Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

Inborn errors of immunity (IEI) are caused by damaging germline variants in single genes. IEI present clinically as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy. While individually rare, the aggregated number of individuals with an IEI represents a significant health burden [1]. Genetic variants cause disease by altering the encoded gene product, such as by abolishing or reducing protein expression and function (null/hypomorphic) or modifying the protein to acquire gain-of-function (GOF) [2‐5]. Mechanisms of disease in IEI depend on the nature of the variant as well as the mode of inheritance. Thus, monoallelic variants can cause disease by haploinsufficiency, negative dominance, or GOF. In contrast, biallelic genetic lesions (homozygous, compound heterozygous) cause autosomal recessive (AR) traits by loss of expression, loss of function (LOF), GOF, or even neomorphic function of the encoded protein, while X-linked recessive traits arise from LOF or GOF variants on the X chromosome, either in hemizygosity in males, or homozygous state in females.

The fact that some monogenic variants are pathogenic clearly highlights the non-redundant and fundamental roles of individual genes and proteins, and associated pathways and cell types, in the development and function of leukocytes and non-hematopoietic cells that contribute to immune homeostasis and host defense [6, 7]. Thus, IEI represent an elegant model linking defined monogenic defects with clinical phenotypes of immune dysregulation. IEI have also revealed mechanisms of disease pathogenesis in, and enabled the implementation of gene- or pathway-specific therapies for the treatment of, rare and common conditions and established fundamental aspects of human immunology [8‐10]. Thus, the study of IEI has enabled profound advances in molecular medicine and human biology.

Since 1970, an international expert committee comprising pediatric and adult clinical immunologists, clinician/scientists and researchers in basic immunology — initially under the auspices of the World Health Organization and currently the International Union of Immunological Societies (IUIS) — has provided the clinical and research communities with an update of genetic causes of immune deficiency and dysregulation https://​iuis.​org/​committees/​iei/​ (Fig. 1A).

IEI are currently categorized into 10 Tables, with subtables segregating groups of disorders into overlapping phenotypes. These tables describe the following: combined immunodeficiencies (Table 1, 3 subtables); combined immunodeficiencies with syndromic features (Table 2; 9 subtables); predominantly antibody deficiencies (Table 3; 3 subtables); diseases of immune dysregulation (Table 4; 7 subtables); congenital defects of phagocytes (Table 5; 4 subtables); defects in intrinsic and innate immunity (Table 6; 9 subtables); autoinflammatory diseases (Table 7; 3 subtables); complement deficiencies (Table 8); bone marrow failure (Table 9), and phenocopies of inborn errors of immunity (Table 10) (Fig. 1B) [5].

The committee strives to publish an updated report approximately every 2 years to consolidate advances and catalog current IEIs (Fig. 1A) [5]. While COVID-19 has delayed producing this report in the desired timeframe, it has also uncovered several new IEI — some of these are highlighted below. Many genetic variants related to IEI have been reported recently. Rather than including every candidate gene reported in the peer-reviewed scientific literature, the committee applies stringent criteria to classify gene defects as novel causes of IEI [11]. These criteria include:

These criteria can be met by publication of multiple cases from unrelated kindreds, including detailed immunologic data, or publication of very few — even single — cases for whom compelling mechanistic data are provided, often revealed from complementary studies in animal or cell culture models. We also considered whether sufficient justification was provided to exclude alternative candidate gene variants identified in single cases, the depth of the clinical descriptions of affected individuals, and the level of immune and mechanistic characterization. This 2022 update and the accompanying “Phenotypical IUIS Classification” publications are intended as resources for clinicians and researchers, as well as guiding the design of panels used for targeted gene sequencing to facilitate genetic diagnoses of IEI. Here, we summarize data on the genetic cause of 55 novel IEI, and 1 phenocopy due to autoantibodies, that have been assessed since the previous update [5] (Supplementary Table 1). Remarkably, 15 of the 55 novel IEI have come from the identification and extensive work-up of single patients. Two themes that are expanded in this new set of genes are narrow infection susceptibility and immune dysregulation, which collectively account for over half of the phenotypes associated with these new genetic etiologies of IEI. This paper increases the number of known genetic defects identified as causing IEI to 485 (Fig. 1A, B; see all Tables and Supplementary Table 1).

