Regarding the adaptive immune response, we present two articles covering regulation of CD4 T helper cell and CD8 T-cell effector cell function. Wang et al. provides an overview of the significance of the balance between the regulation of regulator T cells Tregs and T helper 17 cells, with a focus on how the transforming growth factor TGF cytokine superfamily modulates generation and coordinates Treg and Th17 cell function [ 6 ].

On the other hand, Chen et al. provide an overview of the function of mTOR signaling pathways in generation and maintenance of CD8 T memory cells. The authors also discuss the therapeutic potential of modulating mTOR signaling pathways to restore exhausted CD8 T-cell functionality [ 7 ].

In addition to T lymphocytes, B lymphocytes are vital to the adaptive immune response, as they are the cell type responsible for antibody production.

Germinal centers are essential for producing highly specific antibodies, generating diversity, promoting affinity maturation, and establishing long-term immune memory. In this collection, Playoust et al.

discuss B-cell responses in the tumor context and how the tumor microenvironment can influence the B-cell repertoire as well as the BCR specificity, affinity, and function [ 8 ]. In particular, the authors propose that in-depth analysis of tumor-infiltrating B cells may contribute to cancer diagnosis and treatment.

The lymphatic system functions as a conduit for immune cells to migrate between tissues and lymphoid organs, and it also plays an essential role in removing excess fluid and waste from tissues, thereby contributing to tissue homeostasis and immune surveillance.

The article by Angeli and Lim examines the mechanisms that lymphatic vessels use to detect and translate mechanical cues into biological signals and their function [ 9 ].

In summary, this special collection aims not to cover all aspects of each cell type but to promote new biological aspects of each cell type. We also hope that this special collection will inspire new ideas and discussion regarding these cell types. Medzhitov R.

Recognition of microorganisms and activation of the immune response. Article CAS PubMed Google Scholar. Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol. Article PubMed Google Scholar. Dieterich LC, Seidel CD, Detmar M. Lymphatic vessels: new targets for the treatment of inflammatory diseases.

Bied M, Ho WW, Ginhoux F, Blériot C. Roles of macrophages in tumor development: a spatiotemporal perspective. Cell Mol Immunol.

Qu J, Jin J, Zhang M, Ng LG. Neutrophil diversity and plasticity: Implications for organ transplantation. Wang J, Zhao X, Wan YY. Similarly, rats fed mg vs. These animal study results are reproduced in several double blind, placebo controlled clinical trials. The underlying mechanisms of the immunomodulatory effects of vitamin E have been largely elucidated using animal models combined with the cell-based approaches.

It is proposed that vitamin E can enhance T cell-mediated function by directly promoting membrane integrity and positively modulating the signaling events in T cells while also protecting T cell function indirectly by reducing production of T cell-suppressing factors such as PGE 2 from macrophages as previously reviewed 38 , With regard to the indirect effects, vitamin E has been shown to inhibit PGE 2 production.

PGE 2 suppresses T cell response by activating adenylyl cyclase, thus increasing cAMP levels 43 , PGE 2 has broad effects on different components in both the innate and adaptive immune system 45 — 48 , such as inhibiting T cell proliferation, IL-2 production, and IL-2 receptor IL-2R expression The suppressive effect of PGE 2 on T cells concerns inhibition of several early signaling events that occur after T cell activation 48 , and for some events, the PGE 2 -induced inhibition can be prevented by vitamin E.

Although how vitamin E inhibits PGE 2 production is not completely understood, it has been shown that vitamin E can inhibit enzymatic activity of cyclooxygenases COX 49 , which in turn might be associated with reduced production of peroxynitrite Several studies have determined the protective effects of vitamin E on influenza infection in animal models.

Hayek et al. Similarly, Han et al. Few clinical trials have directly examined the effect of vitamin E supplementation on infection in humans. Meydani et al. However, the controversy exists in this topic of research as studies thus far have demonstrated mixed results.

In contrast to studies reviewed above, results from the Alpha-Tocopherol Beta-Carotene Cancer Prevention ATBC study showed positive, no effect, and even negative effect of vitamin E on pneumonia and the common cold depending on the age, smoking history, residence, and exercise, among other factors, of the subjects 56 — The inconsistent and controversial results for vitamin E's effect on infection may be due to the confounding factors such as the difference in health conditions of participants and the intervention protocols.

Even using the same dose, as in a double-blind trial in the Dutch elderly cohort living in the community, Graat et al. However, obvious differences were noted between the two studies, such as the fact that the study by Graat et al. was conducted in free living participants, and the one by Meydani et al.

was conducted in managed nursing homes. It is hoped that these discrepancies may be resolved in future studies with more standardized design and better characterized populations. The transition metal zinc is an essential micronutrient and it is required for controlling key biological processes that affect normal growth, development, repair, metabolism, and maintenance of cell integrity and functionality Its importance to immune system has been intensively studied as previously reviewed 61 — Zinc deficiency is prevalent in developing countries and it is the fifth leading risk factor for bacterial diarrhea and pneumonia Inadequate intake of zinc is also present in the developed countries, in particular more common in the elderly 66 , 67 , which may contribute to development of immunosenescence.

Zinc is a nutrient crucial for maintaining homeostasis of immune system. Its deficiency negatively impacts immune cell development and functions in both innate and adaptive immunity, as manifested with thymus involution and reduced number of Th1 cells, as well as impaired immune functions including lymphocyte proliferation, IL-2 production, DTH response, Ab response, natural killer NK cell activity, macrophage phagocytic activity, and certain functions of neutrophils [reviewed in 68 — 73 ].

Conversely, correction of zinc deficiency by supplementation can reverse impairment in immune system 69 , and reduce mortality from infectious diseases 62 , In addition to boosting defense-related immune functions, the importance of zinc in maintaining immune tolerance is well-recognized.

Zinc has been shown to induce development of Treg cell population 75 , 76 , and dampen pro-inflammatory Th17 and Th9 cell differentiation 77 , In a related and consistent manner, zinc was shown to drive bone marrow-derived DC to develop into tolerogenic phenotype by inhibiting MHC-II expression and promoting expression of the tolerogenic programmed death-ligands PD-L 1 and 2, tryptophan degradation, and kynurenine production leading to skewed Treg-Th17 balance in favor of Treg Although it is clear that zinc deficiency impairs immune function, proving the assumption that zinc supplementation would enhance immune response has been frustrating and full of controversy, which is more so in human studies.

In animal models for zinc deficiency, zinc repletion has been shown to reverse thymic involution as indicated by an increased thymulin activity, thymus weight, absolute number of T cells in thymocytes, and thymic output in both middle-aged 12 mo 80 and old mice 22 mo 81 , 82 , as well as increase T cell mitogen PHA- or Con A-stimulated lymphocyte proliferation and NK cell activity in old mice In a recent prospective clinical trial, Iovino et al.

However, the effects of zinc supplementation on lymphocyte population are inconsistent. Given that aging is associated with impaired immune function and increased risk of infection, and the elderly is more likely to have zinc deficiency, zinc supplementation has been identified as a part of potential solution for the immunosenescence.

