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A little too much or a little too little: a focus on primary immunodeficiencies

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Every year on 22–29 April, World Primary Immunodeficiency Week offers the opportunity to promote awareness of primary immunodeficiencies (PID) among the public and policymakers, with the aim of encouraging the earliest possible diagnosis and promoting improved treatment and care for people living with PID. In this article, we explore the study of these rare conditions and their implications for understanding and manipulating immunological systems.

Defining primary immunodeficiency

Primary immunodeficiencies (PIs or PIDs), also known as inborn errors of immunity (IEI), are caused by mutations in single genes that affect the development and/or function of immune cells. As a result, patients with PIDs have increased susceptibility to life-threatening infections, which often require life-long or invasive therapeutic interventions. These include stem cell transplantation, gene therapy, prophylactic antibiotics, immunoglobulin replacement and administration of steroids.

Around 10 million people worldwide are thought to live with primary immunodeficiencies, with 70–90% of these cases still undiagnosed. Many of the infections associated with PIDs are common and easily treatable with antibiotics, so doctors may not always consider an underlying immune deficiency disorder as the cause. This can lead to delayed diagnosis and treatment, allowing infections to persist and recur, and increasing the risk of serious complications.

The advent of next-generation sequencing has enabled a surge in the identification of gene defects that cause PIDs and has massively expanded this research area, uncovering tremendous diversity in phenotypes caused by these defects. A total of 485 distinct defects are now included in the 2022 update on the classification of human inborn errors of immunity from the International Union of Immunological Societies (IUIS) expert committee,1 a steep increase from the 430 reported in the 2019 update.

Uncovering immune insights

The study of primary immunodeficiencies has introduced a revolutionary approach to connecting specific genetic abnormalities to immune system malfunctions in clinical contexts. This is significant because it demonstrates that a single gene defect can result in severe clinical outcomes, underscoring the critical roles of individual genes in human immunology. Consequently, PIDs have contributed to a greater understanding of the functions of genes, molecules, signalling pathways and cell types in immune defence and regulation, leading to improved treatments for immune-related diseases.

Perhaps most significantly, advances in molecular medicine as a result of PID research have implications beyond the relatively small number of people with rare primary immunodeficiencies. As PID research reveals more insights into the immune system, this knowledge may be leveraged to improve immunity and immune regulation in the general population.

Overall, the study of primary immunodeficiencies and the impact of genetic variants on immune function represents an exciting and rapidly evolving field, with the potential to improve our understanding of immunological systems and to develop new therapies for patients with immune disorders.

Dr Cindy Ma, Immunodeficiency Section Editor at Clinical & Experimental Immunology said:

IEI represent an unprecedented model to link defined single gene defects to immune dysregulation in clinical settings

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The Goldilocks effect: a little too much or a little too little

The BSI’s official journal, Clinical & Experimental Immunology (CEI), has a dedicated Immunodeficiency section led by Dr Cindy Ma, who heads the Human Immune Disorders Laboratory at the Garvan Institute of Medical Research in Australia. In time for World Primary Immunodeficiency Week at the end of April, CEI published a new Review Series entitled ‘Inborn errors of immunity: The Goldilocks effect – susceptibility to diseases due to a little too much or a little too little’.

The series is edited by Dr Ma alongside Professor Stuart Tangye (also based at the Garvan Institute) and highlights new insights into primary immunodeficiency due to variants in genes that result in loss of function or gain of function of the encoded protein, and the arising disease outcomes.

This collection of reviews covers a diverse range of PIDs, including those caused by loss-of-function and gain-of-function gene defects in the complement pathway, JAK-STAT signalling, NF-kB pathway, DNA-binding protein Ikaros and regulators of the actin cytoskeleton.

Comparing loss-of-function and gain-of-function variants in the same genes has provided important insights into the function of specific proteins. For example, the study of PID has been instrumental in elucidating the role of the transcription factor STAT3 as a critical signalling module in immune responses, metabolism and cancer.2 The discovery of loss-of-function variants in STAT3 as a cause of recurrent skin and pulmonary infection established that STAT3 plays a critical non-redundant role in immunity against some pathogens. Conversely, gain-of function STAT3 variants were found to cause cases of early-onset multiorgan autoimmunity, thereby supporting the idea that STAT3 function needs to be regulated to maintain immune homeostasis.

Find out more by reading the Review Series.

Jasmine Catmull
BSI Marketing & Communications Officer

1. Tangye et al. 2022 Journal of Clinical Immunology 42 1473–1507
2. Mackie et al. 2023 Clinical & Experimental Immunology 212 107–116

BSI member discount 

We are proud to offer BSI members a discount on publication fees. Those submitting to our hybrid journal, Clinical & Experimental Immunology, receive a 33% discount on Open Access charges. For our fully Open Access journals, Discovery Immunology and Immunotherapy Advances, we offer authors a discounted fee of £1,680.