Understanding the Complex Dynamics of Immunosenescence in Multiple Sclerosis: From Pathogenesis to Treatment
Abstract
:1. Introduction
2. Immune System Aging
2.1. Immunosenescence: Adaptive Immunity
2.1.1. Immunosenescence: T Cells
2.1.2. Immunosenescence: B Cells
2.2. Immunosenescence: Innate Immunity
2.2.1. Immunosenescence: Neutrophils
2.2.2. Immunosenescence: Monocytes and Macrophages
2.2.3. Immunosenescence: Natural Killer Cells
2.2.4. Immunosenescence: Dendritic Cells
3. Immunosenescence and Inflammaging
- Senescent cells accumulated within various tissues release pro-inflammatory mediators that have the potential to spread the senescent phenotype to neighboring cells, thereby contributing to age-related inflammation;
- There is an increase in cell debris levels from cell death or damage. Examples of these components include nucleic acids, mitochondrial DNA (mtDNA), cardiolipin, mitochondria, and heat-shock proteins. “Garb-aging” refers to the build-up of DAMPs with aging, which can lead to innate immunity and the release of pro-inflammatory cytokines;
- Age-related declines in autophagy and proteasome activity play a role in the accumulation of misfolded protein aggregates. Consequently, these aggregates serve as triggers for inflammatory pathways.
- The presence of pro-inflammatory circulating microRNA (inflammaMIR) and the age-related accumulation of agalactosylated N-glycans in the blood (one of the most potent indicators of human biological age);
- Nuclear DNA damage and telomere shortening caused by ROS and other agents set off a DNA repair response and stimulate the synthesis of pro-inflammatory molecules;
- Impaired regulation of the complement pathway can cause a local inflammatory response;
- The excessive availability of energy and nutrients can fuel an inflammatory process mediated by metabolic cells, a phenomenon known as “metaflammation”;
4. Immunosenescence in Multiple Sclerosis
4.1. Immunosenescence in Experimental Autoimmune Encephalomyelitis Models
4.2. Particularities of Immunosenescence in Multiple Sclerosis
5. Immunosenescence and Treatment Strategies
5.1. Current Treatments
5.2. Future Prospectives
6. Discussion
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Adaptive Immunity Cell | Changes in Immunosenescence |
---|---|
T cell | Decreased number of naive T cells |
Increased memory T cell population | |
Reduction in TCR repertoire diversity | |
Diminished presence of the CD28 co-stimulatory molecule | |
Increased expression of CD57, KLRG1, TIGIT, and PD1 | |
Distinct cytokine secretion profile (SASP) | |
Shift toward cytotoxicity mediated by NK receptors | |
B cell | Decreased number of naive B cells |
Increased memory B cell population | |
Reduction in BCR repertoire diversity | |
Increase in the population of ABCs | |
Increased autoimmune activity | |
Increase in the population of age-associated B cells |
Type of Pattern-Recognition Receptors | Action |
---|---|
Toll-like receptors | NF-κB activation, activation of MAP kinases pathway to recruit pro-inflammatory cytokines and co-stimulatory molecules, which promote inflammatory responses |
NOD-like receptors | Stimulation of the inflammasome complex and the production of IL-11, IL-18, and IL-33 |
Rig-like receptors | Proximal triggering of the IFN pathway |
Innate Immunity Cell | Changes in Immunosenescence |
---|---|
Neutrophils | Reduced ROS production |
Impaired NET formation | |
Altered adhesion and phagocytosis | |
Monocytes/Macrophages | Impaired migration and chemotaxis |
M2-like over classic M1-like macrophages | |
Reduced TLR expression | |
