPR2 levels is likely to have functional con-
sequences. In the PNS, CASPR2 antibodies could reduce CASPR2 levels
and therefore enhance dorsal root ganglion excitability via differential
regulation of Kv1 channel expression [232], which may interfere with
pain hypersensitivity regulation and cause neuropathic pain. Increased
excitability is also a mechanism found in the CNS in patients with
limbic encephalitis, by reducing the inhibitory input by interneurons
[234].
A further effect could be on Purkinje cells in the cerebellum, as they
express CASPR2 at high levels. In the Giannoccaro study, a moderate
cell loss was observed in the passive transfer animal model [237]. It is
possible that CASPR2 antibodies may lead to neuronal cell loss, another
supporting observation comes from a study that reported CASPR2 an-
tibodies in patients with cerebellar ataxia [238].
Taken together, autoantibodies against CASPR2 have heterogenous
effects in the peripheral and central nervous system, including blocking
of protein-protein interaction and increased internalization, which in
turn may affect signal transduction and neuronal tissue architecture.
What is still lacking is evidence for pathogenicity of the IgG4 subclass,
which could be obtained by passive transfer of purified patient IgG4.
4.2.3. GPIHBP1
Autoantibodies against GPIHBP1 (glycosylphosphatidylinositol-an-
chored high density lipoprotein–binding protein 1) are known to cause
I. Koneczny
hypertriglyceridemia in the “GPIHBP1 autoantibody syndrome” [11].
GPIHBP1 is a protein expressed in capillary endothelial cells that is
required for intravascular lipolysis. GPIHBP1 binds, stabilizes and
transports lipoprotein lipase (LPL) to its site of action in the capillary
lumen, where LPL is then required for lipolysis [239,240,241]. The
autoantibodies against GPIHBP1 block the binding to LPL [10,11], thus
leading to reduced LPL levels, impaired intravascular triglyceride pro-
cessing, and severe hypertriglyceridemia (chylomicronemia). The IgG
subclass was only recently investigated in a single patient, and anti-
bodies were found to be exclusively of the IgG4 subclass [242]. Since
GPIHBP1 antibodies are pathogenic by a blocking mechanism, which is
associated with IgG4 autoantibodies, it is likely that future studies will
identify further patients with predominant IgG4 autoantibodies.
4.2.4. PLA2R
Patients with membranous nephropathy (MN) present clinically
with proteinuria and nephrotic syndrome [243]. In up to 75% of pa-
tients, autoantibodies against phospholipase A2 receptor (PLA2R),
mostly of IgG4 subclass, can be observed [244–249] and patients with
PLA2R antibodies have a more severe disease course than those without
[250]. Not all PLA2R antibodies belong to the IgG4 subclass, there are
cases that are negative for PLA2R-IgG4 [251]. Up to 5% of patients with
lupus nephritis patients have autoantibodies against PLA2R, but not of
the IgG4 subclass [252]. One case with MN presented with IgG1 sub-
class antibodies against PLA2R and ADAMTS13-IgG1 [253]. It is pos-
sible that initially IgG1 and IgG3 antibodies are produced in the acute
phase of disease, followed by a class switch towards IgG4 in the chronic
phase, with both antibodies contributing different disease mechanisms
to pathology [254,255].
PLA2R belongs to the mannose receptor protein family and is ex-
pressed in podocytes [256,257]. The role of PLA2R in the kidney is not
known, but recently it was discovered that PLA2R binds to the At2
complex. This heterotetrametric complex contains the proteins
S100A10 and annexin 2A [258]. Interestingly the At2 complex is as-
sociated with many important functions, such as the remodelling of the
actin cytoskeleton, membrane organization, endo- and exocytosis and
ion channel conductance [259]. The binding epitope for the antibodies
lies in the most n-terminal, cystein-rich region (CyR) [260,261], which
is also the region where the At2-complex binds to PLA2R. Future ex-
periments will show whether perhaps PLA2R antibodies block the
binding between PLA2R and the At2 complex. This could potentially
disturb the organization of the actin cytoskeleton and affect tight
junction assembly, which is important for the podocyte function, and
disruptions of which have been observed in patients with MN [258]. To
date, this has not yet been investigated, but another blocking me-
chanism was proposed to affect cell adhesion of podocytes to collagen
IV [262]. Controversially, in another study PLA2R did not bind to
collagen I or IV [263,264].
