Overview of Immune Tolerance Strategies
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
What is the evidence that peripheral tolerance mechanisms function to control immune responses in humans? The best evidence currently comes from identification of defective genes that are associated with immune mediated diseases. Table 1 lists three genetic defects that identify Fas/Fas Ligand,22 perforin,23 and CTLA-424,25 as strong candidates for genes involved in peripheral tolerance in humans. Fas, also known as APO-1 and CD95, is a member of the tumor necrosis factor family as is Fas ligand. Strains of mice that have mutations in this system are characterized by defects in apoptosis that lead to autoimmune diseases.26 Recently, a related human disease termed autoimmune lymphoproliferative syndrome (ALPS) was found to be characterized by massive nonmalignant lymphoadenopathy of early onset caused by the accumulation of T-cells in the periphery. Analyses show that the impaired pathway involves lymphocyte apoptosis, resulting in overpopulation of lymphocytes and consequent abnormalities.22
Pathophysiology and Clinical Management of Diabetes and Prediabetes
Jeffrey I. Mechanick, Elise M. Brett in Nutritional Strategies for the Diabetic & Prediabetic Patient, 2006
T1DM is caused by T-cell mediated destruction of pancreatic insulin-producing β-cells. Tian et al. [116] have found a novel way to restore central tolerance in NOD mice using hematopoietic stem cells retrovirally transduced to express a protective form of the MHC class II β-chain. As a result, autoreactive T-cells will be killed in the thymus and never get to the pancreatic β-cells [116]. Central tolerance refers to mechanisms of tolerance acting in the thymus or bone marrow, in contrast to peripheral tolerance which occurs in immune cells after they have left the primary lymphoid organs. Pre-clinical studies must be completed before stem cells can be successfully given to humans with T1DM. Some drugs may be synthesized so that they exert their effect only within the areas of inflammation. One example is an engineered TGF-1β that can become activated locally within areas of β-cell inflammation [117,118].
Basics of Allergy
Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial in Textbook of Allergy for the Clinician, 2021
The elimination of auto-reactive T and B cells in the thymus and bone marrow, respectively, through negative selection is called central tolerance (Walker and Abbas 2002). There is evidence that some self-reactive T and B cells manage to escape the negative selection; their receptors may recognize MHC/self-peptide with an affinity that is not high enough to elicit negative selection. Despite the presence of auto-reactive cells, autoimmunity does not develop due to peripheral tolerance. DCs expressing self-peptides are not activated and therefore have very low levels of co-stimulatory molecules. They also secrete IL-10, so the majority of lymphocytes become anergic instead of being activated. Presentation of self-antigens in the absence of co-stimulation may also lead to clonal deletion through apoptosis. Auto-reactive cells as well as inflammatory cells in the peripheral organs are suppressed by a population of CD4+CD25+FoxP3+ cells, called regulatory T cells (Tregs) (Shevach et al. 2001). These cells secrete IL-10 and TGFb and block proliferation of lymphocytes.
Impact of interleukin-32α on T helper cell-related cytokines, transcription factors, and proliferation in patients with type 2 diabetes mellitus
Published in Immunopharmacology and Immunotoxicology, 2023
Shiva Borzouei, Mohammad Gholamian-Hamadan, Mahdi Behzad
Different subsets of CD4+ T cells play an essential role in the induction and regulation of immune functions [12]. In humans, naive CD4+ T cells turn into pro-inflammatory (Th1 and Th17) and regulatory T (Treg) cells via unique transcription factors and cytokines [12]. Th1 cells dominantly express signal transducer and activator of transcription (STAT) 1 and T -box (T-bet) transcription factors. Th1 mainly participates in inflammatory immune responses by the secretion of interferon gamma (IFN-γ) [13]. Th17 cells discriminate by the expression of STAT3 and retinoid-related orphan receptor (ROR) -γt transcription factors. Th17 triggers the immune system by producing IL-17 [13]. Treg cells express STAT5 and forkhead box P3 (Foxp3) transcription factors and produce anti-inflammatory IL-10. This subset of immune cells maintenances peripheral tolerance by the suppression of target cells [14].
CD8+ T lymphocytes are sensitive to NKG2A/HLA-E licensing interaction: role in the survival of cancer patients
Published in OncoImmunology, 2021
Lourdes Gimeno, Isabel González-Lozano, María F. Soto-Ramírez, María V. Martínez-Sánchez, Pedro López-Cubillana, José L. Fuster, Jerónimo Martínez-García, Jorge Martínez-Escribano, José A. Campillo, Eduardo Pons-Fuster, Belén Ferri, Alicia López-Abad, Manuel Muro, Alfredo Minguela
Although educated in the thymus at their immature stages, mature T cells are still sensitive to mechanisms of peripheral tolerance.63 It is therefore reasonable to think that they can also be sensitive to signals that educate and modulate the NK cell functioning. Unfortunately, the mechanisms by which the −21 M/T dimorphism of HLA-B influences CD226 expression and function of NK and CD8+ T cells are mostly unknown. Unlike NK cells, the main activating signal in T lymphocytes is MHC restricted and delivered by the TCR, but similar to NK cells, licensing signals could be modifying CD8+ T-cell metabolism,19 reorganizing cytotoxic granules in their cytoplasm,21 or shifting CD226/TIGIT ratio toward the activating receptor,18,20 which could indeed favor more efficient responses in the T cells of individuals with −21 M alleles.
Chicken toll-like receptors and their significance in immune response and disease resistance
Published in International Reviews of Immunology, 2019
Aamir Nawab, Lilong An, Jiang Wu, Guanghui Li, Wenchao Liu, Yi Zhao, Qimin Wu, Mei Xiao
Several authors describe the second mechanism by which peripheral tolerance is maintained through the activity of regulatory T cells (Tr cells). These cells can be divided into two major classes CD4 and CD25 markers [80]. These marker cells migrate into secondary lymphoid organs, and their growth in the thymus is controlled by transcription factor Foxp3 (forkhead box P3) [83]. Evidence suggests that this class of suppressor cells prevent activation of auto-reactive T cells that escape thymic deletion. Auto-immune disorders are generated due to the absence of these cells [80]. The second class of suppressor cells is categorized by secretion of anti-inflammatory cytokines. Two different cells secrete IL-10 (Tr1) or TGF-β (Th3) [80]. These suppressor cells prevent the destruction of host tissues triggered by chronic inflammatory processes. These cells normally reside in mucosal tissues of the body (lung and gut), and secrete effector cytokines to counter chronic inflammatory conditions at affecting areas [83].
Related Knowledge Centers
- Allergen
- B Cell
- Central Tolerance
- Immune Tolerance
- Immunology
- Lymphatic System
- Autoimmune Disease
- T Cell
- Reactive Lymphocyte
- Antigen