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.

Back to the Present

“…There are many more examples in nature such as the development of the coagulation [19] and complement [20] systems. Together, these show that during evolution, many systems have evolved sequentially within eukaryotic organisms, thus proving the hypothesis of Mills et al [1 ]in this issue. …”

“…In this issue of the Journal of Innate Immunity , Mills et al [1 ]offer a journey back to ancient immunity. By describing 4 different sequential immune responses (SIR), we read a fascinating story about amoebas as free-living macrophages and the distinct circulatory system in early vertebrates such as fish, and how all of this has developed into T and B cells.…”

“…With their concept, the authors present a sequential chain of processes, explaining advanced immune responses which have evolved because of evolutionary developments [1]. When reading the article, one may wonder whether there are other examples to support their conclusions.…”

Cells of Innate and Adaptive Immunity: A Matter of Class?

“…The sequence of immune responses has attracted increasing attention where basic and fast cellular defense is common through evolution while slower and more specific responses appear later [12]. Macrophages are required for all animal life and possess a plethora of key immune functions, not least reflected by their M1 and M2 polarization [13,14,15].…”

Gone with the Wind - Innate Immunity and Airway Inflammation

“…However, despite many years of research, their role in allergic inflammation is still not elucidated [2]. During airway inflammation, initial innate immune responses can be divided into a sequence of events where resolution is important [3]. A prolonged and systemic inflammatory response may affect local host defense, resulting from decreased granulocyte activation as well as the production of reactive oxygen species (ROS) [4,5].…”