Human inborn errors of immunity: An expanding universe

Abstract

Molecular, cellular, and clinical studies of human inborn errors of immunity have revolutionized our understanding of their pathogenesis, considerably broadened their spectrum of immunological and clinical phenotypes, and enabled successful targeted therapeutic interventions. These studies have also been of great scientific merit, challenging a number of immunological notions initially established in inbred mice while revealing previously unrecognized mechanisms of host defense by leukocytes and other cells and of both innate and adaptive tolerance to self.

Figure 1.

Evolution of clinical, pathophysiological diagnostic and therapeutic approach to inborn errors of immunity.

Figure 2.. History and current classification of monogenic inborn errors of immunity.

(A) Number of genes associated with inborn errors of immunity known at the time of various editions of the classification of these disorders; (B) Number of genes responsible for each category of inborn errors of immunity, as reported in the 2020 classification (10).

Figure 3.. Genetic etiologies of Mendelian susceptibility to mycobacterial disease (MSMD).

Interactions between cells involved in the production of (T cells/NK cells) and in the response to IFN-γ (dendritic cells, phagocytes). Proteins whose mutations in the corresponding gene cause isolated MSMD are depicted in green, while those responsible for syndromic MSMD are depicted in red.

Figure 4.. Progress in the treatment of inborn errors of immunity.

Three separate timelines display milestone events in the evolution of cell therapy, gene therapy and pharmacological treatment to address inborn errors of immunity.