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Mohamed ElTanbouly @plasmacellguy.bsky.social · 06/10/2025

Well, a Treg is a T cell. Although another Nobel laureate thinks (thought?) otherwise pmc.ncbi.nlm.nih.gov/articles/PMC...

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 25/01/2025

I tried to access but it says that it's only available to Harvard folks What am I missing? Aside from a Harvard ID card

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 29/12/2024

1-Incredible figure presentation and clarity 2-Eight years of work 3-Favorite statement (reminded me of another statement in an equally authoritative paper). Both are presented in screenshots below. 4-Builds upon earlier work by Peng et al from Jameson group www.sciencedirect.com/science/arti...

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 01/12/2024

Not useless...Technologies are ephemeral but ideas and insights are not :) I was reading this Cell issue celebrating Molecular Biology and this comment is along the lines you described. Amazing how long it took to sequence a bit of DNA. www.cell.com/cell/fulltex...

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 26/11/2024

6) The hinge region of antibodies determines its agonistic potential or lack thereof e.g. human IgG2 (h2b isoform) enhances agonistic activities of Abs (through disulfide shuffling) independent of higher-order crosslinking via FcγRs. PMID: 25500122 www.sciencedirect.com/science/arti...

Figure from https://www.sciencedirect.com/science/article/pii/S1535610814005194

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 26/11/2024

5) Transcytosis: of antibodies through cells (including blood-brain barrier and lung epithelium...etc) via polymeric Ig receptor (pIgR) on these cells This explain early observations of lung epithelial cells shining with intracellular IgA PMID: 781899 bit.ly/Soutar1976

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 26/11/2024

4) Second IgG antibodies form hexamers on cell surface after binding antigen through noncovalent interaction via their Fc regions This triggers the complement cascade PMID: 24626930 bit.ly/Diebolder2014 Side-note: IgM is 100-1000 times better at activating complement than IgG

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 26/11/2024

2) Fab arm exchange is where antibodies swap half-molecules creating natural bispecifics The third constant domain (CH3) (of the Fc) is essential for this A later study showed aa positions 409 (in humans) as essential for his R409 --> exchange K409 --> stable PMID: 21841137 bit.ly/Labrijn

Modified from https://absoluteantibody.com/antibody-resources/antibody-overview/antibody-structure/

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 26/11/2024

1) I don't know how you feel about antibodies, but here are a couple of (less-known) fascinating studies that might enhance your affinity towards these molecules One of these is Fab arm exchange This naturally occurs in vivo in IgG4 antibodies PMID: 17872445 bit.ly/Kolfschoten2...

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 12/11/2023

I agree about positioning. Yes. It remains unanswered. But I think positioning and "help" are also elusive (incompletely understood) from the B cell side. www.cell.com/immunity/ful...

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 12/11/2023

Addendum 2: The 2nd showed that allergen-specific IgA antibodies are not protective per se (that "IgA is good and IgE is bad" oversimplification can be laid to rest) www.science.org/doi/10.1126/...

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 12/11/2023

Addendum 1: the Eisenbarth lab dispelled certain unsubstantiated notions about immunity, first showing that LPS (a TLR ligand known to induce Type I responses) can induce Th2 responses bit.ly/Eisenbarth02

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

21/ pre-Plasma cells have certain interesting features A- They upregulate the canonical PC markers CD138 and also CD28 B-They upregulate Bcl-XL (Bcl2l1) which is an anti-apoptotic regulator shown to suppress ER-stress dependent apoptosis in PCs bit.ly/Gaudette2014

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

20/We then wanted to examine differences between GC B cells destined to become PCs (aka Pre-plasma cells) versus those that go back to the GC for another cycle round so we performed Smartseq on these cells

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

19/ But what was interesting is if you try to compare the mean affinity (Kd) between "Binders" from both GC and PCs, you will find no significant difference, indicating that what this shows is an enrichment in binder % among PCs (and not qualitatively higher affinity per cell)

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

18/And as expected these PC have a higher percentage of binders than contemporaneous GC B cells using both ELISA and more sensitive monomeric binding assays (BLI) and most of these binders are of the IGHV1-72 heavy chain as expected (orange)

Plasma cells are depicted in grey because they are more mature (older) cells if you will, whereas GC B cells are in green as they are earlier on the cellular differentiation trajectory. Of course, a developmental biologist would strongly argue against these definitions because all these cells are technically differentiated, but they will have to contend with the whole Immunology field.