Interestingly, PLA2R autoantibodies may be one rare exception
from the rule that IgG4 does not activate complement. In patient
biopsies, immune deposits containing IgG, also PLA2R-IgG4, PLA2R
and complement were found below the basal surface of podocytes in the
kidney [255,265–267]. While it is to be expected that, especially during
the acute phase of disease, IgG1 and IgG3 may fix complement by the
classical pathway [268], IgG4 may also activate complement in the
chronic phase via the lectin or alternative pathway [41–45]. It is
thought that IgG4 with galactose deficient side-chains binds to man-
nose-binding lectins (MBL) and ficolins [42,46,47,79,269], that then
bind acetylated glycans and MBL-associated serine proteases (MASPs)
that lead to activation of C4 and the formation of the membrane-attack
complex (MAC) [41]. In line with this hypothesis is the observation that
C1q is usually absent from these deposits [255], while C4 and MBL are
present, and MBL levels measured in patient biopsies in Japanese MN
patients correlated with IgG4 [270]. Furthermore, complement may
also be activated via the alternative pathway, since IgG4, C3, C4 and
C5b-9 were found in patients deficient for MBL [271] and ficolin-3
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Autoimmunity Reviews 19 (2020) 102646
[255,272]. Complement activation via the lectin pathway by hypo- or
agalactosylated IgG is a topic of some controversy [273], and further
studies are indicated to investigate the mechanisms of complement
activation in PLA2R positive MN.
Importantly, to prove pathogenicity of PLA2R autoantibodies, and
specifically IgG4, passive transfer animal models would be required,
but unfortunately no appropriate animal model is available because
rodent podocytes do not express PLA2R [274].
One approach to overcome the lack of an animal model to study
complement activation in MN was to immunize mice with a different
glomerular antigen, namely recombinant non-collagenous (NC1) do-
main of human α3(IV) collagen (rh-α3NC1), to induce the production
of pathogenic anti-α3NC1 autoantibodies [275]. In these animals, a role
for the alternative pathway for complement activation is emerging,
since knock-out of a protein from the alternative pathway, despite the
presence of subepithelial immune complexes with IgG deposition,
protected the mice from proteinuria, which is thought to be caused by
complement damage. It remains to be investigated whether the same
applies to human patients with MN and autoantibodies to PLA2R.
Taken together, several potential pathogenic mechanisms for IgG4
have been proposed, including block of protein-protein interaction
between PLA2R and the At2-complex or binding to collagen IV, and
activation of complement via the lectin- and alternative pathway by
hypogalactosylated IgG4 but require further investigation. Validation of
pathogenicity of PLA2R- IgG4 via passive transfer animal models is to
date not possible due to the lack of PLA2R expression in rodents [274].
The development of a PLA2R expressing animal model is therefore of
urgent priority to study the role of PLA2R-IgG4 autoantibodies.
4.2.5. THSD7A
In 3–5% of patients with MN, IgG4 subclass autoantibodies against
thrombospondin type-1 domain containing 7A (THSD7A) are present.
The THSD7A antibodies are predominantly of the IgG4 subclass, but
IgG1 can also be found. There is an association with cancer, as THSD7A
is expressed in different tumours, and increased frequency of malig-
nancy in patients with THSD7A positive MN [264,276]. THSD7A is a
type-1 transmembrane protein, which is normally expressed at the basal
surface of podocytes in the kidney. It is composed of 21 domains, of
which 18 contain predicted B-cell epitope sites [277]. The antibodies
may target a range of domains as they are polyreactive, but the primary
target is the n-terminal region [278].
The function of THSD7A has recently been unravelled, it is a foot
process protein that may interact with extracellular matrix proteins in
the glomerular basement membrane and play a role in cell adhesion,
regulation of cell dynamics and, importantly, slit diaphragm stabiliza-
tion in podocytes [279], and patient antibodies were found to be de-
posited at the slit diaphragm in a passive transfer mouse model [279].
This is in line with observations in patient biopsies, where deposits of
IgG and complement are found at the glomerular basement membrane
[280–284]. One hypothesis is that THSD7A-IgG4 may disrupt the glo-
merular filtration barrier by loss of cell-cell adhesion at the slit dia-
phragm by blocking THSD7A interactions, or by directly affecting its
function, which may cause destabilization of the dynamics of the foot
processes and the slit diaphragm and causing proteinuria [279].
