Are All Primary Immunodeficiency Disorders Inborn Errors of Immunity

It is almost 70 years since the first description of Bruton’s agammaglobulinemia (1). In the last decade there has been a rapid increase in the rate of discovery of new genetic defects in primary immunodeficiency disorders (PIDs), largely due to the advent of Next Generation Sequencing (NGS) (2, 3). NGS utilises massively parallel sequencing to analyse either the exome (WES) or the entire genome (WGS). The International Union of Immunological Societies (IUIS) expert committee of the WHO has curated over 400 such disorders (2). This sequencing revolution has had profound benefits (and some disadvantages) for patients and their clinicians as well as scientists seeking to identify new disorders (4, 5). As termed by Robert Good, these “experiments of nature”, have offered unique scientific insights into functioning of the immune system (6). The many overlapping benefits of genetic confirmation for patients include certainty of diagnosis, prognostic insights and specific treatments (5). It has ushered in the era of personalised medicine. Identification of a gain for function mutation of PIK3CD for example, may lead to specific treatments such as idelalisib in addition to subcutaneous or intravenous immunoglobulin (SCIG/IVIG) replacement. With the rapid increase in the discovery of new genetic defects, there has been a move to name these conditions inborn errors of immunity (IEI) (2). The Merriam Webster dictionary states Inborn is “being a part of the innermost nature of a person or thing” and synonyms include congenital, hereditary and inherited. Inborn thus implies these conditions are genetic and inherited, which will be transmitted to future generations. Errors in this context infer mutations, which are pathogenic and underlie the phenotype of the patient. Although there is an argument for changing the name from PIDs to IEI, or using these terms interchangeably, there are several caveats. Three of the most common conditions, which numerically comprise the majority of patients with PIDs, do not currently have a definable genetic basis; IgA deficiency (IgAD), Common Variable Immunodeficiency Disorders (CVID) and Transient Hypogammaglobulinemia of Infancy (THI). Other well-recognised conditions, which do not have a genetic explanation at this time, include Good’s syndrome and CD4 lymphopenia. Even within well-defined phenotypes such as agammaglobulinemia with absent B cells or Severe Combined Immunodeficiency (SCID), not all patients have a genetic explanation for their disorder ( Figure 1 ). This is a perspective on why these terms are not currently interchangeable and why it may be premature to abandon the term PID in favour of IEI ( Table 1 ). Open in a separate window Figure 1 Illustrating the relationship between Primary Immunodeficiency Disorders (green) and Inborn Errors of Immunity (red). CVID, Common Variable Immunodeficiency Disorders; IgAD, IgA deficiency; SCID, Severe Combined Immunodeficiency; THI, Transient Hypogammaglobulinemia of Infancy.