Erroneous detection of desensitization doses in the prevention of hypersensitivity reactions.

BACKGROUND: Desensitization protocols have empirically established their efficacy and safety in eliminating most of the hypersensitivity reactions to drugs and other allergens. Without such procedures, the offending drugs can otherwise be lethal, for some patients, when singularly administered at therapeutic doses. These binding events and the subsequent signaling cascades have been extensively modulated by different desensitization methods, without any clear explanation as to why it is necessary to use increasing allergen doses. PURPOSE: To use a novel theoretical approach in order to model the desensitization algorithms currently in practice, that seeks to shed light on the mechanism behind their clinical efficacy. METHOD: An approach using signal processing concepts is applied in this work to introduce aliasing as the erroneous detection of higher drug doses responsible for the efficacy of desensitization procedures. RESULTS: Available experimental data is modeled and correct predictions as to the efficacy of the drug treatment procedures are produced. CONCLUSIONS: Desensitization algorithms may benefit from using concepts from signal processing theory in order to avoid hypersensitivity reactions.

Fever temperatures modulate intraprotein dynamics and enhance the binding affinity between monoclonal antibodies and the spike protein from SARS-CoV-2.

Fever is a typical symptom of most infectious diseases. While prolonged fever may be clinically undesirable, mild reversible fever (<39℃, 312 K) can potentiate the immune responses against pathogens. Here, using molecular dynamics and free energy calculations, we investigated the effect of febrile temperatures (38℃ to 40℃, 311 K to 313 K) on the immune complexes formed by the SARS-CoV-2 spike protein with two neutralizing monoclonal antibodies. In analyzing the conformational dynamics of the interactions between the antibodies and the spike protein under different thermal conditions, we found that, at mild fever temperatures (311-312 K), the binding affinities of the two antibodies improve when compared to the physiological body temperature (37℃, 310 K). Furthermore, only at 312 K, antibodies exert distinct mechanical effects on the receptor binding domains of the spike protein that may hinder SARS-CoV-2 infectivity. Enhanced antibody binding affinity may thus be obtained using appropriate temperature conditions.

Temporal Modulation of Drug Desensitization Procedures.

Drug hypersensitivity reactions are an unavoidable clinical consequence of the presence of new therapeutic agents. These adverse reactions concern patients afflicted with infectious diseases (e.g., hypersensitivity to antibiotics), and with non-infectious chronic diseases, such as in cancers, diabetes or cystic fibrosis treatments, and may occur at the first drug administration or after repeated exposures. Here we revise recent key studies on the mechanisms underlying the desensitization protocols, and propose an additional temporal regulation layer that is based on the circadian control of the signaling pathway involved and on the modulation of the memory effects established by the desensitization procedures.

Fever as an evolutionary agent to select immune complexes interfaces.

We herein analyzed all available protein-protein interfaces of the immune complexes from the Protein Data Bank whose antigens belong to pathogens or cancers that are modulated by fever in mammalian hosts. We also included, for comparison, protein interfaces from immune complexes that are not significantly modulated by the fever response. We highlight the distribution of amino acids at these viral, bacterial, protozoan and cancer epitopes, and at their corresponding paratopes that belong strictly to monoclonal antibodies. We identify the "hotspots", i.e. residues that are highly connected at such interfaces, and assess the structural, kinetic and thermodynamic parameters responsible for complex formation. We argue for an evolutionary pressure for the types of residues at these protein interfaces that may explain the role of fever as a selective force for optimizing antibody binding to antigens.