T Cells and Autoimmunity

CHAPTER 6

T Cells and Autoimmunity Vaishali R. Moulton1, Kamalpreet Nagpal, George C. Tsokos Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA 1 Corresponding Author: [email protected]

1 INTRODUCTION T lymphocytes are important in the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). A combination of genetic predisposition, environmental factors such as infections and hormones such as estrogen leads to a breakdown of immune tolerance, resulting in autoantibody production and unchecked expansion of self-reactive T cells, ultimately leading to tissue destruction. Altered T cell signalling events couple with defective gene expression and aberrant cytokine production, thus leading to the abnormal phenotype of T cells in SLE. T cells from patients with SLE are unique in that they bear some features of naı¨ve T cells, such as their low interleukin (IL)-2 production, and yet certain characteristics are reminiscent of an activated/memory cell phenotype such as the rewired T cell receptor (TCR) signalling subunits and aberrant cytokine production.2 The following sections describe the role and regulation of T cells in the pathophysiology of the prototype autoimmune disease SLE.

2 ROLE OF HORMONES Hormones are a crucial component in the pathogenesis of autoimmune disease, as evidenced by the predominant affliction of women: 90% of patients with SLE are women, and the disease is mainly seen among women of reproductive age.3 The role of female hormones in autoimmune disease, specifically in SLE, has been studied both in clinical trials and in mouse models. While the precise cellular and molecular mechanisms of the hormonal contribution to disease are not clear, estrogen is implicated in disease pathophysiology. Most cells including immune cells and T cells express estrogen receptors (ERs) a and b. Estrogen binds to ERs and form dimers that subsequently recognize and Infection and Autoimmunity http://dx.doi.org/10.1016/B978-0-444-63269-2.00005-2

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Figure 1 Select roles of estrogen and estrogen receptors in T cells in SLE.

bind to estrogen response elements within target genes and regulate gene transcription (Figure 1). ERs are emerging as important contributors to autoimmune disease pathogenesis.4 In lupus-prone mice models, ER-a deficiency attenuated disease and prolonged survival.5,6 Estrogen was shown to increase CD40L expression in T cells from patients with SLE compared to healthy individuals.7 Estrogen treatment of T cells from healthy individuals increased expression of the transcriptional repressor cAMP response element modulator (CREM) and suppressed IL-2 production.8 Estrogen is associated with regulation of cytokines, promoting a T helper (Th) 2 cytokine profile and suppressing Th1 cytokines. Mice treated with estrogen were susceptible to infection by Listeria monocytogenes, which correlated with their splenocytes, which produced reduced amounts of IL-2 necessary for cytotoxicity.9 Estrogen was recently found to increase IL-17 production in splenocytes from wild-type mice treated with.10 Estrogen suppresses the expression of FasL affecting T cell apoptosis, suggesting that it may permit the persistence of autoreactive T cells.11 Estrogen administration to peripheral blood mononuclear cell (PBMC)–induced expression of calcineurin messenger RNA (mRNA) expression and encoded enzyme PP2B phosphatase activity in an ER-dependent manner.12

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3 ROLE OF INFECTIONS Environmental influences are an important contributor to SLE pathogenesis, and infectious agents are a crucial component. Pathogenic mechanisms involving infections and autoimmunity include molecular mimicry, lymphocyte bystander activation, superantigens, polyclonal activation, and epitope spreading.13 Viral infections such as the Epstein–Barr virus have long been associated with the triggering of autoimmunity, specifically SLE. Evidence for this connection includes the molecular similarity of the Epstein–Barr nuclear antigen (EBNA) 1 to the common lupus autoantigen Ro and of EBNA-1 and EBNA-2 with an SmD epitope. This crossreactivity of antibodies is important in the initiation of lupus autoimmunity. Following autoantibody production, self-antigens are processed and epitope spreading begins. Patients with SLE show accelerated seroconversion to the Epstein–Barr virus and have higher viral titers compared to healthy individuals; this results from defective CD8 cytotoxic responses that are unable to control viral load. Aberrant T cell responses are observed in patients with SLE with increased interferon-g-producing CD4-positive cells and dysfunctional CD8 T cells.14 Superantigens are proteins produced by bacteria (such as staphylococci and streptococci) or viruses and are capable of binding to the TCR and also with high avidity to major histocompatibility complex class II molecules independent of antigen specificity. Therefore, they can activate large numbers of CD4 T cells, including self-reactive T cells, to aberrantly produce inflammatory cytokines and eventual B cell activation. Inflammatory cytokines can mediate the bystander activation and proliferation of T cells to propagate the autoimmune process and pathology.