Thymulin is a zinc-containing thymic hormone that needs zinc to exert its biological activity 86 , and serum levels of thymulin decline with aging in both mice and humans 87 , Similar to the results in the animal studies mentioned above 80 , 81 , zinc supplementation increased circulating levels of active thymulin in the elderly 66 , 89 , Based on an in vitro study showing that thymulin administration improved the impaired NK cell activity in old mice, the authors suggested that thymulin may in part mediate this effect of zinc Regarding the adaptive immunity, the earlier studies revealed that zinc supplementation was effective in improving DTH response 66 , 94 — More recently, zinc supplementation was shown to increase peripheral blood mononuclear cell PBMC mRNA expression of IL-2 and IL-2R-α a specific subunit of IL-2R in the elderly Barnett et al.

They also observed an increase in T cell proliferation; however this may simply reflect the larger number of T cells present in PBMC before stimulation rather than a change in capacity of T cell expansion Given the importance of zinc to the immune system, in particular its boosting effect on defense-related immune responses, its impact on infection has been studied.

Zinc deficiency is prevalent in children under 5 y of age in developing countries , and a systemic review reported that preventive zinc supplementation was associated with reduction in diarrhea and pneumonia morbidity and mortality in children 3 mo to 5 y of developing countries Several controlled trials have investigated whether zinc supplementation is protective against infection in the elderly population.

A later study by Meydani et al. This speculation is supported by some but not all studies. The supporting evidence includes that low serum zinc levels are associated with several prominent autoimmune diseases such as MS , RA , and T1D Viewed in a larger picture, authors of a recent systematic review and meta-analysis investigated relationship between zinc status and autoimmunity using data from 62 studies that met their inclusion criteria However, although in some cases zinc supplementation was shown to help ameliorate the disease together with relevant changes in immunological events, the causal relationship between zinc deficiency and autoimmune disease is still a matter in debate.

Inflammation is an essential response of a host to infection which helps destroy invading pathogens. However, under certain circumstance the inflammation becomes systemic so that it is harmful and even fatal to the host.

A typical example of this type of systemic inflammatory response is sepsis, a syndrome characterized by organ failure resulting from over-reactive host response to infection. In human sepsis patients and in animal models, low zinc levels probably due to internal redistribution of zinc are associated with increased sensitivity to sepsis and fatality to infection , thus it is proposed that zinc supplementation might be a treatment option to improve the outcomes of sepsis.

In some studies to address this issue, increasing blood zinc levels has been shown to be protective in animal sepsis models , , which is to certain degree echoed by a limited number of clinical trials, mainly in neonates , However, no consensus is reached at present because the benefit of zinc supplementation in sepsis cannot be confirmed in other studies 62 , A key factor involved in this discrepancy is the fact that while immune cells on the host defense side are sensitive to the zinc status, the invading pathogens also require zinc for survival and propagation.

As such, while sequestering zinc is considered a protective response to restrict pathogens, the resulting decline in serum zinc levels may compromise the immune cell functions resulting in adverse effect.

The multiple physiological purposes of zinc level control in the context of infection and sepsis are a topic to be further characterized. From the studies thus far, it is clear that children and elderly are at high risk for zinc deficiency, which is associated with the impaired immune function contributing to the increased morbidity and mortality from infections in these populations.

Improving zinc status by supplementation may be helpful in addressing this problem, particularly for those with low serum zinc levels. However, given the fact that both zinc deficiency and zinc overload impair immune functions leaving a relatively narrow range for delivering benefit, plus the well-recognized heterogeneous manner in response to zinc, further studies are needed to determine the optimal zinc intake for individuals, and these studies should take into account the variations in individual genetic background as well as nutritional and health status.

In addition to being energy-providing macronutrients, many dietary lipids, in particular PUFA, as well as their metabolic products, are capable of regulating cell functions. Of these PUFA, the marine animal-derived n-3 PUFA, composed of mainly eicosapentaenoic acid EPA , and docosahexaenoic acid DHA , have been intensively studied and they are known to greatly impact immune cell functions.

N-6 PUFA, however, are less significant in this regard and in fact they are often used as the control for n-3 PUFA in the studies.

Several recent reviews have provided comprehensive coverage for the role of n-3 PUFA in modulating both innate and adaptive immunity — , thus only emerging novel research is emphasized in this review, with a focus on immunomodulatory mechanisms.

As summarized in the above-mentioned reviews, the potent anti-inflammatory properties of n-3 PUFA is supported by their ability to inhibit production of inflammatory mediators including eicosanoids PGE 2 , 4-series leukotrienes , pro-inflammatory cytokines IL-1β, TNF-α, IL-6 , chemokines IL-8, MCP-1 , adhesion molecules ICAM-1, VCAM-1, selectins , platelet activating factor, and reactive oxygen and nitrogen species.

In addition to inhibiting pro-inflammatory mediators, n-3 PUFA reciprocally increase the production of anti-inflammatory cytokine such as IL One of the underlying mechanisms for the anti-inflammatory actions of n-3 PUFA is thought to concern modulation of gene activation.

Activation of genes for most of the pro-inflammatory mediators is controlled by nuclear factor-kappa B NF-κB , a transcription factor ubiquitous in almost all cell types.

It has been demonstrated that n-3 PUFA inhibits NF-κB signaling , , possibly through interfering with the toll-like receptor 4 TLR4 pathway and its receptor protein MyD88, activating n-3 PUFA membrane receptor GPR, and serving as ligands to bind to and activate PPAR-γ, an anti-inflammatory transcription factor that can trans-repress NF-κB activation.

The most significant breakthrough in n-3 PUFA research is perhaps the discovery that n-3 PUFA are pro-resolution agents by serving as the precursors for several families of pre-resolving mediators, which at least include EPA-derived E-series resolvins, DHA-derived D-series resolvins, and DHA-derived protectins and maresins , Several cell culture and animal studies have demonstrated that resolvins and protectins act to reduce neutrophil infiltration and the inflammatory response, regulate the cytokine-chemokine axis and lower the production of reactive oxygen species — Both resolvin E1 , and maresin 1 have been shown to be protective in animal models of experimental colitis, increasing survival, decreasing disease score and levels of pro-inflammatory mediators.

While this suggests a potential clinical significance, there is very limited data available in humans regarding the immunomodulatory and anti-inflammatory actions of resolvins and maresins. There is ample evidence indicating that n-3 PUFA can modulate cellular and molecular events involved in immune cell activation, particularly those related to cell-mediated immunity.

These T cell-inhibitory actions may be partly attributed to increased lipid peroxidation, modulation of membrane phospholipid composition, and cytoskeletal structure and disruption of lipid rafts — Changes in membrane lipid order are associated with alterations in T cell function , — Most recently, n-3 PUFA have been demonstrated to modulate T cell plasma membranes and oxidative phosphorylation and proliferation The effect of n-3 PUFA on T cell function was also tested in fat-1 mice , , a transgenic mouse model that can endogenously synthesize n-3 PUFA, and the authors demonstrate that alteration in lipid raft formation was one potential mechanism by which n-3 PUFA suppresses T cell function.

