New synthetic molecule prevents autoimmunity without compromising anti-pathogen immunity

In December of 2016 Science Translational Medicine published new study where the authors introduced new, low-molecular weight compound that specifically inhibited autoimmune/allergic responses while sparing anti-pathogen immune response.

This new molecule, AX-024, specifically targets adaptor protein Nck that is involved in low affinity TCR signaling. 

It does not affect signaling delivered via IL-2, BCR or PMA/Ion stimulation.

AX-024 inhibited TLR7/8 agonist, imiquimod (IMQ), induced psoriasis skin symptoms in mice.

Also, AX-024 significantly reduced clinical symptoms associated with mouse model of human multiple sclerosis (MS). Such effect of AX-024 was superior to Fingolimod, a sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing-remitting MS.

Notably, AX-024 in therapeutic dosage did not impair anti-pathogen immunity or memory generation.

In summary, by blocking Nck adaptor protein involved in low-affinity TCR signaling, AX-024 inhibited autoreactivity while preserving necessary capacity for anti-pathogen immunity. Such property makes it desirable candidate for clinical trials in humans.

David Usharauli 

Nociceptor analog, MRGPRX2, mediates pseudo-allergic response to pharmacological compounds

Classical allergic response is mediated via IgE. However, some allergic responses to small peptides, pharmacological or chemical compounds are independent of IgE. 

New study in journal Nature suggests that mechanism for this so called pseudo-allergic response is driven by mast cells expressing nociceptor analog, MRGPRX2 (Mrgprb2 in mouse).

The authors showed that mast cells from mice deficient for Mrgprb2 expression failed to respond to classical mast cell activator (secretagogue), compound 48/80, while retaining IgE mediated responsiveness.

Additional experiments confirmed that Mrgprb2 mediated injection site reactions (ISR) and mast cell histamine release in response to drugs such as Icatibant (bradykinin-receptor antagonist), tubocurarine (skeletal muscle relaxant) and ciprofloxacin (fluoroquinolone antibiotic).

Knowledge of chemical motifs (THIQ) responsible for Mrgprb2 activation will help to prevent and treat pseudo-allergic reactions to life-saving medical drugs.

David Usharauli