4 T CELL SIGNALLING: T CELL RECEPTOR (TCR)–CD3 COMPLEX TCR engagement feeds into an intricate signalling network culminating in gene expression, cytokine production and effector function. TCR signal transduction commences upon the recognition of the cognate peptide– MHC molecule on the surface of antigen-presenting cells (APCs).15,16 The TCR consists of the highly variable a and b chains as part of a complex with the CD3 d, e, g and z chains to form the TCR-CD3 complex.17 While the d, e, and g chains each bear a single immunoreceptor tyrosine activation motif (ITAM), each of the z chains has three ITAMs; thus the zz homodimer has a total of six motifs, making it a critical signal transducer of T cells.18 In naı¨ve T cells, antigen recognition is followed by a clustering of the TCR, the

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co-receptor molecule (CD4 or CD8) as well as CD45 into lipid-rich microdomains called lipid rafts.2 The TCR lacks any intrinsic enzymatic activity and instead relies on the Src family of kinases, particularly Lck, to initiate signalling by phosphorylating the six ITAMs on CD3z chains.19–21 This renders the CD3 zeta-chain capable of binding zeta-associated protein (ZAP70) kinase, which is also phosphorylated by Lck. This causes a conformational change and an increase in the enzymatic activity of ZAP70, leading to phosphorylation of its target molecules, including the adaptor molecules linker for activation in T cells (LAT) and SLP-76.22 The phosphorylated LAT molecules, in turn, recruit and activate a number of downstream signalling molecules, forming the LAT signalosome and transmitting the signal downstream into distinct pathways. Ras–mitogen-activated protein kinase (MAPK) is activated through the guanine nucleotide exchange factor. In addition the enzyme phospholipase Cg is activated.23,24 The activation of these pathways ultimately causes an increase in intracellular calcium and the activation of various transcription factors such as nuclear factor (NF)kB, NF of activated T cells (NFAT) and activator protein (AP) 1. The activation of these transcription factors is followed by their nuclear translocation and induction of target gene transcription, T cell growth, and differentiation. Signalling initiated from the TCR also leads to actin mobilization, cytoskeletal rearrangements as well as activation of integrins by inside-out signalling.25,26 T cells from patients with SLE present with abnormal attributes and characteristics that contribute to disease progression and pathology, with distinct aberrations in early and late signalling (Figure 2).

4.1 Defects in Early T-Cell Signalling T cells isolated from patients with SLE display amplified activation in response to antigen recognition. These cells show increased tyrosine phosphorylation of signalling proteins as well as an enhanced calcium influx.27 In contrast to cells from healthy individuals, lipid rafts in SLE T cells are pre-clustered and ready for activation.28 In addition, they have an abnormal representation of some of the key molecules involved in signalling. Defective expression and activity of the tyrosine phosphatase CD45 leads to a decreased expression of the kinase Lck in lipid rafts in SLE T cells. In addition, there is increased expression of Fc receptor (FcR) g, spleen tyrosine kinase (Syk), and phospholipase Cg.29 The importance of lipid raft clustering is demonstrated by a study where cholera toxin, an agent that forces the clustering of lipid rafts, exacerbated the disease in a mouse model of lupus.30

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Figure 2 T cell receptor in normal and SLE T cells.

The increased calcium response is due at least in part to the reorganization/ rewiring of the TCR complex in SLE T cells. In these cells, the expression of the CD3z chain is decreased compared to healthy individuals.31 This decrease is accompanied by an increase in the levels of FcRg, a homologous protein that structurally and functionally replaces the CD3z molecule in the TCR–CD3 complex.32 FcRg has only one ITAM (compared to three in CD3z) and couples to Syk instead of ZAP70. This leads to defective signalling through the TCR, culminating in increased calcium influx. The decreased expression of CD3z is attributed to a number of different defects: abnormal transcription, decreased mRNA stability, alternate splicing and protein degradation. The key role that this rewiring plays in SLE T cells is shown by the inhibition of Syk, wherein the defective calcium influx in SLE T cells is corrected.33 In another study, restoring the levels

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of CD3z in SLE T cells restored the IL-2 production, thus emphasizing the importance of the CD3z chain in T cell signalling.34