This conclusion largely concurs with the findings made in studies using dietary fish oil supplementation , Interestingly, the T cell-suppressive effects of n-3 PUFA are not universal to all T cells.

It has been shown that n-3 PUFA inhibit Th1 and Th17 differentiation, but have little effect on Th2 and Treg development , , — , or even increase Th2 and Treg populations as seen in T1D model mice NOD mice In addition to the direct actions on T cells, studies have suggested that n-3 PUFA may modulate the functions of APC to indirectly affect T cell functions.

N-3 PUFA can also modulate B cell functions including activation, antigen presentation, cytokine production, and antibody generation N-3 PUFA may target B cells to inhibit MHC-II accumulation at the immune synapse, resulting in impaired activation of cognate T cells , N-3 PUFA appears to promote B cell activation and their production of cytokines and antibodies — , which may involve Th2 cytokines, however the exact mechanism is largely elusive.

Given the differential effects within the T cell population and the potent anti-inflammatory functions of n-3 PUFA, protective effects of n-3 PUFA have been reported in conditions of chronic inflammation such as asthma, IBD, including Crohn's disease and ulcerative colitis, and autoimmune disorders such as RA [reviewed in , , — ].

For conditions of chronic inflammation, animal models and human studies support a beneficial role of n-3 PUFA in disease modulation. N-3 PUFA have been demonstrated to be protective in animal studies of IBD, both transgenic models fat-1 mice and experimental models of colitis , , a chronic inflammatory condition in the gut.

Yet, not all pre-clinical models support a beneficial role of n-3 PUFA on disease progression, with some animal studies indicating that large n-3 PUFA doses may exacerbate the disease , The inconstancies in findings from animal studies, likely due to different doses of n-3 and experimental methods, need to be considered when translating conclusions to humans.

In clinical trials in humans, dietary supplementation with n-3 PUFA appears to beneficially affect histological and clinical parameters of IBD , However, a Cochrane systematic review and meta-analysis concluded that data was insufficient to suggest n-3 PUFA as a primary treatment for IBD suggesting that further research needs to be done regarding the efficacy of n-3 PUFA on disease progression and remission of IBD.

Several randomized controlled clinical trials have demonstrated an improvement in clinical outcomes of asthma, a chronic inflammatory condition of the airways, with n-3 PUFA supplementation — Yet not all findings are consistent regarding the improvement of symptoms , , which can be related to variance in n-3 PUFA dose, population studied and study design A meta-analysis and systematic review concluded that fish oil supplementation was unlikely to be beneficial in primary prevention of allergic diseases, including asthma , which is consistent with the conclusion of an United Sates government technical report It has also been suggested that n-3 PUFA may be clinically relevant regarding autoimmune disorders.

Results from a systematic review and two meta-analyses , on marine n-3 PUFA and RA suggest that clinical outcomes related to immune function including joint swelling and pain, disease activity, and use of non-steroid anti-inflammatory drugs are consistently and modestly improved with n-3 PUFA administration.

T1D is another organ-specific autoimmune disease involving pancreatic β cells attacked by autoreactive T cells. A retrospective study reported that long-term dietary intake of n-3 PUFA starting at 1 year of age was associated with reduced risk of developing islet autoimmunity in children with familial T1D Similarly, Norwegian infants receiving cod liver oil in the first year of life was associated with a significantly lower risk of T1D, which was likely due to n-3 PUFA rather than vitamin D because no difference was observed in those receiving other vitamin D supplements These results are supported by animal studies using the appropriate disease models.

For example, long-term dietary intervention with n-3 PUFA in NOD T1D model mice reduced T1D incidence and severity, together with decreased pro-inflammatory T cell subsets Th1, Th17 and cytokines, and increased anti-inflammatory T cell subsets Th2, Treg The primary genera of probiotic microorganisms include Lactobacillus L.

Lactobacillus and Bifidobacterium have a long history of being safely used in the form of dairy products, and they are also found to be a part of the gut microbiota.

Dietary intake of probiotics allows their intimate interaction with the gut mucosa and mucosal immune system which host the largest part of body's immune cells.

Probiotics modulate immune and inflammatory response in gut through their interaction with intestinal epithelial cells , , M-cells in Peyer's patches , , and DC , Effects of probiotics on the mucosal system are not limited to gut, with modulatory effects observed in the other locations of the mucosal system such as upper respiratory tract Increasing evidence suggests that probiotics may also positively impact the systemic immune system , , — Several studies have indicated that probiotics could induce pro-inflammatory cytokines to facilitate immune response against infection, and they may also induce anti-inflammatory cytokines to mitigate the excessive inflammatory reaction leading to a balanced homeostasis [reviewed in , , ].

It is worth noting that the effect of probiotics on cytokine production may be strain-dependent given the mixed results showing that consuming probiotics induces IFN-α [ B. lactis HN, ], reduces TNF-α [ L.

rhamnosus GG, ] and IL-2 [ B. animalis ssp. Lactis Bb12, ], and has no effect on IFN-γ, IL-1β, and IL-2 [ L. casei , ]. Probiotics can benefit innate immunity by impacting intestinal epithelial cells, phagocytic APC DC and macrophages.

Epithelial cells not only serve as physical barrier but also emerge as active interphase between foreign microorganisms or food components and the body, and in doing so they participate in controlling the body's immune response Some strains of probiotics can modulate mucosal immunity by colonizing on epithelium and stimulating the epithelial secretion of signaling molecules or directly acting on immune cells in the mucosal immune system, in particular DC, which protrude through epithelial junction.

In terms of defense function, probiotic lactobasilli are shown to increase intestinal IgA secretion and improve the resistance to infection , Lactobasilli are also shown to modulate innate immunity and DC function.

Administration to mice with two B. strains of lactobasilli isolated from healthy centenarians enhanced NK cell activity and phagocytic activity of macrophages , and coupled with probiotics L.

fermentum strain PL and L. plantarum strain PL enhanced the phagocytic capacity of peritoneal leukocytes Mice receiving L. paracasei Ag , which together suggest that probiotics may enhance specific immunity by promoting APC function.

Providing further support, Vidal et al. showed that following vaccination with keyhole limpet hemocyanin KLH , old mice fed L. Consistent with the results from animal studies, human studies have reported that certain strains of probiotics could impact the innate immunity.

Healthy, older individuals receiving B. The immuno-enhancing effect has been demonstrated with use of different strains of probiotics including L. casei DN , L. lactis , 3. Evidence for the beneficial effect of probiotics on adaptive immune responses largely relates to their modulatory role in promoting vigorous effector functions of both T and B cells while maintaining the regulatory functions of immune system preventing autoimmune inflammatory response.

While it is difficult to characterize how probiotics affect T cell polarization and their effector functions, including particular spectrum of cytokine production, because their effects in this regard are widely varied depending on the strains used, it appears that they promote production of Th1 cytokines IFN-γ, IL-2, IL, TNF-α , Th17 cytokines IL, IL , Treg cytokines IL, TGF-β , but inhibit Th2 cytokines IL-4 , In animal studies, age-related decline in producing T cell cytokine IFN-α and IFN-γ by mitogen-stimulated splenocytes was reversed after administration of viable L.

bulgaricus and S. Similarly, administration of B. Favorable effects of probiotics on both APC and cell-mediated functions suggest a potential benefit for increasing vaccination efficacy, which is particularly important in the older individuals who have lower response to vaccines than the younger individuals thermophilus and L.

