Inhibitory oligodeoxynucleotides − therapeutic promise for systemic autoimmune diseases?

Abstract

SummaryRecent studies have shed new light on a possible link between the innate activation of plasmocytoid dendritic cells and marginal zone B cells and the pathogenesis of systemic lupus erythematosus. Animal studies have identified that this response requires the Toll-like receptor 9 (TLR9). Engagement of the TLR9 by various ligands, including non-canonical CpG-motifs, can cause or aggravate pathogenic autoantibody production and cytokine secretion in lupus. Attempts to neutralize this activity either by blocking the acidification of the endosomal compartment with chloroquine and related compounds, or by preventing the interaction between the CpG-DNA sequences and TLR9 using inhibitory oligonucleotides could be a promising therapeutic option for lupus.

Detection of Retinal Changes in Patients on Long Term Chloroquine/Hydroxy Chloroquine Therapy Using Optical Coherence Tomography

“…This has been supported by experimental studies which have shown that hydroxy chloroquine is a less potent enhancer of lipofuscinogenesis compared to chloroquine in the retinal pigment epithelial cells [3]. It has also been documented that both the drugs block activation of Toll like receptors (TLR) on dendritic cells and inhibit the TLR signaling [4][5][6]. HCQ retinopathy has been reported in more than 1% of patients after 5-7 years of usage of the drug and its incidence did not correlate with the age, daily dose or the weight of the patient [7].…”

“…Over years, several tests have been used to diagnose chloroquine retinopathy, which include Amsler grid testing, colour vision testing, and central visual field charting [2][3][4][5][6][7][8][9][10]. Recent studies with spectral domain Optical Coherence Tomography (SD-OCT), multifocal Electro-retinogram (mf ERG), fundus auto fluorescence show promising results in the early detection of chloroquine toxicity [8,9].…”

TLR2 synergizes with both TLR4 and TLR9 for induction of the MyD88-dependent splenic cytokine and chemokine response to Streptococcus pneumoniae

“…TLR9] could recapitulate the MyD88 -/-phenotype. While bacterial DNA contains immunostimulatory CpG motifs that signal through TLR9, recent reports have shown that certain oligodeoxynucleotides rich in poly G or GC sequences are suppressive (sODN) and interfere with this interaction (31)(32)(33)(34). The activity of sODN is dominant over TLR9 stimulation by CpG-ODN (35).…”

Microbial nucleic acids pay a Toll in kidney disease

“…By using synthetic CpGoligodeoxyribonucleotides (ODN), distinct nucleotide sequences have now been identified that provide maximal stimulation or even inhibitory effects in cells of either human or murine origin (38,44).…”