Fig. 2

Adaptive immunity with novel signal 4, the metabolic RF recognition. The adaptive immunity is characterized by Ag specificity and immunologic memory leading to TC and BC activation. There are two types of adaptive immunity: TC immunity (cell-mediated immunity) and BC immunity (humoral immunity). Classically, each involves three activating signals. We propose a novel signal 4 (metabolic RF recognition) mediated by metabolic sensor. a TC immunity. TC activation involves four distinct signals. In signal 1 (Ag recognition), the Ag peptide is presented by MHC on the APC to Ag-specific TCR on TC. Signal 2 (immune checkpoints) involves ligand and receptor binding on APC and TC. Signal 3 responds to inflammatory cytokine stimulation. The novel signal 4 describes metabolic RF using a metabolic sensor leading to MC (APC) differentiation, inflammatory cytokine production, and the enhancement of signals 2 and 3. b BC immunity. BC activation involves Ag binding to BCR (signal 1), ligand and receptor binding (signal 2), cytokine stimulation (signal 3), and metabolic RF recognition (signal 4). Words in red emphasize our newly proposed signal. Abbreviations: APC antigen present cell, Ag antigen, BC B cell, BCR B cell receptor, RF risk factor, HHcy hyperhomocysteinemia, MHC major histocompatibility complex, MC monocyte, sCD40L soluble CD40 ligand