NK Cells | Increased CD56dim and decreased CD56bright subset |
Reduced cytotoxic activity | |
Defective degranulation capacity | |
Dendritic Cells | Increased ROS production |
Impaired phagocytic capabilities and antigen presentation | |
Decreased responsiveness to TLR stimulation | |
Reduced production of type I and II interferons | |
Enhanced pro-inflammatory cytokine secretion |
SASP Molecule | Role |
---|---|
IL-1 | Pro-inflammatory |
IL-6 | Pro-inflammatory activity contributing to inflammation and DNA damage |
IL-7 | Promotes B lymphocyte growth and T lymphocyte activation |
IL-11 | Hematopoiesis and tissue cell proliferation |
IL-15 | Necessary for T cell regulation; high levels are pro-inflammatory |
IL-8 | Chemotaxis and enhancement of pro-inflammatory activity |
CXCL1 | Neutrophil activation |
MCP2 | Monocyte chemotaxis |
TNFα | Induces apoptosis |
VEGF | Blood vessel formation |
IGF-1 | Proliferation and apoptosis |
Molecule | Cut-Off Age | Impact on Annual Relapse Rate Vs. Placebo | Impact on Disability Progression Vs. Placebo |
---|---|---|---|
Teriflunomide | <38 years | ↓ | ↓ |
≥38 years | ↓ | no impact | |
Dimethyl fumarate | <40 years | ↓ | ↓ |
≥40 years | ↓ | no impact | |
Fingolimod | <40 years | ↓ | no impact |
≥40 years | no impact | no impact | |
Siponimod | <50 years ≥50 years | n/a | ↓ ↓ |
Cladribine | <40 years ≥40 years | ↓ ↓ | ↓ ↓ |
Ocrelizumab | <45 years ≥45 years | ↓ ↓ | ↓ ↓ |
Value | Score | |
---|---|---|
Age | <45 years | 2 points |
45–55 years | 1 point | |
>55 years | 0 points | |
MRI activity | ≥3 new or enlarged T2 lesions or 1 gadolinium-enhancing lesion | 2 points |
<3 new or enlarged T2 lesions and no gadolinium-enhancing lesion | 1 point | |
Stable disease | <4 years | 2 points |
4–8 years | 1 point | |
>8 years | 0 points |
Treatment | Adverse Events Increased with Age |
---|---|
Fingolimod | Reduction of heart rate Hypertension HSV1/VVZ reactivation PML Malignancies (frequently affecting the skin) |
Natalizumab | PML HSV1/VVZ reactivation |
Cladribine | HSV1/VVZ reactivation Malignancies (frequently solid tumors) |
Ocrelizumab | HSV1/VVZ reactivation Hypogammaglobulinemia Malignancies (frequently breast cancer) PML |
Siponimod | Hypertension Diabetes Macular edema |
Dimethyl fumarate | Lymphopenia PML (frequently related to grade 3 lymphopenia) |
SCAP | Senolytic Drug |
---|---|
Bcl-2/Bcl-XL | Navitoclax A1331852 A1155463 Fisetin |
PI3K/Akt/ROS | Quercetin Piperlongumine Fisetin |
p53/p21/serpine | Quercetin Fisetin FOXO related molecule |
Ephrins/dependence receptors/tyrosine kinases | Dasatinib Piperlongumine |
HIF-1α | Quercetin Fisetin |
HSP-90 | Tanespimycin Geldanamycin Alvespimycin |
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Neațu, M.; Hera-Drăguț, A.; Ioniță, I.; Jugurt, A.; Davidescu, E.I.; Popescu, B.O. Understanding the Complex Dynamics of Immunosenescence in Multiple Sclerosis: From Pathogenesis to Treatment. Biomedicines 2024, 12, 1890. https://doi.org/10.3390/biomedicines12081890
Neațu M, Hera-Drăguț A, Ioniță I, Jugurt A, Davidescu EI, Popescu BO. Understanding the Complex Dynamics of Immunosenescence in Multiple Sclerosis: From Pathogenesis to Treatment. Biomedicines. 2024; 12(8):1890. https://doi.org/10.3390/biomedicines12081890
Chicago/Turabian StyleNeațu, Monica, Ana Hera-Drăguț, Iulia Ioniță, Ana Jugurt, Eugenia Irene Davidescu, and Bogdan Ovidiu Popescu. 2024. "Understanding the Complex Dynamics of Immunosenescence in Multiple Sclerosis: From Pathogenesis to Treatment" Biomedicines 12, no. 8: 1890. https://doi.org/10.3390/biomedicines12081890