Novel gene defects have been found for most categories of IEI, including novel causes of:

Some of these novel genetic findings link common clinical phenotypes that converge on a shared pathway. Examples in this update include:

The discovery of novel IEI continues to demonstrate that distinct types of variants (GOF, LOF, mono-allelic, bi-allelic, exon splicing) in the same gene can cause disparate clinical conditions. This update includes AR and AD forms of IKZF2 (HELIOS) [20‐23] and IL6ST [31‐33] deficiency, as well as AD RIPK1 LOF [85, 86], AR GOF TMEM173/STING [70], AR LOF TBK1 [82], and mono-allelic IKZF1 GOF [52] variants which complement previous reports of AR RIPK1 deficiency, AD GOF TMEM173/STING, AD TBK1 deficiency, and mono-allelic IKZF1 inactivating variants, respectively [5]. AR GOF variants in CEBPE also represent a novel IEI [51]. Notably, these variants resulted in neomorphic function of the C/EBPε transcription factor, causing dysregulated expression of >400 genes, ~15–20% of which are not normally targeted by C/EBPε [51]. This may represent the prototype for neomorphic variants causing IEI.

Intriguingly, specific variants in STAT2 or IKBKG — which are already well-known to cause IEIs — have recently been reported that cause very distinct phenotypes from those previously associated with pathogenic variants in these genes. STAT2 plays a ying/yang role in type 1 IFN signalling. Thus, it is responsible for not only inducing, but also restraining, responses elicited via IFNαR1/2 complexes [110]. This regulatory role of STAT2 is mediated by binding to and recruiting USP18 to IFNαR2, which then prevents further recruitment of JAKs to type 1 IFN receptors, thereby attenuating IFNα signalling [110]. Bi-allelic variants in STAT2 that specifically affect amino acid R148 (STAT2^R148Q/W) have now been reported [79, 80]. These STAT2^R148Q/W variants are LOF for binding to USP18 [79, 80, 110]. Consequently, STAT2^R148Q/W prevents USP18-mediated restraint of type 1 IFN signalling. It is important to appreciate that while STAT2^R148Q/W is not intrinsically GOF, the net outcome of loss of STAT2-mediated regulation of type 1 IFN signalling is reminiscent of other Mendelian IFN-opathies. Indeed, STAT2^R148Q/W is a phenocopy of USP18 deficiency [110], which is clearly distinct from severe susceptibility to some live attenuated viral vaccines and viral infections typical of individuals with null/nonsense mutations in STAT2 [110]. Lastly, unique variants in IKBKG that result in deletion of exon 5 were found to cause an autoinflammatory disease which is also very different from ectodermal dysplasia and immunodeficiency that is typically associated with hypomorphic IKBKG variants that impair NEMO expression and/or function [92‐94].

Somatic/mosaic disease-causing mutations in TLR8 [58] and UBA1 [97] have also been identified, even though the pathogenic alleles were detected in only 5–30% of most blood cells (TLR8) [58] or 50–85% of myeloid cells but not in lymphocytes of fibroblasts (UBA1) [97]. These findings are an important reminder to consider the nature of genetic variants identified from unbiased next-generation sequencing, recognizing multiple mechanisms of pathogenicity for the same gene. This is highlighted by at least 40 genes having multiple entries in the current update to reflect these distinct modes of disease pathogenesis (Supplementary Table). This also emphasizes the crucial need to undertake in-depth in vitro functional validation of any variant considered to be potentially pathogenic. Alternatively, it signifies the difficulty in excluding a candidate pathogenic variant without functional testing. It also underscores the need to consider variants detected at low allelic frequencies that may represent somatic/mosaic, rather than germline, variants. These findings also predict that somatic variants in key immune genes will be frequently discovered as causes of novel IEI in the not-too distant future [111].

