Treg cells need a little Helios to function

Regulatory T cells (T_REG cells) are required to maintain tolerance to self and maybe even to foreign antigens, such as commensal bacteria-derived antigens. But how exactly T_REG cells keep other immune cells in check is not clear. 

Simply speaking, paradox with T_REG cells is that if T_REG cells are too potent or constantly "active" then they should prevent any immune response to any antigens. If T_REG cells are not constantly "active", then what signal(s) activate them? and if active T_REG cells are "inhibited" by infection and they regain their inhibitory functions once infection is cleared, how is such system coordinated? Basically, none of the available models can satisfactorily explain full spectrum of T_REG cells biology. Hence the reason why translation of basic knowledge about T_REG cells for clinical application is so slow.

So, every time we see new paper about T_REG cells we hope that we can acquire "some" missing information. In this regards, lets examine new paper in Science from Harvey Cantor's lab. There, the authors found that presence of transcription factor Helios is necessary to stabilize T_REG cells phenotype.

This is a simple, observation-type paper. Initially, the authors showed that starting from 5 months of age, mice deficient for Helios develop auto-antibodies to self antigens.

Next, using adoptive transfer experiments in combination with bone marrow chimera, the authors showed that Helios-deficient T_REG cells lacked suppressive function.

Finally, the authors showed that Helios-deficient T_REG cells displayed unstable phenotype and could be induced to express effector cytokines.

In summary, this study showed that Helios played an important role in stability of T_REG cells phenotype, especially during the ageing process. Of note, other studies with Helios-deficient mice did not observe the same phenotype. The authors claim that it has to do with the age difference of the experimental mice used in those earlier experiments. But genetic difference between mice colony itself or their gut flora could not be dismissed without proper experimentation.

David Usharauli    

Nucleoprotein in Flu vaccine mimics brain protein and may cause autoimmune sleepiness

Narcolepsy is a chronic neurological condition characterized by excessive daytime sleepiness. It causes are unknown. It is suggested that deficiency or inhibition of endogenous brain peptide called hypocretin (orexin) and produced by hypothalamus could recapitulate narcolepsy's symptoms.

New study in Science Translational Medicine suggested that immune cross-reactivity between Flu vaccine component and brain's hypocretin receptor could have caused autoantibody mediated narcolepsy following 2009 Flu H1N1.

First, the authors showed that nucleoprotein (NP) from flu vaccine Pandemrix (that caused narcolepsy) and NP from flu vaccine Focetria (that did not cause narcolepsy) have sequence similarity to human hypocretin receptor. These two NPs differed in only 1 amino acid from each other (isoleucin vs. methionine).

Next, the authors showed that serum samples from Pandermrix cohort, but not from Focetria cohort, reacted with human hypocretin receptor in a sensitive cell-based assay (note high reactivity in healthy Finish group). 

Importantly, the authors showed that this immune reactivity of Pandemprix vaccinated serum samples to human hypocretin receptor could be inhibited by short Flu NP peptides  (both from Pandemprix and Focetria) and or by hypocretin receptor (positive control). It suggested that at the antibody level, there is no difference between NP from Pandemrix or Focetria. The authors could not analyze T cell part.   

In summary, the authors suggested the following hypothesis: high level of NP protein in Pandemrix flu vaccine (compared to Focetria) could have induced robust anti-NP antibody titre that later "somehow" have managed to cross human brain blood barrier (BBB) and caused autoimmune narcolepsy is HLA susceptible individuals. However, it is not clear how autoantibody could have got access to hypothalamic cells expressing hypocretin receptors.

Vaccine are important for human health. However, human HLA diversity and natural mimicry at the protein and peptide level could produce autoimmunity in certain individuals.  

David Usharauli