The Development Of T Cell Self Tolerance Biology Essay

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During the early stages of development B and T lymphocytes may exhibit specificity for self-antigen. Such cells are potentially dangerous and need to be eliminated before they develop into fully immune-competent cells, a process termed self-tolerance.

The development of T cell self-tolerance occurs in the thymus; the majority of thymocytes with T cell receptors specific for self are removed as a consequence of self-antigen presenting thymic epithelial cells (ref 1 in 25). The processes governing self-tolerance in the thymus are termed positive selection, whereby thymocytes that cannot recognise class I and class II self-MHC are destroyed, and negative selection in which thymocytes that bind MHC/self-antigenic peptide with high affinity are stimulated to die by apoptosis. However the process of negative selection is not without its flaws/faults, consequently self-reactive CD4+ T cells are identifiable/dectable in the periphery of healthy individuals. Giving that not all self-antigens are expressed in the thymus, and negative selection is not 100% efficient, additional tolerance mechanisms, including T cell anergy and ignorance, operate in the periphery to control and avoid the activation of peripheral self-reactive T cells. Such mechanisms are crucial for avoiding autoimmunity; however errors do occur resulting in the activation of autoreactive cells, hence the development of autoimmune disease.

B cell tolerance!!

Lymphocytes and T1D

Research conducted on NOD mice and humans?? has pointed at/to T lymphocytes being implicated in the development and progression of type 1 diabetes. There is evidence to suggest that a combination of CD4+ and CD8+ cells are required for the manifestation of T1D. Cells extracted from the spleen of NOD mice and introduced into immunosuppressed recipients were only capable of transferring diabetes in the presence of both CD4+ and CD8+ cells; neither splenic T cell subclass was able to mediate T1D in the absence of the other population (ref 12 in 31 which is just paper 27).

Pathogenic CD4+ T cells involved in T1D exhibit a T helper (TH1)-cell phenotype. TH1 cells are the principle mediators of cell-mediated immunity, whereas TH2 cells are involved in humoral responses e.g. allergic reactions. It has been suggested that TH1 cells are involved in the aggressive stage of the disease, whereas TH2 cells infiltrate the pancreas slowly and do not induce T1D (ref hill 2003 in 28). TH1 cells produce interleukin-2 (IL-2) and interferon-γ (IFNγ) which stimulate cytotoxic CD8+ T cells, which release other mediator substances that are toxic to the insulin producing β-cells, (ref 98 in 3 or ref 76 in favourites) (maybe slot in at the end, more relevant position). Administration of the cytokine interleukin-12 (IL-12), which drives the differentiation of naïve CD4+ T cells into TH1 cells, has been shown to accelerate the progression of T1D (ref 6 in 6). Administration of IL-12 to NOD mice induces the premature onset of T1D; furthermore CD4+ T cells present in the pancreatic infiltrate primarily express a TH1 phenotype. A potential role of IL-12 in T1D induction has been demonstrated via the use of IL-12 antagonists (8 and 9 in 6). Administration of antagonists, before the onset of insulitis, causes a shift in the pancreatic-infiltrating CD4+ T cells of NOD mice to the TH2 type and reduces the incidence of the disease. Conversely the incidence and developmental time course of T1D is similar in NOD mice that have undergone genetic abolition of IL-12 and controls (ref 10 in 6). However it is possible that NOD mice deficient in IL-12 have other cytokines to compensate for its absence.

Slot something at the beginning of this paragraph so it flows from the previous; sounds too abrupt! The destruction of β-cells by T cells might occur in numerous ways. A proposed mechanisms for CD8+ cell-induced β-cell death involves the direct lysing of β-cells presenting islet peptides by MHC class I-molecules on their surface. This process is mediated via the perforin/granzyme pathway and the direct interaction of Fas/FasL (ref 9 and 10 in 22). Release of perforin and granzyme from cytotoxic granules present in CD8+ T cells results in β-cell death by utilising the same basic cellular machinery that gives rise to apoptosis. Activation of the death receptor Fas (CD96) by Fas ligand (FasL)-expressing activated T cells initiates an intracellular signalling cascade in which caspase 3 cleaves I-CAD, releasing an active DNase which eventually leads to DNA degradation, membrane blebbing and thus ultimately β-cell apoptosis. Both CD4+ and CD8+ cells produce cytokines, including interferon-γ (IFNγ), which are implicated in the effector mechanisms giving rise to β-cell death; IFNγ induces the expression of Fas need a ref for this and increases the efficiency of antigen presentation by up regulating the expression of class I and II MHC molecules as well as unmasking β-cell antigens for immune recognition (ref 6 in 18). INFγ also has an additional role; inducing macrophages to become cytotoxic, releasing pro-inflammatory cytokines including interleukin-1β (IL-1β) and tumour necrosis factor (TNF) (need ref!). This interaction of/between T cell cytokines with/and macrophages undoubtedly intensifies the autoimmune stress on β-cells, promoting their destruction. (new para?) Similar to IL-12, inhibition of endogenous IFNγ results in protection from T1D, yet the genetic absence of IFNγ does not prevent diabetes from developing in NOD mice, but it does increase the tome to onset (ref 11 in 6). From these observations it is likely that a deficiency in IFNγ, or IL-12, permits the development of compensatory mechanisms which are unavailable in unmanipulated NOD mice.

role of Il-2 and TNF alpha, if it has a role, also T cell signalling B cells!!

