Proteins are essential components of cellular life, uniquely translating genetic information into a vast array of molecular actions. This functional versatility depends on proteins acquiring specific three-dimensional conformations known as native states, which underpin their activity. However, these native states are often only marginally stable due to the delicate balance of forces that stabilize and destabilize protein structures. While this marginal stability allows proteins to remain functional, responsive, and adaptable, it also makes them prone to misfolding and aggregation, particularly in the presence of factors such as mutations, post-translational modifications, or non-physiological changes in their microenvironment.

Protein misfolding and aggregation are associated with a wide and heterogeneous group of disorders collectively referred to as protein misfolding diseases. These conditions involve diverse pathogenic mechanisms, generally categorized into those caused by the loss of function of the misfolded protein and those resulting from the harmful interactions between misfolded proteins, soluble oligomers, and aggregates with cellular components.

Given the immune system's surveillance role, it is logical to expect that, in many protein-misfolding diseases, the accumulation of misfolded proteins and aggregates would trigger an immune response. The nature and impact of this response can vary widely: in some cases, it facilitates the clearance of misfolded species and aggregates, offering protection; in others, it becomes a significant contributor to disease pathogenesis, exacerbating harmful processes.
Growing evidence supports the view that the immune response plays a pivotal role in the pathogenesis of neurodegenerative disorders. Conversely, the risk of an excessive immune response has complicated the development of active immunotherapy for these diseases. Light chain-derived (AL) amyloidosis exemplifies the complex relationship between the immune system and protein-misfolding diseases. In AL amyloidosis, the light chains of antibodies—a component of the immune system—misfold and aggregate as amyloid, initiating a cascade of pathogenic events that cause organ dysfunction and can lead to patient death if not effectively treated. Notably, the propensity of light chains to aggregate into amyloid fibrils and preferentially deposit in certain organs (organ tropism) seem to be driven by factors related to somatic hypermutations and immunoglobulin gene segment recombination, which are key to generating a diverse antibody repertoire. Additionally, antibody-based strategies to enhance the immune system's physiological mechanisms for clearing misfolded proteins and aggregates are being explored as therapeutic approaches in AL amyloidosis.

Consequently, the role of the immune system in the pathogenesis of misfolding diseases and the use of its armamentarium in novel therapeutic approaches for these disorders have become topics of interest for a broad spectrum of professionals, from pathologists and physicians who care for patients with protein misfolding diseases to researchers dedicated to basic, clinical, and translational studies.

This Research Topic of Frontiers in Immunology invites research articles and timely reviews on all aspects of;
- The pathogenesis of protein misfolding diseases,
- The role of the immune system in these disorders, and
- Novel therapeutic strategies based on immune system components aimed at treating affected patients.

Dr. Comenzo receives steering committee fees from Janssen Biotech for advisory services. All other Topic Editors declare no conflict of interest

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Friends and Foes at the Interface between Immune System and Protein Misfolding and Aggregation