Similarly, a short period 7 d of L. GG or L. lactis supplementation had no effect on humoral response induced by Salmonella typhi oral vaccine in healthy adults These results emphasize the importance of identifying optimal periods and doses of supplementation for probiotic intervention.

More relevant to clinical application, probiotics have been shown to enhance the host's resistance against infection. For example, studies have reported that fermented milk containing Lactobacillus reduced the duration of respiratory and gastrointestinal infections — , and reduced the risk of the common cold casei DN for 3 wk had shorter duration of winter infections gastrointestinal and respiratory compared to those in the control group 7 vs.

Since the probiotics used in these studies contained both the strain L. casei DN and the yogurt cultures which include L.

thermophiles , as well as their fermented metabolites, it is difficult to distinguish the relative contributions of these components as well as the likely synergistic effects among them.

There is increasing interest in investigating the effect of probiotics apart from the general effects of yogurt. Mane et al. reported that the institutionalized healthy older persons who consumed a mixture of L.

Beneficial effect of probiotics on the immunity and defense function has been observed in some studies but the reproducibility of this effect is still a widely recognized problem in the field. In addition, for those positive effects observed, the exact working mechanisms have not been well-elucidated.

A generally accepted notion is that these effects of probiotics are related to their capability of reinforcing the intestinal barrier and helping maintain normal permeability, competing with pathogenic microorganisms in the gut for nutrients and attachment to the gut epithelium, and regulating immune cell functions to clear infection while preventing excessive response and inflammation.

Probiotics exert their protective effects against infection through multiple mechanisms. A unique character separating them from other nutrients and non-nutrient phytochemicals is the fact that they are bacteria themselves, and a prominent mechanism for their anti-infection property is their direct impact on pathogens independent of immune system.

They compete with pathogens for colonizing epithelium and also release antimicrobial substances together leading to an unfavorable microenvironment for pathogens. From the experimental aspect, the in vitro studies can be used to assess the direct effect of probiotics on different immune cells, usually by co-culturing them and then measuring the change in phenotype and functionality of the targeted cells.

In the in vivo setting, however, it is difficult to distinguish the direct effect from indirect effect. Thus, study on probiotics should take into account the gut microbiota large picture. It is increasingly recognized that gut microbiota are in fact the constituents of our body and they significantly impact a variety of physiological functions including immunity.

Probiotics have also been tested in improving allergies. found that participants receiving Lactobacillus casei Shirota drink for 5 mo had lower antigen-induced production of IL-5, IL-6, and IFN-γ in PBMC, as well as increased IgG and decreased IgE levels in serum compared to the placebo group; however, no difference in clinical symptoms was observed In a later trial with similar design but larger sample size and more comprehensive outcome measures, the same group found difference between probiotics and control groups in several immunologic parameters suggesting favorable effect of probiotics on allergy, however, they once again failed to detect difference in primary effect on clinical endpoints By viewing many other trials which demonstrated mixed results, it is reasonable to conclude that evidence is lacking to support the beneficial effect of probiotics on allergy at present.

As with their immuno-modulating and anti-infection effects, this may be related to several factors that should be addressed in the future as discussed in the followings. Although promising, many claimed health benefits of probiotics have not been substantiated by intervention studies.

Probiotics include a wide variety of species and they in turn are composed of many strains, either naturally occurring or intentionally modified, which have been used in different studies. It is likely that the probiotics' immune-modulating effect is strain-specific.

Thus, the positive or negative findings in certain strains should not be generalized for drawing conclusions, and likewise, beneficial effects observed on certain strains cannot be extrapolated to other strains without direct experimental evidence. Additionally, the interaction among probiotics adds further challenge, which may be predicted by simply summing up their respective effects when administered individually.

On the side of subjects being tested, their health status is a factor known to significantly influence the magnitude or even direction of response to a given probiotic intervention. For example, several strains of Lactobacilli and Bifidobacteria have been shown to differentially affect the Th1 and Th2 responses in PBMC from healthy and allergy patients , and Lactobacillus GG administration stimulated expression of phagocytosis receptors in normal healthy individuals but suppressed induction of these receptors in milk-hypersensitive individuals It is also worth pointing out that results from animal studies cannot be directly extrapolated to humans before being validated by clinical trials.

The other thing should in mind given the well-known fact that negative results tend to be not submitted or get rejected after submission, it is conceivable that there must be more studies than reported that have failed to prove efficacy of probiotics in favorably impacting immune function and related diseases.

Nevertheless, the mechanisms underlying the reported effects of probiotics have not been well-elucidated, and obtaining such information would help identify effective probiotics for developing preventive and therapeutic strategies as well as nutritional support in targeted diseases.

It is no doubt that fulfilling this task requires tremendous effort which not only involves screening individual probiotics, the combination of various strains and doses, and the timing and supplementation period needed, but also includes consideration of individual's health status and disease type.

EGCG is the most abundant and also most biologically active, which is believed to be a primary factor responsible for green tea's health benefit.

Green tea and EGCG have been shown to be effective in modulating multiple aspects of innate and adaptive immunity In the innate immune system, in vitro EGCG supplementation dose-dependently reduces neutrophil migration induced by chemokine IL-8 , and neutrophil chemotaxis toward cytokine-induced neutrophil chemoattractant-1 The oral administration of green tea extract or EGCG is shown to inhibit neutrophil recruitment to the inflammation sites in several animal studies such as mouse model of inflammatory angiogenesis , and rat model of ovalbumin-induced allergy , and to inhibit neutrophil proteolytic enzymes in a rat smoking model Similarly, EGCG is also shown to inhibit monocyte migration by reducing secretion of the chemokine monocyte chemotactic protein-1 MCP-1 and its receptor CCR2 expression However, this is not without controversy as some investigators have reported varying results.

For example, studies have shown that in vitro EGCG supplementation may increase production of the inflammatory mediator PGE 2 and mRNA expression of COX-2 in RAW The discrepancy in reported EGCG effect may be related to the varied experimental settings and procedural differences.

Among other things, it is possible that basal levels of inflammatory status may cause a host to respond in different manner to EGCG administration and as such, the nature and magnitude of EGCG effect may vary depending on inflammation state under normal or disease condition.

DC as APC are also affected by EGCG. It has been reported that EGCG retards bone marrow-derived DC maturation and inhibits their functions as indicated by reduced ability to capture Ag dextran , secrete IL, and express CD80, CD86, and MHC class I and II, culminating in impaired APC function in inducing Ag-specific T cell-mediated response allogeneic T cell proliferation and IL-2 production Similar effects were reported in a study using human peripheral blood monocytes-derived DC A very limited number of studies have examined how EGCG impacts other innate immune cells such as NK cells, mast cells, and basophils; however, they are largely cell-based studies and the results are insufficient for a meaningful speculation.

