Immunity system complexity: production at high speed (Introduction)

by David Turell , Friday, January 12, 2024, 18:30 (315 days ago) @ David Turell

New study on immune capacity for production of antibodies:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/12_january_2024/416...

Optimized transfer RNA (tRNA) codon use can speed up antibody generation.

"Antibodies are critical for human health, providing long-lived and exquisitely specific immunity to pathogens. Plasma cells secrete tens of thousands of antibody molecules every second and sustain this output continuously for several decades. Plasmablasts and plasma cells [collectively, antibodysecreting cells (ASCs)] are generated following the activation and differentiation of B cells, which involves complete reprogramming of the transcriptional machinery and remodeling of the endoplasmic reticulum and Golgi apparatus. ASCs have co-opted the unfolded protein response (UPR), a stress response, to accommodate the exceptional rate of protein synthesis and secretion required. On page 205 of this issue, Giguère et al. reveal that mRNA encoding antibody genes is enriched with codons recognized by modified transfer RNA (tRNA). This codon optimization is accompanied by an increase in tRNAs with complementary modifications, which serves to enhance antibody biosynthesis by ASCs. This has wider implications for therapeutic protein production, vaccine design, and beyond.

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"Giguère et al. found that, relative to other genes, antibody mRNA sequences from both human and mouse ASCs display a conserved bias toward codons recognized by inosine-34– modified tRNA and that ASCs are enriched with tRNA with inosine modifications. In a mouse model, reducing the frequency of inosine-34–dependent codons resulted in decreased antibody production, confirming that coordination of inosine-34–dependent codon bias and inosine tRNA abundance is a mechanism to enhance antibody biosynthesis. Understanding the regulatory mechanisms governing tRNA modification requires further research.

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"Giguère et al. revealed that codon usage plays a role in the selection of B cells into the memory compartment. Following activation, B cells undergo affinity-based selection to expand rare clones with the strongest antigen-binding variable regions. By examining the human postvaccination antibody repertoire, Giguère et al. identified an enrichment in I34-dependent codons in the mRNA encoding the antigen binding domains (variable regions) of plasma cells and memory B cells relative to the naïve B cell repertoire.

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"Deciphering the intricate network of signaling pathways and regulatory factors driving tRNA remodeling in ASCs is crucial; understanding how tRNA modifications affect translational fidelity, efficiency, and protein folding during antibody synthesis warrants further investigation.

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"Whether altered tRNA pools influence broader aspects of cellular fitness beyond antibody production remains unknown. The study by Giguère et al. provides a foundational understanding of tRNA remodeling and codon usage in humoral immunity, representing a paradigm shift in our understanding of translation dynamics."

Comment: this study shows that DNA in immune cells has many hundreds of genes to drive the production of antibodies at the rates described in the first paragraph. All under very precise controls. God not needed to ever intervene.

The study abstract:

S. Giguère et al., Science 383, 205 (2024)

"Antibodies are produced at high rates to provide immunoprotection, which puts pressure on the B cell translational machinery. Here, we identified a pattern of codon usage conserved across antibody genes. One feature thereof is the hyperutilization of codons that lack genome-encoded Watson-Crick transfer RNAs (tRNAs), instead relying on the posttranscriptional tRNA modification inosine (I34), which expands the decoding capacity of specific tRNAs through wobbling. Antibody-secreting cells had increased I34 levels and were more reliant on I34 for protein production than naïve B cells. Furthermore, antibody I34-dependent codon usage may influence B cell passage through regulatory checkpoints. Our work elucidates the interface between the tRNA pool and protein production in the immune system and has implications for the design and selection of antibodies for vaccines and therapeutics."