Dysregulated equilibrium between pathogenic and regulatory T cells leads to immune disease

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mTOR integrates multiple signals during T cell activation

The differentiation of naïve CD4 cells into specific Th cell type in vivo is a complex process which requires these cells to integrate various environmental cues delivered by APCs in the secondary lymphoid organs [4, 75]. Naïve T cell interacting with APCs often encounter combination of cytokines with both pro and anti-inflammatory activity. There is also a considerable variation in the strength of the signal delivered by APCs in terms of avidity of interaction with MHC-II. How naïve T cells integrate all these signals and enter lineage commitment is a fascinating problem to be understood. The question how biological systems integrate multiple signals is still a “black-box”, However mammalian target of rapamycin (mTOR) has emerged as a kinase which is involved in integration various environmental signals and regulation of cells energy demands for growth and development [76]. mTOR consists of two protein complexes mTORC1 and mTORC2; mTORC1 is activated by PI3-kinase, Akt and Rheb whereas, mTORC2 is activated by PI3-K and enhances the phosphorylation of Akt (Figure 4) [77]. mTORC1 is rapamycin sensitive and mTORC2 is resistant to rapamycin [76]. Probing into the role of mTOR in immune cells has revealed many exciting observations. With respect to T cell biology, genetic deletion of mTOR resulted in impaired development of Th1, Th2 and Th17 cells. This effect was due to inability of these cells to activate STAT pathway upon stimulation. Interestingly mTOR deficient T cells developed into Foxp3 expressing Tregs independent of TGGβ [78, 79]. Interestingly mTOR keeps a check on expression of Foxp3 in Tregs [80], thus mTOR plays crucial role in differentiation naïve Th cells into effector Th cells (Th1, Th17 and Th2) and negatively regulates expression of Foxp3 in Tregs.

T cells in autoimmunity : shifting paradigms from Th1/Th2 to Th17/Tregs

Initially autoimmunity and many immunological disorders were explained on the basis of imbalance of Th1/Th2 responses. Th1 cells were considered to be pathogenic while Th2 cells were attributed with inhibitory functions [81]. IFNγ, the principle cytokine of Th1 cells was found in the target tissues of at the peak of EAE and CIA [82-84]. Adoptive transfer of Th1 cells was sufficient to induce disease in mouse models of type1 diabetes and EAE [85]. Administration of IFNγ in MS exaggerated the disease [86]. Mice deficient in T-bet and STAT4 were unable to produce IFNγ and were resistant to development of experimentally induced EAE [87, 88]. Administration of anti-IL12 was beneficial in EAE and CIA [86]. All together, these studies supported hypothesis that self-antigen specific IFNγ-producing Th1cells are the pathogenic cells in many autoimmune conditions. However, some key experiments performed in EAE required the revision of this theory. The flaws of the theory include: IFNγ injections protected against EAE, antibodies to IFNγ worsened EAE, IFNγ knockouts mice were more susceptible to EAE, and TNF knockouts had an exaggerated EAE and administration of TNF protected mice from EAE (Table 1) [89-94].
These contradictory findings and the experiments to understand the role of the cytokine IL-23 in EAE have helped to decipher the paradox of Th1/th2 hypothesis. IL-23 is a heterodimeric cytokine with p40 and p19 subunit. The p40 subunit is common to Th1 inducing IL-12 and IL- 23. Mice deficient in IL-23 were resistant to various animal models of autoimmunity like IBD, Collagen arthritis and EAE [95, 96].

Dysregulated equilibrium between pathogenic and regulatory T cells leads to immune disease

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) is a condition resulting from mutations in foxp3 gene resulting dysfunctional Tregs [15]. Compromised functions of Tregs are known to be associated with many autoimmune diseases such as MS, autoimmune polyglandular syndrome type II, SLE, type 1 diabetes, psoriasis, myasthenia gravis, RA, and chronic ITP [66, 123-126]. Depletion of Tregs before and after induction of autoimmune disease leads to exaggerated disease with increased cellular and humoral responses [127]. Adoptive transfer of Tregs in the animal models of autoimmunity decreased severity of the disease [14, 18]. Recovery phase of many inflammatory diseases is associated with increase in number of Tregs in the target organs. Thus, Tregs actively regulate autoimmunity throughout the lifespan and are indispensible for maintenance of immune homeostasis [16]. Reprogramming of Tregs by pathogenic T cells and various inflammatory agents renders them less suppressive. Pathogenic Th17 cells are known to develop at the cost of Tregs under severe inflammatory situations of increased IL-6 [41, 128]. Thus, balance between regulatory and effector T cells functions appears crucial for homeostasis and is intricately controlled by various pro and anti-inflammatory mediators [58, 73].