4.2 Defects in Downstream Signalling Events SLE T cells have defects in the MAPK signalling pathways, especially extracellular signal–regulated kinase (ERK) signalling pathway. Defective Ras signalling, decreased levels of ras guanyl nucleotide releasing protein 1 (RasGRP1) and abnormal protein kinase Cd activation are some of the factors contributing to this defect.35–37 SLE T cells also exhibit increased levels of the protein phosphatase (PP) 2A, which contributes to defective ERK signalling.38 Abnormalities in the ERK cascade ultimately contribute to DNA hypomethylation via its effect on the enzyme DNA methyltransferase (DNMT) 1. DNA hypomethylation is one of the hallmarks of T cells from patients with SLE and a key feature contributing to the development of disease.39 Dysfunction of mitochondria is another anomaly seen in SLE T cells, with hyperpolarization and excessive production of reactive oxygen species, leading to oxidative stress. Mammalian target of rapamycin (mTOR) is a kinase that acts as a sensor of the mitochondrial membrane potential. SLE T cells exhibit higher levels of mTOR.40 In addition to its effect on mitochondrial polarization, high levels and activation of mTOR lead to lower levels of CD3z through lysosomal degradation.41

4.3 Increased Cell Death in SLE T Cells Mitochondrial hyperpolarization also leads to increased death of T cells by necrosis, as opposed to spontaneous apoptosis in the absence of oxidizing agents.42,43 Mitochondrial hyperpolarization as well as increased reactive oxygen species modify the expression of cytokines such as IL-10 and tumor necrosis factor (TNF)-a, thus leading to increased death of SLE T cells by necrosis.44 Increased cell death of SLE T cells by apoptosis as well as necrosis exacerbates the inflammation by providing extracellular nuclear material.

4.4 Defects in Gene Expression The expression and function of various transcription factors is altered in T cells isolated from patients with SLE, affecting gene expression of many different signalling intermediates as well as effector molecules that are key to the optimal functioning of the T cell.

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CD3z/FcR1g Aberrant expression and activity of Elf-1, a transcription factor belonging to the Ets family of transcription factors, is responsible for skewing the CD3z-toFcR1g ratio in SLE T cells.45 Elf-1 reciprocally regulates CD3z and FcR1g, leading to reduced levels of the former and higher expression of the latter.46 CREB/CREM cAMP-controlled transcription factors CREB (cAMP response element binding protein) and CREM are two antagonistic transcription factors that are defectively regulated in SLE T cells.47 Phosphorylated (p) CREB acts as a transcriptional activator, whereas pCREM is a repressor of transcription. The ratio of these two proteins at a specific site within the IL-2 promoter determines the expression levels of IL-2. In the case of SLE T cells, the highly expressed PP2A causes dephosphorylation of CREB, whereas increased activity of the calcium-activated calmodulin kinase (CAMK) IV leads to increased pCREM levels and increased binding to the target gene.48 The result is a reduction in the levels of the cytokine IL-2 produced by SLE T cells upon activation.49

4.5 Epigenetic Changes in SLE Epigenetics comprise stable and heritable changes that modify gene expression without changing the underlying genomic sequence.50 Such changes broadly include CpG DNA methylation and histone modifications. DNA methylation One of the most efficient methods of gene silencing is DNA methylation by the DNMT enzymes to the 50 carbon position of cytosine in CpG dinucleotides.51 Abnormalities in the DNA methylation system can lead to an increase or decrease in the expression of that particular gene. A generally hypomethylated state of T cells has been reported in SLE.52 It has been shown that defective protein kinase Cd activity, as well as enhanced PP2Ac levels, lead to abnormal ERK/MAPK pathway activation and ultimately reduced DNMT1 expression and activity53,3838. Some examples of methylation-sensitive genes that are hypomethylated in lupus T cells include CD40L, CD11a, cytokines IL-4, IL-6, IL-10, and the serine threonine phosphatase PP2A.54–56 Histone modifications Histones are the building blocks of chromatin and are amenable to various post-translational modifications that can affect the functional abilities of chromatin. Some of the modifications include acetylation, methylation,

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phosphorylation, sumoylation, and ADP-ribosylation.57 The silencing of the IL-2 locus by the recruitment of histone deacetylase 1 by the transcriptional repressor CREMa is an example of a histone modification that plays a role in SLE.58 Acetylation of histone residues is associated with transcriptional activation and their removal by repressing transcription.

