Table 2.
Comparison between antigens, symptoms, animal models, HLA associations and responsiveness to immunosuppression between IgG4-AID and IgG4-RD.
| Antigen | Localisation of antigen | Disease | Symptoms | Organ affected | Evidence of passive transfer | Evidence through active immunisation | Ig type | Response to immunosuppressants | HLA associations |
|---|---|---|---|---|---|---|---|---|---|
| Carbonic anhydrase II | Cytoplasm | IgG4-RD | Pseudotumours, fibrosis. Varies according to organ affected. | Pancreas, bile ducts, sallivary and lacrimal glands, kidneys, retroperitoneum, aorta, orbits | No | Yes | IgG4 | Yes | HLA-DQB1*0401, HLA-DRB1*0405, HLA-DRB1*16, FCGR2B |
| Plasminogen binding protein type A/UBR2 | Cytoplasm and nucleus | No | No | Total IgG | |||||
| Lactoferrin | Pancreatic juice | No | No | Total IgG | |||||
| Pancreatic secretory trypsinogen inhibitor (SPINK1) | Pancreatic juice | No | No | Total IgG | |||||
| Trypsinogens | Pancreatic juice | No | No | Total IgG | |||||
| Annexin A11 | Cytoplasm, cell membrane | Yes | No | IgG1 and IgG4 | |||||
| Laminin 511-E8 | Extracellular matrix | Yes | Yes | IgG1 and IgG4 | |||||
| Galectin 3 | Extracellular matrix, cytosol and nucleus | No | No | IgG4 and IgE | |||||
| Prohibitin | Nucleus, cytoplasm and mitochondria | No | No | IgG4 | |||||
| Desmoglein 1 | Cell membrane | Pemphigous foliaceous | Blistering lesions | Skin | Yes | Yes | IgG4 and IgG1 | Yes | HLA-DRB1*0404, *1402, *1406, or *0102 |
| Desmoglein 3 | Cell membrane | Pemphigus vulgaris | Blistering lesions | Skin | Yes | No | IgG4 and IgG1 | Yes | HLA-DRB1*14, HLA-DRB1*04:02, HLA-B*38, HLA-B*55 |
| Muscle-specific kinase | Cell membrane | MuSK myasthenia gravis | Weakness and atrophy of neck, tongue, shoulder and bulbar muscles. | Muscles (Motoneural junction) | Yes | Yes | IgG4 | Yes | HLA-DQB1*05, HLA-DRB1*13, HLA-DRB1*16 |
| Contactin 1 | Cell membrane | Chronic inflammatory demyelinating polyradiculoneuropathy | Subacute neuropathy, sensory ataxia and tremor. | CNS and PNS | Yes | No | IgG4 | Variable | HLA-DQB1*02 |
| Neurofascin 155 | Cell membrane | Yes | No | IgG4 | Variable | ||||
| CASPR1 | Cell membrane | No | No | IgG4 | Variable | ||||
| Neurofascin 140/186 | Cell membrane | No | No | IgG4 | Variable | ||||
| ADAMTS13 | Blood circulation | Thrombotic thrombocytopenic purpura | Thrombotic events | Blood | Yes | No | IgG1 and IgG4 | Yes | HLA-DRB1*11, HLA-DRB1*08:03 |
| CASPR2 | Cell membrane | Isaac’s syndrome, Morvan’s syndrome, limbic encephalitis | Epilepsy, behavioural and mental abnormalities, autonotmic instability, motor and sensory neuropathy. | CNS and PNS | Yes*** | No | IgG4 | Variable | HLA-DRB1*11:01 |
| LGI1 | Cell membrane | LGI1-associated limbic encephalitis, Isaac’s syndrome | Epilepsy, behavioural and mental abnormalities, seizures, dystonia, sensory and motor neuropathy. | CNS and PNS | Yes*** | No | IgG4 | Variable | HLA-DRB1*07:01 |
| PLA2R | Cell membrane | Membranous nephropathy | Oedema, fatigue, changes in urine | Kidneys | Yes | Yes**** | IgG4 | Yes | HLA-DQA1, HLA-DRB1*1501, HLA-DRB1*0301 |
| THSD7A | Cell membrane | Yes | No | IgG4 | Yes | ||||
| Alfa-enolase | Cell membrane | No | No | IgG4 and IgG1 | Yes | ||||
| Superoxide dismutase 2 (SOD2) | Mitochondria | No | No | IgG4 and IgG1 | Yes | ||||
| Aldose reductase | Cytoplasm | No | No | IgG4 and IgG1 | Yes | ||||
| GPIHBP1 | Cell membrane | GPIHBP1 autoantibody syndrome | Severe hypertriglyceridemia | Blood | No | No | IgG4 | Needs more studies | |
| Laminin 332 | Cell membrane | Mucous membrane pemphigoid | Blistering mucosal lesions, mainly in the oral cavity and conjunctivae | Mucosa | Yes | No | IgG4 | Yes | HLA-DQB1*0301 |
| Type IV Collagen | Extracellular matrix | Goodpasture syndrome, epidermolysis bullosa acquisita (EBA) | Haemoptysis, changes in urine/blistering lesions | Lungs and kidneys, skin | Yes | Yes | IgG1 and IgG2 | Yes | HLA-DRB1*1501/HLA-DR15, HLA-DRB1*15:03 |
| IgLON5 | Extracellular matrix | IgLON5 parasomnia | gait instability, non-REM and REM parasomnia, cognitive decline, movement disorders. | CNS | No | No | IgG1 | Variable | HLA-DRB1*10:01-DQB1*05:01 |
| DPPX | Cell membrane | Anti-DPPX encephalitis | Weight loss, gastrointestinal symptoms, cognitive-mental dysfunction, tremor, seizures, autonomic dysfunction. | CNS | No | No | IgG4 and IgG1 | Variable | |
| ANCA | Cytoplasm | ANCA-related vasculitides | Fatigue, haemoptysis, muscle pain, changes in urine | Blood vessels, kidneys | Yes | Yes | IgG1, IgG3, IgG4 | Yes | HLA-DRB1*04, HLA-DRB1*07, HLA-DRB1*09, HLA-DRB3, HLA-DRB1*13, HLA-DQ |
| Bullous pemphigoid antigen 180 | Cell membrane | Bullous pemphigoid Bullous pemphigoid |
Blistering lesions Blistering lesions |
Skin | Yes | Yes | IgG1 | Yes Yes |
HLA-DQB1*0301 HLA-DQB1*0301 |
| Bullous pemphigoid antigen 230 | Cytoplasm | Skin | Yes | Yes | IgG1 | ||||
| IFN 1, IL-17A, IL-22 | Extracellular matrix | Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy | Chronic candidiasis, hypothyroidism, hypogonadism | Skin, mucosa, endocrine organs, lungs, bowels | No | No | IgG1 and IgG4 | Yes*/** | |
| P200 (laminin gamma1) | Cell membrane | Anti-p200 pemphigoid | Blistering lesions | Skin | No | No | IgG4 | Needs more studies |
*Only the autoimmune manifestations respond to immunosuppressants.
** Ruxolitinib might be effective in the treatment of chronic mucocutaneous candidiasis in patients with STAT1 gain-of-function mutations.
***Did not trigger all the symptoms observed in patients.
****Knock-in PLA2R mice spontaneously developed MN.