Composition, pharmacology and indications of IVIg

IVIg is a therapeutic concentrate of polyclonal IgG obtained from pools of plasma of a large number of healthy blood donors. Preparations of IVIg contain at least 96% of IgG with traces of IgA and IgM (Table 2). The repertoire of IVIg is relatively wide as it obtained from large number of donors [129]. IVIg has a high content of self-reactive NAbs (Natural antibodies) which can bind to various self-antigens and pathogen specific antibodies [130]. Initially used as replacement therapy for patients with immune deficiencies, IVIg is now widely used for the treatment of a large number of autoimmune and systemic inflammatory diseases including ITP, neuromuscular and neuro-immunological diseases such as acute Guillain–Barré syndrome, myasthenia gravis, acute or chronic inflammatory demyelinating polyneuropathy, or stiff person syndrome [131] (Table 3). IVIg is also proven valuable for refractory dermatomyositis or multifocal motor neuropathy. The efficacy of IVIg in relapsing–remitting multiple sclerosis (RRMS) is not as extensively documented as for other disease modifying drugs, but available data suggest its beneficial effects in this condition and IVg is used as second line drug for patients not responding or not supporting first-line treatment. [132]. Dose regimen of IVIg is according to the therapeutic goals, As a replacement therapy IVIg is used at 300-500 mg/kg body weight every 3-4 weeks. As an immunomodulatory/anti-inflammatory therapy it is used at 1-2 g/kg, administered at once or divided into 5 daily doses; additional maintenance dose at 4-6 week interval [133, 134]. IgG plasma concentration of 12-14 mg/ml and 20-35 mg/ml is reached after replacement and high dose therapy, respectively [135].

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Immunoregulatory mechanisms of IVIg in autoimmune and inflammatory diseases

Several mutually non-exclusive immunoregulatory effects of IVIg have been described that apparently contribute in synergy to an effective therapy in various clinical settings [137]. IVIg contains a wide range of anti-idiotypic antibodies that regulate autoreactive B-cell clones and neutralize pathogenic autoantibodies [134, 138, 139]. IVIg saturates the IgG transport receptor [6, 140], which leads to accelerated catabolism of pathogenic auto-antibodies and modulates the affinity of FcγR on phagocytic cells. Studies based on animal models of antibody mediated autoimmunity show that IVIg up-regulates inhibitory FcγRIIB on splenic macrophages [141]. FcγRIIB mediated beneficial effect of IVIg is known to be dependent on α2,6-linked of sialic acid to galactose on the glycan at Asn297 in the CH2 region of Fc fragment small fraction of IgG (sIgG). IVIg contains a small fraction (1-2%) of sIgG in it. sIgG fraction of IVIg or α2,6 sialylated recombinant human IgG1 Fc protein could reproduce the benefits of IVIg when used at much lower dose [142]. sIgG has been demonstrated to interact with the C-type lectin receptor (SIGN-R1) on myeloid cells that up-regulates the expression of FcγRIIB on ‘effector MΦ’ via TH2 pathway [143]. IVIg attenuates complement-mediated damage by scavenging to the activated C3b fraction of C3 [144, 145]. The interaction of IVIg with complement proteins, therefore, prevents the generation of the C5b–9-membrane attack complex and subsequent complement-mediated tissue damage in muscle microvasculature and brain [145-147]. IVIg modulates cytokine and chemokine production by various cell types: decreased levels of the pro-inflammatory cytokine IL-1 and increased levels of IL-1R antagonist have been reported in patients following IVIg infusion; TGF-α1 was down-regulated in the muscles of dermatomyositis patients who responded to IVIg therapy; Other studies have shown reduced synthesis of IL-2, IL-3, IL-12, IL-22, and GM-CSF following IVIg therapy [147-150]. IVIg contains antibodies that interact with cytokines and membrane molecules such as the T-cell receptor, cytokine or chemokine receptors, CD4, CD40 and CD95, which have important roles in the balance between auto-reactivity and tolerance [151, 152]. Further, IVIg is shown to exert an impact on the cellular compartment of the immune system; IVIg directly interacts cells of adoptive immunity like B cells, T cells and that of innate immunity and modulate their functions [153]. The maturation state of key APCs like DC is known to regulate immune response and tolerance. Immature and semi-mature DC presenting antigens are known to maintain tolerance by inducing Tregs while mature DC induces strong immune response [154]. IVIg inhibits maturation and function of DC, also modulates the pattern of cytokines secreted by these cells. By down-regulating the interferon-γ-mediated differentiation of DCs, and by inhibiting the uptake of nucleosomes, IVIg might exert an immunoregulatory effect in patients with lupus [155, 156]. In addition, IVIg-treated DC ameliorates ongoing autoimmune disease in vivo upon adoptive transfer [157]. IVIg also modulates in vivo and in vitro T-cell responses by impairing antigen presentation [158].

Table of contents :

Acknowledgements
Abbreviations
Résumé
1. Introduction
1.1. Immune system
1.2. Immune homeostasis and activation
1.3. T cell polarization and Th cells subsets.
1.3.1. Th1 cells
1.3.2. Th2 cells
1.3.3. Th17 cells
1.3.4. Regulatory T cells
1.4. mTOR integrates multiple signals during T cell activation
2. T cells in autoimmunity : shifting paradigms from Th1/Th2 to Th17/Tregs
2.1. Th1/Th2 hypothesis and the emergence of Th17 cells
2.2. Dysregulated equilibrium between pathogenic and regulatory T cells leads to immune disease
3. Intravenous Immunoglobulin
3.1. Composition, pharmacology and indications of IVIg
3.2. Immunoregulatory mechanisms of IVIg in autoimmune and inflammatory diseases.
3.3. Modulation of the Tregs by IVIg
4 Multiple sclerosis/ EAE is an organ specific T cell mediated auto-immune disease
5 Hypothesis and aims
6 Results
7 Discussion and Perspectives
8 References
Annexes

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