TH2-driven manifestations of inborn errors of immunity

Abstract

Monogenic lesions in pathways critical for effector functions responsible for immune surveillance, protection against autoinflammation, and appropriate responses to allergens and microorganisms underlie the pathophysiology of inborn errors of immunity (IEI). Variants in cytokine production, cytokine signaling, epithelial barrier function, antigen presentation, receptor signaling, and cellular processes and metabolism can drive autoimmunity, immunodeficiency, and/or allergic inflammation. Identification of these variants has improved our understanding of the role that many of these proteins play in skewing toward T_H2-related allergic inflammation. Early-onset or atypical atopic disease, often in conjunction with immunodeficiency and/or autoimmunity, should raise suspicion for an IEI. This becomes a diagnostic dilemma if the initial clinical presentation is solely allergic inflammation, especially when the prevalence of allergic diseases is becoming more common. Genetic sequencing is necessary for IEI diagnosis and is helpful for early recognition and implementation of targeted treatment, if available. Although genetic evaluation is not feasible for all patients with atopy, identifying atopic patients with molecular immune abnormalities may be helpful for diagnostic, therapeutic, and prognostic purposes. In this review, we focus on IEI associated with T_H2-driven allergic manifestations and classify them on the basis of the affected molecular pathways and predominant clinical manifestations.

Keywords: Inborn errors of immunity; allergic inflammation; asthma; atopic dermatitis; atopy; dysregulation; eosinophilia; immunomodulation; mast cell dysregulation; primary atopic disorders; primary immunodeficiency.

FIG 1.

Outline of pathways implicated in genetic disorders of the immune system associated with atopic disease. Red backgrounds indicate genes/gene products with causal variants associated with increased function, and yellow backgrounds indicate decreased function. Mix of 2 suggests that both GOF and LOF can cause atopy. CBM, CARD11-BCL10-MALT1; IFNGR1/2, IFN-γ receptor 1/2; TCR, T-cell receptor.