Mohamed ElTanbouly Profile picture
Mar 29, 2023 17 tweets 7 min read Read on X
(1) The plasma cell (PC) field has been booming and blooming in the past two years

Some dogmas and notions were quietly taken apart

An #immunology 🧵
(2) First, a pervasive dogma was that germinal centers are the sole origin of long-lived PCs

There is accumulating evidence that LLPCs can originate from T-cell-independent (extrafollicular) responses

bit.ly/Fidler1975
bit.ly/Bortnik2012
bit.ly/Bortnik2013 Figure 1 from PMID: 22529295
(3) Even within a GC-derived response, if you genetically label PCs prior to GC formation, you still get Long-lived plasma cells during this nascent extrafollicular response

bit.ly/Koike2023

Koike et al. here elegantly making use of two "timestamping" genetic tools Figure 4 of PMID: 36515679
(4) Hai Qi and co. saw a similar IgM long-lived PC germline (no somatic hypermutations) repertoire enriched in public clones supporting the studies above

bit.ly/Liu2022 Figure 7 of PMID 36316480
(5) And so did Fooksman and colleagues in a more recent preprint
biorxiv.org/content/10.110…
(6) One could have presumed this answer in the light of evolution since lampreys do not have germinal centers (personal communication) and indeed retain the features of long-lived antibody immunity (and live for ≤ 8 years)
(7) The second pervasive (rather intuitive) notion is that memory B cells replenish the long-lived PC pool based on a high-profile study using in vitro human memory B cells
(8) However, several studies in mice and macaques definitely dispelled this suggestion

via anti-CD20 depleting memory B cells and even removing lymph nodes and spleen.

bit.ly/Ahuja2008
bit.ly/Langley2022
bit.ly/Hammarlund2017
(9) The third dogma is that plasma cells once they find their "effector" sites (i.e. bone marrow or intestines...etc) become immotile and just sit around PMID: 24777940
(10) Fooksman and colleagues show in a paradigm-shifting study that BM PCs recirculate to other bones and the spleen even in the absence of immunization

At the span of hours (heroic intravital imaging)

bit.ly/Benet2021
(11) Some of these less motile plasma cells cluster around areas of high APRIL (survival cytokine) density

These are enriched in LLPCs

biorxiv.org/content/10.110… Figure 2E of https://www.biorxiv.org/content/10.1101/2023.02
(12) Another prevailing notion was that mature plasma cells no longer have competent B cell receptors

Which is intuitive and stems from the CORRECT findings that

A-LLPC (IgG) PCs don't need antigen to survive

bit.ly/Manz1998
(13)

B-LLPCs downregulate their surface BCR in favor of the secreted antibody (Also TRUE)

However, it turns out that mature IgM PCs express both surface BCR and the coreceptor CD79

bit.ly/Blanc2016 TD = T-dependent and TI= T-independent  Figure 4 from PMID:
(14) Not just IgM, but also IgA and IgE PCs...Actually, Allen and co. recently showed that BCR engagement by IgE PCs triggers their death 🪦

bit.ly/Wade-Vallance2…
(15) This finding may help explain why mice and humans have so few IgE plasma cells

It may be that they are continuously eliminated by what could help your conventional B cell survive.
(16) So the point is, some PCs still express surface BCRs that can competently signal...What does it mean?

Not sure yet.
(17) There remains 3 more intriguing phenomena that go against prevailing dogma, but I guess we should wait for these to be published by the various groups interested in plasma cells before musing on this platform.

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More from @Plasmacellguy

Nov 10, 2023
1/Where do I start?

Is it at Von Behring and Kitasato who were the first to discover that immunization of animals with diptheria and tetanus toxins resulted in soluble substances in the serum that neutralize these same toxins making them harmless?
bit.ly/VonBehring1890

From "The generative grammar of the immune system" by Niels K Jerne (EMBO, 1985) PMID: 2410261  Also see his Nobel lecture of the same title.
2/Which later led to a big development in anti-sera therapeutics against multiple diseases

e.g. J. Bordet's work on cholera

(nicely summarized here )bit.ly/Bordet1895
bit.ly/Bordetsummary
3/Later, it became clear that these "substances" (antibodies) are proteins and are made up of γ-globulins


And 8 years after, it was known that these antibodies are made by plasma cells

(microscopy) bit.ly/TiseliusKabat1…
bit.ly/Fagraeus1947
bit.ly/Coons1955

PMID: 19870831  10.1084/jem.69.1.119  Serum protein separation shows that antibodies are γ-globulins
PMID: 18897986 https://www.nature.com/articles/159499a0
Read 25 tweets
Mar 1, 2022
(1) A lot of Immunologists are (justifiably) obsessed with T cell exhaustion.

Very few discuss memory inflation 📈 despite its relevance to #vaccines and #aging

#Immunology #TCELL

Diagram and background info mainly from bit.ly/OHara2012
(2) Inflation: induction of memory [CD8+] T cells that increase in frequency over time to >10% of the entire T cell pool in blood and higher abundance in peripheral tissues (e.g. liver and lung)
(3) First reported (to my knowledge) in a mouse model of CMV (MCMV)

Recall (by contrast) how chronic LCMV (clone 13) induces T cell exhaustion
bit.ly/Holtappels2000
bit.ly/Karrer2003
Read 18 tweets
Jan 25, 2022
1/Truly inspiring and [by far] my favorite talk (so far) @Midwinter_Immun

quick 🧵
2/Kagan and co. address the outstanding question: How can you activate and program a dendritic cell to promote protective (including antitumor) immunity?

Same as, why have DC-based vaccines and all cancer vaccines failed thus far?
3/The key is in keeping the DC alive and active during stimulation.

Most adjuvants (e.g. LPS, alum, polyI:C) induce pyroptosis which (while triggering local inflammation) limits the activity and costimulatory potential of a dendritic cell
Read 17 tweets
Sep 9, 2021
Inspired by @philipcball's question, here is a 🧵of some of the most beautiful #biology experiments (in my opinion)

Disclaimer: Not in order and no details (links provided)
1-Messelson-Stahl discovery of semi-conservative DNA replication (Okay that's obvious but bear with me)

Year: 1958

Side-note: notice how humble the paper title is.

Paper ➡️pnas.org/content/44/7/6…

Summaries ➡️
➡️
2-Hershey-Chase:

Viruses replicate by way of their nucleic acids (not proteins)

DNA is the origin of hereditary material

Year: 1952

Paper ➡️ rupress.org/jgp/article-pd…

Summary ➡️
Read 21 tweets
Oct 20, 2020
Our review on peripheral T cell tolerance is now online in @NatRevImmunol

Link rdcu.be/b8LRt

I want to state a few relevant points in this 🧵

#Science #Immunology #AcademicTwitter Image
Most studies and perspectives focus on one mechanism of tolerance and few have seriously considered all these together in the context of T cell differentiation.

We attempted to draw a conceptual framework for the known tolerance checkpoints at each stage of the T cell lifespan
In summary, we present 6 main tolerance hallmarks:
Quiescence
Ignorance
Anergy
Exhaustion
Senescence
Death
Read 9 tweets

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