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Navigating the alphabet soup of immunodeficiency

Article-Navigating the alphabet soup of immunodeficiency

Shutterstock Understanding immunodeficiency .jpg
Understanding IEI, MIDD, PID, PIRD and SID can provide improved diagnosis and potential for the application of precision medicine.

The acronyms in Clinical Immunology are gradually increasing because of the identification of novel immune disorders and the expansion of our understanding of immunopathogenesis. The term primary immunodeficiency (PID) is now being superseded by an inborn error of immunity (IEI).

This change is partly driven by the recognition that such disorders may not only involve impaired immune response to infection, but also autoimmunity, lymphocytic infiltration, and malignancy. Indeed, the terms primary immune dysregulatory disorder (PIRD) and monogenic immune dysregulation diseases (MIDD) have been recently coined and encapsulate the subset of IEI, which involve loss of normal inflammatory control and immune tolerance mechanisms, predominantly characterised by autoimmunity. The rate of discoveries in IEI research is truly astounding, with the number of IEI’s increasing from 191 in 2011 to 485 in 2022 according to the International Union of Immunological Societies (IUIS) classification.

The evolution of the IUIS classification over recent years has also recognised the importance of immune dysregulation. Defining the responsible genetic variant(s) can result in practical clinical benefit for the patient, which may include:

  • A more accurate clinical diagnosis
  • More specific advice regarding prognosis
  • Opportunity for tailored therapies for certain IEI’s
  • Consideration for haematopoietic stem cell transplantation for certain IEI’s
  • Genetic counselling for the family: siblings and future family planning

Advances in clinical care and research in IEI disorders have been facilitated by multi-centre national and international collaborations — increasing the number of patients with specific rare disorders enables the elucidation of clinical and immunological features, genetic diagnosis, response to therapy, and prognosis. For example, the Middle East and North African (MENA) IEI registry recently published a report based on MIDD patients from 11 MENA countries, and this international group published guidelines for IEI diagnosis and management to improve care of patients within the region.

In the UK, the National Institute of Healthcare and Research Bioresource undertook a whole genome sequencing (WGS) study of sporadic PID patients. A range of disparate causative molecular defects were identified e.g. in NFKB1 (nuclear factor B subunit 1), and TACI/TNFRSF13B (transmembrane activator and CAML interactor).

However, in many PID patients, the search for a molecular diagnosis has not yet been fruitful despite the use of clinical gene panels and WGS. It is also recognised that different variants (gain or loss of function, mono-allelic, bi-allelic and exon splicing) affecting the same gene can produce different clinical presentations.

One of the best examples illustrating the value of genetic diagnosis impacting therapeutic options was the discovery by Dr. Bernice Lo in her previous laboratory at the National Institute of Health in the USA and Dr. Michael Jordan at Cincinnati Children’s Hospital Medical Center. When LRBA deficiency was first described, the function of LRBA was not really known and so how LRBA deficiency caused an immunodysregulatory disorder was unclear.

Dr. Lo and colleagues discovered that in the absence of LRBA in patient T cells, CTLA-4 was degraded by lysosomes, indicating that LRBA plays a role in preventing CTLA-4 from lysosomal degradation. They showed that LRBA helps to maintain a pool of CTLA-4 inside the cells that allow for the rapid mobilization of CTLA-4 to the cell surface for its function. Since CTLA-4 is a crucial and potent inhibitory molecule for regulating immune responses, deficiency of CTLA-4 could explain the immunodysregulatory disease characteristic of LRBA deficiency.

Dr. Bernice Lo and Prof. Mohammed Yousuf Karim.jpg

Dr. Bernice Lo and Prof. Mohammed Yousuf Karim

Several LRBA-deficient patients had organ involvement that was refractory to various immunosuppressive drugs. However, treatment with abatacept, a chimeric CTLA-4 and Ig Fc fusion protein drug, was found to be a highly effective therapy for LRBA-deficient patients. Since the immune dysregulation in LRBA deficiency is due to insufficiency of CTLA-4 protein, replacement of CTLA-4 through treatment with abatacept functions as a targeted or precision therapy. This finding illustrated the importance of unravelling the molecular etiology of IEI for the implementation of precision medicine.

The use of a broadening range of immunomodulatory medications, including biologic drugs, in autoimmune disease or malignancy is leading to an epidemic of secondary immunodeficiency (SID). The best example is the development of clinically significant secondary antibody deficiency in a subset of patients treated with B-cell targeting therapies (BCTT), with some patients requiring immunoglobulin replacement. The numbers of SID patients are much higher than the number of patients with antibody deficiency related to PID.

To complicate matters further, it now emerges that the boundaries between PID and SID can be blurred. For example, BCTT use in children with autoimmune disease, especially for autoimmune cytopenia, can lead to hypogammaglobulinemia. In a subset of these children, clinical gene panels and/or WGS have identified underlying IEIs that account for both the autoimmune manifestations and the antibody deficiency.

In a landmark Italian study of children with autoimmune hemolytic anaemia, immune thrombocytopenia, or Evan’s syndrome treated with BCTT, the identified IEIs have involved variants in the following genes: ADA2 (adenosine deaminase 2), ARTEMIS, NFKB1, PIK3CD (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta), and TACI.

In summary, the improved classification of immunodeficiency disorders, supported by advances in genetic diagnosis, has enabled Immunology to enter a golden age of discovery. Already, there are early examples of translation into patient care, illustrating the potential for the application of precision medicine to benefit our patients.

References available on request.


Prof. Mohammed Yousuf Karim, MD FRCP FRCPath, is the Clinical Professor in Immunopathology, College of Medicine at Qatar University, and Division Chief, Haematology/Immunology/Transfusion at Sidra Medicine. Dr. Bernice Lo, PhD, is the Principal Investigator, Research Branch, Sidra Medicine, and Adjunct Assistant Professor, College of Health and Life Sciences at Hamad Bin Khalifa University. Both are based in Doha, Qatar.



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