Management of Inborn Errors of Immunity in the Genomic Era

Abstract

Inborn errors of immunity are a group of rare diseases characterized by a wide variety of manifestations, including unusually severe infections, cancer susceptibility, and exaggerated inflammation that disrupts organ function. As of 2022, over 450 gene deficiencies have been classified under ten categories, where numbers are constantly increasing. The range of inborn errors of immunity varies considerably, from mild infections to serious multisystemic disease. Whereas patients with T cell defects are liable to a broad range of pathogens, selected inborn errors of immunity may predispose hosts merely to a narrow range of microorganisms. Dysregulated immune responses often cause autoimmune manifestations that may target any organ or lead to severe allergies. Therefore, presentation to any medical discipline is possible. Historically, inborn errors of immunity have been associated with short life expectancy and poor life quality, but intensive research into the field has revolutionized this assumption. Especially with the aid of translational investigations, our clinical practice has transformed from a predominantly phenotype-driven management into one that is reinforced by an etiology-driven therapy. This review summarizes the recent advances in molecularly targeted treatment approaches in various inborn errors of immunity conditions, with many success stories corroborating the power of genomic medicine. The principles of applications learned from these rare monogenic traits, in which the functional impact of the molecular pathways is clear-cut, may be instructive for developing basic concepts toward precision therapy of the common immune-mediated disorders, including autoimmunity, infectious diseases, and allergy, which affect mass populations.

Figure 1.

Factors related to the heterogeneity of disease presentations in IEI and a basic diagnostic algorithm. The presenting features and the clinical course of a particular IEI disorder depend on multiple factors. While the chief affected immune compartment determines the basic pattern of clinical expression, there is a considerable variability in the age at onset and target organ involvement within many IEI forms. Several factors, including the encountered pathogens and the former medical interventions employed, might modify the disease course (A). A basic algorithm for IEI diagnosis and management is presented (B). The figure was created using Biorender.com. IEI, inborn errors of immunity; SCID, Tx: treatment.

Figure 2.

Possible ways of IEI diagnosis and the model of treatment effect by various interventions on the IEI course. The timing of diagnosis is a critical factor that determines disease outcome and can occur in multiple ways, as indicated (A). A schematic of potential factors that can modify the symptomatology and the natural history of an IEI disease is shown. The efficacy of different therapeutics may vary for a given disorder, with no treatment effect to partial response in certain aspects, or with the capacity to change the natural course of the disease. Intervention 3 in this example may represent an etiology-driven therapy, and intervention 1 may be a phenotype-driven therapy that relieves only a component of the disease (B). The figure was created using Biorender.com. IEI, inborn errors of immunity.

Figure 3.

Depiction of the possible mechanisms by which various gene mutations cause IEI. A gene mutation underlying an IEI may alter the gene product (protein) in different ways (A). This alteration may affect professional immune cells or the soluble components of the immune system. Occasionally, impaired functions of the non-professional cells that contribute to host immunity may also cause IEI (B). The clinical manifestations of IEI are produced by abnormalities in the development, maintenance, or function of the affected compartments. While insufficient immune responses predispose the host to infections or cancer, dysregulated immune reactions produce exaggerated inflammation, resulting in autoimmunity or severe allergies (C). The figure was created using Biorender.com. IEI: Inborn errors of immunity.

Figure 4.

Timeline showing the major advances in the cellular therapies, pharmacotherapy, and the gene therapy approaches in various IEI disorders. (A) The curative treatment approaches toward IEIs using cellular therapies date back to 1960s. In subsequent years, considerable advances in the field were made; for example, the successful application of haploidentical transplantation and less toxic conditioning regimens broadened the use of cellular therapies including IEIs and non-IEI metabolic disorders (top panel). Selected examples of etiologically targeted pharmacologic treatment approaches in IEI are presented (bottom panel). (B) Corrective gene therapy approaches used in IEI treatment are summarized. ADA, adenosine deaminase; APDS, activated phosphoinositide 3-kinase delta syndrome; CGD, chronic granulomatous disease; GOF, gain of function; HSCT, hematopoietic stem cell transplantation; IEI, Inborn errors of immunity; IgRT, immunoglobulin replacement therapy; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; JAK, Janus kinase; LAD, leukocyte adhesion defect; LRBA, lipopolysaccharide-responsive beige-like anchor; LTR, long terminal repeat; LV-gene therapy, lentiviral gene therapy; rhG-CSF, recombinant human granulocyte colony-stimulating factor; SCID, severe combined immune deficiency; SIN, self-inactivating; STAT, signal transducer and activator of transcription; TALEN, transcription activator-like effector nuclease; TCR, T cell receptor; 𝛾RV-gene therapy, 𝛾 retroviral gene therapy; WAS, Wiskott-Aldrich Syndrome; XL-SCID, X-linked SCID.