**4.2. ER stress and adaptive immune response**

The presence of β cell specific autoantibodies is a marker for autoimmune diabetes (66). IRE1/XBP1 axis is required for the differentiation of antibody-producing B lymphocytes. IRE1 is necessary for the Ig gene rearrangement, production of B cell receptors, and lympho‐ poiesis. The expression multiple UPR components including BiP, GRP94, and XBP-1 is upregulated during the differentiation of B cells (67). Mice with a deficiency of IRE1 in hematopoietic cells have a defective differentiation of pro-B cells towards pre-B cells (68). XBP-1, an IRE1 downstream molecule, is also involved in the differentiation of B cell and antibody production by mature B cells. It was found that the engagement of B-cell receptor induces ubiquitin-mediated degradation of BCL-6, a repressor for B-lymphocyte-induced maturation protein 1 (69), while B-lymphocyte-induced maturation protein 1 negatively reg‐ ulates the expression of B-cell-lineage-specific activator protein (70), a repressor for XBP-1 (71). In line with these results, B lymphocytes deficient in B-lymphocyte-induced maturation protein 1 failed to express XBP-1 in response to LPS stimulation (72). The expression of XBP-1 is rapidly up-regulated when B cells differentiate into plasma cells. Furthermore, XBP-1is able to initiate plasma cell differentiation when introduced into B-lineage cells. XBP-1-deficient lymphoid chimeras have a defective B-cell-dependent immune response due to the absence of immunoglobulin and plasma cells (30). In addition to IRE1/XBP-1 axis, ATF6 axis may also implicated in the differentiation of B cells, as increased ATF6 cleavage is found in differentiating B cells (67). However, PERK axis does not seem to be involved in the B-cell differentiation and maturation (68;73).

tor 2 (NRF2) (79;80). Therefore, deficiency of PERK markedly increases ROS accumulation in response to toxic chemicals (79;81). The IRE1 axis of UPR can activate NFκB, a key regulator in inflammation, by recruiting IκB kinase (82). As a result, loss of IRE1 reduces the activation of NFκB activation and production of TNF-α (82). In addi‐ tion, the IRE1 axis can also activate JNK, and subsequently induce the expression of in‐ flammatory genes by activating activator protein 1 (AP1) (83). ATF6, the third axis of UPR signaling, can also activate NFκB pathway and induce inflammatory response. Therefore, suppression of ATF6 reduces NFκB activation caused by BiP degradation (84).

Endoplasmic Reticulum (ER) Stress in the Pathogenesis of Type 1 Diabetes

http://dx.doi.org/10.5772/52644

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**Figure 4. UPR-mediated inflammatory signaling.** UPR regulates inflammation through a variety of mechanisms in‐ volving ROS, JNK, and NFκB. PERK promotes ATF4 and NRF2, which then suppress ROS production by activating anti‐ oxidant pathway. Upon activation, IRE1/TRAF2 complex recruits IKK (IκB Kinase), leading to the phosphorylation of IκBα and subsequent activation of NFκB. IRE1/TRAF2 can also activate JNK, followed by the activation of AP1. XBP-1 induced by IRE1 can also induce the expression of various genes implicated inflammation. Furthermore, cleaved ATF6

can promote inflammation via activating NFκB.

Activation of T lymphocyte, another important adaptive immune cell, seems also involves UPR. TCR engagement, the first T cell activation signal, induces the expression of ER chap‐ erons including BiP and GRP94. Inhibition of protein kinase C, a serine/threonine protein kinase downstream of TCR signaling, suppresses the activation of ER stress response in‐ duced by T cell activation (74). IRE1/XBP-1 axis regulates the differentiation of effector CD8+ T cell. IRE1/XBP-1 pathway is activated in effector CD8+ T cell during acute infection. IL-2 promotes XBP-1 mRNA transcription, while TCR ligation induces the splicing of XBP-1 mRNA. The differentiation of CD8+ T cell is reduced by suppression of XBP-1 (75). Other than IRE1/XBP-1, CHOP is also involved in the functionality of T cells. A recent report sug‐ gests GTPase of the immunity-associated protein 5 (Gimap5) mutation in BioBreeding dia‐ betes-prone rat, a model for type 1 diabetes, leads to ER stress and thus induces spontaneous apoptosis of T cells. Inhibition of CHOP protects Gimap5-/- T cells from ER stress-induced apoptosis (76).
