Protein Misfolding and Aggregation of Pathological IgG Light Chains in Oncohematological Dyscrasias: From Molecular Pathways to Clinical Implications.

Neoplastic transformation of B cells of the post-germinative center can lead to oncohematological dyscrasias, which often results in an abnormal production of monoclonal immunoglobulin light chains. The non-physiological production of large amounts of IgG light chains leads to the formation of extracellular deposits called 'aggregomas' and rare conditions such as light chain crystal deposition disease. Kidney manifestations and heavy-chain deposition disease can also occur in plasma cell dyscrasias, emphasizing the role of IgG misfolding and aggregation. This minireview describes molecular mechanisms of IgG light-chain aggregation, as well as the consequences and therapeutic implications of IgG light chain misfolding in these disorders. By elucidating the mechanisms of IgG light chain misfolding and aggregation, researchers can identify specific molecular and cellular pathways. This knowledge opens the door to novel therapeutic targets, offering the potential for interventions that can either prevent the initial misfolding events, promote the proper folding and processing of immunoglobulins, or enhance the clearance of misfolded proteins and aggregates. These protein folding-related issues persist even after the successful elimination of the malignant B cells. Such targeted protein-folding therapies could significantly improve patients' quality of life and contribute to their recovery. Thus, a deep understanding of IgG light chain misfolding and its consequences not only sheds light on the complex biology of oncohematological dyscrasias but also opens the way for innovative treatment strategies that could transform patient care in these conditions, instilling hope and motivation in the healthcare professionals and researchers in this field.