Slower rescue of ER homeostasis by the unfolded protein response pathway associated with common variable immunodeficiency

Kuribayashi, Juliana Sayuri; Bombardieri, Cíntia R.; Baracho, Gisele V.; Aliberti, Júlio; Machado, Fabiana S.; Kalil, Jorge; Guilherme, Luiza; Kokron, Cristina Maria; Rizzo, Luiz Vicente; Camargo, Maristela Martins de

doi:10.1016/j.molimm.2008.01.013

Cited by 9 publications

(13 citation statements)

References 31 publications

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“…B cells from both CVID patients had a slower rate of proliferation when compared to B cells from a healthy donor (Supporting information, Fig. S1a), similarly to what we observed previously [29]. Immortalization of B cells by infection with EBV did not disrupt the ability of these cells to translate and export IgM to the cell's surface (Fig.…”

Section: Discussionsupporting

confidence: 87%

“…In sum, published findings and our new findings support early down-regulation of the UPR in some patients [29,55], caused probably by non-lethal defects of the UPR. Such a non-lethal defect was recently described for SEC61A1 in B cells from patients with primary hypogammaglobulinemia [56].…”

Section: Discussionsupporting

confidence: 85%

“…Further, we examined the possibly delayed activation of the UPR in B cells from a CVID patient, as reported by previous studies . Delayed UPR in that patient resulted in an accumulation of unfolded immunoglobulin chains in the ER and failure at secreting properly folded IgM.…”

Section: Discussionmentioning

confidence: 79%

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Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients

Bhatt

Stan²,

Pinhata

et al. 2020

Clinical and Experimental Immunology

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Summary B cells orchestrate pro‐survival and pro‐apoptotic inputs during unfolded protein response (UPR) to translate, fold, sort, secrete and recycle immunoglobulins. In common variable immunodeficiency (CVID) patients, activated B cells are predisposed to an overload of abnormally processed, misfolded immunoglobulins. Using highly accurate transcript measurements, we show that expression of UPR genes and immunoglobulin chains differs qualitatively and quantitatively during the first 4 h of chemically induced UPR in B cells from CVID patients and a healthy subject. We tested thapsigargin or tunicamycin as stressors and 4‐phenylbutyrate, dimethyl sulfoxide and tauroursodeoxycholic acid as chemical chaperones. We found an early and robust decrease of the UPR upon endoplasmic reticulum (ER) stress in CVID patient cells compared to the healthy control consistent with the disease phenotype. The chemical chaperones increased the UPR in the CVID patient cells in response to the stressors, suggesting that misfolded immunoglobulins were stabilized. We suggest that the AMP‐dependent transcription factor alpha branch of the UPR is disturbed in CVID patients, underlying the observed expression behavior.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 85%

See 1 more Smart Citation

Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients

Bhatt

Stan²,

Pinhata

et al. 2020

Clinical and Experimental Immunology

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“…Studies showed that LPS induced ER stress in lung [45], human B cells [46] and liver [47]. Plasma LPS was not measured in the present study.…”

Section: Discussioncontrasting

confidence: 66%

Toll-Like Receptor 4 Knockout Mice Are Protected against Endoplasmic Reticulum Stress Induced by a High-Fat Diet

et al. 2013

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The purpose of this study was to investigate whether toll-like receptor 4 (TLR4) is implicated in the development of endoplasmic reticulum stress (ER stress) observed after a high-fat diet (HFD) in liver, skeletal muscle and adipose tissue. TLR4−/− and C57BL/6J wild-type mice (WT) were fed with chow or HFD (45% calories from fat) during 18 weeks. An oral glucose tolerance-test was performed. The animals were sacrificed in a fasted state and the tissues were removed. TLR4 deletion protected from body weight gain and glucose intolerance induced by HFD whereas energy intake was higher in transgenic mice suggesting larger energy expenditure. HFD induced an ER stress in skeletal muscle, liver and adipose tissue of WT mice as assessed by BiP, CHOP, spliced and unspliced XBP1 and phospho-eIF2α. TLR4−/− mice were protected against HFD-induced ER stress. Then, we investigated the main signaling downstream of TLR4 namely the NF-κB pathway, expecting to identify the mechanism by which TLR4 is able to activate ER stress. The mRNA levels of cytokines regulated by NF-κB namely TNFα, IL-1β and IL-6, were not changed after HFD and phospho-IκB-α (ser 32) was not changed. Our results indicate that TLR4 is essential for the development of ER stress related to HFD. Nevertheless, the NFκ-B pathway does not seem to be directly implicated. The reduced fat storage in TLR4−/− mice could explain the absence of an ER stress after HFD.

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“…This function justifies their study as candidate genes for IgAD predisposition. In fact, defects in the unfolded protein response, including diminished splicing of XBP-1 mRNA, were described in one patient with common variable immunodeficiency [13], a disorder also characterized by defective antibody production and with a postulated partially overlapped etiology with IgAD. However that defect did not seem to be caused by mutations in the XBP1 gene.…”

Section: Discussionmentioning

confidence: 99%

Lack of evidence of a role of XBP1 and PRDM1 polymorphisms in Spanish patients with immunoglobulin A deficiency

et al. 2009

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Slower rescue of ER homeostasis by the unfolded protein response pathway associated with common variable immunodeficiency

Cited by 9 publications

References 31 publications

Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients

Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients

Toll-Like Receptor 4 Knockout Mice Are Protected against Endoplasmic Reticulum Stress Induced by a High-Fat Diet

Lack of evidence of a role of XBP1 and PRDM1 polymorphisms in Spanish patients with immunoglobulin A deficiency

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