Little is known regarding the humoral immunity except that in vitro EGCG was shown to inhibit B cell proliferation , Wu et al. reported that in vitro supplementation with physiologically relevant levels of EGCG 2.

EGCG also inhibited antigen-specific T cell proliferation by affecting both T cells and APC while the direct effect on T cells appeared to be predominant The T cell-suppressive effect of EGCG was confirmed in the in vivo study in which mice were fed a diet containing 0.

However, some other studies reported different results which include EGCG-induced upregulation in mRNA levels of Th1 cytokines IL-2 and IFN-γ and Th2 cytokines IL-5 and IL in Jurkat cells , and increased IL-2 production in response to PMA and PHA in human PBMC These discrepant findings may be related to the different experimental conditions such as cell type, EGCG concentration, and stimulation condition used.

In addition, sometimes altered cytokine levels may not necessarily tell the situation in their synthesis. For example, EGCG did not affect IL-2 levels in the culture of T cells stimulated for 24 h or shorter, but caused a dose-dependent elevation of IL-2 in 48 h cultures Further tests showed that EGCG did not affect IL-2 synthesis as confirmed by intracellular staining and mRNA levels, but instead, it reduced IL-2R expression, which together suggest that higher levels of IL-2 might result from increased IL-2 accumulation due to a reduction in IL-2R-mediated IL-2 internalization and utilization This hypothesis was supported by a later study showing that EGCG-mediated inhibition of IL-2R involves all three IL-2R subunits: IL-2Rα, IL-2Rβ CD, shared with ILR , and γc CD, shared with IL-7R and ILR , as well as their downstream signaling events The mechanisms for EGCG-induced inhibition of cytokine production and T cell proliferation are yet to be clearly elucidated; however, some evidence from in vitro studies suggests an involvement of EGCG-induced interference with early signaling events in T cell activation.

It has been reported that in Jurkat T cells, EGCG inhibits the early stages of the T cell signaling pathways including activation of Zap70, LAT, phospholipase Cγ1, ERK, MAPK, and transcription factor AP-1 ; the cyclin dependent kinase inhibitor p27 Kip1 , a negative regulator of cell cycle progression, was identified as a molecular target of EGCG From the reported effects of EGCG on immune cell functions, particularly its anti-inflammatory, T cell-suppressing, and differentiation-modulating effects on T cell subset development, EGCG appears to have a potential benefit in clinical application for preventing and mitigating T cell-mediated autoimmune diseases.

Indeed, administration of EGCG has been shown to improve several autoimmune diseases in respective rodent models including experimental autoimmune encephalomyelitis EAE, for human multiple sclerosis, or MS , collagen- or Ag-induced arthritis for RA , the chemically-induced colitis for IBD , and the non-obese diabetic mouse strains for Sjogren's syndrome [reviewed in , ].

In the earlier studies, the beneficial effect of EGCG in these autoimmune diseases is largely attributed to EGCG's anti-inflammatory properties. However, thus far almost all the evidence is from animal studies, and the efficacy and safety for EGCG's clinical application in human diseases remain to be established.

It is well-established that nutritional inadequacy greatly impairs the functioning of the immune system. In addition, it is increasingly recognized that nutrient intake, above what is currently recommended, may beneficially affect immune function, modulate chronic inflammatory and autoimmune conditions, and decrease infection risk.

This includes both macronutrients lipids such as n-3 PUFA and micronutrients zinc, vitamin D and vitamin E , in addition to phytochemicals and functional foods probiotics and green tea. Many of these nutritive and non-nutritive food components are related in their functions to maintain or improve immune function including inhibition of pro-inflammatory mediators, promotion of anti-inflammatory functions, modulation of cell-mediated immunity, alteration of APC function, and communication between the innate and adaptive immune systems.

Figure 1 provides a schematic summary of the immuno-modulating features for the six types of food components discussed in this review.

It should be in mind that this simplified picture cannot cover complete outcomes in the respective research, nor can it accurately reflect the controversial issues present. It is particularly worth mentioning that effects of probiotics cited in the figure are based on the results for some strains.

Considering the well-recognized strain-specific feature of the biological effects of probiotics, caution should be taken in data interpretation and extrapolation. Figure 1. Immune cell functions affected by vitamins D and E, zinc, n-3 PUFA, probiotics, and EGCG. D, vitamin D; E, vitamin E; Z, zinc; n-3, n-3 PUFA; PB, probiotics; EG, EGCG; , increase; , decrease.

Effects of probiotics cited here are for some strains; given the strain-specific nature for the effects of probiotics, these results should not be generalized.

The properties of the nutrients, phytochemicals, and functional foods in modulating immune function have significant implications for inflammation-mediated conditions. Both animal and human studies have presented promising findings suggesting a clinical benefit of vitamin D, n-3 PUFA and EGCG in chronic inflammatory conditions, n-3 PUFA and EGCG in autoimmune disorders, and vitamin D, vitamin E, zinc and probiotics in protection against infection.

However, the discrepancy in results from many studies adds the challenge and complexity of nutritional immunology research; as the result, there is no clear consensus at this time regarding the clinical relevance of these dietary components.

In some cases, results in human studies are not always consistent with pre-clinical animal models, or the immunomodulatory effects have not yet been examined in humans. Moreover, there is great variation among human study designs, the doses used, and the populations of study, demonstrating a need for more standardized clinical trial designs, better characterized populations, more information for determining the intervention dose used, and more meaningful outcome measurements chosen.

Particularly for zinc, vitamin E, n-3 PUFA and probiotics, clearly there is need to establish the optimal doses for maximum clinical benefits, which may likely differ depending on the age, genetic background, and nutritional and health status of the population of study.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Any opinions, findings, conclusion, or recommendations expressed in this article are those of the authors and do not necessarily reflect the view of the U. Department of Agriculture. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This work was supported by the U. Department of Agriculture, Agriculture Research Service under Specific Cooperative Agreement , and the National Research Foundation of Korea NRFR1A1A1A EL is the recipient of a Canadian Institutes of Health Research Postdoctoral Fellowship.

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As the immune system becomes overworked, the body loses its ability to respond to invaders quickly and efficiently. This leads to more toxic build-up and creates a cycle of poor health. It is a gentle detoxifying formula for individuals with a normal to strong constitution. Support and modulation of the adrenal system is indispensable in the regulation of ion balances, as well as being a final site of integration for the stress response.

Formulas to take: Loving Energy® - The ingredients in Loving Energy® are often used for relieving stress and exhaustion, for support of the lungs and the adrenal system. Used by Taoist monks to replenish adrenal reserves while praying for peace on earth, this formula is equally appreciated by those who care, support, and creatively give on a daily basis.

Available as a traditional alcohol tincture or alcohol free. Keeping the body balanced by supporting detoxification and replenishing with phytonutrients repels invaders and keeps the immune system strong. Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity.

Current Clin. doi: Evidence-based efficacy of adaptogens in fatigue and molecular mechanisms related to their stress-protective activity. In: Bonn K. International Evidence—Based Complementary Medicine Conference; Armidale, Australia.

