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This effect is mediated by interleukin 12 (IL-12) made by effector cytokines, chiefly IFNγ. 92-94 Factors that diminish
macrophages that activates the NK and Th1 cells, and by the Th1 response raise concerns about blunting overall
IFNγ made by NK cells and Th1 cells that activates the efficiency of the anti-viral immune response.
macrophages and stimulates the macrophages to more It may be crucial in specific patients to downregulate
rapidly and fully destroy pathogens they have phagocytosed. an excessive Th2 dominance, in order to promote an
This is central to the adaptive immune response to viral adequate Th1 response. Many factors common in chronic

illness. Th1 response also promotes CD8 cytotoxic illness can drive the patient into Th2 dominance, including
T lymphocytes (CTL’s) which are essential to antiviral stress chemistry (cortisol and NE), 70,71 sleep disruption,
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immunity. (CD8 cells are not immune suppressive, despite asthma, 95,96 and GI tract inflammation, 96,97 among others.
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the lingering terminology). Asthma patients are known to be predominantly Th2
In a study of COVID-19 patients, the total number of dominant, as are patients with allergic or atopic immune
NK cells and CD8 cells has been shown to be markedly styles. 93
decreased, with markers also showing their function to be Diminished reduced glutathione (GSH) status is also
exhausted. Importantly, NK cell and CD8 cell numbers and associated with loss of IFNγ, increase in IL-4, and a shift
function rebound during patient recovery. By contrast, a away from adequate Th1 response and into Th2
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case report involving a single patient showed significant dominance. 98-100 This is especially concerning in light of
Th17 cell activation and CD8 cells that were highly cytotoxic the mutually reinforcing roles of ROS and TGFβ in
and produced copious granzymes and perforin, perhaps inflammation and fibrosis discussed earlier. Depletion of
associated with the specific treatment strategy employed in GSH in lung epithelial lining fluid (ELF) carries concerns
the case. This highlights the necessity of attending to each about loss of anti-inflammatory protection in lung as
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case through the lens of attention to the individual patient’s well as a shift away from anti-viral Th1 response referenced
underlying immunology, with crucial attention to the above.
balance of immune surveillance and activation on one side Additional concern regarding excessive Th2 response
and the need to downregulate excessive inflammatory to the detriment of adequate Th1 comes from evidence
activation on the other. that coronaviruses, in this case coronavirus NSP6 protein,
Crucially, the IFNγ generated by both NK cells and interferes with proper formation of autophagosomes in
Th1 cells drives macrophages to execute a more aggressive such a way as to prevent merging with lysosomes. The
program of destruction of the pathogens the macrophages result may be interference with the ability of immune cells
have engulfed by phagocytosis. Supporting NK cell and to kill virus. It’s noteworthy that IFNγ (the primary Th1
102
90
Th1 cell activation drives the production of IFNγ, cytokine) is required for autophagosome formation and
supporting this function. that IL-4 (the primary Th2 cytokine) interferes with this
There is a prevailing concern in the literature about process. 103-105 The machinery of autophagy is known

macrophages and DCs being infected and destroyed by generally to be required for macrophage phagocytosis and
the SARS-CoV-2 virus. It is established in immunology autodigestion of phagosome contents. Thus, the emphasis
1
that viruses can escape from phagosomes after engulfment on Th1 may have an added utility if SARS-CoV-2 also
by macrophages and DCs. Normally, the macrophage or targets interference with autophagy as a component of its
DC can handle this event through proteasomal degradation pathogen evasion strategy.
and subsequent presentation of the viral antigen via Lastly, animal coronavirus models have shown that
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MHC-1 to naïve T cells that become CD8 cytotoxic mast cells residing in the respiratory submucosa may play
T lymphocytes (CTL’s) that kill the infected cell, so the a mixed role, including the generation of Th2
virus can’t use the cell machinery to replicate. However, pro-inflammatory cytokines under the influence of viral
given the concern about the SARS-CoV-2 virus engaging stimulation and IgE, an antibody type associated with Th2
pathogen evasion strategies that include delaying style immune reaction. Mast cells are stimulated by
macrophage responses and potentially destroying interleukin-5 (IL-5), a cytokine secreted by Th2 cells.
macrophages, a key way to push back against this effect Quercetin has been shown in many human studies to
would be to shorten the time course between macrophage/ modulate mast cell degranulation. 107
DC phagocytosis of a virion (viral protein/viral particle)
or virally infected cell and the time point at which the Target 4 – Anti-Inflammatory Support
engulfed material is lysosomally degraded. This is a generally The key targets in inhibiting inflammation are the
recognized function of IFNγ. NLRP3 inflammasome, and Nuclear factor kappa B
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(NFkB).
Th2 Dominance Patterns Can Thwart the Attempt to NLRP3. This is the inflammasome currently
Support Th1 Response hypothesized to drive lung inflammation and some
In some patients, there may be a cause for concern ARDS fatality risk in COVID-19. The role of the
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regarding a prevailing Th2 dominance. Th2 cells make NLRP3 inflammasome in sepsis has been reviewed.

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interleukin-4 (IL-4), inhibits the production of Th1 cell Inflammasome assembly causes the affected cell to

14 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print Yanuck—Immuno-physiological Approach to COVID-19