There is supporting evidence that the antibodies may affect THSD7A
function, as experiments on primary murine podocyte cells and primary
glomerular epithelial cells in vitro show an effect of THSD7A antibodies
on focal adhesion, including cytoskeletal rearrangements, formation of
stress fibres and increased focal adhesion signalling [285,286]. There
are also findings that support a blocking mechanism, as THSD7A anti-
bodies induced the detachment of THSD7A expressing HEK293 cells
[285]. These mechanisms are thought to be independent of comple-
ment-activation, as disease could be reproduced in passive transfer
animal models using anti-THSD7A antibodies that were produced in
rabbits [286], or with affinity purified THSD7A patient antibodies
[285]. Still, complement activation may contribute to pathology.
I. Koneczny
Passive transfer of patient serum to mice led to late complement acti-
vation [285]. Renal biopsies showed increased MBL and THSD7
staining, and elevated levels of lectin pathway components were found
in patient serum and led to complement activation and reproduction of
disease in mice [287].
Taken together, THSD7A antibodies may be pathogenic by both a
blocking mechanism and complement activation via the lectin pathway.
What is still lacking are experiments using purified IgG4 subclass an-
tibodies as well as a passive transfer of patient IgG4 to experimental
animals to demonstrate pathogenicity of IgG4.
4.2.6. Laminin 332
Patients with anti-laminin mucous membrane pemphigoid (MMP,
formerly known as anti-epiligrin cicatricial pemphigoid, AECP) suffer
from blistering of mucosal membranes, mainly the oral mucosa, but
also of conjunctival, nasal, anogenital, pharyngeal, laryngeal and oe-
sophageal mucosa, and occasional also from blistering of the skin
[288]. In 20% of cases the patients have autoantibodies against laminin
332 (Lam 332, previously named laminin 5, epiligrin, kalinin, nicein, or
BM600) [288–292]. In some patients IgG4 was predominant [293], and
serum levels of Lam 332 antibodies was found to correlate with disease
activity [288]. Interestingly, approximately 30% of anti-laminin-MMP
patients also present with associated malignancy, mostly solid tumours
[294–298].
Lam 332 is located in the skin in the epidermal basement mem-
brane, where it plays a role in keratinocyte adhesion [299,300], and a
recent study found that Lam 332 antibodies led to the detachment of
keratinocytes in vitro, suggesting a blocking mechanism similar to
Dsg1/3 antibodies in pemphigus [301]. Furthermore, passive transfer
of total IgG from patients with predominant IgG4 to SCID mice with
human skin grafts led to the development of non-inflammatory skin
blisters in the human skin [302]. This supports a non-inflammatory
antibody mechanism by blocking [301], as it would be expected by
IgG4. However, further studies are required to pinpoint the patho-
genicity to the IgG4 subclass, both in vitro and in vivo.
4.3. IgG4 autoantibodies with unclear contribution to pathogenicity (Class
III)
Class III IgG4-AIDs diseases where a) not enough data is present to
estimate the role of IgG4 for pathogenicity, or b) the pathogenicity of
IgG4 is unlikely, because a Fc-dependent pathogenic mechanism is
present, e.g. complement activation, or other, complex mechanisms are
at work, which make it unlikely that IgG4 is a key pathogenic player.
4.4. Class IIIa IgG4 autoimmune diseases
4.4.1. Caspr1
There are only few publications on patients with CIDP that have
IgG4 subclass antibodies against Caspr1, which is another protein lo-
cated at the paranode of motoneurons (Fig. 7) or complexed Caspr1/
CNTN1 [154,155,303]. Overall there is not enough data available yet to
determine pathogenicity of Caspr1-IgG4.
4.4.2. NF 140 and NF 186
In very few patients with CIDP, neurofascin −140 and −186
(NF140, NF186) which are also expressed at the paranodes of moto-
neurons (Fig. 7) were found as the main targets of autoantibodies. IgG
subclasses were described in one study, in which four were pre-
dominantly of IgG4 and one IgG3 [303], and in one case file additional
antibodies against CNTN1 were present [304]. To date there is not
enough information to determine the pathogenic status of NF140- and
NF186-IgG4.
