Sequential Immune Responses: The Weapons of Immunity

Abstract

Sequential immune responses (SIR) is a new model that describes what 'immunity' means in higher animals. Existing models, such as self/nonself discrimination or danger, focus on how immune responses are initiated. However, initiation is not protection. SIR describes the actual immune responses that provide protection. SIR resulted from a comprehensive analysis of the evolution of immune systems that revealed that several very different types of host innate responses occur (and at different tempos) which together provide host protection. SIR1 uses rapidly activated enzymes like the NADPH oxidases and is present in all animal cells. SIR2 is mediated by the first 'immune' cells: macrophage-like cells. SIR3 evolved in animals like invertebrates and provides enhanced protection through advanced macrophage recognition and killing of pathogens and through other innate immune cells such as neutrophils. Finally, in vertebrates, macrophages developed SIR4: the ability to present antigens to T cells. Though much slower than SIR1-3, adaptive responses provide a unique new protection for higher vertebrates. Importantly, newer SIR responses were added on top of older, evolutionarily conserved functions to provide 'layers' of host protection. SIR transcends existing models by elucidating the different weapons of immunity that provide host protection in higher animals.

Fig. 1

SIR. SIR1: all animal cells have basic protective responses. One such type is NADPH oxidases (Nox enzymes) that rapidly self-assemble and produce superoxide. SIR2: separate innate killer cells appeared with additional phagocytic and killing abilities (mainly through the Nox-2 enzyme). SIR3: from about fishes onward in evolution, innate cells acquired enhanced abilities to recognize pathogens, resulting in transcribed enzymes and more powerful killing molecules like NO. SIR4: macrophages developed the ability to process and present antigens to T cells in combination with major histocompatibility molecules (MHC-I or MHC-II) resulting in clonal proliferation. DAMP = Damage-associated molecular patterns; PAMP = pathogen-associated molecular patterns; iNOS = inducible nitric oxide synthase.