IgG4-related disease
4.6/100.000 in Japan. A variable vessel vasculitis (mostly phlebitis), around 60yrs and 60% are
men, except for head and neck disease, where there is a slight female preponderance and a
younger onset. The proliferative variant is more common in Asians, who also have higher serum
IgG and IgG4, whereas the fibrotic variant is more common in Whites. IgG4 is generally
considered an anti-inflammatory antibody, as it has a low affinity for target antigens and is
unable to bind FcγR and C1q receptors. Despite the prominence of IgG4-positive plasma cells in
IgG4-RD, CD4+ and CD8+ may play a more central role in the pathophysiology of the disease.
Develops tumors but not granulomas. Not necrotizing, not granulomatous.
IgG4 physiology
IgG1 and IgG3 can fixate complement and opsonize pathogens, while IgG4 only activates
complement under special circumstances (high antibody and antigen concentrations). IgG4 is
<5% of total IgG. The Fc portion in IgG4 antibodies has a high affinity for antigens and FcγRIIb
(inhibitory), but low affinity for stimulatory FcγRs and C1q (therefore cannot typically activate
the classical pathway). However, there are situations where IgG4 can activate the complement
pathway. The first is via recruiting mannose-binding lectins and activating the lectin pathway
(observed in anti-PLA2R membranous nephropathy). The second is through mutations of the Fc
region, enabling these molecules to form hexamers and bind to C1q. These molecules can also
activate the complement system using the classical pathway when there is high antigen density
and high antibody concentration. Hence, IgG4 has anti-inflammatory properties and it is
involved both in health (ex. tolerance in allergies) and in disease, such as curbing immune
responses against helminthic infections.
IgG4 in allergy: development of tolerance in atopic patients (ex. beekeepers). IgG4
competitively binds to allergens, thus hindering the formation of IgE-antigen immune
complexes. Furthermore, it also binds to FcγRIIb (inhibitory), preventing the degranulation of
mast cells and the cascade that would lead to allergic responses.
Diseases mediated by IgG4 antibodies: myasthenia gravis (anti-MuSK are IgG4),
pemphigus folliaceous (anti-Dsg1 are IgG4), TTP (anti-ADAMTS13 are initially IgG1 but
chronically IgG4). However, the role of IgG4 in IgG4-RD itself requires further elucidation; do
they target autoantigens or do they regulate the (unknowingly provoked) inflammation?
Pathophysiology
In IgG4-RD it is not clear if high IgG4 are pathogenetic or an epiphenomenon.
Within germinal centers, oligoclonal expansion of autoreactive B cells is promoted via
the presentation of autoantigens by Tfh and fDCs which promote IgG4-producing differentiation,
via the production of IL-10 and IL-4 in combination with DCs producing BAFF. This switch is
driven by Th2 and Tregs. Activated B cells migrate into pathological tissues, eventually
promoting CD4+ and CD8+ activation and differentiation. Oligoclonally expanded B-cells and
plasmablasts contribute to fibroblast activation through the secretion of PDGF-β. CD8+
contribute to tissue damage and fibrosis by inducing apoptosis and by secreting pro-fibrotic
molecules such as TGF-β, IL-1 and IFN-γ. The reduction of circulating CD8+ following B cell-
directed therapy does indeed support the concept that B cells act as APCs to these pathogenic T
cells. In addition to B cells and T cells, macrophages also infiltrate the affected tissues and clear
apoptotic debris through efferocytosis and release IL-10 and pro-fibrotic molecules such as TGF-
β, thus participating in the resolution of inflammation and fuelling tissue fibrosis.
, Criteria
Diagnostic
Classification
EULAR 2019: sensitivity & specificity: 98%
Entry step
Exclusion criteria
Points (weighted and per domain)
Total points for classification: entry + no-exclusion + ≥20 points
Caveats: if the disease is confined to atypical sites (ex. the MSK system or sinonasal structures),
it cannot be classified as IgG4-RD because it would not meet the entry criteria. Also, the criteria
exclude the possibility that a patient with IgG4-RD has an overlapping autoimmune disease (ex.
if ANA [+] is found in SLE). Last, typical disease lesions that usually show mild tissue and serum
IgG4 responses (retroperitoneal fibrosis, Riedel thyroiditis) generally do not reach a sufficiently
high score to be classified as IgG4-RD, when they occur in isolation.
Clinical
Nearly any organ can be affected. The course is indolent, without acute inflammation and
without fever (it’s a classification exclusion criterion).