4.4.3. Type IV collagen
Patients with Goodpasture syndrome present with rapidly
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Autoimmunity Reviews 19 (2020) 102646
progressive glomerulonephritis, with or without pulmonary haemor-
rhage, which may be precipitated or reoccur after renal transplants
[305,306]. The patients have autoantibodies that target the α3NC1
domain of collagen type IV in the glomerular basement membrane in
the kidney. Importantly, passive transfer of patient IgG reproduced the
disease in animals [307]. To date it is known that a subgroup of patients
has autoantibodies of the IgG4 subclass, and these patients are clinically
described as predominantly female, smokers, presenting with severe
lung engagement and relatively mild or no renal disease
[305,308–310]. IgG4 autoantibodies were temporal occurring and re-
occurring with lung haemorrhage [308,309], but it is not known if and
how they contribute to the pathology. Furthermore, these patients also
may have IgG1–3 subclass antibodies that could contribute to the dis-
ease [308,311]. Studies on purified patient IgG4 are required to de-
termine whether these are pathogenic.
4.4.4. Α-enolase, SOD2 and AR
In patients with membranous nephropathy, IgG4 and IgG1 anti-
bodies against α-enolase, manganese superoxide dismutase (SOD2) and
aldose reductase (AR) can be detected. Α-enolase is expressed in tubular
kidney cells and in liver epithelia, where it works as a catalyst of the
dehydration of 2-phosphoglycerate to phosphoenolpyruvate in glyco-
lysis. Anti-α-enolase, anti-SOD2 and anti-AR antibodies were found,
together with the antigen and C5b-9, in laser capture micro-dissected
glomeruli of MN patients and in the serum [312,313]. The problem
with these antigens is, that they are primarily located intracellularly
(e.g. as shown in the human protein atlas, https://www.proteinatlas.
org/), which would be a reason to exclude them as targets in IgG4-AID.
There are, however, studies that suggest cell surface expression of these
targets [313], and it was even found that cell-surface expressed α
-enolase in endothelial cells acts as a plasminogen receptor [314].
Therefore it is thinkable that cell-surface expressed α-enolase, AR or
SOD2 may be a targets for IgG4 antibodies, but it is still equally possible
that these are intracellularly expressed antigens, and that the IgG4
antibodies were produced as a by-product, after an initial tissue damage
by another antibody (e.g. PLA2R) that opens up the cell membrane and
exposed intracellular antigen to immune cells, which may have led to
the production of antibodies against intracellular targets. This is likely,
since PLA2R-IgG4 were present in patient serum simultaneously with
antibodies against α -enolase, SOD2 and AR [249,315]. Therefore it
cannot be excluded that these antibodies were produced secondary to
PLA2R (or THSD7A, or other antibodies), and would have only re-
levance as biomarker, similar to autoantibodies against intracellular
titin in patients with AChR myasthenia gravis [316]. It is not clear if
these antibodies have a pathogenic mechanism of their own, and if they
are the primary pathogenic entity. In vitro studies on the pathogenic
action and passive transfer experiments with purified IgG4 should shed
light on the role of anti- α -enolase, anti-AR and anti-SOD2 antibodies.
4.4.5. P200
Patients with antibodies against p200 at the dermal-epidermal-
junction develop an autoimmune subepidermal blistering disease
named anti-p200 pemphigoid [317,318]. The patients are usually be-
tween 50 and 70 years of age with a mean age of onset of 65.5 years
[319], but disease may also occur in children [320]. Clinically the pa-
tients present with tense skin blisters, in approximately 50% of cases
also with urticarial plaques, and the histology shows subepidermal
blistering, often with mild to dense inflammatory infiltrates (neu-
trophils, eosinophils) in the upper dermis. P200 is located within the
lower lamina lucida of the basement membrane zone, outside the
hemidesmosomes and the antibodies were found to be of IgG4 subclass
[321,322]. In up to 20% of cases, other autoantibodies were present,
including BP180, BP230, lam332 and type VII collagen [319], and one
patient with p200 antibodies also had additional antibodies to lam332
and CNTN1 [323]. This overlap suggests that intra- and intermolecular
epitope spreading events may lead to diversification of the antibodies to
I. Koneczny
recognize a range of different antigens. Importantly, the precise epi-
tope/antigen in p200 is not clear. P200 was identified from dermal
extracts as a protein of 200 kDa size and is an extracellular matrix
glycoprotein [324]. Up to 90% of the sera also recognized laminin γ1,
and it was initially thought that the main antigenic target had been
discovered [325,324,326]. In one patient, IgG4 anti-laminin γ1 titers
correlated with disease severity, but the patient also had anti-laminin
332 antibodies [327]. Serum from patients with anti-p200 pemphigoid
induced dermal-epidermal splitting in cryosections of human skin, but
the effect was lost when the serum was depleted of antibodies that
recognized the c-terminus of human laminin γ1 or laminin 111 or the
whole laminin γ1 chain. Furthermore, injection of rabbit derived anti-
mouse laminin γ1 specific antibodies or active immunization did not
induce blistering in mice [328,329]. Therefore the role of laminin γ1
antibodies for pathogenicity is unclear, which suggests the presence of a
second type of autoautoantibody in the serum. Patient serum was
clearly pathogenic in an ex vivo model but not when total IgG was
depleted, and induced dermal-epidermal separation, suggesting an an-
tibody-mediated tissue damage [328]. However, we know almost
nothing about the role of IgG4 autoantibodies for pathogenicity. The
most important task would be to determine the precise epitope re-
cognized by the pathogenic autoantibodies, and study if these are of
IgG4 subclass as well, followed by passive transfer of purified IgG4 from
patient serum.
