Table 1.
Pathogenic process of AOSD.
| Process | Factors | Pathogenic roles and clinical association | References |
|---|---|---|---|
| Genetic background | HLA class I (HLA-B17, B18, and B35) HLA class II (HLA-DR2, DR4, DRB1*12, and DRB1*15) |
Disease susceptibility | (10, 11) |
| HLA-Bw35 and HLA-DRB1*14 HLA-DRw6 HLA-DRB1*1501 (DR2) and HLA-DRB1*1201 (DR5) HLA-DQB1*0602 (DQ1) IL-18 MIF MEFV, TNFRSF1A LILRA3 |
Mild, self-limiting disease Joint involvement Chronic disease course Chronic and systemic disease Higher production of IL-18 Higher production of MIF, liver dysfunction Disease susceptibility, severe disease Disease susceptibility, inducing formation of NETs |
(12–14) (15) (16) (17) (18) |
|
| Triggers | Viruses (rubella, measles, echovirus 7, coxsackievirus B4, cytomegalovirus, Epstein-Barr virus, parvovirus B19, hepatitis virus, influenza virus, adenovirus, and human immunodeficiency virus), | PAMPs | (19–22) |
| SARS-CoV-2 Bacteria (Mycoplasma pneumonia, Chlamydia pneumonia, Yersinia enterocolitica, Brucella abortus, and Borrelia burgdorferi) |
Macrophage activation PAMPs |
(19) (1, 23–25) |
|
| Solid cancers and hematologic malignancies (necrotic tumor cells) | DAMPs | (1, 26, 27) | |
| Innate immune system | Hyperactivated macrophages | Produce proinflammatory cytokines (IL-1β, IL-18, TNFα, and IL-6) and chemokines Enhanced phagocytosis Stimulate the release of ferritin |
(19, 28) |
| Hyperactivated neutrophils Low activation of NK cells |
Release cytokines/chemokines and communicate with macrophages NETs formation MAS pathogenesis |
(29, 30) (31–34) |
|
| Acquired immune system | Hyperactivated Th1 cells Hyperactivated Th17 cells Low activation of Tregs |
Correlation with clinical activity score and serum IL-18 levels IFNγ activates macrophages Correlation with severity score, serum ferritin levels, and proinflammatory cytokines Disease activity affects the stability of Tregs |
(28, 35) (36, 37) (38) |
| High production of ferritin | Increased ferritin from activated macrophages | Stimulate inflammatory pathways, correlation with disease activity | (1, 19, 39–43) |
| Proinflammatory cytokines | High levels of IL-18 and IL-1β High levels of IL-6 and TNFα High levels of IL-1β and IL-6 Increased IFNγ level compared with IL-18 IL-18 PLAC8 IL-10 IL-38 |
Systemic disease Arthritis Fever and skin rash Development of MAS Triggers Th1 response inducing the secretion of IFNγ by cytotoxic CD8+ and NK cells Suppresses the synthesis of pro-IL-1β and pro-IL-18 via enhanced autophagy in monocytes Inhibits the production of IL-1β, IL-6, and TNFα from monocytes induced by IFNγ Inhibits the activation of NLRP3 inflammasome in macrophages |
(1, 3, 44, 45) (46) (47) (48, 49) |
MIF, macrophage migration inhibitory factor; MEF, Mediterranean fever; TNFRSF1A, tumor necrosis factor receptor superfamily member 1A; LILRA3, gene name for leukocyte immunoglobulin-like receptor A3; NETs, neutrophil extracellular traps; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; MAS, macrophage activation syndrome; Tregs, regulatory T cells; NK, natural killer; PLAC8, placenta-specific 8; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain 3.