One of most profound outcomes of discovering the genetic cause of an IEI is the ability to ascribe unequivocally non-redundant, as well as redundant, functions to a specific gene in human immunity. Classic examples of this are the fundamental requirement for IL2RG in humans for the development of T and NK cells, but not B cells, and the essential role of STAT3 for CD4⁺ T cell differentiation into Th17 cells and subsequent host defense against fungal infections, but not for the generation of most other CD4⁺ T cell effector populations [112]. Findings included in this update confirm data from mice on the importance of FNIP1 and SPI1 (encoding PU.1) during human B cell development [35‐37] and the fundamental regulatory role of PD-1 (encoded by PDCD1) in human immune function [47]. However, and perhaps counter to all expectations and immunology dogma relating to T cell co-stimulation, CD28 is required for host defense against HPV but is largely redundant in the face of other infectious pathogens [28]. Who would have thought!

The latest IEI have also revealed critical roles for genes not previously strongly associated with immune regulation and/or host defense. For instance, we have now learned that:

The discovery of these novel IEIs provides opportunities to further extend our understanding of human immunity and immune regulation.

The emergence of novel pathogens poses potential health risks to the general population due to the lack of substantial pre-existing immune memory. More critically though, individuals with specific germline genetic variants — causing known and unknown IEIs — may be at greater risk of experiencing more severe disease following infection than the general population. The COVID-19 pandemic has indeed revealed genes and pathways essential for anti-SARS-CoV2 immunity. Genomic studies discovered that ~2–3% of cases of severe life-threatening SARS-CoV2 infection resulted from germline LOF/LOE variants in the type 1 IFN signaling pathway: TLR3, UNC93B1, TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2 [113]. These findings are reminiscent of earlier studies that identified variants in these genes in individuals susceptible to life-threatening infections with other viruses, including influenza virus, HSV-1, and live viral vaccines [114]. Hemizygous deleterious variants have also been identified in TLR7 in ~1% of males who developed severe/fatal COVID-19 [66‐68]. Thus, X-linked TLR7 deficiency represents a novel IEI predisposing to severe COVID-19.

The importance of type 1 IFN in anti-SARS-CoV2 immunity was also realized by the finding that ~10–20% of patients with severe COVID-19 have high levels of neutralizing serum autoantibodies (autoAbs) against type 1 IFNs; these were not detected in asymptomatic infected individuals [100‐104]. Collectively, these studies defined a non-redundant role for type 1 IFNs in host defense against SARS-CoV2 infection and established that autoAbs against type 1 IFN phenocopy an IEI.

The goals of the IUIS Expert Committee on IEI are to increase awareness, facilitate recognition, promote optimal treatment, and support research in the field of clinical immunology. Since the last IEI update, we have continued to witness the ongoing rapid identification, and molecular, biochemical, and cellular characterization, of genetic variants that cause human diseases by disrupting host defense or immune regulation. The 55 novel gene defects reported here bring to total number of IEI to 485 (Fig. 1A, B), thus underscoring the power of next-generation sequencing technologies and sophisticated functional validation of candidate pathogenic variants to (1) identify novel gene defects underlying human disease, (2) elucidate mechanisms of disease pathogenesis, (3) define non-redundant functions of key genes in human immune cell development, host defense and immune regulation, (4) expand the immunological and clinical phenotypes of IEI, and (5) implement gene-specific therapies. These fundamental discoveries continue to highlight the critical contributions of IEI to our broader understanding of basic, translational, and clinical immunology, as well as molecular medicine. And we will no doubt observe novel insights into basic and clinical immunology with the next wave of novel IEIs.