Immunomodulation in Congenital Immunodeficiencies: Targeting Innate and Adaptive Pathways

Abstract

Primary immunodeficiency diseases (PIDs) or congenital immunodeficiencies are a heterogenous group of more than 450 genetically inherited diseases that involve defects in development, regulation or functioning of the immune system. Such conditions impair both innate and adaptive immunity, exposing patients to frequent infections, autoimmunity and inflammatory complications, as well as malignancy. Traditionally, supportive strategies including immunoglobulin replacement and prophylaxis with antimicrobial agents have been of significant use to management of the conditions. Nevertheless, current developments in immunological and molecular medicine are changing the horizon towards mechanism-directed immunomodulatory regimens targeting pathogenic cellular and molecular lesions. Unlike other recent reviews that would generally list novel agents by category, or focus on just a few key mechanisms to understand gene therapy/Hematopoietic Stem Cell Transplantation (HSCT), this review offers a synthesis of immunomodulatory strategies, centred around pathways, of both innate (e.g., Toll-like receptor stimulation, interferon signalling, and natural killer (NK) cell enhancement) and adaptive (e.g., T-cell reinstatement, B-cell regulation, and cytokine inhibition) immune axes. It explicitly reports the association between each strategy and its underlying immunology. We considered the newer modalities, such as cytokine mimics, immune checkpoint inhibition, gene therapy and gene editing, and small-molecule inhibitors (e.g., Janus kinase [JAK] and mechanistic target of rapamycin [mTOR] inhibitors), in the context of clinical rationale, molecular specificity, response durability, and long-term safety. One of our key contributions is our precision-focused immunology through omics, which describes how a multi-omics profile can be applied to classify PID endotypes, predict therapeutic responsiveness, and select interventions tailored to the individual. We also discuss useful and ethical obstacles to action, such as access inequities, doubts about the long-term immune effects, and ethical issues relating to pediatric gene editing. All these developments highlight the potential of the new era of precision immunomodulation to improve outcomes in congenital immunodeficiency disorders.