The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy
Abstract
:1. Introduction
2. NKG2D and NKG2D-L
2.1. NKG2D Receptor
2.2. NKG2D-L
3. Role of NKG2D/NKG2D-L in Autoimmune Diseases
3.1. SLE
3.2. RA
3.3. Multiple Sclerosis (MS)
3.4. Type I Diabetes (T1DM)
3.5. Inflammatory Bowel Disease (IBD)
3.6. Celiac Disease (CeD)
4. NKG2D and NKG2D-L Are Key Targets in Autoimmune Diseases
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
NK | Natural killer |
NKG2D | Natural killer group 2 member D |
NKG2D-L | NKG2D ligand |
SLE | Systemic lupus erythematosus |
RA | Rheumatoid arthritis |
MS | Multiple sclerosis |
T1DM | Type I diabetes |
IBD | Inflammatory bowel disease |
CeD | Celiac disease |
TCR | T-cell receptor |
Klrk1 | Killer cell lectin-like receptor K subfamily member 1 gene |
KLRD1 | Killer cell lectin-like receptor D1 |
KLRC | Killer cell lectin-like receptor C |
DAP10 | DNAX-activating protein 10 |
DAP12 | DNAX-activating protein 12 |
YXXM | Tyr-XX-Meth |
PI3K | Phosphatidylinositol 3 kinase |
Grb2 | Growth factor receptor binding protein 2 |
ITAM | Immunoreceptor tyrosine-based activation motif |
ZAP70 | Zeta chain-related protein kinase 70 |
Syk | Splenic tyrosine kinase |
IL-15 | Interleukin-15 |
MIC | MHC class I chain-related protein |
ULBP | UL16-binding protein |
MICA | MHC class I chain-related protein A |
MICB | MHC class I chain-related protein B |
Mult-1 | Murine UL-16-binding protein-like transcript 1 |
MHC-I | Major histocompatibility complex class I |
TM | Transmembrane |
GPI | Glycosylphosphatidylinositol |
sMIC | Soluble MIC |
sNKG2DL | Soluble NKG2D-L |
CNS | Central nervous system |
sMICA | Soluble MICA |
sMICB | Soluble MICB |
IL-10 | Interleukin-10 |
IFN | Interferon |
TNF-α | Tumor necrosis factor-α |
SLEDAI | SLE Disease Activity Index |
SNP | Single nucleotide polymorphism |
FLS | Fibroblast-like synovial cells |
Tregs | Regulatory T cells |
AE | Antigen epitope |
C3G | Anthocyanin-3-O-glucoside |
Sirt6 | Sirtuin6 |
EULAR | European League Against Rheumatism |
CSF | Cerebrospinal fluid |
EAE | Experimental autoimmune encephalomyelitis |
sULBP4 | Soluble ULBP4 |
GM-CSF | Granulocyte-macrophage colony-stimulating factor |
IFN-γ | Interferon-γ |
RR-MS | Relapsing multiple sclerosis |
HbA1c | Hemoglobin A1c |
CD | Crohn’s disease |
UC | Ulcerative colitis |
IEC | Intestinal epithelial cells |
TL1A | Tumor necrosis factor (TNF)-like cytokine 1A |
DSS | Dextran sulfate sodium |
TGF-β | Transforming growth factor beta(β) |
Xbp1 | X-box binding protein 1 |
ER | Endoplasmic reticulum |
CDAI | Crohn’s Disease Activity Index |
LOT | Loss of oral tolerance |
IELs | Intraepithelial lymphocytes |
ACD | Active celiac disease |
TDCA | Taurodeoxycholic acid |
CTL | Cytotoxic T-lymphocyte |
Cyst-LTs | Cysteinyl leukotrienes |
HSP70 | Heat shock protein 70 |
SCID | Severe combined immunodeficiency |
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Title | Clinical Trial No. | Status | Actual Enrolment | Conditions | Phase | Year Last Updated |
---|---|---|---|---|---|---|
Predictive Factors of ANTI-TNF Response in Luminal Crohn’s Disease Complicated by Abscess | NCT02856763 | Completed | 125 participants | Crohn’s disease | / | 20 January 2021 |
Safety and Efficacy Study of JNJ-64304500 in Participants With Moderately to Severely Active Crohn’s Disease | NCT02877134 | Completed | 388 participants | Crohn’s disease | Phase 2 | 17 February 2023 |
A Study of JNJ-64304500 as Add-on Therapy in Participants With Active Crohn’s Disease | NCT04655807 | Withdrawn (sponsor decision) | / | Crohn’s disease | Phase 2 | 1 September 2021 |
Safety and Efficacy of NNC 0142-0000-0002 in Subjects With Moderately to Severely Active Crohn’s Disease | NCT01203631 | Completed | 78 participants | Inflammation Crohn’s disease | Phase 2 | 1 August 2016 |
Efficacy of NNC0142-0002 in Subjects With Rheumatoid Arthritis (RA) | NCT01181050 | Completed | 63 participants | Inflammation rheumatoid arthritis | Phase 2 | 3 October 2016 |
First-in-man Trial of NNC0142-0002 in Patients With Rheumatoid Arthritis | NCT00927927 | Completed | 65 participants | Inflammation rheumatoid arthritis | Phase 1 | 3 October 2016 |
Disease | Immune Cell Type | Observed NKG2D Ligands | Biological Effects of NKG2D-NKG2DL | Refs. |
---|---|---|---|---|
SLE | NKG2D+CD4+ T cell NK cell | MICA sMICB | secretion of IFN, TNF-α, and granzyme promotes expansion | [48,49] |
RA | NKG2D+CD4+ T cell NK cell | MICA sMICA | direct cytotoxicity decreased NKG2D expression | [43,64] |
MS | NKG2D+CD4+ T cell NKG2D+CD8+ T cell NK cell | sULBP4 | promotes migration promotion of CD8+T cell motility enhances production of pro-inflammatory cytokines GM-CSF and IFN-γ | [78,81] |
T1DM | NKG2D+CD8+ T cell NK cell | RAE-1 | direct cytotoxicity | [89,95,99] |
IBD | NKG2D+CD4+ T cell | MICA | secretion of IFN-γ | [104] |
CeD | NKG2D+IEL cell | MICA | direct cytotoxicity | [122] |
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Wei, L.; Xiang, Z.; Zou, Y. The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy. Int. J. Mol. Sci. 2023, 24, 17545. https://doi.org/10.3390/ijms242417545
Wei L, Xiang Z, Zou Y. The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy. International Journal of Molecular Sciences. 2023; 24(24):17545. https://doi.org/10.3390/ijms242417545
Chicago/Turabian StyleWei, Leiyan, Zhiqing Xiang, and Yizhou Zou. 2023. "The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy" International Journal of Molecular Sciences 24, no. 24: 17545. https://doi.org/10.3390/ijms242417545