4.6 Alternative Splicing A common theme in the aberrant gene expression observed in T cells from patients with SLE is the abnormal processing of mRNA, resulting in abnormal expression and/or activity of proteins encoded by these variants. For example, abnormal alternative splicing of the CD3 zeta 30 untranslated region results in the deletion of a large 500-bp fragment that contains elements essential for the stability of the transcript.59 Increased expression of this aberrant isoform contributes to the reduced expression of the CD3z chain and therefore to the rewired TCR.60 By mass spectrometry discovery approaches, the serine arginine-rich splicing factor (SRSF) 1 or splicing factor 2/alternative splicing factor was found to bind and regulate alternative splicing of the CD3z 30 untranslated region. Interestingly, reduced expression of SRSF1 correlated with CD3z expression in T cells from patients with SLE.61 CD44, an important adhesion and differentiation molecule in T cells, has a very complex gene structure and bears numerous spliced isoforms, of which specifically the variable (v) 3 and v6 variants were found to be increased in SLE T cells and conferred increased migration capacity.62 The CREM gene bears multiple promoters and produces distinct products with opposing functions in gene transcription. CREMa is a repressor, whereas CREM tau2a is an activator. Inducible cAMP early repressor isoforms are also isoforms of the CREM gene and are repressors. Increased expression and activity of CREMa contributes to the defect in IL-2 transcription and low IL-2 production in SLE T cells.63

5 COSTIMULATORY PATHWAYS APCs capture, process, and present antigen-specific sequences to T cells through the interaction of the cognate peptide–MHC complex on the surface of APCs and the TCR on the T cell. This interaction is, however, insufficient to propagate downstream signals and requires help from other costimulatory pathways to continue and sustain the signal (Figure 3). In addition to propagating the signal, costimulatory signals also are required to keep the signalling in check and attenuate it when necessary so that

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Figure 3 Costimulatory molecule interactions between T cells, B cells and APCs.

immune tolerance is not breached. Some of the well-characterized costimulatory molecules and their role in the pathophysiology of SLE are presented in the following sections.

5.1 CD28–CD80/86 During the early stages of T cell activation, CD28, which is expressed on T cells, couples to the CD80 (B7-1)/CD86 (B7-2) molecules on APCs.64 CD80/86 are constitutively expressed on dendritic cells but are inducible in B cells as well as other APCs such as monocytes. Activation of the CD28-B7 interaction provides a potent signal (in addition to the

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TCR–MHC interaction) for the production of various cytokines such as IL-2 and IL-6.65 The interaction between CD28 and CD80/86 has received much attention with respect to SLE. A number of studies have demonstrated amelioration of the disease upon blockade of this interaction in murine models of lupus.66 Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a receptor present on the surface of T cells and transmits an inhibitory signal to T cells. It is similar in structure to CD28 and can bind to both CD80 as well as CD86. However, CTLA4 binds to CD80/86 with much higher affinity, thus outcompeting CD28 and attenuating the signal. Abatacept (a CTLA4–immunoglobulin fusion molecule) has been used in clinical studies to block the CD28: CD80/86 stimulation and led to the amelioration of autoimmune-driven inflammation.67

5.2 Inducible Costimulator–B7RP1 Another costimulatory pathway related to CD28-CD80/86 is the inducible co-stimulator (ICOS) B7–related protein 1 (B7RP1) pathway.68 ICOS is structurally functional to CD28 and is expressed on activated T cells. It binds to B7RP1, which is expressed on B cells as well as dendritic cells and monocytes. ICOS activation induces class switching and antibody production by B cells. It has been reported that ICOS is highly expressed on the CD4 + T cells of patients with autoimmune diseases such as rheumatoid arthritis and SLE.69

5.3 CD40L-CD40 Activated T cells express CD40L on their surface, which binds to CD40 on the surface of B cells, APCs, and non-immune cells such as epithelial, endothelial, and renal tubular cells.70 The ligation of CD40 and CD40L can deliver strong signals, which can drive B cell differentiation, maturation, and isotype switching.71 A number of autoimmune diseases exhibit an increased surface expression of CD40L on their T cells, and this is correlated with increased autoantibody production.72,73 Moreover, in lupus-prone mice, blockade of CD40L has been shown to prevent the development of SLE.74

