Inborn errors of immunity (IEI)

Find out more about this terminology, the link with primary immunodeficiencies and the phenotypical classification


What are inborn errors of immunity? 

Recently, the terminology ‘IEI’ appeared in the literature: “to capture the broad range of phenotypes associated with these [PID] disorders, the term ‘inborn errors of immunity’ (IEI) has been proposed."1

The ‘International Union of Immunological Societies’ (IUIS) expert committee has published genotypic and phenotypical classification of IEI.2,3 They have curated over 400 disorders, based on 430 genetic single-gene defects and classified them into 10 tables. Each of these tables include 36 to 64 disorders, with a year-on-year increase.

  •  Table I - Immunodeficiencies affecting cellular and humoral immunity
  •  Table II - Combined immunodeficiencies with associated or syndromic features
  •  Table III - Predominantly antibody deficiencies
  •  Table IV - Diseases of immune dysregulation
  •  Table V - Congenital defects of phagocyte (number or function)
  •  Table VI - Defects in intrinsic and innate immunity
  •  Table VII - Autoinflammatory diseases
  •  Table VIII - Complement deficiencies
  •  Table IX - Bone marrow failure
  •  Table X - Phenocopies of inborn errors of immunity

The terms IEI and PID are often used interchangeably in the literature. Currently, the term PID is still preferred to IEI.4 Although there is an argument for changing the name from PID to IEI, or using these terms interchangeably, there are several caveats, as three of the most common PIDs (which comprise the majority of patients with PID) do not currently have a defined genetic basis (IgA deficiency, common variable immunodeficiency and transient hypogammaglobulinemia of infancy). Even within well-defined phenotypes such as agammaglobulinemia or severe combined immunodeficiency (SCID), not all patients have a genetic explanation for their disorder. 

Between 2015 and 2020, the number of gene defects identified as underlying inborn errors of immunity has nearly doubled.2
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1. Notarangelo LD, et al. Human inborn errors of immunity: An expanding universe. Science immunology 2020; 5:eabb1662
2. Tangye SG, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2020; 40:24-64
3. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Picard C, Puck J, Torgerson TR, Casanova JL, Sullivan KE. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020 Jan;40(1):24-64. doi: 10.1007/s10875-019-00737-x. Epub 2020 Jan 17. Erratum in: J Clin Immunol. 2020 Feb 22;: PMID: 31953710; PMCID: PMC7082301.
4. Ameratunga R, Longhurst H, Lehnert K, Steele R, Edwards ESJ, Woon ST. Are All Primary Immunodeficiency Disorders Inborn Errors of Immunity? Front Immunol. 2021 Jul 21;12:706796. doi: 10.3389/fimmu.2021.706796. PMID: 34367167; PMCID: PMC8335567.

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