Classification of Primary Immunodeficiencies (Inborn Errors of Immunity)
Primary immunodeficiencies are classified into 10 major categories based on the principal immunologic mechanisms disrupted, encompassing 485 distinct genetic disorders as of the 2022 IUIS classification 1.
Major Classification Categories
The current classification system organizes inborn errors of immunity into the following categories 2, 3:
1. Combined B- and T-Cell Immunodeficiencies
This includes:
- Severe Combined Immunodeficiency (SCID): Complete absence of specific immunity with T-B- phenotypes (e.g., IL-2R gamma chain, JAK3, RAG1/RAG2 defects) or T-B+ phenotypes (e.g., ADA, Artemis defects) 2
- Less severe combined immunodeficiencies: Including hyper-IgM syndromes, ZAP-70 deficiency, MHC class I/II deficiencies 2
2. Predominantly Antibody Deficiencies
This is the most common category, accounting for approximately 50% of all IEI 2. It includes:
- Agammaglobulinemia: X-linked (Bruton, 85% of cases) and autosomal forms with absent/extremely low B cells 2
- Common Variable Immunodeficiency (CVID): Variable reduction in ≥2 major immunoglobulin classes with impaired specific antibody responses 2
- Milder deficiencies: Selective IgA deficiency (most common, 1:300-700 in white populations), IgG subclass deficiency, specific antibody deficiency, transient hypogammaglobulinemia of infancy 2
3. Diseases of Immune Dysregulation
Includes 2:
- Hemophagocytic syndromes (often fulminant, triggered by viral infections)
- Autoimmune lymphoproliferative syndromes (ALPS)
- IPEX syndrome (FOXP3 defects)
- APECED (AIRE defects)
- STAT1/STAT3 gain-of-function mutations
4. Congenital Defects of Phagocyte Number, Function, or Both
Features 2:
- Chronic Granulomatous Disease (CGD): Most common phagocyte defect with oxidative metabolism impairment (incidence 1:200,000)
- Severe congenital neutropenias (SCN1-5)
- Leukocyte adhesion defects
5. Defects in Intrinsic and Innate Immunity
Including complement deficiencies, TLR defects, and NK cell deficiencies 2
6. Autoinflammatory Disorders
Genetic disorders causing aberrant inflammatory responses 2
7. Complement Deficiencies
Each representing <1% of total IEI 2
8. Bone Marrow Failure Syndromes
9. Phenocopies of Inborn Errors of Immunity
Including autoantibody-mediated conditions 1
10. Syndromic Immunodeficiencies
Prominent syndromes include 2:
- Wiskott-Aldrich syndrome
- DiGeorge syndrome
- Ataxia-telangiectasia
- Hyper-IgE syndromes
Clinical Presentation Patterns
The classification reflects diverse clinical phenotypes 3, 4:
- Infection susceptibility (traditional hallmark)
- Immune dysregulation: Autoimmunity, autoinflammation
- Malignancy: Particularly hematologic (lymphoma, leukemia) 5
- Severe atopy: Early-onset atopic dermatitis, food allergies 6
- Lymphoproliferation
Key Epidemiologic Features
- Overall incidence: 1:2,000 to 1:10,000 live births for symptomatic IEI 2
- SCID incidence: 1:58,000 live births in the US 2
- Male:female ratio: 5:1 in children, approaches 1:1 in adults 2
- Higher incidence in consanguineous populations 2
Evolution of Classification
The IUIS Expert Committee updates this classification every 2 years, with the most recent comprehensive update in 2022 documenting 485 disorders (55 novel defects added) 1. An interim 2021 update identified 26 additional monogenic defects 7, demonstrating the rapid pace of discovery through next-generation sequencing.
The classification serves dual purposes: a genotypic classification for molecular diagnosis and a phenotypic classification for bedside clinical recognition 3, 8. The phenotypic approach uses diagnostic algorithms based on clinical and laboratory features within each of the 10 broad categories, facilitating systematic evaluation and timely diagnosis.