Introduction
Dysregulation of innate immunity
Dendritic cells (DCs)
Type I interferon (IFN) in SLE
Interaction between pattern recognition receptors (PRRs) and DCs
Neutrophils
Dysregulation of adaptive immunity
T cells
T-cell signaling alteration
T-cell receptor (TCR)-CD3 signaling pathway
CD44–Rock–ERM signaling pathway
PI3K-Akt-mTOR signaling pathway
T-cell subsets and imbalance
Imbalance of Th1/Th2 cells
Cytokines | Source | Physiological effect | Trends in SLE | Functions in SLE |
---|---|---|---|---|
IL-2 | Activated T cells and NK cells | To induce T cell proliferation and maintain immune tolerance | ↓ | The decrease of IL-2 promotes T cells to differentiate into Th17, inhibits apoptosis and activates autoimmune T cells |
IL-4 | Th2 cells | Promote humoral immunity, inhibit cellular immunity | ↓ | Promote the production of IgG dsDNA antibody; promote the occurrence of lupus nephritis |
IL-6 | Macrophage, T and B lymphocytes and other immune cells | Participate in inflammatory response and immune response | ↑ | B cells express high levels of IL-6R and bind to IL-6 to promote B cells to produce IgG and dsDNA, resulting in immune damage |
IL-10 | Macrophage, monocyte, T and B lymphocytes | It has both anti-inflammatory and inflammatory functions | ↑ | Promote the activation and proliferation of B cells while inhibiting the function of APC and Th1 |
IFN-γ | Activated T cells and NK cells | Regulate immune response and fight tumors | ↑ | Promote the activation of B cells |
TNF-α | Mononuclear macrophages | Involved in the inflammatory process of autoimmunity | ↑ | Promote the expression of major histocompatibility complex antigens, producing immune responses |
Imbalance of Th17/Treg cells
T follicular helper (Tfh) cells
B cells
Classic T–B cells interactions
B-cell subsets
Potential therapeutic targets in SLE
Targeting innate immunity
Type | Agents | Targets for agents | Clinical evaluation |
---|---|---|---|
IFN targeting therapies | Rontalizumab | Anti-IFNα | Did not meet the end point |
Sifalimumab | Anti-IFNα | No clinical benefits with AE of herps zoster | |
AGS-009 | Anti-IFNα | Safe and well tolerated in phase I RCT | |
JNJ-55920839 | Anti-IFNβ | Phase I RCT is ongoing | |
Anifrolumab | Anti-IFNAR | Safe and effective in reducing IFN signature | |
AMG-811 | Anti-IFNγ | Safe and well tolerated with no significant benefits | |
IFN-K | IFNα inhibition | Safe and well tolerated with no significant benefits | |
pDC targeting therapies | BIIB059 | Anti-BDCA2 | Safe and effective in reducing IFN signature |
JNJ-56022473 | Anti-CD123 | Phase I RCT is ongoing | |
ABT-199 | Bcl-2 inhibitor | Outcome of phase I trial is pending |
Targeting adaptive immunity
T-cell target therapies
Type | Mechanism of action | Agents | Targets for agents | Clinical evaluation |
---|---|---|---|---|
B-cell targeting therapies | Blocking B-cell surface antigen | Rituximab | Anti-CD20 | Effective in refractory SLE. Allergic response is the main AE |
Ofatumumab | Anti-CD20 | Effective in increasing C3 and C4, decreasing anti-dsDNA. Infection is the main AE | ||
TRU-015 | Anti-CD20 | Phase I RCT is terminated | ||
Obinutuzumab | Anti-CD20 | Safe and well tolerated in phase I trial | ||
Epratuzumab | Anti-CD22 | Phase III trial did not meet the primary end points | ||
SM03 | Anti-CD22 | Safe and well tolerated | ||
XmAb 5871 | Anti-CD19 | Phase II trial is ongoing | ||
Milatuzumab | Anti-CD74 | Outcomes of phase I trial is pending | ||
Blocking B-cell survival factors | Belimumab | Anti-BAFF | Effective in improving time to first flare and exhibiting a steroid sparing effect | |
Blisibimod | Anti-BAFF | Effective in increasing C3 and C4 levels and decreasing urinary protein | ||
Atacicept | Anti-BAFF/APRIL | Got Several efficacy, but trials were terminated for fatal infections | ||
B-cell tolerization | Abetimus sodium | Anti-immunoglobulin receptor on B cells | Clinical trials were terminated | |
T-cell targeting therapies | Blocking co-stimulatory factors | Abatacept | Competing with CD28 | Effective in increasing C3 and C4, decreasing anti-dsDNA levels |
BG9588 | Anti-CD40 | Clinical trials were terminated for thromboembolic event | ||
Dapirolizumab | Anti-CD40L | Safe and well tolerated in phase I trial | ||
MEDI-570 | Anti-ICOS | Outcomes of phase I trial is pending | ||
AMG557 | Anti-ICOSL | Outcomes of phase I trial is pending | ||
Theralizumab | Anti-CD28 | Phase II trial is ongoing |
B-cell target therapies
Other target therapies
Type | Agents | Targets for agents | Clinical evaluation |
---|---|---|---|
Targeting cytokines | Tocilizumab | Anti-IL-6 receptor | Effective in increasing C3 and C4, decreasing anti-dsDNA levels |
Etanercept | Anti-TNF | Safe and well tolerated | |
BT063 | Anti-IL-10 | Phase II trial is ongoing | |
Targeting complement | Eculizumab | Anti-C5 | Randomized trials are ongoing |
Targeting IC | SM101 | Anti-IC | Safe and well tolerated, no serious AE |
Targeting kinases of the intracellular machinery | Evobrutinib | Anti-BKT | Randomized trials are ongoing |