A defect of thymus-dependent self-tolerance to insulin-secreting ß cells in the pathogenesis of type 1 diabetes

in Pontell, E. B. (Ed.) Immune Tolerance Research Developments (2008)

Presentation of neuroendocrine self in the thymus: toward a novel type of vaccine/immunotherapy

in Drug Design Reviews - Online (2004), 1

Slightly after the emergence some 400 millions years ago of the first signs of adaptive immune response, tolerogenic pathways developed in order to preserve the integrity of self from potential autoimmune ... [more ▼]

Slightly after the emergence some 400 millions years ago of the first signs of adaptive immune response, tolerogenic pathways developed in order to preserve the integrity of self from potential autoimmune toxicity. Amongst those tolerogenic pathways, the thymus occupies a central place both by deleting self-reactive T cells that are produced in the thymus during random recombination of gene segments encoding the variable parts of the T-cell receptor for antigen (TCR) (negative selection), and by generating self-antigen specific regulatory T cells (Tr). A repertoire of neuroendocrine-related genes are transcribed by thymic stromal cells — epithelial and ‘nurse’ cells (TEC/TNC), dendritic cells (DC) and macrophages (MF) — in such a way that a dominant protein precursor is expressed in the thymus environment. Oxytocin (OT) and neurokinin A (NKA) are the dominant thymic precursors for the neurohypophysial hormone and tachykinin families, respectively. With regard to the insulin gene family, all members are transcribed following a precise cell topography and hierarchy in the profile of gene expression: IGF2 (TEC/TNC) > IGF1 (MF) >> INS (medullary TEC and/or DC). This hierarchy implies that IGF-2 is more tolerated than IGF-1, and much more than Insulin (Ins). The low level of INS transcription in the thymus also explains why Ins displays immunogenic properties, as well as the significant prevalence (±40%) of anti-Ins autoantibodies in the general population. Ins administration failed in providing tolerance or protection toward islet ß cells in type 1 diabetes (T1D). In contrast, the presentation of IGF-2 B11-25, the homologous sequence of Ins B9-23, to peripheral blood mononuclear cells (PBMC) isolated from DQ8+ T1D adolescents significantly increases IL-10 secretion and IL10 expression. Given the potent regulatory/suppressive properties of IL-10 on the autoimmune response toward islet ß cells, these data support that IGF-2 derived sequences constitute a strong basis for the development of an antigen-specific driven tolerogenic approach for T1D prevention and/or cure. [less ▲]

Thymus and T cells

in Smith, Barry H.; Adelman, George (Eds.) Encyclopedia of Neuroscience, 3rd Edition (2004)

Evidence for intimate interconnections between the three major systems of cell communication, the nervous, endocrine and immune systems, has opened important novel research perspectives. Neuroimmune ... [more ▼]

Evidence for intimate interconnections between the three major systems of cell communication, the nervous, endocrine and immune systems, has opened important novel research perspectives. Neuroimmune-endocrine interactions are now established as crucial factors for the control of body development and homeostasis. In distant species and invertebrates, the foundations of both the neuroendocrine system and innate immunity were coexisting until now without any apparent problem. Some 400 millions years ago, in a relatively short period after agnathan fishes (e.g., hagfish and lamprey), adaptive immunity emerged in the first gnathostomes, cartilaginous fishes (e.g., shark and ray). Somatic recombination machinery characterizes adaptive immunity and is responsible for the random generation of the huge diversity of immune receptors able to recognize infectious antigens. The emergence of this novel form of immune defenses exerted a so potent pressure that structures and mechanisms developed along the paths of lymphocyte traffic to impose immunological self-tolerance, that is, the inability of the immune system to attack the host organism. Together with the generation of diversity and memory, self-tolerance constitutes a fundamental property of the immune system. The progressive rise in the level of immune diversity and complexity also explains why self-tolerance failures (i.e., organ-specific autoimmune diseases) were increasingly detected during evolution, the maximum being currently observed in the human species. The first thymus appeared in cartilaginous fishes (chondrichthyes), concomitantly with the emergence of rudimental forms of adaptive immunity. Though some forms of tolerance induction already takes place in primary hemopoietic sites (fetal liver and bone marrow), antigen-dependent B-cell tolerance is primarily due to an absence of T-cell help. Among all lymphoid structures, the thymus is the only organ specialized in the establishment of central self-tolerance. The thymus crucially stands at the crossroad between the immune and neuroendocrine systems. In this organ responsible for thymopoiesis—T-cell generation—(Kong et al., 1998), the neuroendocrine system regulates the process of T-cell differentiation from the very early stages. In addition, T lymphocytes undergo inside the thymus a complex educative process that establishes central T-cell self-tolerance of neuroendocrine principles (Geenen et al., 1992; Martens et al., 1996). Within the thymus, a confrontation permanently occurs between previously established neuroendocrine principles and a recent system equipped with recombination machinery promoting stochastic generation of response diversity. Contrary to a previous assumption, the thymus functions throughout life (Poulin et al., 1999; Geenen et al., 2003) and plays a fundamental role in the recovery of a competent T-cell repertoire after intensive chemotherapy or during highly active antiretroviral therapy (Mackall et al., 1995; Douek et al., 1998). [less ▲]

Thymic T-cell tolerance of neuroendocrine functions: physiology and pathophysiology

in Halbhuber, Karl-Jürgen; Kinoshita, Yoshihiro (Eds.) Recent Advances in the Immunobiology of the Thymus (2001)

Thymic neurohypophysial peptide-mediated signaling and T-cell differentiation

in FASEB Journal (2001), 15