Table 2.

Overview of the characteristics and experimental evidence for the IgG4-mediated autoimmune diseases.

Antigen	Disease	Symptoms	Prevalence	HLA association	Target organ	Main immunogenic region	Passive transfer confirmation in experimental animals	Disease mechanism	VDJ gene usage	Reference
ADAMTS13	Thrombotic thrombocytopenic purpura	Thrombocytopenia, microangiopathic hemolytic anemia resulting in organ failure	13 per million	HLA-DRB1*11	Vasculature	Cysteine-rich spacer domain	N/A	Inhibition of ADAMTS13-dependent von Willebrand factor cleavage	VH1-3, VH1-69, VH3-30, VH4,28	74, 79, 84
CASPR1	Chronic inflammatory polyneuropathy	Progressive weakness, sensory disturbances, neuropathic pain	3 cases	N/A	Paranode of Ranvier on motor neurons	N/A	N/A	Blocking of CNTN1–Caspr1–NF155 complex	N/A	76, 82
CASPR2	Limbic encephalitis, neuromyotonia and Morvan syndrome	Impaired cognition, seizures, fasciculations and cramps, sometimes autonomic dysfunction and insomnia	~ 200 patients have been described thus far	N/A	Juxtaparanode of Ranvier on motor neurons and inhibitory neurons in the CNS	Discoidin domain, but with many epitopes all over the extracellular domain; glycosylation independent	N/A	Inhibition of Caspr2–TAG1 interaction altering gephyrin clustering	N/A	72, 89
Contactin1	Chronic inflammatory polyneuroathy	Severe symmetric sensory and motor polyradiculoneuropathy, poor IV Ig response	3–7% of CIDP patients	N/A	Paranode of Ranvier on motor neurons	Ig-like domain dependent on N-glycans	Yes, IgG4 and IgG1	Inhibition of CNTN1–CASPR1 interaction disrupting node of Ranvier	N/A	83
Desmoglein1	Pemphigus foliaceus	Acantholysis (skin blistering)	2–10 per million in central Europe, with higher incidence among specific ethnic groups	HLA-DRB1*4, DRB1*14 Different HLAs associated with specific ethnic groups and geography	Skin keratinocyte desmosomes	N-terminal cadherin-like domain 1 and 2; glycosylation independent	Yes	Inhibition of trans-adhesion	VH1, VH3	75
Desmoglein3	Pemphigus vulgaris	Acantholysis (skin blistering) and blisters on mucosal membranes	2–10 per million in central Europe, with higher incidence among specific ethnic groups	HLA-DRB1*4, HLA-DRB1*08, HLA-DRB1*14 HLA-DQB1*5 Different HLAs associated with specific ethnic groups and geography	Skin keratinocyte desmosomes and mucous membranes	N-terminal cadherin-like domain 1 and 2; glycosylation independent	Yes	Inhibition of trans-adhesion between desmoglein3 receptors, signaling inhibition and desmosome shrinkage	VH1-46 VH1, VH3, VH4	75
IgLON5	Non-REM and REM parasomnia with sleep breathing dysfunction and a tauopathy	Disordered sleep and ventilation, sometimes with brain stem, gait, cognitive, or movement disorders	At least 30 patients have been identified	HLA-DQB1*0501 HAL-DRB1*1001	Brain neuropil	Ig-like 2 domain; glycosylation independent	N/A	IgG1 caused IgLON5 cluster internalization; IgG4 has unknown effects	N/A	77
LGI1	Limbic encephalitis	Memory, behavioural, and orientation deficits; faciabrachial dystonic seizures, often with hyponatremia	~ 300 patients have been described	HLA-DR7 HLA-DRB4	CNS predominantly in hippocampus and temporal cortex	EPTP repeat and leucine-rich repeat domain	Yes	Inhibition of Lgi1-ADAM interaction and AMPAR clustering	N/A	12, 86
MuSK	Myasthenia gravis	Fatigable muscle weakness	2–9 per million	HLA-DR14-DQ5	Muscle/neuromuscular junction	N-terminal Ig-like domain; glycosylation independent	Yes, IgGtotal and IgG4	Inhibition of MuSK–LRP4 interaction and AChR clustering	N/A	81
Neurofascin140/186	Chronic inflammatory polyneuroathy	Severe symmetric sensory and motor polyradiculoneuropathy.	4 patients described thus far	N/A	Motor neurons, (para)node of Ranvier	Ig-like domains; fibronectin V domain	N/A	N/A	N/A	11
Neurofascin155	Chronic inflammatory polyneuroathy	Aggressive, distal, sensorimotor neuropathy, poor response to IV Ig	~ 3–7 % of CIDP patients	N/A	Motor neurons, (para)node of Ranvier	N-terminal Ig-like domain; fibronectin III,IV domain	N/A	Inhibition of cell adhesion at paranodal junction	N/A	83
PLA2R1	Membranous nephropathy	Proteinuria, nephritis	70% of membranous nephropathy patients	HLA-DQA1 HLA-DRB1	Kidney, podocytes	N-terminal Cys-R domain; fibronectin II domain and CTLD1 domain	No, as antigen is not expressed on podocytes in rodents	Perhaps inhibition of PLA2R binding to collagen	N/A	73, 85, 87
THSDA7A	Membranous nephropathy	Proteinuria, nephritis	5% of membranous nephropathy patients	N/A	Kidney, podocytes	N/A	Yes	Binding to THSDA7A alters cytoskeletal organization through unknown mechanism	N/A	87