Immune Responses in the Liver. Annual Review of Immunology. Institute for Chronic Diseases, University of Calgary. Overview of Gut Immunology. PMID: DOI: Alexander Panossian and Georg Wikman.

Published online Jan Terrence Deak. Dynamics and hormonal mechanisms. Dhabhar FS, Miller AH, McEwen BS, Spencer RL. J Immunol. SHOP All PRODUCTS. BIORAY Infant. BIORAY Kids®. BIORAY Daily®. BIORAY Professional®. RAYZ made for Teens. Where to Start. Bioray Difference.

About BIORAY Kids®. About BIORAY. Contact Us Feedback. Find Store. Your cart is empty. Why is it Important? How does it work? inhibitors of TMPRSS2 can stop activation of viral protein, 3. antibodies against S1 and S2 can prevent attachment with host ACE-2, and 4.

a fusion inhibitor can prevent viral entry. Our nonspecific immunity produces a rapid response to viral infection and acts as the first line of defense. This allows our body time to prepare the specific immunity that needs to be triggered. It is always there in our body and responds as soon as a pathogen invades our body Innate immunity involves physical and chemical barriers and includes cellular response.

Major cell types involved in this are leukocytes, neutrophils, monocytes, eosinophils, basophils, and natural killer cells While, neutrophils and monocytes carry out phagocytosis of the invaded pathogen to impart the innate cellular response, natural killer cells kill the invaded pathogen by inducing apoptosis.

Apart from this, the complement system also plays a vital role in innate immunity Innate immune response quickly responds to the SARS-CoV-2virus whenever a healthy person comes in contact with an infected person Figure 2A.

Various studies have reported these symptoms in COVID patients 52 , But viruses that escape from the mucus and cilial lining of the trachea finally reach the alveoli and enter type-2 pneumocytes As the virus replicates in these cells, patients remain asymptomatic up to two weeks post-infection.

But continuous virus replication causes a cellular injury that involves the synthesis and secretion of inflammatory mediators like leukotrienes, prostaglandin, and histamine, which make up the second line of the innate response 54 , The main goal of inflammation is to isolate, destroy, and inactivate the invader, remove debris, and repair the injured tissue.

Due to inflammation, circulating neutrophils and monocytes rush to the site of infection, where they start phagocytosis of the invading virus Figure 2 Innate immune response against SARS-CoV A Early innate immune response and development of symptoms. Host immune response activatestype-2 pneumocytes invaded by the virus.

Inflammatory cytokines IL-1, IL-6, and TNF-1α activate the macrophages. Macrophages in acute cases release small proportions of inflammatory markers that not only attract the circulatory monocytes and neutrophils at the site but also increase the body temperature.

B Delayed innate immune response and development of severe pneumonia. Circulating inflammatory mediators IL-1, IL-6, and TNF-α in blood further exacerbate the acute innate immune response by increasing the chemotactic effect of monocytes and neutrophils towards the lungs.

The monocytes and neutrophils leak out through the endothelial cells and enter into the alveoli. The second type of macrophages, i. As a result, excess fluid accumulates in the alveoli resulting in severe pneumonia. Further, these cells also secrete IL-1, IL-8, and TNF-α,enhancing the chemotactic effect of the circulating monocyte and neutrophil cells to squeeze through blood capillaries to reach the extravascular region and finally the alveoli Macrophages also secrete IL-1 and TNF-α, which act on the hypothalamus which causes high fever and acts upon the bone marrow, which causes leukocytosis Virally infected cells also produce a lot of interferons IFNs which play an essential role in innate IFN-α and β and adaptive immune responses IFN-γ Phagocytosis is followed by the formation of pseudopodia, the engulfment of the virus and the formation of the phagosome, and then a fusion of lysosome-containing vesicles which causes hydrolysis and the degradation of the ingested virus antigens.

In neutrophils, the viral antigens are finally released into the extracellular region from where they reach the lymph nodes and activate B; cells in the adaptive immune system.

Along with that, if the engulfed virus is too strong to be degraded into antigens, then the neutrophils undergo self-lysis through a free radical-induced mechanism There is one more mechanism known as neutrophil extracellular traps NETS by which neutrophils can inhibit viral replication.

The nucleic material released from degraded neutrophils moves to the extracellular region, binds to the antigen with its histone protein, and causes lysis of that antigen. Then, cathepsin-like enzymes initiate hydrolysis of the complex thus formed 60 , Monocytes have a different fate after phagocytosis.

The hydrolyzing released antigens are not released into the circulation but are thoroughly processed inside the monocytes and expressed on the major histocompatibility complex-I and II. MHC-I is expressed by all nucleated cells, but MHC-II is only presented by the antigen-presenting cells macrophages, dendritic cells, and B-lymphocytes The monocyte-derived macrophages reach the lymph nodes, which also stimulate an adaptive immune response.

The complement system is a significant player in the immune system. It further enhances microbial clearing by phagocytic cells utilizing liver complement proteins and antibodies The complement system involves the activation of a cascade of reactions with the attachment of antibodies on the antigen to form a membrane attack complex MAC , which includes a channel in the antigen cells.

Water and ions leak out from the cells, and ultimately lysis of antigenic cells takes place There are three pathways through which the complement system can act:. Classical pathway: The pathway is initiated to bind antibodies to the antigen present on the foreign cell.

C1 is the first complement protein that attaches to the Fc part of the antibody. Subsequently, complement proteins C4, C2, C3b, C5b, C6, C7, C8, and C9 bind to each other and form a long complex. The complex breaks at the interface of C3band C5b.

The pentameric complex comprises an MAC that leads to the lysis of cells. The remaining complex acts as opsonin for the circulating macrophages and is phagocytized. Released complement C3a and C5a are acted upon by the protease released by mast cells, which are activated and augment the inflammatory response by attracting monocytes and neutrophils and further augment the inflammatory response Alternative pathway: The complement protein directly binds without an antibody with an antigen present on the foreign cell and initiates a cascade reaction that involves subsequent attachment with C5b, C6, C7, C8, and C9.

Finally, the complex breaks at the interface of C3b and C5b, and the rest of the steps are like the classical pathway Lectin pathway: The pathway starts with the binding of lectin with mannose molecules present on the antigen.

Attachment of lectin is followed by complement proteins C4, C2, C3b, C5b, C6, C7, C8, and C9. The rest of the steps are like the classical pathway Apart from the circulating complement proteins, virally infected cells produce interferons released into the extracellular region and bind with the receptors on healthy cells and stimulate them to produce degrading enzymes.

When these healthy cells get infected with the same virus, the enzymes activate and kill the invading virus. The enzymes break the viral messenger RNA and thus viral protein synthesis Further, IFNs enhance the phagocytic activity of macrophages, stimulate the production of antibodies by βcells, and enhance the killing power of natural killer cells and cytotoxic T cells Natural killer cells, a special kind of lymphocyte cells, are the next fighters of the innate immune response.

These cells kill only those cells which lack MHC-I on their surface Once they come in contact with cells, they release perforin and create pores in the plasma membrane of the invaded cells. Consequently, ions and water rush inside the infected cell leading to cell swell and burst Unfortunately, the dysregulated innate immune response is observed in COVID patients.

