Do ribosomal protein alterations affect ER stress response in CVID?

Sir—The interesting paper by Bhatt et al. on unfolded protein response (UPR) in B cells from common variable immunodeficiency (CVID) patients highlights the complex nature of this acquired immunodeficiency disorder 1. This paper allows understanding of endoplasmic reticulum (ER) stress response in the early hours, as longer exposures to tunicamycin or thapsigargin would have activated pro‐apoptotic pathways and eventual cell death 2. The interesting finding that some CVID patients have a delayed ER stress response suggests other mechanisms at play, and one explanation could be that loss in specific ribosomal proteins as deficiency in some of these can protect against ER stress, at least in Saccharomyces cerevisiae 3. Steffen et al. report in their paper that cells with deletion of the ribosomal protein RPL23A varied dramatically in their response to tunicamycin (increased generation time by 3.3‐fold) 3, which may be relevant in the mammalian cell, but of course more complex than in the yeast ribosome. The ER membrane‐embedded protein sensor, inositol, requiring enzyme 1 (IRE1), is the most evolutionary conserved sensor, and interacts with translating ribosomes on the ER surface, and a region within the sarcin–ricin loop in the 60S subunit that IRE1 localizes with the ribosome has been clearly identified 4. This certainly shows that IRE1 may be affected by changes in the ribosome protein machinery.

It is therefore possible that certain UPR responses lead to apoptosis of immunoglobulin (Ig)A‐specific B cells leading to selective IgA deficiency which, with time, can progress to CVID in some individuals (such as with TNFRSF13B encoding TACI). We have previously reported that loss of function of ribosomal proteins can lead to a CVID‐like phenotype 5, 6. These patients had a defined ribosomal defect and developed CVID at various stages in their lives, but the varied complications and variable progression of immunodeficiency suggests that mechanisms such as UPR and response to ER stress were very different in each patient. This is also highlighted in the paper by Bhatt et al. and it is probable that, like chaperone proteins can help patients with cystic fibrosis 7 we also need to look at other treatment approaches in our CVID patients beyond simply replacing immunoglobulins. It is possible that replacement with immunoglobulin infusions alters ER stress and influences the ribosomal protein machinery, which may be even more complex, but not impossible to understand.

Disclosures

None declared.