The most commonly affected organs are:
4.6/100.000 in Japan. A variable vessel vasculitis (mostly phlebitis), around 60yrs and 60% are
men, except for head and neck disease, where there is a slight female preponderance and a
younger onset. The proliferative variant is more common in Asians, who also have higher serum
IgG and IgG4, whereas the fibrotic variant is more common in Whites. IgG4 is generally
considered an anti-inflammatory antibody, as it has a low affinity for target antigens and is
unable to bind FcγR and C1q receptors. Despite the prominence of IgG4-positive plasma cells in
IgG4-RD, CD4+ and CD8+ may play a more central role in the pathophysiology of the disease.
Develops tumors but not granulomas. Not necrotizing, not granulomatous.
IgG4 physiology
IgG1 and IgG3 can fixate complement and opsonize pathogens, while IgG4 only activates
complement under special circumstances (high antibody and antigen concentrations). IgG4 is
<5% of total IgG. The Fc portion in IgG4 antibodies has a high affinity for antigens and FcγRIIb
(inhibitory), but low affinity for stimulatory FcγRs and C1q (therefore cannot typically activate
the classical pathway). However, there are situations where IgG4 can activate the complement
pathway. The first is via recruiting mannose-binding lectins and activating the lectin pathway
(observed in anti-PLA2R membranous nephropathy). The second is through mutations of the Fc
region, enabling these molecules to form hexamers and bind to C1q. These molecules can also
activate the complement system using the classical pathway when there is high antigen density
and high antibody concentration. Hence, IgG4 has anti-inflammatory properties and it is
involved both in health (ex. tolerance in allergies) and in disease, such as curbing immune
responses against helminthic infections.
IgG4 in allergy: development of tolerance in atopic patients (ex. beekeepers). IgG4
competitively binds to allergens, thus hindering the formation of IgE-antigen immune
complexes. Furthermore, it also binds to FcγRIIb (inhibitory), preventing the degranulation of
mast cells and the cascade that would lead to allergic responses.
Diseases mediated by IgG4 antibodies: myasthenia gravis (anti-MuSK are IgG4),
pemphigus folliaceous (anti-Dsg1 are IgG4), TTP (anti-ADAMTS13 are initially IgG1 but
chronically IgG4). However, the role of IgG4 in IgG4-RD itself requires further elucidation; do
they target autoantigens or do they regulate the (unknowingly provoked) inflammation?
Pathophysiology
In IgG4-RD it is not clear if high IgG4 are pathogenetic or an epiphenomenon.
Within germinal centers, oligoclonal expansion of autoreactive B cells is promoted via
the presentation of autoantigens by Tfh and fDCs which promote IgG4-producing differentiation,
via the production of IL-10 and IL-4 in combination with DCs producing BAFF. This switch is
driven by Th2 and Tregs. Activated B cells migrate into pathological tissues, eventually
promoting CD4+ and CD8+ activation and differentiation. Oligoclonally expanded B-cells and
plasmablasts contribute to fibroblast activation through the secretion of PDGF-β. CD8+
contribute to tissue damage and fibrosis by inducing apoptosis and by secreting pro-fibrotic
molecules such as TGF-β, IL-1 and IFN-γ. The reduction of circulating CD8+ following B cell-
directed therapy does indeed support the concept that B cells act as APCs to these pathogenic T
cells. In addition to B cells and T cells, macrophages also infiltrate the affected tissues and clear
apoptotic debris through efferocytosis and release IL-10 and pro-fibrotic molecules such as TGF-
β, thus participating in the resolution of inflammation and fuelling tissue fibrosis.
, Criteria
Diagnostic
Classification
EULAR 2019: sensitivity & specificity: 98%
Entry step
Exclusion criteria
Points (weighted and per domain)
Total points for classification: entry + no-exclusion + ≥20 points
Caveats: if the disease is confined to atypical sites (ex. the MSK system or sinonasal structures),
it cannot be classified as IgG4-RD because it would not meet the entry criteria. Also, the criteria
exclude the possibility that a patient with IgG4-RD has an overlapping autoimmune disease (ex.
if ANA [+] is found in SLE). Last, typical disease lesions that usually show mild tissue and serum
IgG4 responses (retroperitoneal fibrosis, Riedel thyroiditis) generally do not reach a sufficiently
high score to be classified as IgG4-RD, when they occur in isolation.
Clinical
Nearly any organ can be affected. The course is indolent, without acute inflammation and
without fever (it’s a classification exclusion criterion).
The most commonly affected organs are:
