Why is an antimalarial drug, hydroxychloroquine, used as a rheumatological immunosuppressant in disorders such as systemic lupus erythematosus (SLE)?
Hydroxychloroquine (HCQ), originally developed as an antimalarial, has become a cornerstone in the treatment of autoimmune diseases, including systemic lupus erythematosus (SLE), primary Sjögren’s syndrome, and rheumatoid arthritis. How does this drug help address the challenges posed by these autoimmune diseases?
1. Interference with lysosomal activity and autophagy:
HCQ increases the pH within intracellular lysosomes, interrupting the autophagy of macromolecules and antigen processing in antigen-presenting cells. This leads to diminished T cell stimulation, providing an advantage in autoimmune conditions like SLE by modulating immune responses.
2. Inhibition of toll-like receptors (TLRs):
TLRs are essential components of our innate immunity, identifying foreign pathogens and triggering immune responses. In SLE, the body mistakenly recognizes its own DNA and RNA, causing inflammation. HCQ can curb the activation of TLRs, especially TLR7 and TLR9, which recognize self-RNA and DNA, respectively. By reducing the activation of these TLRs, HCQ can decrease the inflammation and symptoms associated with SLE.
3. Reduction of cytokine production:
HCQ downregulates pro-inflammatory cytokines, pivotal in SLE-associated inflammation and tissue damage. HCQ achieves this through several means, such as (a) impairing TLR-driven cytokine production and secretion, (b) inhibiting interferon gamma (IFN) type I responses in immune cells through disruption of GMP-AMP synthase (cGAS) signalling, and (c) blocking pathways activated by tumor necrosis factor (TNF) and interleukin (IL-1b) by inhibiting NADPH oxidase (NOX).
3. Inhibition of B- and T-cell activation through Ca2+signalling:
T-cells recognize antigens via T-cell receptors (TCRs) on their surface. A critical step following this recognition is the surge in intracellular calcium ion (Ca2+) levels. HCQ hampers this Ca2+ release from the endoplasmic reticulum, thus limiting T-cell activation. Furthermore, as the expression of CD154 on T-cells (essential for B-cell activation) is regulated in a Ca2+-dependent manner by nuclear factor of activated T-cells (NFAT), HCQ’s effect on Ca2+ also curtails B-cell activation, further reducing autoimmune activity.
4. Anti-thrombotic effects:
Patients with SLE have an elevated risk of blood clots. HCQ offers antithrombotic properties, likely interfering with clotting factors and platelet aggregation, providing an added advantage for SLE patients.
In summary:
Hydroxychloroquine’s diverse mechanisms make it a powerful treatment choice for SLE. By intervening in various immune pathways, HCQ offers a well-rounded approach to mitigating the overactive immune responses characteristic of the autoimmune disease SLE.
Reference
Nirk EL, Reggiori F, Mauthe M. Hydroxychloroquine in rheumatic autoimmune disorders and beyond. EMBO Mol Med. 2020 Aug 7;12(8):e12476. doi: 10.15252/emmm.202012476. Hydroxychloroquine in rheumatic autoimmune disorders and beyond | EMBO Molecular Medicine (embopress.org)
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