1/ Thread on immunity in the respiratory system: how it does and doesn't work (i.e. myths), simplified as much as I could. I’ll use the apropos of a new press release by Imperial College. To avoid mainstream media fantasies, let's use the original piece. imperial.ac.uk/news/207333/co…
2/ The main pillars of mucosal immunity in the respiratory system are:
– Innate immunity. This ancient part includes the physical barrier: mucus production and continuous flow upwards, driven by ciliary epithelial cells. There are also phagocytes ("eating cells") and…
3/ …other cellular components that produce signaling molecules, set traps, etc.

– Adaptive immunity
---> B & plasma cells that release antibodies into the airways through the single cell layer called the epithelium.
4/ These antibodies (Ab) are called secretory immunoglobulins (SIgA mainly), bind pathogens and can be similarly specific as their systemic counterparts. They can even cross-link pathogens to mucus, inactivating them.
5/ Their special part is a secretory component, very rich in added sugar chains (glycans). This "band" is missing from circulating IgA, and there is a very good reason why mucosal surfaces utilize this subtype. See my mini thread on the war of glycans here
6/ B cells develop immune memory, meaning that upon reinfection with the same or very similar pathogen specific Ab are released.
---> Antigen presenting, mainly dendritic cells.

Next
---> T-cells. These can be categorized into 2 main types:
7/ CD4+ "helper" cells in specific forms against various pathogens. They help innate cells as well as B cells to fight invaders in an optimal way. CD8+ cells which are killer lymphocytes but specialized to hunt down our own infected cells.
8/ Both play fundamental roles in mucosal immunity.

A substantial impairment in any of the above components leads to profoundly higher susceptibility to severe infections. Yes, even mucus and its flow is a very important player.
9/ OK, now let's talk a bit about systemic Ab, which tend to grab all the attention. Are these integral parts of mucosal immunity? Well, not really. They mostly come into the picture when ALL other barriers mentioned above fail.
10/ That is exactly why disease severity, more precisely systemic dissemination of the virus, is linked to higher serum Ab levels. Those people who fight off the infection with primary defenses produce lower and more quickly waning systemic Ab levels. That's perfectly normal.
11/ One last question to mucosal immunity in the airways: Does it have its own memory? You bet it does. Not only B/plasma cells can enter this memory phase, but both CD4+ and CD8+ T-cell types as well. Yes, they keep sitting in the airway walls for decades, waiting for…
12/ …the same or a fairly similar pathogen to attack. This is a lasting type of immune memory.
Now, back to the press release at hand. The major claim is that SYSTEMIC Ab quickly wane, and that it raises serious doubts not only about lasting, but also herd immunity.
13/ How quickly this decay happens depends on the methods of determination, e.g. Ab against which antigens are used, the method sensitivity itself, e.g. quick test vs. fancy lab techniques, etc. In line with this, another study just 2 weeks ago…
14/ …concluded that this decay is not so rapid at all. uahs.arizona.edu/news/uarizona-…
What is more, memory B cells persist even if antibodies disappear! See

The authors of the new Imperial College study are cautious and fair enough with their interpretations:
15/ "Our study shows that over time there is a reduction in the proportion of people testing positive for antibodies. "It remains unclear what level of immunity antibodies provide, or for how long this immunity lasts." they continue.
16/ Now, let's see how clueless or malevolent commenters in mainstream media interpret the very same study:
"We can see the antibodies and we can see them declining and we know antibodies on their own are quite protective." says Prof Wendy Barclay to the BBC.
17/ If you have read the above, you already know that these Ab are only protective against severe systemic disease. They cannot prevent upper respiratory symptoms or even a mild pneumonia, not to mention becoming infectious. The article also makes more bold claims…
18/ "The researchers say their findings do not scupper hopes of a vaccine, which may prove more effective than a real infection." To prevent respiratory symptoms & infectiousness, an animal model study showed that 8-times normal (!) level of systemic Ab is necessary to develop.
19/ I don't think that the first wave of vaccines even aims for that, especially not in the most vulnerable (whom they typically exclude from trials), and especially not in a lasting way.
Prof Jonathan Heeney, a virologist at the University of Cambridge, goes even further…
20/ …and claims that this result "puts a 'nail in the coffin' in the idea of herd immunity". When virologists became immunity deniers out of hobby is anyone's guess. theguardian.com/world/2020/jul… You are now equipped with the understanding of the basics of mucosal immunity in…
21/ …the respiratory system, so feel free to evaluate this remark yourself. For Prof Jonathan Heeney, the immunity denier, we recommend a good review: annualreviews.org/doi/full/10.11…
(It’s of course a great piece for anybody interested.)
End

