Primary immunodeficiency disorders, now known as Inborn errors of immunity, are a group of rare diseases affecting different arms of immune system. With the increased use of next generation sequencing, novel genes are being identified that have broadened our understanding of different clinical and immunological phenotypes. International Union of Immunological Societies have been updating the genetic causes for primary immunodeficiency disorders since 1970 [1]. Since 2013, the expert committee has started updating the phenotypic classification for the ease of practicing physicians [2]. In the last update, the inborn errors of immunity were classified in to nine categories, some of which were sub-classified in two categories based on severity of the disease [2]. The latest update has ten categories with a new category of bone marrow failures and 65 new disorders with total number of disorders reaching 430 (Fig.1) [1,3]. Different modes of inheritance and distinct mechanisms like loss of function, gain of function, haploinsufficiency and dominant negative forms leading to different phenotypes are reported for 35 genes (Fig.2).

Prepared from: SCID-Severe combined immunodeficiency disorder, CID-Combined immunodeficiency disorder, EDA ID-Anhidrotic ectodermodysplasia with immunodeficiency, CVID-Common variable immunodeficiency disorder, MSMD- Mendelian susceptibility to mycobacterial disease.

Fig. 1 New disorders included in the 2019 update.

Prepared from: XL- X linked inheritance, SM- Somatic mutations, DN- Dominant negative, HP- Haploinsufficiency.

Fig. 2 Genes with multiple modes of inheritance and mechanisms.

In the category of Immunodeficiencies affecting cellular and humoral immunity, eight new genes are added. An autosomal dominant (AD) gain of function in RAC2 gene causes recurrent bacterial and viral infections and may also be associated with neutropenia and lymphoproliferation. ICOSL deficiency patients have recurrent viral respiratory tract infections (RTI) with slowly progressive neutropenia and may have chronic diarrhea. IKAROS deficiency patients present with opportunistic infections like P.jirovecii, and agammaglo-bulinemia. These patients are at an increased risk to develop B cell ALL. Polymerase deficiency patients are of short stature and had recurrent respiratory tract and skin infections with molluscum contagiosum and viral warts. Rel A Haploinsufficiency patients have increased inflammatory cytokines signaling causing chronic mucocutaneous ulceration. c-Rel deficiency causes increased susceptibility to opportunistic organisms like Salmonella, Cryptobacterium, Cytomega-lovirus and Mycobacterium tuberculosis. FCHO1 deficient patients have failure to thrive, lympho-proliferation with predisposition to recurrent infections.

In Combined immunodeficiency with associated or syndromic features twelve new disorders have been added. LIG1 deficiency patients have growth retardation, increased sensitivity to radiation and sunlight with recurrent bacterial and viral infections. FOXN1-haploinsufficient patients also have recurrent bacterial and viral infections with eczema, dermatitis and nail dystrophy. Chromosome 11q23 deletion which causes Jacobsen syndrome have growth retardation, facial dysmorphism, warts and recurrent RTI. Seven disorders have been added with features like Hyper IgE syndrome due to mutations in IL6R, IL6ST, ZNF341, ERBB2IP,TGFBR1,TGFBR2 and loss of function forms in CARD11. Recurrent bacterial, viral and fungal infections with ectodermal dysplasia is also seen due to gain of function mutations in IKBKB. Other syndromic defects are also listed (Fig. 1). A dominant negative form of STAT5b deficiency with eczema and growth failure without immune defects like the autosomal recessive (AR) form is also added in this category.

In predominantly antibody deficiencies due to severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells four disorders are added. p110d deficient patient have severe bacterial infections and autoimmune complications like inflammatory bowel disease (IBD). AR forms of E47 transcription factor deficiency are more severe than the AD forms and present with recurrent bacterial infections and failure to thrive. SLC39A7 (ZIP7) deficiency present at an early age with recurrent infections, blistering dermatosis and may have thrombocytopenia. Hoffman syndrome due to TOP2B deficiency present with recurrent infections with limb anomalies and facial dysmorphism. Four new disorders with Common variable immunodeficiency phenotype have been described (Fig. 1). AD forms of AID deficiency causing Hyper IgM phenotype with lymphadenopathy and autoimmunity is also mentioned.