4.5. Class IIIb IgG4 autoimmune diseases
4.5.1. ANCA
Antineutrophil cytoplasmic antibodies (ANCA) are present in pa-
tients with small vessel vasculitis, collected under the term ANCA-as-
sociated vasculitides (AAV). One of these AAVs is granulomatosis with
polyangiitis (GPA, also named Wegener's granulomatosis). GPA is an
immune-mediated systemic necrotizing vasculitis often affecting the
upper respiratory tract, lung, and kidney [330]. The antibodies target
the proteinase 3 (PR3) and myeloperoxidase (MPO), which are ex-
pressed in neutrophils and monocytes. Interestingly ANCAs are of the
IgG1, IgG3 and IgG4 subclass, with different IgG subclass profiles in
different patients, some with predominant IgG4, IgG3 or IgG1
[331,332]. It is thought that PR3-ANCA bind to PR3 on the surface of
neutrophils via the Fab, while simultaneous bind with the Fc to the
FcγRs and this leads to neutrophil activation and generation of reactive
oxygen species. What is interesting is that isolated patient IgG4 ANCA
were able to elicit the activation of neutrophils, despite the fact that
IgG4 has reduced affinity for FcγR [331]. Perhaps here Fc-Fc interac-
tions of IgG4 with antibodies of other subclasses may have been in-
volved, or bi-specific IgG4 could cross-link PR3 with another surface
molecule that also led to the activation of neutrophils. A further study
with chimeric IgG4-PR3-ANCA with similar results adds evidence for an
engagement with Fcγ receptors (FcγR; although not Fcγ RI) or other
surface molecules [333].
According to the literature, it is clinically challenging to distinct
between GPA and IgG4-RLD, as GPA mimics IgG4-RLD, with high levels
of IgG4+ plasma cells, sometimes elevated IgG4 serum levels and the
presence of fibrosis [334–336] [334], but there are also cases pre-
senting with both PR3-ANCA positive GPA and IgG4-RLD [337,338] or
ANCA-positive IgG4-RLD in the absence of AAV [339–342]. This led to
the suggestion that there may be a new overlap syndrome between AAV
and IgG4-RLD [343–346].
Another recent study found no overlap between GPA and IgG4-RLD,
despite the presence of elevated serum IgG4 [347]. Interestingly a de-
crease of total IgG4 measured using IgG4:IgG1 RNA ratio was asso-
ciated with remission in patients with GPA [348], putting an emphasis
on the relevance of IgG4 for this disease, though this study did not look
at ANCA specific IgG4 and the patients selection criteria included that
elevated (PR3)-ANCA had to be present at one point in the patient's
history, not specifically at the time of the study. In addition, there are
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Autoimmunity Reviews 19 (2020) 102646
also reports of co-occurrence of ANCAs with PLA2R antibodies [349],
but these were less frequently of the IgG4 subclass [350].
It is clear that further systematic clinical studies are necessary,
perhaps with the aim to develop more comprehensive guidelines to help
improve diagnosis and to clarify if and how GPA and IgG4-RLD are
associated, and to investigate the role of ANCAs in IgG4-RLD.
It seems to me that the presence of ANCAs, that is, antigen-specific
autoantibodies, is certainly somewhat more reminiscent of IgG4-AID
than IgG4-RLD, where antigen-specific IgG4 is rarely observed, on the
other hand the presence of fibrosis, elevated serum IgG4 and IgG4+
plasma cell infiltrates are reminiscent of IgG4-RLD. At this point it is not
clear at all whether ANCA-IgG4 positive GPA is an IgG4-AID, an IgG4-
RLD, neither or even both.
