β cell ER stress and the implications for immunogenicity in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by hyperglycemia due to progressive immune-mediated destruction of insulin-producing pancreatic islet β cells. Although many elegant studies have identified β cell autoantigens that are targeted by the autoimmune response, the mechanisms by which these autoantigens are generated remain poorly understood. Normal β cell physiology includes a high demand for insulin production and secretion in response to dynamic glucose sensing. This secretory function predisposes β cells to significantly higher levels of endoplasmic reticulum (ER) stress compared to nonsecretory cells. In addition, many environmental triggers associated with T1D onset further augment this inherent ER stress in β cells. ER stress may increase abnormal post-translational modification (PTM) of endogenous β cell proteins. Indeed, in other autoimmune disorders such as celiac disease, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis, abnormally modified neo-antigens are presented by antigen presenting cells (APCs) in draining lymph nodes. In the context of genetic susceptibility to autoimmunity, presentation of neo-antigens activates auto-reactive T cells and pathology ensues. Therefore, the ER stress induced by normal β cell secretory physiology and environmental triggers may be sufficient to generate neo-antigens for the autoimmune response in T1D. This review summarizes what is currently known about ER stress and protein PTM in target organs of other autoimmune disease models, as well as the data supporting a role for ER stress-induced neo-antigen formation in β cells in T1D.

Keywords: ER stress; autoimmunity; neo-antigen; post-translational modification; type 1 diabetes; β cell.

Figure 1

Signaling pathways of the unfolded protein response. (A) When protein folding proceeds normally, the protein sensors of ER stress (PERK, ATF6, and IRE1) are bound and held in their inactive state by GRP78. (B) When misfolded proteins accumulate in the ER lumen, GRP78 binds misfolded proteins, thereby releasing the protein sensors of ER stress and allowing for the activation of the cytoprotective UPR. PERK autophosphorylates in trans, then activates eIF2α by phosphorylation to attenuate translation of additional non-chaperone proteins. ATF6 translocates to the Golgi apparatus and is cleaved to yield a transcription factor that up-regulates the expression of molecular chaperones to aid in the folding of accumulated proteins in the ER. IRE1 autophosphorylates in trans and splices XBP-1 mRNA. The spliced mRNA encodes a transcription factor that up-regulates the expression of additional molecular chaperones and UPR proteins to relieve ER stress. If ER stress is too great or prolonged, the UPR induces expression of pro-apoptotic proteins such as CHOP.

Figure 2

Environmental triggers associated with T1D exacerbate β cell ER stress. Environmental factors such as viral infection, chemicals, ROS, dysglycemia, and pancreatic inflammation are associated with onset of T1D. Each of these environmental triggers of T1D also increases β cell ER stress above the inherently high levels induced by normal β cell physiology.

Figure 3

Regulation of ER Ca²⁺ concentrations. (A) Under normal conditions, Ca²⁺ concentrations are higher in the ER lumen than in the cytosol. This balance is maintained by SERCA pumps that bring Ca²⁺ into the ER lumen, and Ca²⁺ channels (RyR and IP₃R) that release Ca²⁺ into the cytoplasm as needed for normal cellular signaling. (B) During ER stress, the Ca²⁺ gradient across the ER membrane is disturbed, leading to Ca²⁺ release from the ER and increased Ca²⁺ concentrations in the cytoplasm.

Figure 4

ER stress induces neo-antigen formation in β cells. (A) During normal conditions, proteins are translated and properly folded in the ER lumen. (B) During ER stress, proper protein folding is inhibited and misfolded proteins accumulate. (C) Ca²⁺ is released from the ER, significantly increasing the concentration of cytosolic Ca²⁺. (D) Heightened Ca²⁺ in the cytosol increases the activity of PTM enzymes, such as Tgase2 and PAD. (E) Activated Tgase2 and PAD modify β cell proteins, generating neo-antigens for the autoimmune response in T1D.