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  • Review Article
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The endoplasmic reticulum stress response in immunity and autoimmunity

Nature Reviews Immunology volume 8, pages 663–674 (2008)Cite this article

Key Points

  • Misfolded proteins cause intracellular stress, which induces the unfolded-protein response (UPR). The UPR is a three-pronged signalling pathway that induces genes which cause cells to acquire a secretory phenotype.

  • The branches of the UPR are mediated by the three endoplasmic reticulum (ER)-resident proteins: inositol-requiring 1 transmembrane kinase/endonuclease 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6 (ATF6). These branches interact and have feedback mechanisms to regulate the activity of the UPR.

  • X-box binding protein 1 (XBP1), which lies downstream of IRE1, is crucial for the development of plasma cells, which secrete large amounts of immunoglobulin. The malignant variants of plasma cells, known as myeloma cells, are also dependent on an intact UPR, offering a therapeutic target for myeloma therapies. XBP1 is also important in the development and survival of dendritic cells, and suppression of XBP1 impairs the growth of a dendritic-cell tumour.

  • Abnormalities of the UPR may explain early events in the pathogenesis of autoimmunity: misfolded proteins can be immunogenic, stressed cells can be unable to maintain tolerance of autoreactive cells, and autoreactive cells can be less susceptible to the programmed cell death that occurs in cells with unrecoverable levels of ER stress.

  • The UPR represents a potential therapeutic target. Drugs that enhance UPR activity can be protective in autoimmune conditions such as ankylosing spondylitis, in which abnormal protein folding is thought to drive the disease, whereas drugs that impair the UPR may be beneficial in conditions in which malignant or autoreactive cells rely on the UPR for survival.

Abstract

Many exogenous sources of stress can lead to cell death. In recent years, endogenous cellular sources of stress have also been identified, including the stress that arises from the accumulation of unfolded proteins within a cell's endoplasmic reticulum (ER). To counterbalance this type of ER stress, higher eukaryotic cells possess a three-pronged signal-transduction pathway termed the unfolded-protein response (UPR). This Review focuses on the role of the UPR in the mammalian immune system and how manipulation of this complex signalling pathway may be of therapeutic benefit in human disease.

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Figure 1: Complexity and crosstalk in the three axes of the unfolded-protein response.
Figure 2: Schematic representation of the network of known plasma-cell differentiation factors.
Figure 3: Potential mechanisms whereby the unfolded-protein response might allow autoimmunity.

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Acknowledgements

We would like to acknowledge F. Martinon, C. Hetz and P. Thielen for their critical review of the manuscript, and K. Nevis for preparation of the manuscript.

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Authors and Affiliations

  1. Department of Infectious Diseases and Immunology, Harvard School of Public Health, 651 Huntington Avenue, Boston, 02115, Massachusetts, USA

    Derrick J. Todd, Ann-Hwee Lee & Laurie H. Glimcher

  2. Division of Rheumatology, Department of Medicine, Allergy and Immunology, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Derrick J. Todd & Laurie H. Glimcher

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  1. Derrick J. Todd
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Correspondence to Laurie H. Glimcher.

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L.H.G. holds equity in, and is on the corporate board of directors of, the Bristol-Myers Squibb pharamceutical company.

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Glossary

Plasma cells

Non-dividing, terminally differentiated, immunoglobulinsecreting cells of the B-cell lineage.

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Caspases

A family of cysteine proteinases that are involved in the initiation and effector stages of apoptosis.

Ubiquitin

A small protein that is attached to other proteins by ubiquitin ligases. Depending on the mode of attachment, ubiquitin can either activate signalling function or target a protein for destruction by the proteasome.

Programmed cell death

A common form of cell death that is also known as apoptosis. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation. Apoptosis involves cell shrinkage, chromatin condensation in the periphery of the nucleus, plasma-membrane blebbing and DNA fragmentation into segments of ∼180 base pairs. Eventually, the cell breaks up into many membrane-bound 'apoptotic bodies', which are phagocytosed by neighbouring cells.

Recombination activating gene-2 (RAG2) blastocyst complementation system

A chimeric mouse model that is used to study the function of a gene in the adaptive immune system. This system is used when germline deletion of a gene of interest (for example, X-box binding protein 1 (XBP1)) results in an embryonic lethal phenotype. Embryonic stem cells from Xbp1−/− mice are injected into RAG-deficient blastocysts, with the resulting mouse being a chimera of the two. Because of the RAG mutation, mature B and T cells in these chimeric mice are strictly of the Xbp1−/− lineage.

Class switching

The somatic-recombination process by which immunoglobulin isotypes are switched from IgM to IgG, IgA or IgE.

Pro-B cell

A cell in the earliest stage of B-cell development in the bone marrow. Pro-B cells are characterized by incomplete immunoglobulin heavy-chain rearrangements and are defined as CD19+ cytoplasmic IgM− or, sometimes, as B220+CD43+ cells (by the Hardy classification scheme).

B2 cells

Conventional B cells. B2 cells reside in secondary lymphoid organs and secrete antigen-specific antibodies.

B1 cells

B1 cells express CD5, respond quickly to antigen, produce antibodies of broad specificity and do not depend on MHC class II-mediated T-cell help.

Germinal centre

A lymphoid structure that arises in follicles after immunization with, or exposure to, a T-cell-dependent antigen. It is specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.

Conventional DCs

A subset of dendritic cells (DCs) that already display the morphology and function of a DC under steady-state conditions.

Plasmacytoid DCs

A subset of dendritic cells (DCs) that has a morphology which resembles that of a plasmablast. Plasmacytoid DCs produce large amounts of type I interferons in response to viral infection.

Small interfering RNAs

(siRNAs). Short double-stranded RNAs of 19–23 nucleotides that induce RNA interference, a post-transcriptional process that leads to gene silencing in a sequence-specific manner.

Immune tolerance

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β2-microglobulin

(β2m). A single immunoglobulin-like domain that non-covalently associates with the main polypeptide chain of MHC class I molecules. In the absence of β2m, MHC class I molecules are unstable and are therefore found at very low levels at the cell surface.

Epitope spreading

The de novo activation of autoreactive T cells by self-antigens that have been released after B- or T-cell-mediated bystander damage.

Inflammatory bowel disease

(IBD). A group of conditions of unknown aetiology in which the intestinal mucosa is chronically inflamed. IBD includes Crohn's disease and ulcerative colitis.

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(EAE). An experimental model for the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Atherosclerosis

A chronic disorder of the arterial wall characterized by endothelial-cell damage that gradually induces deposits of cholesterol, cellular debris, calcium and other substances. These deposits finally lead to plaque formation and arterial stiffness.

E3 ubiquitin ligase

The enzyme that is required to attach the molecular tag ubiquitin to proteins that are destined for degradation by the proteasomal complex.

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Todd, D., Lee, AH. & Glimcher, L. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol 8, 663–674 (2008). https://doi.org/10.1038/nri2359

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