Inborn Errors of the Immune System Associated With Atopy

Abstract

Atopic disorders, including atopic dermatitis, food and environmental allergies, and asthma, are increasingly prevalent diseases. Atopic disorders are often associated with eosinophilia, driven by T helper type 2 (Th2) immune responses, and triggered by disrupted barrier function leading to abnormal immune priming in a susceptible host. Immune deficiencies, in contrast, occur with a significantly lower incidence, but are associated with greater morbidity and mortality. A subset of atopic disorders with eosinophilia and elevated IgE are associated with monogenic inborn errors of immunity (IEI). In this review, we discuss current knowledge of IEI that are associated with atopy and the lessons these immunologic disorders provide regarding the fundamental mechanisms that regulate type 2 immunity in humans. We also discuss further mechanistic insights provided by animal models.

Keywords: T cell; TCR; atopy; barrier function; cytokine; cytoskeletal; inborn errors of immunity (IEI).

Figure 1

Disrupted barrier function and the atopic march. (A) Disrupted skin barrier through primary disorders of the skin or external factors enable allergen entry; uptake by dendritic cells in the presence of alarmin signals such as TSLP and IL-33 promotes dendritic cell maturation and migration to the draining LN. Genes noted in red indicate monogenic IEI affecting this pathway. (B) Dendritic cells present allergen-derived peptide:MHCII to naive CD4⁺ T cells to induce Th2 effector cells and Tfh cells that drive IgE responses to allergen. (C) A portion of Th2 cells traffic back to skin and permanently reside as tissue-resident memory cells to drive local inflammation through release of type 2 cytokines such as IL-4, -5, and -13 upon re-encountering allergen. (D) Systemic IL-33 from keratinocytes and IL-25 from intestinal tuft cells synergize to activate ILC2s, which in turn produce IL-4 and activate mast cell degranulation (anaphylaxis) in response to oral allergen exposure.

Figure 2

IEI influencing CD4⁺ T-cell activation and differentiation. (A) Genes noted in red involved in the actin cytoskeleton and formation of the immunological synapse. (B) T-cell receptor (TCR) signaling genes influence the generation of Th2 cells and type 2 inflammation. (C) IEI associated with the IL-6-STAT3 cytokine signaling pathway.

Figure 3

IEI influencing the T-cell repertoire can manifest as severe atopy. (A) Left, resting polyclonal T cells in a normal (WT) immune repertoire. Right, oligoclonal expansion of T cells in leaky SCID, often leading to Th2 skewing and eosinophilia (Omenn syndrome). (B) Left, normal balance between regulatory T cell (Treg) and effector T cell (Teff) functions. Right, mutations affecting Treg number or function leading to autoimmune and atopic phenotypes.