Fig. 2
From: Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunity
Inborn errors of immunity (IEI) impairing the induction of peripheral tolerance. In the absence of adequate costimulation, the recognition of self-antigens displayed by immature dendritic cells has a tolerogenic outcome, resulting in anergy or clonal deletion. Tissue damage, however, can break the ‘immune privilege’ at the tissue or subcellular level, facilitating the presentation of self-antigens. If this happens in a milieu supporting dendritic cell activation, such as in the presence of uncontrolled proinflammatory cytokine signaling or in the context of persistent infection or Treg dysfunction, an autoimmune T-cell response can be primed and result in the activation of autoreactive B cells. The source of B-cell autoreactivity is either aberrant central B-cell tolerance or de novo generation in the context of a germinal center reaction (not shown). Monogenic immunodeficiency disorders affect peripheral tolerance by enhancing the capacity of antigen-presenting cells to prime T cells, by compromising Treg function or reducing their counts, by enhancing antigen receptor-mediated activation of lymphocytes and/or by impairing tolerogenic aspects of antigen receptor signaling; monogenic disorders and the level at which they impair peripheral tolerance are highlighted in red [GOF gain-of-function, APDS activated PI3Kδ syndrome, DADA2 deficiency of ADA2]
