The article "Effects of Protein Aggregates: An Immunologic Perspective" by Amy S. Rosenberg, published in the *AAPS Journal* in 2006, explores the immunological mechanisms by which protein aggregates enhance immune responses to therapeutic proteins. The review highlights that protein aggregates, particularly particulate forms, are potent inducers of antibody responses, even in the absence of T-cell help. This is due to the ability of multivalent protein species to cross-link B-cell receptors (BCRs), activating B cells and targeting proteins for class II major histocompatibility complex (MHC)-loading compartments, which facilitates T-cell help for antibody production. The review discusses the importance of maintaining the native conformation of therapeutic proteins to minimize immunogenicity and the role of product formulation in preventing aggregate formation. It also examines the clinical impact of protein aggregates, such as severe hypersensitivity reactions and neutralizing antibodies, and the need for rigorous risk assessment and manufacturing controls to ensure product safety. The article emphasizes the importance of using orthogonal methods to assess product aggregates and the potential risks associated with changes in container closures and manufacturing processes. Overall, the review underscores the critical need for manufacturers to minimize aggregate formation and to implement robust quality control measures to prevent adverse immune responses in therapeutic protein products.The article "Effects of Protein Aggregates: An Immunologic Perspective" by Amy S. Rosenberg, published in the *AAPS Journal* in 2006, explores the immunological mechanisms by which protein aggregates enhance immune responses to therapeutic proteins. The review highlights that protein aggregates, particularly particulate forms, are potent inducers of antibody responses, even in the absence of T-cell help. This is due to the ability of multivalent protein species to cross-link B-cell receptors (BCRs), activating B cells and targeting proteins for class II major histocompatibility complex (MHC)-loading compartments, which facilitates T-cell help for antibody production. The review discusses the importance of maintaining the native conformation of therapeutic proteins to minimize immunogenicity and the role of product formulation in preventing aggregate formation. It also examines the clinical impact of protein aggregates, such as severe hypersensitivity reactions and neutralizing antibodies, and the need for rigorous risk assessment and manufacturing controls to ensure product safety. The article emphasizes the importance of using orthogonal methods to assess product aggregates and the potential risks associated with changes in container closures and manufacturing processes. Overall, the review underscores the critical need for manufacturers to minimize aggregate formation and to implement robust quality control measures to prevent adverse immune responses in therapeutic protein products.