On Analyzing How the Th1/Th2 Phenotype of an Immune Response Is Determined: Classical Observations Must Not Be Ignored

Abstract

How an antigen interacts differently with lymphocytes and other cells of the immune system, to result in the generation of distinct classes of immunity, is one of the most basic questions of immune regulation. Understanding the nature of these “decision criteria” is central to developing effective medical interventions. Clinical observations lead to the recognition that much disease is due to an inappropriate class of immunity being generated, inappropriate because damaging, as in autoimmunity and allergies, or inappropriate because ineffective, against pathogens and cancer. I argue that the prevalent, contemporary conceptual frameworks, employed to analyze the nature of the decision criterion controlling the Th1/Th2 phenotype of the immune response, are implausible, as they ignore pertinent, classical observations. I outline reasons for favoring a different framework, that takes these observations into account, and explore its pertinence to the design of strategies of medical intervention.

The Prognostic Value of Eosinophil Recovery in COVID-19: A Multicentre, Retrospective Cohort Study on Patients Hospitalised in Spanish Hospitals

“…On the other hand, eosinophil recovery could be a marker of Th2 switching [ 33 , 34 , 35 ], thus possibly indicating a different inflammatory response to SARS-CoV-2 and leading to less susceptibility to ARDS. This is a highly interesting explanation that should be studied further, because it could well lead to new therapeutic strategies for COVID-19.…”

“…Different immunological profiles [ 33 , 34 , 35 ] have been described in other inflammatory diseases of both autoimmune and infectious origin. The ones most commonly described are the Th1 pathways (involving the so-called Th1 cytokines of IL-12, IFN, and TNF-α, leading to activation of CD8+ T cells and classically activated macrophages), the Th2 pathways (mediated by IL-4, IL-5, and IL-13, leading to activation of eosinophils, alternatively activated macrophages, and B-lymphocytes), and the Th17 pathways (mediated by IL-1, IL-6, and the inflammasome, leading to IL-17 and IL-22) [ 34 , 35 , 36 ].…”

Evaluation of Susceptibility and Innate Immune Response in C57BL/6 and BALB/c Mice DuringCandida albicansEndophthalmitis

“…[61][62][63] The effect of inflammatory cytokines on Th1/Th2 skewing has been shown to play a protective or detrimental role against pathogens. 64 For example, TNFα has been shown to promote macrophage activation in Th1 environment leading to protection, while, in the presence of Th1+Th2 response it causes necrosis during Mycobacterial infection. 65 Similarly, different dosages of Leishmania major have been shown to skew the Th2 versus Th1 response in Th2-dominant BALB/c mice leading to its susceptibility or resistance.…”

Pathogen Dose in Animal Models of Hemorrhagic Fever Virus Infections and the Potential Impact on Studies of the Immune Response

“…One possible explanation is that the number of antigen-specific CD4 T cells activated upon recognition of antigen determines, in part, the Th1/Th2 nature of the immune response. This “threshold hypothesis” has been described in detail previously, and both in vitro and in vivo evidence of its effects have been characterized [ 54 , 55 , 56 , 57 , 58 , 59 ]. Briefly, this idea is built upon evidence showing that cooperation between antigen-specific CD4 T cells is required for their activation, following recognition of cognate antigen presented by APC, and suggests that a low number of responding CD4 T cells specific for antigen, with minimal CD4 T cell interactions leads to Th1 responses, while greater levels of interaction between CD4 cells leads to Th2 responses [ 54 , 55 ].…”