Contemporary Challenges in Diagnosis and Treatment of Predominantly Antibody Deficiency

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Editorial

15 August 2022

Editorial: Contemporary challenges in diagnosis and treatment of predominantly antibody deficiency

Rohan Ameratunga

,

Hassan Abolhassani

,

Paul J. Maglione

and

Emily S. J. Edwards

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Editors

4

Emily S.J. Edwards

Monash University

Rohan Ameratunga

Auckland City Hospital

Hassan Abolhassani

Department of Medical Biochemistry and Biophysics, Karolinska Institutet (KI)

Paul J Maglione

Chobanian & Avedisian School of Medicine, Boston University

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About

Predominantly antibody deficiencies (PAD) are the most prevalent form of Primary Immunodeficiencies affecting >1:25,000 individuals globally. Almost all affected individuals suffer from infectious complications including severe and recurrent infections, particularly of the respiratory tract. Lifelong immunoglobulin replacement therapy (IgRT) and prophylactic antibiotics reduce the infectious burden. However, these therapeutics fail to alleviate non-infectious complications including autoimmunity, gastrointestinal disease, allergic reactions, lymphoproliferation, and malignancy experienced by most PAD patients. These complications are difficult to treat and are the predominant cause of early mortality and morbidity in this population. Furthermore, non-infectious complications often overshadow the infectious phenotype underlying a median diagnostic delay of up to 9 years. This comes at a significant cost to the healthcare system due to increased hospitalizations and irreversible organ damage in these patients.

The genetic etiology of disease has the power to dramatically transform patient treatment shifting clinical care from non-specific therapies including IgRT to targeted therapies including mechanism-based treatments and hemopoietic stem cell transplantation. However, despite significant advances in genomics, there is a low rate of genetic diagnosis in PAD (20%-50% based on the tested population). This demonstrates the genetic complexity of disease, which in combination with the clinical and immunological heterogeneity of this disorder prevents patient access to precision medicine. The late-onset of disease, low rate of consanguinity, and low diagnostic rate suggest that multiple genetic and non-genetic factors including epigenetic alterations contribute to disease pathogenesis. As such improved knowledge of the cellular and molecular mechanisms driving PAD is required to develop new strategies for precise diagnosis and pre-symptomatic identification, improved patient stratification, prognostication, and ultimately targeted treatment of patients and precise genetic consultation for the family members.

In this Research Topic, we welcome the submission of Original Research and Review articles related to the topics outlined below, especially:

1. Genetics – strategies to improve identification of rare monogenic variants in PAD and identify new genetic markers of disease in different entities of early to terminal B cell defects.

2. Transcriptomics - Changes in transcriptional regulation related to dysregulation of cellular processes required for robust immune system function.

3. Epigenetic changes in immune cells driving disease and their implications for patient treatment.

4. Approaches for functional validation of genetic, transcriptional, and epigenetic modifications as drivers of disease pathogenesis in asymptomatic/mild PAD (selective Ig isotypes defects) versus severe forms (hyper IgM syndrome, agamma- or hyperglobulinemia).

5. Novel approaches for PAD patient stratification and impact of different IgRT treatment in each category.

6. New immunological, genetic, transcriptional and epigenetic biomarkers for monitoring of the development, prognostication and treatment of immune dysregulation in PAD.

We acknowledge the initiation and support of this Research Topic by the International Union of Immunological Societies (IUIS). We hereby state publicly that the IUIS has had no editorial input in articles included in this Research Topic, thus ensuring that all aspects of this Research Topic are evaluated objectively, unbiased by any specific policy or opinion of the IUIS.