Mechanisms That Regulate Peripheral Immune Responses to Control Organ-Specific Autoimmunity

School of Health Sciences, University of Notre Dame Australia, 19 Mouat Street, Fremantle, WA 6959, Australia.
Clinical and Developmental Immunology (Impact Factor: 2.93). 04/2011; 2011(1740-2522):294968. DOI: 10.1155/2011/294968
Source: PubMed


The immune system must balance the need to maintain a diverse repertoire of lymphocytes to be able to fight infection with the need to maintain tolerance to self-proteins. The immune system places strict regulation over the ability of T cells to produce the major T cell growth factor interleukin 2 as this cytokine can influence a variety of immune outcomes. T cells require the delivery of two signals, one through the antigen receptor and a second through the costimulatory receptor CD28. The immune system uses a variety of E3 ubiquitin ligases to target signaling proteins that function downstream of the TCR and CD28 receptors. Mutations in these E3 ligases can lead to a breakdown in immune tolerance and development of autoimmunity. This paper will examine the role of a range of E3 ubiquitin ligases and signaling pathways that influence the development of T-cell effector responses and the development of organ-specific autoimmune diseases such as type 1 diabetes.

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Available from: Gerard F Hoyne
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    • "In the complex signaling network downstream of the TCR, there are several possibilities. Interventions are for example possible at the level of E3 ligases (Hoyne, 2011) (Figure 2). As therapeutic targets, the SHP protein tyrosine phosphatases have been proposed (Irandoust et al., 2009). "
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    ABSTRACT: Cytotoxic CD8 T cells mediate immunity to pathogens and they are able to eliminate malignant cells. Immunity to viruses and bacteria primarily involves CD8 T cells bearing high affinity T cell receptors (TCRs), which are specific to pathogen-derived (non-self) antigens. Given the thorough elimination of high affinity self/tumor-antigen reactive T cells by central and peripheral tolerance mechanisms, anti-cancer immunity mostly depends on TCRs with intermediate-to-low affinity for self-antigens. Because of this, a promising novel therapeutic approach to increase the efficacy of tumor-reactive T cells is to engineer their TCRs, with the aim to enhance their binding kinetics to pMHC complexes, or to directly manipulate the TCR-signaling cascades. Such manipulations require a detailed knowledge on how pMHC-TCR and co-receptors binding kinetics impact the T cell response. In this review, we present the current knowledge in this field. We discuss future challenges in identifying and targeting the molecular mechanisms to enhance the function of natural or TCR-affinity optimized T cells, and we provide perspectives for the development of protective anti-tumor T cell responses.
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    • "Cukrzyca typu 1 jest chorobą o podłożu autoimmunizacyjnym , w której inicjacji jak i modulowaniu odpowiedzi immunologicznej skierowanej przeciwko antygenom komórek β wysp trzustkowych ważną rolę odgrywa wiele różnych populacji komórek immunokompetentnych. W ujęciu klasycznym cukrzyca typu 1 należy do chorób autoimmunologicznych , w których odpowiedź ze strony układu immunologicznego ogranicza się do konkretnego narządu, a właściwie grupy komórek, gdzie w lokalnych węzłach chłonnych autoreaktywne limfocyty CD4 + ulegają aktywacji, stymulując odpowiedź Th1 i w efekcie apoptozę komórek beta wysp trzustki na drodze mechanizmów zależnych od limfocytów cytotoksycznych, komórek NK, makrofagów [1]. Wiadomo obecnie, że w patogenezie zaburzeń w cukrzycy bardzo ważną rolę odgrywają limfocyty T regulatorowe i ostatnio intensywnie badane Th17 [2] [3]. "

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    ABSTRACT: OTHER THEMES PUBLISHED IN THIS IMMUNOLOGY IN THE CLINIC REVIEW SERIES Allergy, Host Responses, Cancer, Autoinflammatory Diseases, Type 1 diabetes and viruses. Historically, the development of type 2 diabetes has been considered not to have an autoimmune component, in contrast to the autoimmune pathogenesis of type 1 diabetes. In this review we will discuss the accumulating data supporting the concept that islet autoreactivity and inflammation is present in type 2 diabetes pathogenesis, and the islet autoimmunity appears to be one of the factors associated with the progressive nature of the type 2 diabetes disease process.
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