4.5.2. BP 180 and BP 230
In a subgroup of patients with bullous pemphigoid (BP), antibodies
of IgG4 and IgG1 subclass against parts of the basal keratinocyte
hemidesmosomal proteins BP antigen 230 (BP 230) and BP antigen 180
(BP 180) [351,352–356]. The role of IgG4 in BP is not clear. Auto-
antibodies bind to the basement membrane zone (BMZ) of the epi-
dermis and fix complement, which is observed as C3 deposition at the
BMZ, and recruit granulocytes, and animal studies showed that pa-
thogenicity depends on the presence of the Fc, the ability to activate
complement, the presence of neutrophil elastase or matrix metallo-
protease (MMP) and mast cells [357–359]. This pathogenic mechanism
is clearly dependent on IgG1 subclass antibodies, since IgG4 subclass
antibodies do not fix complement and do not recruit immune cells, and
the pathogenicity is thought to be mediated solely by binding of the Fab
fragment. A group of patients does not show complement depositions at
the BMZ [19], indicating a second pathogenic mechanism. IgG and F
(ab)2 fragments (which bind divalently) from BP patients was found to
internalize BP 180 by the macropinocytic pathway in keratinocyte
cultures [360] and induce the detachment of the cells from the dish
[361].
These findings were reproduced in vivo, showing skin detachment,
blister formation and loss of BP 180 in the lesions from neonatal BP 180
-humanized, C3-deficient mice [362]. The increased internalization
suggests also a mechanism of antibodies other than of the IgG4 sub-
class, but a detachment of cells by a blocking antibody of IgG4 subclass
could be possible. There is to date no proof that IgG4 is pathogenic in
the context of BP, indeed one study showed a protective role for IgG4
by blocking binding of pathogenic IgG1 and IgG3 in vivo [363]. Studies
with purified antibody subclasses will be necessary to detect any pa-
thogenic role of IgG4.
4.5.3. DPPX
A group of patients with encephalitis have IgG4 and IgG1 subclass
autoantibodies against dipeptidyl-peptidase-like protein 6 (DPPX).
DPPX is a protein that regulates the expression of voltage-gated po-
tassium channels in the myenteric plexus, hippocampus, cerebellum
and striatum. Patients with DPPX autoantibodies usually have pro-
dromal symptoms of diarrhea and substantial weight loss (around
20 kg), followed by an onset of neurological symptoms [364–366]. This
suggests a link between the brain and the “gut brain” in the context of
neuroimmunology. There is further evidence as patients with gastro-
intestinal diseases also have increased frequencies of antineuronal an-
tibodies, though not against DPPX [367].
DPPX antibodies were found to induce a reversible loss of DPPX and
Kv4.2 from the cell surface of cultured enteric nervous system neurons,
and they also caused hyperexcitation in cultured hippocampal neurons
[365,366]. However, the pathogenic mechanism of cross-linking and
endocytosis of antigen is associated with IgG1–3 antibodies, not with
IgG4. This suggests that IgG1–3 and not IgG4 are the pathogenic anti-
bodies. Unless further evidence turns up, DPPX encephalitis may not be
an IgG4-AID.
I. Koneczny
4.5.4. IgLON5
Similarly, a pathogenic mechanism for IgG1, but not IgG4, has been
demonstrated in IgLON5 parasomnia. IGLON family member 5
(IgLON5) is a glucosyl-phosphatidyl-inositol anchored protein located
in the CNS, and that may mediate membrane stabilization. Anti-IgLON5
antibodies are associated with IgLON5 parasomnia which is a severe
autoimmune disease characterized by abnormal sleep behaviour.
Interestingly, there is also a tauopathy in these patients, which suggests
a very unusual connection between autoimmunity and neurodegen-
eration [368–371]. The IgLON5-IgG1 antibodies have been demon-
strated to induce irreversible cross-linking and endocytosis of antigen
[18]. The loss of IgLON5 is thought to destabilize the cytoskeleton,
which may also affect microtubule stability and hyperphosphorylation
of microtubuli-associated tau protein, which might cause the tauopathy
[368]. Importantly, it was demonstrated that the cross-linking and
endocytosis depends on divalent binding, as IgG4 or Fabs were not able
to internalize IgLON5 [18], which emphasizes the relevance of valency
for pathogenicity.