A higher level of pro-inflammatory cytokines like IL-1, IL-6, TNF-α, and chemokines 6are noted in the serum of severely infected patients 71 Figure 2A.

A higher number of neutrophils and a lower number of lymphocytes are also observed in the patients. Cytokines and chemokines have an essential role in the innate immune response A recent clinical report of 41 patients from the Huanan sea food market reported a high level ofIL-2, IL-7, IL, IP,Granulocyte colony-stimulating factor G-CSF , MCP-1, MIP 1-α, and TNF-α, particularly in those patients who were in the ICU The presence of IL-2 in COVID patients indicate activation of the adaptive immune response IL-7 works at all stages of T cell development Raised levels of IL-7showed that adaptive immune response is rapidly required in patients involved in the above study IL is an anti-inflammatory cytokine secreted by the regulatory T cells, macrophages, dendritic cells, Th1, and Th2 cells.

Irrespective of its source, IL inhibits the functions of macrophages and dendritic cells and limits the functions of Th1 and Th2 cells as well as that of natural killer cells It is previously reported that IL production increases dysregulated immune response as it can damage the host cells. High expression of IL in COVID patients could be one reason behind the delayed and weak adaptive response Elevated granulocyte colony-stimulating factor G-CSF is a hematopoietic growth factor indispensable for the proliferation of and differentiation in neutrophils Higher levels of G-CSF could be the main reason behind the observed neutropenia in COVID patients IPor CXCL is a 10kDa protein secreted by leukocytes, neutrophils, eosinophils, monocytes, epithelial, and endothelial cells in response to IFN-γ, which acts upon the CXCR3 receptors present on the activated T cells, β-lymphocytes, natural killer cells, dendritic cells, and macrophages It is reported that IL plays an essential role in T cell trafficking in various infections caused by parasites like Toxoplasma gondi Monocyte chemoattractant protein-1 MCP-1 , also known as CCL-2, plays an important role in chemotactic monocytes and macrophages and has a repairing role in the damaged tissue.

The said effect of MCP-1 is already reported in previous studies Production of MCP-1 by monocytes involves the infection of monocytes with the virus, which then releases INF-β, which acts on other leucocytes.

These leucocytes secrete some unknown soluble substance that stimulates the monocytes to secrete MCP-1 protein for chemotactic purposes. The upsurged level of MCP-1 reported in the above study showed the involvement of monocytes and macrophages at the injury site due to SARS-CoV-2 Macrophage inflammatory protein1α MIP-1α or CCL-3 is the next cytokine observed in patients with SARS-CoV Various studies have reported that MIP-1α enhances leukocyte trafficking at the site of infection The movement of the leucocytes towards the injury site further augments the inflammatory response through TNF-α, IL-1, and IL Therefore, to stop further inflammatory response, inhibition of MIP-1α becomes crucial.

A study on the same has already shown reduced recruitment of neutrophils when MIP-1α was selectively inhibited by an anti-MIP-1α antibody Tumor necrosis factor-α TNF-α is the master regulator of inflammation.

It is known that TNF-α contributes to inflammation by participating in vasodilation and edema formation, enhancing adhesion of leucocytes to the epithelium, regulating blood coagulation, inducing oxidative stress in inflammation, and finally by inducing fever Augmented TNF-α in the above study further evidenced the development of strong inflammation in SARS-CoV-2 patients.

Zhou et al. They observed a heightened immune response by taking samples directly from the bronchoalveolar lavage BAL instead of taking blood samples. Cell composition analysis of BAL fluid of COVID patients showed neutrophils, eosinophils, dendritic cells, and mast cells.

Interestingly, like previous studies, raised NLR was also observed in this study, which again confirms the role of NLR in COVID pathogenesis They also observed pro-inflammatory cytokines and chemokine genes IL-1B, CXCL, CXCL-8, and CCL-2 along with specific antiviral interferon-stimulating genes ISGs like IFIT and IFITM in BAL.

IFIT and IFITM genes belong to the family of genes called IFITs expressed by the infected viral cell to initiate INFs synthesis in nearby healthy cells and thus play an important role in the host innate immune response It is previously reported that IFIT-coded proteins interfere with the viral translation process and thus with the viral replication process The raised levels of INFs in COVID patients would result due to overexpression of IFIT and IFITM genes to combat viral infection in nearby healthy cells They also observed an upregulated level of calgranulin genes with pleiotropic functions in inflammatory disorders SA8, SI00A Interestingly, the upregulatedIL-1RN and SOCS3 were also observed, which confirms feedback inhibition of cytokines as both these genes have an antagonistic function on cytokine synthesis.

Among the upregulated cytokines, CXCLis observed as highly expressed in all SARS-CoV-2 patients, highlighting its role in COVID pathogenesis CXCLhas a major chemoattractant role in the mucosal tissue during cellular injury, especially in the lungs.

The chemotactic neutrophils further exacerbate inflammation by CXCL-8, CXCL, and CXCL-2 as these cytokines play a crucial role as neutrophil chemoattractants While most studies on SARS-CoV-2 shed light on the innate immune response, few studies also reported activation of the adaptive immune response in COVID patients.

A recent survey of 34 hospitalized patients evidenced the activation of humoral-mediated response part of the adaptive immune response in SARS-CoVinfected patients. The blood antibodies, IgG and IgM levels, were carefully monitored for up to four months.

It was concluded that IgG antibody level continuously kept increasing after recovery in SARS-CoVinfected patients while the blood level of IgM first increased and then kept on decreasing. This study evidenced the activation of B cells producing specific antibodies against SARS-CoV-2antigens Another study was carried out by Eugenia Ziying Ong and colleagues, who reported a high-level expression of IL-1 in severe cases of SARS-CoV-2 A similar study was conducted using the blood samples of COVID patients.

The severity of infection was described based on cytokines IL-6, IL-8, and IL in cellular microparticles cMPs. These cMPs were reported to contain cellular receptors, cytoplasmic proteins, nucleic acids RNA, micro-RNA, and DNA , and cytokines.

A high number of cMP was written in the blood of COVID patients compared to that of healthy persons. Upon cytokine analysis, a higher level of IL-6, IL-8, and IL was detected in severe pneumonia patients. Low levels of IL-6 secreted by macrophages can protect the lung alveoli.

Still, the excessive release of IL-6 can adversely affect them by inducing fibrinogen activation and activation of coagulation factors, inhibit endothelial repair, and thus increase the permeability of blood vessels which causes inflammatory lung injury.

IL-8, with its strong neutrophil chemotactic and activation potential, can further induce inflammation. Like IL-6, a low level of IL-8 protects the lungs, but a higher level can damage them. On the other hand, IL has an anti-inflammatory action and can monitor the host immune response through T helper cells; it can also inhibit overexpression of pro-inflammatory cytokines and thus can serve as the best prognostic marker to control the host immune response along with IL-6 and IL-8 There is an increase in antibody-secreting cells ASCs , follicular helper T cells TFH-cells , and SARS-CoVspecific IgM in mildly infected patients, and IgG is observed before symptomatic recovery.