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More from @gerdosi

8 Oct
Bacteria-fighting neutrophils in the URT ⬆️ risk of viral infections. Implications are huge, pinpointing a potential unifying mechanism. In metabolic diseases a similar elevation of activated neutrophils occurs. What about periodontitis in severe COVID-19? imperial.ac.uk/news/206253/ba…
From the study:
“those who resisted infection showed a transient boost in mucosal markers of innate immune activation for several days after viral administration and no subsequent viral replication.”
In the meantime everybody is obsessed with antibodies circulating in the arms?
Two major components of mucosal immunity largely ignored in respiratory infections. SIgA is the other one:
“Prior RSV-specific nasal IgA correlated significantly more strongly with protection from [PCR-]confirmed infection than serum neutralizing antibody”
atsjournals.org/doi/10.1164/rc…
Read 4 tweets
24 Aug
1/ Below is a perfect example of how we can fall victim of our presumptions, and why understanding underlying mechanisms, or when applicable, design/evolution, is fundamentally important.
This is about water in the door of my car.
2/ Were you aware that (rain, washing, etc.) water is can normally get into the doors of a car and leave through exit holes at the bottom?
Quite obviously, I wasn’t.
I'm not a completely theoretical person, yet I just didn't know about this. It cost me about 2 hours.
3/ I assumed, or more precisely, I was confident that the several liters (~1 gallon) of water wobbling in the left rear door was the result of a faulty section in the insulation. Nothing else even came to my mind that could've altered my approach to fix the problem.
Read 4 tweets
5 Aug
Short thread.
If you’re not through COVID-19 yet I really hope that you’ve spent the last couple of months preparing for it. Losing beer belly, being out in the sun, and eating nutrient dense, fat soluble vitamin-rich foods. Definitely don’t rely only on vaccines if you’re…
…(metabolically) obese. Why? By now, it’s clear that obese are not only susceptible to more severe COVID, but also to influenza.
➡︎ Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 Influenza A virus onlinelibrary.wiley.com/doi/full/10.10…
What’s more, vaccines don’t work quite as well in obese people as in the (metabolically) healthy. See e.g.
➡︎ Obesity is associated with impaired immune response to influenza vaccination in humans
nature.com/articles/ijo20…
Read 4 tweets
24 Jul
This is not the first study that identifies obesity as the single biggest factor that is associated with progression to pneumonia in COVID-19. The authors suggest hyperleptinemia as the underlying mechanism.
The immunomodulatory functions of leptin next… medrxiv.org/content/10.110…
2 reviews
Leptin in inflammation and autoimmunity sciencedirect.com/science/articl…

Leptin as an immunomodulator sciencedirect.com/science/articl…
A bit more recent and more specific,
“leptin also signals through the Jak/STAT and Akt pathways, among others, to modulate T cell number and function. Thus, leptin connects metabolism with the immune response.“
nature.com/articles/s4136…
Read 4 tweets
24 Jul
Immunocompromised people can get severely ill or even die of infections with cold coronaviruses. Eventually, immune function/suppression falls on a spectrum and has various causes. Advanced age and hormonal imbalances are typical examples, the latter observed in e.g. T2 diabetes. Image
"This study shows that all known non-SARS HCoVs can be found in stools of children with acute gastroenteritis."
Infection of the digestive system is not unique to SARS coronaviruses, although HCoVs are usually not the main pathogens that cause diarrhea. sciencedirect.com/science/articl…
Infecting the central nervous system has also been described, sometimes with nasty effects. Image
Read 5 tweets
16 Jul
Nasal immunization could be the most efficient and potentially least harmful against coronaviruses, in line with the primary role of the mucosal barrier in providing protection. cell.com/immunity/fullt…
“mortality in 12- to 22-month-old mice infected with SARS-CoV or IAV was reduced from 80 to 100% to 0 to 10% by treatment with a TLR3 agonist, poly(I·C), with concomitant increased expression of interferon (IFN) and other proinflammatory molecules”
jvi.asm.org/content/86/21/…
Looking at systemic antibody levels in connection with respiratory infections is counterproductive. Let’s focus on healthy physiology/basic (mucosal) immunology, instead of centering on traditional vaccinations.
jvi.asm.org/content/77/21/…
Read 6 tweets

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