Keywords

Primary immunodeficiency diseases are a relatively young field of medicine. Patients with primary immunodeficiencies may have different clinical presentations, such as severe infections and/or neoplasia and/or autoimmune diseases (Fig. 1.1). The development of medical practices, such as respiratory support, rehydration therapy, microbiology diagnostics, vaccination, and antibiotics, greatly reduced the mortality and morbidity of infectious disease in the general population and paved the way to the description of the first PIDs.

Fig. 1.1
figure 1

Schematic representation of clinical outcomes in patients with primary cellular immunodeficiencies. Patients with primary cellular immunodeficiencies may have different clinical presentations, such as severe infections (e.g., respiratory or gastrointestinal infections) and/or neoplasia (e.g., gastric cancer, brain tumors, oral-esophageal cancers, hematopoietic malignancies) and/or autoimmune diseases (e.g., autoimmune thyroiditis or diabetes, eczema, autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED), immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome)

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There were a few reports describing peculiar clinical syndromes before World War II that have been years later characterized as PIDs, such as ataxia-telangiectasia syndrome and severe congenital neutropenia [1]. However, Colonel Ogden Bruton is credited with the formal discovery of the first PID in 1952, Bruton’s agammaglobulinemia, when he serendipitously found that a boy with a history of 18 pneumonias had an absent gamma fraction on protein electrophoresis [2].

The description of patients with X-linked hyper-IgM syndromes contributed to the understanding of the B-T interaction [3] and culminated in the discovery of mutations of the CD40-CD40L system in the early 90s. The study of autosomal recessive hyper-IgM syndromes elucidated the functions of activation-induced cytidine deaminase (AID) and uracil-N glycosylase (UNG) in class-switch recombination and ATM and PMS2 in DNA repair [4].

Many PIDs represent inestimable human models for the study of the function of the immune system, with implications beyond the clinical immunology field, such as cancer, autoimmune disease, transplantation, and infectious disease.

Defects in immune regulation have been associated with hyper-inflammation, lymphoproliferation, and autoimmunity.

The paradoxical co-occurrence of immunodeficiency with autoimmunity puzzled researchers for many years. The naïve definitions of autoimmunity as an “excess of immunity” and immunodeficiency as “lack of immunity” were incompatible with the clinical evidence [5].

The study of patients with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED) and immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome contributed to the discovery of regulatory T cells, and their master regulator FOXP3, and the thymus mechanisms for purging autoreactive T cells, by presenting self-antigen expressed under the regulation of AIRE.

CTLA-4 deficiency and defects in CTLA-4 recycling (LRBA and DEF6) present as PID with prominent autoimmunity. In 2018 James Allison and Tasuku Honjo received the Nobel Prize for cancer immunotherapy with checkpoint inhibitors, such as anti-CTLA-4, and interestingly the main side effects of these medications are immune-related adverse events (IRAEs) [6].

In the last decade, next-generation sequencing (NGS) led to the collapse of sequencing time and costs and brought a revolution in the PID field. The discovery of the molecular mechanisms behind PID is helping the development and application of personalized and targeted therapies [7].

The genomic revolution brought an unprecedented rate of discoveries, helping dissect the complexity of the genetic heterogeneity and pleiotropy of IEI. The last International Union of Immunological Societies (IUIS) IEI classification, published in 2019, includes over 430 separate entities [8].

A pivotal contribution of the IEI field has been the discovery of the mechanisms underlying immune redundancy and how some defects lead to susceptibility to a restricted spectrum of pathogens. These efforts brought recognition of IL-17 as a key player in mucosal immunity against fungi [9], the TLR-3 pathway in herpes encephalitis [10], and the IL-12/IFNγ axis in disseminated mycobacteria infections [11].

The translation of the study of these rare genetic diseases in large-scale genomic efforts enabled the description of the first common genetic polymorphism causing predisposition to mycobacterial disease. The TYK2 p.P1104A variant was shown to abrogate IL-23 signaling but not IL-12 signaling [12].

Moreover, since the immune response is under strong pressure by natural selection, the study of variants in the immune system can help to distinguish genes that are essential, redundant, or advantageous for human survival. These studies can provide information about the evolution of the immune system and the history of past epidemics [13].

Similarly, in the current SARS-CoV-2 pandemic, defects of type I interferon production and signaling were found to underlie life-threatening COVID-19 pneumonia in previously healthy patients [14].

The efforts to treat PIDs helped lay the foundations for hematopoietic stem cell transplantation. The first inhuman gene therapy was carried out in a boy with adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID) [15].

Going into the future, IEI are at the forefront of immunology and medical research.