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 

ADAMTS-like protein 5 (ADAMTSL5) is a melanocyte-derived auto-antigen in psoriasis

Psoriasis is a chronic skin inflammatory disorder characterized by thickening of skin epidermal layer. Psoriasis is considered autoimmune diseases due to presence of activated T cells within epidermal layer in affected skin and clinical benefits of antibody therapy directed against cytokines such as IL-23 and IL-17. However, the exact (auto)antigen[s] targeted by T cells are not well known.

This short paper from Journal of Experimental Medicine suggests that a disintegrin and metalloprotease with thrombospondin motifs-like-5 protein (ADAMTSL5) expressed by melanocytes is a psoriasis-specific auto-antigen.

This study is continuation of earlier studies showing that (a) HLA-C*06:02 allele occurs in more than 60% of psoriatic patients, and (b) psoriatic lesion contains high frequency of Vα3S1⁺/Vβ13S1⁺ CD8 T cells. Now, using in vitro HLA transfection experiments the authors showed that Vα3S1⁺/Vβ13S1⁺ T hybridoma recognized HLA-C*06:02⁺melanocytes [but not keratinocytes or fibroblasts] in a HLA I-specific manner.

Next, using bioinformatics approach in combination with in vitro hybridoma activation assay (NF-κB-GFP readout), the authors identified ADAMTS-like protein 5 (ADAMTSL5) as a potential auto-antigen in psoriasis.

ADAMTSL5 was highyl expressed by both primary and cell line melanocytes (WM278).

Finally, the authors showed that ADAMTSL5 derived peptide stimulated psoriatic T cells but not T cells from healthy individuals.

In summary, this study showed that melanocyte-derived ADAMTSL5 represents auto-antigen in psoriasis. The authors claim that this is a first definitive report of showing psoriasis as a truly autoimmune diseases.

David Usharauli

Antibody targeting IL-23(p19 subunit) beats psoriasis

Psoriasis is a common skin inflammation of autoimmune nature. If there is any disease that benefited from the fundamental immunological research is Psoriasis.

Initially thought to be a purely skin disorder, now it is firmly established that immune system's attack on it own skin tissue plays a major role in driving clinical signs of psoriasis. Pioneering studies with α-p40 antibodies suggested that IL-12 might have been involved in psoriasis. However discovery of IL-23 (that consisted of p40 and p19 subunits) in 2001 opened up new era in our understanding of molecular mechanisms behind psoriasis pathology.

New study in Nature provided additional data to clearly establish that selective targeting of IL-23 drastically improves psoriasis's skin pathology.

The authors showed that three, monthly intravenous injections of humanized antibody targeting p19 subunit of IL-23 (Tildrakizumab) could drastically reduce psoriatic skin pathologies in absolute majority of patients that lasted for at least 1 year.

α-p19 antibody injections reduced hyper-keratinization and hyper-proliferation in psoratic skin lesions.

In summary, this study suggests that IL-23 system that includes IL-17 are intimately involved in psoriatic skin pathology and its targeting (maybe simultaneously with α-IL-17 ) could finally bring the needed relief to people suffering from this skin disorder.

 David Usharauli