In diseases of immune dysregulation, one new disorder is added in familial hemophagocytic lymphohistiocytosis syndrome, SLC7A7 defect leading to lysinuric protein intolerance which may be associated with pulmonary alveolar proteinosis and bleeding tendencies. Three new disorders with regulatory T cell (Treg) defects are CD122 deficiency with lympho-proliferation and autoimmunity, DEF6 deficient patient had enteropathy, hepatosplenomegaly and cardio-myopathy and FERMT1 deficient patients with severe dermatosis. TGFB1 deficiency and RPIK1 defects are new causes of immune dysregulation with colitis and CD137 deficiency a cause of increased susceptibility to Epstein-Barr virus and lymphoproliferation.

Two new disorders with congenital neutropenia are SRP54 deficiency with exocrine pancreatic deficiency and neurodevelopmental delay and ELF1 defect an additional cause for Shwachman-Diamond syndrome. A new form of functional phagocytic defect due to CYBC1 deficiency causes inflammatory gastrointestinal symptoms with recurrent bacterial infections.

Mendelian susceptibility to mycobacterial disease involves three new genes namely IL12RB2, IL23R and SPPL2A, all of which predispose to mycobacterial and salmonella infections and a homozygous P1104A in TYK2 gene which is associated with increased risk of tuberculosis. CIB1 deficiency causes increased risk of epidermodysplasiaverruciformis (EV). IRF9 deficient patients are at an increased risk of severe influenza infections. IFNAR1 patients have severe disease after yellow fever and measles vaccination. Severe varicella zoster virus infections may be seen due to RNA polymerase III deficiency. DBR1 deficiency can cause herpes simplex encephalitis (HSE) along with other viral infections of brain stem. IRF4 haploinsufficiency is included under other inborn errors of immunity related to leukocytes presenting as Whipple disease.

Nine new disorders with Autoinflammatory phenotype are added in the update which include DNASE2 deficiency with features likeAcardi-Goutieres Syndrome, DNASE1L3 deficiency causing pediatric systemic lupus erythematosus, OAS1 deficiency causing pulmonary alveolar proteinosis and skin rashes, an AD form of MEFV gene mostly M694del causing familial Mediterranean fever and NLRP1 GOF variant causing juvenile onset recurrent respiratory papillomatosis, corneal scarring and palmoplantar carcinoma. Non-inflammasome related conditions included are ALPI and TRIM22 deficiency causing IBD, mutations in PSMG2 gene causing auto-immune hemolytic anemia, lipodystrophy and panniculitis with CANDLE like phenotype and T cell lymphoma subcutaneous panniculitis-like (TIM3 deficiency).

In complement deficiency disorders GOF variants of C1S and C1R defects causing periodontal Ehlers-Danlos like phenotype causing hyperpigmentation and skin fragility are included in the new update.

To summarize, with frequent use of whole exome sequencing and whole genome sequencing the list of monogenic disorders will keep on increasing in times to come. With new genetic defects being identified,specific targeted therapies can be used increasingly like in patients with mutations in JAK1, STAT1, STAT3, PIK3CD, DFE6, CTLA4, LRBA, IL12Râ2, IL23R AND IL18BP genes [1].With clinical and immunophenotypic correlation of newer genes being identified, our understanding of immunology is bound to evolve.

Contributors: BU: conceived and written the manuscript. MM revised the manuscript for important intellectual content. The final manuscript was approved by all authors.

Funding: Indian Council of Medical Research (ICMR); Competing Interests: None stated.

REFERENCES

1. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, 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;

2. Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, et al. International Union of Immunological Societies: 2017 Primary Immuno-deficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol. 2018;38(1):96-128.

3. Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol. 2020: 11; 1-16.