ELISA affinity data showing IGHV1-72 in orange and all other HC in grey.

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

17/Glossing over many Bruegelian details, we found that over time genetically-labeled PCs were retaining the NP-binding heavy chain whereas GC B cells were diversifying

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

14/As in previous work by Victora, Nussenzweig and Phan groups we used s.c. immunization of popliteal lymph nodes because these are particularly devoid of GC B cells and PCs in the absence of immunization, so at least early on, everything will be specific to your immunogen

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

11/Building upon this and a lot of work, we addressed the same question in a polyclonal system using genetic lineage tracing in S1pr2.CreERT2 inducible fluorescent reporter which predominantly labels GC B cells (and some activated B cells) S1pr2 model bit.ly/Shinnakasu2016

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

10/ Using the same model they comprehensively show later that these high-affinity GCs complete their transition into PCs using help from T follicular helper cells (supporting earlier work showing that T cell help is critical for PC differentiation in GCs) bit.ly/Kr%C3%A4utle...

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

9/Using this elegant model, they track what mutation increases the affinity of these cells and show that predominantly, if not exclusively, the high-affinity GC B cells become PCs.

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

7/Does affinity regulate B cell and plasma cell responses? If so, how? Many papers addressed this longstanding question bit.ly/Phan2006 bit.ly/49wRVLi bit.ly/OConnor2006 but I will discuss my favorite by Phan et al.

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

7/ Where does affinity enhancement take place? In a T-cell dependent response, answer is Germinal Centers (GCs) where B cells move between light and dark zones until they get sufficient T cell "help" into the PC compartment. bit.ly/3MC7yHu bit.ly/Victora22

First description of dark and light zone in germinal centers
Rohlich, K. 1930. Beitrag zur Cytologie der Keimzentren der Lymphknoten. ¨ Z. Mikrosk. Anat. Forsch. 287–297

I have the text available as pdf through interlibrary loan if you need it

From PMID: 35113731
"Germinal Centers" 2022
https://www.annualreviews.org/doi/10.1146/annurev-immunol-120419-022408

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

6/On the molecular side, Eisen & Siskind showed antibody affinity against the immunogen increases proportionally throughout the response. bit.ly/EisenSiskind64

Eisen's interview as part of AAI's oral history: https://www.aai.org/About/History/Past-Presidents-and-Officers/HermanNEisen Full transcript available at https://www.aai.org/AAISite/media/About/History/OHP/Transcripts/Trans-Inv_003-Eisen_Herman_N-2012_Final.pdf

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

5/Other papers include bit.ly/Sprent1971 bit.ly/GowansMcGreg... Cooper et al. also showed the these lymphocytes are B cells bit.ly/Cooper1965 And Glick et al.'s popular Poultry paper ~a decade earlier bit.ly/Glick1956

PMID: 14276257
Delineation of the Thymic and Bursal Lymphoid Systems in the Chicken
DOI: 10.1038/205143a0

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

4/Then two critical discoveries happened: The cellular origin of plasma cells turned out to be lymphocytes as initially proposed by Gowans & McGregor bit.ly/Gowans1962 Several papers definitively showed this but my favorite is this bit.ly/Rowley1972

Immunology: the making of a modern science
ISBN-10 ‏ : ‎ 0122740203
ISBN-13 ‏ : ‎ 978-0122740206

Page 71 of "The mysterious lymphocyte" by J. L. Gowans

PMID: 4115130
https://doi.org/10.1084/jem.136.3.499

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

3/Later, it became clear that these "substances" (antibodies) are proteins and are made up of γ-globulins bit.ly/TiseliusKaba... And 8 years after, it was known that these antibodies are made by plasma cells bit.ly/Fagraeus1947 bit.ly/Coons1955 (microscopy)

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

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 11/11/2023

B cells and plasma cells 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.

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 30/10/2023

2) Then came the term “interleukin” from a discussion at the Ermatingen meeting Mizel, Paetkau, K. Smith, S. Gillis retired to a bar. In the ensuing discussion, they all agreed that there were not a 100 different factors, as described in the meeting, but a much smaller number

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Mohamed ElTanbouly @plasmacellguy.bsky.social · 30/10/2023

1)Stanley Cohen was the first to propose the term #cytokine (in 1974) ; "an umbrella term under which all these misunderstood factors could huddle". #Immunology bit.ly/4156495

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