Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies

Abstract

A broad spectrum of autoimmunity is now well described in patients with primary immunodeficiencies (PIDs). Management of autoimmune disease in the background of PID is particularly challenging given the seemingly discordant goals of immune support and immune suppression. Our growing ability to define the molecular underpinnings of immune dysregulation has facilitated novel targeted therapeutics. This review focuses on mechanism-based treatment strategies for the most common autoimmune and inflammatory complications of PID including autoimmune cytopenias, rheumatologic disease, and gastrointestinal disease. We aim to provide guidance regarding the rational use of these agents in the complex PID patient population.

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

“…4 Autoimmune cytopenias are a common AI/I manifestation encountered across PIDs, and reports suggest that PID is subsequently diagnosed in up to 50% of paediatric cases of refractory multilineage autoimmune cytopenia (Evans syndrome). 9,10 This high prevalence of autoimmune cytopenias in PID was also apparent within our cohort with 7/16 of participants developing autoimmune cytopenia of one or more cell lineages (Table 1). Therefore 'difficult-to-treat' Evans syndrome may indicate an underlying PID and is a frequent AI/I in clinical care.…”

“…Multisystem AI/I poses further challenges, as one AI/I manifestation may respond to a therapy, whereas another can remain refractory to the same therapy. It is hoped that ‘precision medicines’ targeted to the underlying genetic abnormality will provide a more holistic therapeutic option for multisystem AI/I 10 , 40 , 41 . Currently, due to the rarity of individual monogenic PIDs, there is a relative lack of large‐scale studies of these precision treatments, and financial limitations within health‐care systems still limit the wide‐scale adoption of precision medicine at the bedside.…”

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

“…Traditional treatments for PID consist of prophylaxis against infection, with antimicrobials and immunoglobulin, iatrogenic immunomodulation with high inherent risk associated with additional untargeted immunosuppression, and bone marrow transplantation in severe cases. Precision therapies now include targeted immunosuppression in cases of autoimmune/inflammatory manifestations and gene therapy to correct germline errors in autologous haematopoietic stem cells . These therapeutic approaches have the potential to dramatically improve the prognoses for patients with PID .…”

“…6,7 These therapeutic approaches have the potential to dramatically improve the prognoses for patients with PID. [7][8][9] Precision treatments, as well with genetic family counselling and preimplantation diagnostics, are only possible with knowledge of the causal monogenic variant in patients, and recent progressions in diagnostics and treatments underline the importance of genomic investigations in the clinical care of patients with PID. 10,11 Current genomic methodologies used for the investigation vary from Sanger sequencing of single candidate genes, to NGS gene panels, whole exome sequencing (WES) and now whole genome sequencing (WGS).…”

Primary Immunodeficiency: New Insights and Practical Clinical Approaches

“…The articles found here start with reviews of 2 of the more prevalent medical complications of primary immune deficiency: autoimmunity by Walter et al 1 and lung disease by Schussler et al 2 In both articles, the central themes concern how immune dysregulation, a common aspect of immune deficiency, leads to additional organ dysfunction, the mechanisms that underlie these events, and how understanding these processes has led to improved treatment and more targeted therapies. In a third clinical management review, de la Morena 3 describe her recent compilation of data describing the overall phenotypes found in a large cohort of subjects with the hyper-IgM syndrome, concentrating on the X-linked version of this immune defect.…”