T cells clearly have a fundamental/significant role in the destruction of β-cells and pathogenesis of T1D, but there is also data indicating an involvement of the other lymphocyte cell type: B cells. Autoantibodies to the β-cell antigens glutamic-acid decarboxylase 65 (GAD65), the β-cell hormone pro-insulin/insulin and pancreatic islet tyrosine phosphatase islet-cell antigen 2 (IA2) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) RECOGNISED BY t CELLS!! have been detected in the serum of patients suffering from T1D. However little evidence exists to suggest autoantibodies contribute to the pathogenesis of T1D; they may simply be secondary responses to an existing underlying destructive process (ref 29). B cell depletion in NOD mice has been shown to impair the development of T1D (ref 19 and 20 in 31); conversely a description exists of a patient with X-linked agammaglobulinaemia, a human immunodeficiency resulting in failure of B cell precursor maturation and poor antibody production, who developed T1D (ref 22 in 31). Thus B cells may be implicated in antigen presentation; maintaining islet autoantigen-specific T cell activity (ref 19 and 23 in 31).

Autoantibodies produced by B cells are considered to be markers of T1D and are found to be present in the serum of the majority of patients with T1D at the time of diagnosis. The presence of these autoantibodies in serum can be used to identify subjects at increased risk of developing the disease; the individual presence of autoantibodies can also represent the progression of T1D. The number of autoantigens recognised by autoantibodies, and in all probability also by autoreactive T cells, increases over time in humans during the development of the disease (ref 16 in 18). In NOD mice, intramolecular and intermolecular spreading of reactivity to islet self-antigens, resulting in the spread of the autoimmune response to multiple self-epitopes, has been identified in T cells (ref 5 in 18). Recent studies have pointed towards a sequential hierarchy in the reactivity to islet cell autoantigens. Eliminating the immune responses to insulin has been shown to prevent the development of T1D, whereas the disease still manifests itself at a normal rate in NOD mice which lack IGRP (ref 19 and 20 in 18). The absence of T1D in NOD mice deficient in insulin, in addition to the early appearance of insulin autoantibodies in subjects with the disease and the high prevalence of insulin-specific T cells located within the pancreatic and draining lymph nodes of T1D suffers, has suggested a primary role for insulin in initiating the autoimmune process (ref 16, 17 and 18 in 18). The risk of developing autoimmune diabetes increases proportionately with the amount of autoantibodies present signifying/implying a strong link between antigenic spreading and disease pathogenesis (ref 20 and 21 in 18). Thus it is conceivable that the process of antigenic spreading is applicable to autoreactive T-cell responses, which are capable of β cell destruction. The death of β cells results in the release of new antigens which can then be presented by APCs leading to activation of T cells specific for these new antigens and thus further spreading of the immune response.

Carry on to include stuff below, eliminating insulin and IGRP… then maybe talk about role of insulin auto antigen, which is in the paragraph above in paper 18, and also the role of the aire in insulin stuff in the thymus if have room once finished the lit review include other autoantigens GFAP, in paper 18 and the murder mystery..

Following stimulation by the antigen/MHC II complex and co-stimulation naïve CD4+ T cells express receptors for IL-2 and secrete IL-2 which causes proliferation of the activated CD4+ T cell. Antigen/MHC class I stimulation results in CD8+ T cells expressing IL-2 receptors which proliferate and differentiate into Tcs when stimulated by IL-2 which is produced by CD4+ T cells. Although not essential for the differentiation of CD8+ T cells cytokines such as IL-4, IL-10 and IFN-γ can promote the process and thus result in the generation of more Tcs. FROM LIT REVIEW!!!

Innate immune cells and T1D

Need some sort of introduction

The role of macrophages

Although many studies have implicated T cells in having a dominant role in the pathogenesis of autoimmune diabetes, several studies highlight/call attention to the contribution of macrophages in the disease (ref 24,25,26,27 and 28 in 31). The presence of macrophages in the infiltrated islet of NOD mice has previously been documented; blockage of the macrophage adhesion-promoting receptor CR3 has also been shown to prevent islet infiltration by both macrophages and T cells, and subsequently inhibit the development of T1D (ref 24 in 31). A role of macrophages as vital/crucial accessory cells involved in the differentiation of autoreactive effector T cells has been demonstrated in NOD mice that have had their macrophage population depleted and subsequently/consequently been rendered incapable of producing cytotoxic T cells (ref paper 22).

Macrophages have also been associated with a deleterious effect on β-cells via the production of IL-1β and TNF (ref 29 and 30 in 31). Prolonged exposure to IL-1β + TNFα and/or the T-cell cytokine IFNγ results in the loss of β-cell functioning, eventually evolving into cell death. IL-1β activates the transcription factor nuclear factor (NF)-κB in rodent and human pancreatic islet cells(ref 4 in 4). NF-κB has been implicated in the control of multiple gene regulatory networks that have the potential to directly contribute to β-cell apoptosis. Exposure of β-cells to IL-1β alone has proven insufficient in triggering β-cell death; yet when in combination with IFNγ Ì´50% of the insulin-producing islet cells undergo apoptosis after 6-9 days. This suggests that the IFNγ signal transduction pathway synergises with IL-1β signalling bringing about/initiating/eliciting β-cell death. Furthermore, pancreatic β-cells express high levels of IL-1 receptor and appear to be more sensitive to IL-1β-induced apoptosis when compared to other islet endocrine cells. IL-1β and TNF, in addition to the T cell cytokine IFNγ, are also capable of inducing the expression of reactive oxygen species (ROS), such as nitric oxide, by β-cells; ROS are capable of facilitating β-cell apoptosis.

In addition to soluble mediators resulting in β-cell death, direct cell-cell contact has been proposed as a further pathway leading to the macrophage-mediated destruction of β-cells (ref paper 22). Full stop of semi colon? Electron micrographs of islet infiltrates have revealed the presence of macrophages adjoining dying β-cells. This reveals an additional role for pancreatic recruited macrophages in the destructive stage of autoimmune diabetes.

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