4.5.5. Cytokines
Autoimmune polyendocrinopathy–candidiasis–ectodermal dys-
trophy (APECED) is a severe autoimmune syndrome caused by muta-
tions in the autoimmune regulator (AIRE) gene [372]. AIRE is a tran-
scription factor that induces the ectopic expression of peripheral tissue
self-antigens by thymic medullary epithelial cells that negatively select
autoreactive T-cells and so help to maintain self-tolerance. Therefore,
mutations in AIRE lead to severe autoimmunity, initially directed
against unusual targets – in infancy or childhood – such as the Th17/
Th22 system, causing chronic mucocutaneous candidiasis (CMC), the
parathyroids, the adrenal cortex and/or the conjunctiva, nails or teeth.
That may be followed by more typical autoimmune conditions such as
vitiligo, alopecia, thyroid disease or type I diabetes. Usually at diag-
nosis, most patients have high titres of neutralizing autoantibodies
against cytokines, such as type I interferon (IFN I), interleukin (IL)-17A,
IL-17F and IL-22 [373–375].
While anti-IFN I antibodies may protect against further auto-
immunity [373], those against IL-17A/F and IL-22 correlate with re-
duced numbers of Th17/ Th22 cells and with CMC. These cytokine
antibodies are predominantly of IgG1 and IgG4 subclass, sometimes
exclusively” Th2-type” IgG4s [375]. Patients with thymomas show in-
triguing (a) serological similarities and (b) clinical differences: (a) high
titres of antibodies neutralizing IFN-Is (≥70%), and/or IL-17 s or IL-22,
again correlating with CMC (< 5%; [375]); (b) endocrine auto-
immunity is infrequent (< 5%) whereas myasthenia gravis is common
(≥30%). The obvious connecting thread with APECED is that the
neoplastic epithelial cells in most thymomas fail to express AIRE, but
nevertheless generate numerous developing T cells in a disorganised
environment where failure to tolerize seems likely (Nick Willcox, per-
sonal communication).
Since APECED is a very complex disease, it would be interesting to
study pathogenic and protective functions of IgG4 anti-cytokine anti-
bodies by passively transferring purified patient IgG4 to healthy ex-
perimental animals. To date, that has only been undertaken with one
anti-IL-22 IgG1 antibody cloned from an APECED patient, which im-
paired fungal clearance [376]. In a mouse model with Aire deficiency,
autoreactive B-cells appeared important mainly for priming T-cells ra-
ther than producing pathogenic antibodies [377]. However, there is a
new rat model for APECED that reflects more of the patients' symptoms
and serology, with Th2-type IgG1s and IgMs and IgAs, against cytokines
[378]. It would be interesting to study the contribution of the different
antibody subclasses in these rats by passively transferring their cloned
IgGs to normal animals. Whether these thymus-associated autoimmune
syndromes should be added to the list of’IgG4 autoimmune diseases' is
debatable, as the proportion of IgG4 to total autoantibody varies so
much between patients, and the pathogenic potential of any of the
antibodies has yet to be definitively established. In the meantime, they
14
Autoimmunity Reviews 19 (2020) 102646
must add intriguing new clues to the mechanisms of autoimmunization.
5. Conclusion
IgG4-AID are rare and severe diseases that are hallmarked by the
presence of antigen-specific autoantibodies of the IgG4 subclass. In
contrast to IgG4-RLD the autoantibodies have specific antigenic targets
and are directly pathogenic by blocking protein-protein interactions.
IgG4 autoantibodies target antigens that are located in four distinct
organs: 1) the central and peripheral nervous system, 2) the kidney, 3)
the skin and mucous membranes and 4) the vascular system including
soluble antigens in the blood circulation. In this review we could
identify six class I (verified) and seven class II (likely) IgG4 autoimmune
diseases, and identified 16 antigens for class III IgG4 autoimmune dis-
eases, with insufficient data or evidence suggesting other pathogenic
players than IgG4.
Declaration of Competing Interest
None.
Acknowledgements
We thank Nick Willcox for scientific advice and feedback on
APECED. Figures were created using BioRender Software. We also
thank Wolfgang Bauer for scientific advice. Inga Koneczny is funded by
a Hertha Firnberg project (project number T996-B30) by the Austrian
Science Fund (FWF). T996-B30
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