5.4 Signalling Lymphocytic Activation Molecules The signalling lymphocytic activation molecule (SLAM) family comprises nine members that are type I transmembrane receptors belonging to the immunoglobulin superfamily.75 These receptor molecules provide potent co-stimulatory signals and are recognized as important immunomodulatory

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molecules with roles in T cell function and B cell activation as well as lineage commitment during hematopoiesis, cell survival and cell adhesion.76,77 SLAM molecules have a tyrosine-rich motif through which they can interact with SH2 domain–containing proteins such as the SLAM-associated protein.76 Genome-wide association studies of the families of patients with SLE have identified a susceptibility locus on chromosome 1 that harbors the SLAM genes.78,79 Among the SLAM family members, SLAMF3 and SLAMF6 are expressed at higher levels in SLE T cells compared to T cells from healthy individuals.80

5.5 CD44 And Cell Adhesion/Migration CD44 is a glycoprotein expressed on the T cell surface and is involved in cell adhesion, migration, and signalling. It binds to its ligand, hyaluronic acid, in tissues and helps T cells to migrate into peripheral tissues. In cells it functions in association with its signalling partners ezrin, radixin, moiesin (ERM) and requires pERM for its adhesive capacity.81 SLE T cells have an elevated surface expression of certain isoforms of CD44 and are found in aggregated lipid rafts along with ERM.82 High levels of CD44 as well as pERM have been reported in kidney infiltrates of patients with lupus, suggesting that signalling through CD44 enables the migration of T cells into kidneys.62 ERM signalling molecules are phosphorylated by rho-associated protein kinase. Inhibiting rho-associated protein kinase or blocking the activation of CD44 pathways inhibits the migration of T cells.

6 CYTOKINES Cytokines are small proteins secreted by cells in both the innate and adaptive immune systems and can regulate diverse functions in the immune response. Dysregulation of cytokines and their consequent signalling networks are an important component of the pathogenesis of autoimmune disease. In SLE, a number of cytokines are aberrantly expressed and, through their effects on immune cells, facilitate abnormal cellular and humoral responses; they also directly mediate tissue pathology and damage.83 CD4 Th cell differentiation is driven by specific cytokines: IL-12 drives a Th1 differentiation important for cell-mediated immunity against intracellular pathogens, IL-4 is required for a Th2 differentiation necessary for a humoral response against extracellular pathogens and a combination of IL-6, transforming growth factor (TGF)-b, IL-23 and IL-21 drive Th17 differentiation, which is important for certain types of bacterial and fungal infections.84 TGF-b in the absence

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of inflammation drives regulatory T cell (Treg) generation, and IL-6 with IL-21 lead to T follicular helper cell differentiation (Figure 4). The differentiation into these specific cell types is controlled by lineage-specific transcription factors. T-bet and GATA-3 are important for Th1 and Th2 differentiation, respectively. Retinoid-related orphan receptor (ROR) gt and RORa are activating factors for IL-17 transcription. FoxP3 is the transcription factor important for Tregs, whereas Bcl-6 is important for T follicular helper cell differentiation.

Figure 4 Diagram depicting naïve CD4 T cell differentiation into Th1, Th2, Th17, Treg and Tfhsubsets. Cytokines and transcription factors involved in lineage-specific differentiation are indicated.

