DCs play a pivotal role in the balance between immunity and tolerance. DCs are important in the induction of both central and peripheral tol erance. In the former, DCs play a role in the deletion of autoreactive T cells in the thymus. In the latter, DCs in their steady state induce T cell deletion, energy, or generation of regulatory T cells, which interfere with the IL-2 production and proliferation of effector T cells against self. Peripheral tolerance is critical as they limit harmful immune responses to antigens that may not have been available during thymic selection, as well as limiting autoreactive T cells that may have escaped central tolerance. DCs induce peripheral tolerance via a variety of mechanisms, including the activation status of DCs such that resting DCs, in the absence of stimulatory signals necessary for their maturation, can induce robust T cell tolerance against immunodominant anti gens. These tolerogenic effects of DCs may be mediated through the engagement of inhibitory TCRs, such as PD-1 and CTLA-4, which act synergistically. Additionally, tolerogenic DCs can produce immunosuppressive factors such as indoleamine 2, 3-dioxygenase (IDO), as well as IL-10, TGF-β, IL-35, which induce Tregs and inhibit effector T cell functions. Dysregulation of mechanisms orchestrating tolerance induction by DCs leads to autoimmune diseases. Some of these auto immune diseases are detailed as follows.
Systemic lupus erythematosus (SLE) is a chronic autoimmune dis ease affecting multiple organ systems. SLE results from a dysregulated immune system, in which CD4+ T cell and B cell tolerance is impaired, leading to high levels of circulating autoreactive antibodies, in particular against nuclear material. Dysregulation of DCs, including alterations in subset frequency and localization, overactivation of cDCs and pDCs, and functional defects in DCs, is associated with the pathogenesis of SLE. DCs from SLE patients exhibit altered CD40, CD86, Fcγ receptor, and PD-L1 expression. Activated cDCs may promote lupus pathogenesis by presenting RNA-associated proteins and chromatin to self-reactive T cells. Abnormalities associated with pDC-derived type I IFN, due to for example persistent stimulation of TLR7 and TLR9 by endogenous nucleic acids, also contribute to the autoimmune responses in SLE. Furthermore, DCs may also enhance B cell function and antinuclear autoantibody production.
Another autoimmune disease that is associated with increased type I IFN activity is Aicardi–Goutières syndrome (AGS). AGS is an inflammatory encephalopathy that clinically mimics a congenital viral infection despite the absence of virus. AGS is caused by the mutations of several genes involved in nucleic acid metabolism. These mutations may lead to the accumulation of endogenous nucleic acid products, which are then sensed by pDCs, upregulating type I IFN production that is associated with AGS pathogenesis.
Rheumatoid arthritis (RA) is a common chronic autoimmune disease that causes joint pain and its pathogenesis is strongly associated with autoreactive CD4+ T cell functions. Accumulating evidence supports DCs’ involvement in RA pathogenesis. Both myeloid and pDCs are found at elevated numbers in the synovial fluid surrounding the joints of RA patients, where they produce pro-inflammatory molecules and contribute to joint inflammation. Although the exact mechanisms through which DCs contribute RA initiation and progression are not fully appreciated, DCs are shown to present MHC class II-restricted self-antigens and induce autoreactive CD4+ T cells, which propagate RA.
DCs are involved in the pathogenesis of other autoimmune dis eases as well, including multiple sclerosis, type I diabetes, inflammatory bowel disease, and idiopathic inflammatory myopathies. Overall, DCs’ role in the development of autoimmune diseases is mediated either via direct activation of self-reactive T or B cells or indirectly by creating a pro-inflammatory environment that interrupts the maintenance of tolerance against self-antigens. When considering treatment approaches for these autoimmune diseases, there is a need to identify and define the balance between regulatory and pathogenic DC roles.
