Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunity

Abstract

In addition to susceptibility to infections, conventional primary immunodeficiency disorders (PIDs) and inborn errors of immunity (IEI) can cause immune dysregulation, manifesting as lymphoproliferative and/or autoimmune disease. Autoimmunity can be the prominent phenotype of PIDs and commonly includes cytopenias and rheumatological diseases, such as arthritis, systemic lupus erythematosus (SLE), and Sjogren's syndrome (SjS). Recent advances in understanding the genetic basis of systemic autoimmune diseases and PIDs suggest an at least partially shared genetic background and therefore common pathogenic mechanisms. Here, we explore the interconnected pathogenic pathways of autoimmunity and primary immunodeficiency, highlighting the mechanisms breaking the different layers of immune tolerance to self-antigens in selected IEI.

Keywords: Autoimmunity; Inborn errors of immunity; Primary immunodeficiencies; Rheumatic diseases.

Fig. 1

Inborn errors of immunity (IEI) impairing the induction of central T-cell tolerance. AIRE medullary thymic epithelial cells (mTECs) express an array of tissue-specific antigens. Autoreactive T-cell precursors recognizing self-antigens with relatively high avidity undergo clonal deletion (negative selection) or differentiate into natural regulator cells (Tregs). However, some autoreactive T cells skip central tolerance and escape the thymus. Monogenic immunodeficiency disorders affect antigen presentation by mTECs, clonal deletion or T-cell differentiation into natural Tregs; monogenic disorders and the level at which they impair or likely impair central T-cell tolerance are highlighted in red [APECED autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy, IPEX immunodysregulation, polyendocrinopathy, enteropathy and X-linked]

Fig. 2

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]

Fig. 3

The interconnected pathogenic pathways of autoimmunity and primary immunodeficiency. Autoimmune disorders may result in immunodeficiency through the production of autoantibodies or through disease-intrinsic mechanisms, whereas the immune defects underlying immunodeficiency can affect the induction or the maintenance of immune tolerance and cause autoimmunity