Does physiological β cell turnover initiate autoimmune diabetes in the regional lymph nodes?

Schneider Children's Medical Center of Israel, Petah Tikva, Central District, Israel
Autoimmunity Reviews (Impact Factor: 7.93). 06/2006; 5(5):338-43. DOI: 10.1016/j.autrev.2006.02.005
Source: PubMed


The initial immune process that triggers autoimmune beta cell destruction in type 1 diabetes is not fully understood. In early infancy there is an increased beta cell turnover. Recurrent exposure of tissue-specific antigens could lead to primary sensitization of immune cells in the draining lymph nodes of the pancreas. An initial immune injury to the beta cells can be inflicted by several cell types, primarily macrophages and T cells. Subsequently, infiltrating macrophages transfer antigens exposed by apoptotic beta cells to the draining lymph nodes, where antigen presenting cells process and amplify a secondary immune reaction. Antigen presenting cells evolve as dual players in the activation and suppression of the autoimmune reaction in the draining lymph nodes. We propose a scenario where destructive insulitis is caused by recurrent exposure of specific antigens due to the physiological turnover of beta cells. This sensitization initiates the evolution of reactive clones that remain silent in the regional lymph nodes, where they succeed to evade regulatory clonal deletion.

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Available from: Nadir Askenasy, Oct 06, 2015
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    • "The pancreas is frequently affected in systemic autoimmune disorders, some of which result in acute hyperglycemia [19] [20]. Diabetes is not the only disorder with such pathogenesis: autoimmune thyroiditis is a prevalent inflammatory reaction in a tissue located in the vicinity of a hyperactive lymphoid trunk responsible for neutralization of inhaled and digested antigens [17]. Thus, irrespective of the initial insult that induces the autoimmune process, evasion of pathogenic clones from immune surveillance or inadequate suppression of physiological anti-islet reactivity, genetic, environmental and local predisposing factors amplify the immune reaction. "
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    ABSTRACT: Two competing hypotheses are proposed to cause autoimmunity: evasion of a sporadic self-reactive clone from immune surveillance and ineffective suppression of autoreactive clones that arise physiologically. We question the relevance of these hypotheses to the study of type 1 diabetes, where autoreactivity may accompany the cycles of physiological adjustment of β-cell mass to body weight and nutrition. Experimental evidence presents variable and conflicting data concerning the activities of both effector and regulatory T cells, arguing in favor and against: quantitative dominance and deficit, aberrant reactivity and expansion, sensitivity to negative regulation and apoptosis. The presence of autoantibodies in umbilical cord blood of healthy subjects and low incidence of the disease following early induction suggest that suppression of self-reactivity is the major determinant factor.
    Autoimmunity reviews 12/2012; 12(5). DOI:10.1016/j.autrev.2012.12.004 · 7.93 Impact Factor
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    • "These functions reflect primarily transition to controlled yet arbitrary culture conditions that differ substantially from the physiological environment of these cells. Treg operate within the infiltrates at the site of inflammation [48], [49], under continuously changing cytokine and cellular environments and antigenic stimuli [12], [50]. We have previously postulated that transition to arbitrary in vitro culture conditions causes proliferative anergy [37], whereas Treg cycle at faster rates than naïve/effector T cells in vivo [28], [31], [46]. "
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    ABSTRACT: Regulatory T cells (Treg) play a significant role in immune homeostasis and self-tolerance. Excessive sensitivity of isolated Treg to apoptosis has been demonstrated in NOD mice and humans suffering of type 1 diabetes, suggesting a possible role in the immune dysfunction that underlies autoimmune insulitis. In this study the sensitivity to apoptosis was measured in T cells from new onset diabetic NOD females, comparing purified subsets to mixed cultures. Apoptotic cells are short lived in vivo and death occurs primarily during isolation, manipulation and culture. Excessive susceptibility of CD25(+) T cells to spontaneous apoptosis is characteristic of isolated subsets, however disappears when death is measured in mixed splenocyte cultures. In variance, CD25(-) T cells display balanced sensitivity to apoptosis under both conditions. The isolation procedure removes soluble factors, IL-2 playing a significant role in sustaining Treg viability. In addition, pro- and anti-apoptotic signals are transduced by cell-to-cell interactions: CD3 and CD28 protect CD25(+) T cells from apoptosis, and in parallel sensitize naïve effector cells to apoptosis. Treg viability is modulated both by other T cells and other subsets within mixed splenocyte cultures. Variations in sensitivity to apoptosis are often hindered by fast proliferation of viable cells, therefore cycling rates are mandatory to adequate interpretation of cell death assays. The sensitivity of purified Treg to apoptosis is dominated by cytokine deprivation and absence of cell-to-cell interactions, and deviate significantly from measurements in mixed populations. Balanced sensitivity of naïve/effector and regulatory T cells to apoptosis in NOD mice argues against the concept that differential susceptibility affects disease evolution and progression.
    PLoS ONE 12/2010; 5(12):e15684. DOI:10.1371/journal.pone.0015684 · 3.23 Impact Factor
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    • "Sustained immunosuppression after transplantation is accompanied by clinical remission (C). Autoimmunity might resurface either because of formation of new autoreactive clones (recurrence, D) or reactivation of residual autoimmune cells (relapse, E). secluded within the tissue and regional lymphatics [16]. The antiislet diabetogenic cells in NOD mice are relatively resistant to regulation through activation-induced cell death [17] and are less sensitive to T regulatory (Treg) cell-mediated suppression [18] [19]. "
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    ABSTRACT: Bone marrow transplantation has been adoptively transferred from oncology to the treatment of autoimmune disorders. Along with extension of prevalent transplant-related concepts, the assumed mechanism that arrests autoimmunity involves elimination of pathogenic cells and resetting of immune homeostasis. Similar to graft versus tumor (GVT) reactivity, allogeneic transplants are considered to provide a better platform of immunomodulation to induce a graft versus autoimmunity reaction (GVA). It is yet unclear whether recurrence of autoimmunity in both autologous and allogeneic settings reflects relapse of the disease, transplant-associated immune dysfunction or insufficient immune modulation. Possible causes of disease recurrence include reactivation of residual host pathogenic cells and persistence of memory cells, genetic predisposition to autoimmunity and pro-inflammatory characteristics of the target tissues. Most important, there is little evidence that autoimmune disorders are indeed abrogated by current transplant procedures, despite reinstitution of both peripheral and thymic immune homeostasis. It is postulated that non-specific immunosuppressive therapy that precedes and accompanies current bone marrow transplant strategies is detrimental to the active immune process that restores self-tolerance. This proposition refocuses the need to develop strategies of immunomodulation without immunosuppression.
    Journal of Autoimmunity 10/2009; 33(3-4):255-9. DOI:10.1016/j.jaut.2009.09.002 · 8.41 Impact Factor
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