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6.1 IL-2 T cells from patients with SLE produce aberrantly low amounts of the vital cytokine IL-2. IL-2 is important in autoimmune disease because it is not only necessary for the proliferation and function of Tregs but also vital for activation-induced cell death, which is important for the deletion of autoreactive T cells. In addition, IL-2 is important for cell-mediated immunity, which is crucial because patients with autoimmune disease are susceptible to infections caused by either immunosuppressive therapy or dysregulated immune responses. Tregs qualified by the CD4+ CD25+ or CD4+CD25+FoxP3 + phenotype are impaired in proliferation in human autoimmune disease accounting for their reduced numbers and function.85 Studies of IL-2 and IL-2 receptor knockout mice have shown that these mice develop severe spontaneous autoimmune disease and succumb to lymphoproliferative disease.86 A deficiency of Tregs in these mice is thought to account for the unchecked proliferation of lymphocytes, leading to lymphadenopathy.87 Whereas IL-2 production is reduced and is protective for autoimmunity, it also has been ascribed a pro-inflammatory role in selective target tissues, rendering its role in disease complicated.88 IL-2 knockout and FoxP3deficient scurfy mice both develop multi-organ inflammation, but the IL-2 knockout mice do not develop skin and lung inflammation. It was shown that IL-2 controls the migration and localization of both Th1 and Th2 CD4 T cells in an organ-specific manner. IL-2-deficient mice demonstrated a lack of trafficking receptors and Th2 cytokines (IL-4, IL-5, IL-13) important for skin and lung inflammation, revealing a target organ-specific pro-inflammatory role for IL-2. IL-2 gene expression is controlled mainly at the transcriptional and posttranscriptional levels. Transcription factors NFAT, AP1, and NF-kB, among others, are key factors that bind to cognate sites within the IL-2 promoter (Figure 5). Upon T cell activation, TCR signalling induces intracellular signalling cascades that ultimately lead to the translocation of NFAT and NF-kB into the nucleus and initiate transcription of IL-2. In SLE T cells, reduced amounts and activity of NF-kB and AP1 are thought to contribute to lower IL-2 expression. Whereas NFAT is increased in SLE T cells, hence activating CD40L expression, NFAT in conjunction with AP1 is necessary for IL-2 transcriptional activation.89 Therefore, the lack of AP1 is important in the IL-2 defect. A role for SRSF1, an RNA binding protein, was recently identified in IL-2 production by indirectly activating IL-2 transcription. SRSF1 expression was reduced in patients with SLE, more so in patients

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Figure 5 Signalling pathways and transcription factors involved in IL-2 production in T cells.

with active disease. Interestingly, forced expression of SRSF1 into SLE T cells rescued IL-2 production.90 In addition to these factors, a balance between the transcription factors CREM and CREB is important in IL-2 regulation. Both factors compete for binding to a cAMP response element site at the -180 position within the IL-2 promoter. In SLE T cells, disruption of this balance is thought to contribute to the reduced IL-2 expression. Protein kinase A phosphorylates and PP2A dephosphorylates CREB. Reduced activity of protein kinase A and increased expression of PP2A leads to reduced availability of pCREB. Increased expression of CREM is attributed to the increase in transcription mediated by the SP1 transcription factor and binding to the CREM promoter. CREM is phosphorylated by the calciumregulated kinase CAMKIV. CAMKIV is increased in SLE T cells, and therefore increased pCREM leads to IL-2 repression. Serum from patients with SLE induced the increased binding of CREM to the IL-2 promoter through activation of CAMKIV,91 and T cells from MRL/lpr lupus-prone mice also showed increased levels of CAMKIV. CAMKIV inhibitor treatment was able to prevent and correct autoimmunity and disease pathology in lupus-prone mice.92

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6.2 IL-17 IL-17 (IL-17A, IL-17F) is a pro-inflammatory cytokine that is essential for host defence against bacteria and fungi. Its importance in autoimmune disease pathogenesis was recently uncovered in both human patients and animal models. IL-17 is produced by a subset of activated CD4 T cells under inflammatory conditions. Increased levels of IL-17 in the serum and increased numbers of IL-17-producing cells were demonstrated in patients with SLE. Increased IL-17 was found in target organs such as skin, lungs kidneys, indicating the role of IL-17 in local tissue damage. Patients with lupus nephritis had increased numbers of IL-17-producing double-negative T cells in the kidneys.93 Increased expression also was noted in muscle tissue from patients with autoimmune myositis.85 IL-17 recently has emerged as an important driver of pathogenic inflammation and is considered a key underlying element in the pathogenesis of autoimmune diseases such as SLE, multiple sclerosis and others. IL-17 gene transcription is controlled by the RORgt and RORa transcription factors. RORgt drives differentiation of Th17 cells and is exclusively expressed by them. IL-17 is thought to be the key cytokine mediating inflammation, as demonstrated in numerous autoimmune diseases including SLE and multiple sclerosis . In addition to its role in inflammation, it also affects other cell types such as B cells. When treated with IL-17, PBMCs from patients with lupus nephritis produced increased amounts of double stranded DNA autoantibodies and IL-6, suggesting the role of IL-17 in B cell regulation. When stimulated under pro-inflammatory conditions, CD4 T cells, including cytokines IL-6, IL-23, IL-21, and TGF-b, differentiate into the Th17 phenotype and produce IL-17. IL-21 is necessary to initiate IL-17 production, whereas IL-23 is required to maintain IL-17. An IL-23 receptor deficiency lowered IL-17 production in lupus-prone mice; more important, these mice were protected from the development of disease.94 IL-6, IL-21, and IL-23 bind to their respective receptors and, through the JAK–signal activator and transducer (STAT) signalling pathway, activate the same transcription factor, STAT3, which can directly bind to the IL-17 and IL-21 genes. T cells from patients with SLE were found to have increased STAT3 activity. This also was associated with their enhanced capacity for chemokine-mediated migration.83

6.3 IL-6 IL-6 is a pleiotropic cytokine secreted by a large variety of cells and mediates its effects through activation and differentiation of immune cells including

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T and B lymphocytes.95 IL-6 exerts its effects on target cells via the IL-6 receptor, which has two components: the 80-kDa IL-6R a chain, which is the IL-6 binding chain, and the IL-6R b chain (glycoprotein 130), which is the signal transducing chain. The pathogenic role of IL-6 has been demonstrated in both human SLE and murine lupus disease. IL-6-deficient MRL/lpr mice show delayed disease development and reduced renal pathology, including immunoglobulin G and C3 complement deposition.96 In pristane-induced lupus, IL-6-deficient mice showed less-severe kidney disease and reduced levels of autoantibodies.97 In other mice models such as BWF mice, administration of IL-6 increases, but blocking IL-6 reduces, the production of anti-DNA autoantibodies. In addition, an acceleration of renal pathology, increased expression of MHC class II on mesangial cells and increased expression of glomerular ICAM-1 was observed in female BWF mice administered the human IL-6 cytokine. As in mice, elevated levels of IL-6 have been observed in patients with SLE and have been shown to correlate variably with disease severity or anti–double strand DNA autoantibodies. Increased numbers of IL-6-producing cells in the PBMCs of patients with SLE correlates with disease severity; autoreactive T cell clones from patients produce large amounts of IL-6, which in turn mediates effects on B cells. IL-6 is known to promote B cell activation and autoantibody production in SLE, as evidenced by exogenous administration of IL-6 as well as by neutralizing antibodies.98

6.4 TNF-a TNF-a is secreted by activated macrophages and other immune cells including monocytes and T cells. TNF-a mediates its effects through two distinct receptors—TNFR1 (p55) and TNFR2 (p75)—and can induce either proinflammatory or anti-inflammatory pathways, depending on receptor engagement. Through the TNF receptor 1, apoptosis and anti-inflammatory pathways are triggered via the Fas-associated death domain and caspase cascade.95 Alternatively, recruitment of TNF receptor-associated factor 2 is pro-inflammatory via activation of NF-kB and JNK and MAPK pathways. These pathways also are activated when TNF-a engages TNF receptor 2. The effects of these opposing functions of TNF-a—as a pro-inflammatory or an immunoregulatory cytokine—have been demonstrated in autoimmune disease as well. Many studies have shown the pathogenic role of TNF-a in mice. MRL/lpr mice were found to have increased TNF-a levels in serum and in kidneys, which correlated with disease,99,100 and TNF blockade

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treatment proved advantageous in this mouse strain. Anti-TNF treatment also led to reduced development of autoantibodies, proteinuria and immunoglobulin G deposition in the kidneys of lupus-prone mice.101,102 On the other hand, TNF-a-deficient SLE mice showed exacerbated disease, and recombinant TNF-a administration in BWF mice was beneficial. These contradictory roles of TNF-a in disease reflect the dual function of this cytokine in pro- and anti-inflammatory processes. Similar to the studies in mice, data from human studies are complicated. While some studies found elevated levels of TNF-a in serum and disease correlation in patients with SLE, others did not.103,104 In addition to the circulating TNF-a, tissue-specific cytokine expression may contribute locally to tissue pathology in SLE. Increased expression of the TNF-a gene and protein was demonstrated in kidney biopsies from 52% of patients with lupus nephritis.105 Reduced expression of TNF adaptor proteins—TNF receptor-associated factor 2, TNF receptor 1–associated DEATH domain, Fas-associated death domain and receptor interacting protein 1—in PBMCs from patients with SLE may contribute to the anti-apoptotic effects and increased survival of autoreactive cells,106 whereas increased expression of these adaptor proteins was found in kidneys from patients with lupus nephritis,107 which may account for the local inflammatory effect of TNF-a. Thus the systemic and local effects of TNF-a may be uncoupled via the distinct actions on TNF receptors and adaptor molecules such that it has a systemic immune modulatory function and a local pro-inflammatory effect.

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