In severely infected patients, a high level of differentiation of subsets of macrophages has been reported. RRR et al. first found four subgroups of macrophages classified as FCN1, SPP1, and FABP4 markers in severely infected patients.

These express higher inflammatory mediators like cytokines, CCL-2, CCL-3, CCL5, IL-8, CXCL, and CXCL11, and hence play a major role in inflammation of the alveolar sac.

Contrary to this, subgroup3 macrophages, i. The relative concentration of the two types of macrophages would determine if there would be an inflammation response or repairing action on the alveoli. It is previously reported that the lipid surfactant is essential for the efficient working of alveoli as it has a major role in reducing alveolar surface tension.

A decrease in the productivity of the surfactant can lead to the collapse of the alveolar sac and hence respiratory failure in the infected patients. In severely infected patients, dysregulated innate immune systems accumulate fluid in the gap between alveolar and endothelial cells and cause difficulty breathing.

Most recent studies have reported these symptoms in COVID patients Adaptive immune response specifically kills bacterially and virally infected cells. It uses three reactions: humoral response, antibody-mediated response, and cell-mediated response, which uses specific cytotoxic cells It is activated when neutrophils release phagocytized antigen fragments into the circulation and when antigen-presenting cells macrophage, dendritic cells reach the lymph nodes Figure 3 Further, the differentiation of βcells into antibody-secreting cells depends on IL-4 provided by activated T helper cells.

The antigen on MHC-II is recognized by the T cell receptor TCR. The final step in the activation of T helper cells involves secretion of IL-1, and it binds toIL-1 R on the T helper cells Figure 4. As a result, T helper cells get activated and undergo auto-activation with IL-2,and T helper cells 1 Th1 proliferate into numerous T helper 2 cells Th2 ,which further enhances the expression of IL-4 and IL The secreted IL-4 and IL-5 serve essential functions on β cells.

IL-4 enhances the colonial expansion of βcells, and IL-5 triggers their differentiation into antibody-secreting plasma cells Secreted antibodies neutralize the circulating antigen and enhance the clearing of the pathogen by activating the complement system, as discussed above.

Poor activation of antibodies secreting βcells has been reported in COVID patients. According to the findings of one study, antibodies were produced against the RBD of the spike protein and nucleoprotein in the COVID patients with a high viral load. After 20 days of hospitalization, viral RNA was continuously detected in the posterior oropharyngeal saliva of those patients, indicating poor activation of βcells Figure 3 Activation of adaptive immune response in lymph nodes.

The killing of viral-infected cells damages the type-2 pneumocytes which is followed by accumulation of fluid in the space inside the alveoli.

Excessive mechanical injury to the alveolar cells damages the alveolar epithelium and thus causes respiratory failure which ultimately develops into ARDS. Figure 4 Normal adaptive immune response.

Activated CTL, B cells, and natural killer cells after being activated in the lymph nodes translocate towards the lungs. In the lungs, CTL and NK cells starts clearing the SARS-CoVinfected cells. Both these cells kill cells by the inducing apoptosis in the target cells by secreting granzymes which form perforins in the target cells.

Consequently, ions start leaking, and initiated apoptosis can be observed by formation of membrane blebs. The small membranes blebs are then phagocytosed by the neutrophils. Antibodies secreted from the B cells inhibit the virus replication by neutralization.

Antibodies also help in opsonization and phagocytosis of the virus by neutrophils. Once stimulated by the antigen, CTLs from lymph nodes start traveling towards the site of infection through the bloodstream. The antigen on the MHC-II is read by the CTLs, which in response starts producing perforin and granzymes.

Perforin creates pores in the virally infected cells through which granzymes enter the same cell and initiate apoptosis of the infected cell The adaptive immune response also comes into action along with the innate immune response in severely infected patients.

Along with these cells, natural killer cells, although a part of innate immunity, play an important role in killing SARS-CoVinfected cells. Firstly, all those cells that lack MHC-1 protein on their surface are killed. Secondly, all those cells with the MICA protein on their surface are killed.

Thirdly, all those cells with attached IgG antibodies on their surface antigen are also killed. Natural killer cells also induce apoptosis in the target cells. Another important point is that adaptive immunity clears the viral infection and memorizes the invading pathogen, and protects us from future infections from the same pathogen At the same time, abnormally delayed adaptive immune response was observed in some patients infected with COVID Zheng et al.

stated that cytotoxic T lymphocytes and NK cells are dispensable in controlling the viral infection. They conducted a study on 68 COVID patients to monitor their CTLs and NK cell levels in their blood plasma Figure 5. The NK cells and CTL are responsible for clearing the virus-infected cells and since the virus here does not want to be removed by the NK cells and CTL, enhancing NKG2 expression on these cells helps achieve that objective.

This could explain why some COVID patients remain asymptomatic for a long time. Moreover, a decrease in the levels of NKG2 and the cytokines above are reported.

This makes NKG2 a vital drug target in the immune checkpoint to prevent SARS-CoV-2 replication Delayed or no activation of T cells is further supported by another study conducted on three positive COVID patients and10 healthy persons, which concluded that delayed response is a trick used by the SARS-CoV-2 virus to prolong its infection and to maintain a febrile environment so that it can enhance community transmission These cells are specific for viral infection, and their lower number indicates severe dysregulation in the adaptive immune response Figure 5 Exhaustion of adaptive immune response.

In some patients of infected with SARS-CoV-2, although adaptive immune response was observed to be activated by the presence of CTL, NK, and B cells, none of these cells were found killing the virally infected cells.

The special behavior shown by these cells was termed as exhaustion of NK, CTL, and B cells. Furthermore, these cells were also observed to be expressing NKG2 on their surfaces making NKG2 as important drug target.

Monalizumab, a NKG2 receptor inhibitor, has been reported to clear a phase-II clinical trial. Lung alveoli are spaces for gaseous exchange in and out of the body. The soft lining of the alveoli consists of a single layer of type-1 and type-2 pneumocytes.

Type-1 cells mainly function in gaseous exchange, but type-2pneumocytes also secrete lung surfactant in addition to gaseous exchange to reduce surface tension.

Continuous secretion of the surfactant from type-2 pneumocytes prevents the lungs from collapsing. The same thing is observed with SARS-CoV-2 infection, which binds toACE-2 pneumocytes and stops surfactant secretion.

Infected type-2 pneumocytes trigger the host immune response by releasing inflammatory mediators that act upon the alveoli resident macrophages Activated macrophages release cytokines IL-1, IL-6, and TNF-α, which activate chemotactic immune cells circulating in the bloodstream.

They also act locally on the endothelial cells causing a gap between tight junctions. Due to vascular permeability of the endothelial cells, fluid leakage in the gap between alveolar epithelial and blood vessel endothelial cells increases, and vascular fluid accumulates around the alveoli damaging the epithelial cells.

Blood neutrophils are attracted at the site of the infection and release reactive oxygen species, which start destroying the alveolar epithelium. Following neutrophils, monocytes also reach the site and increase phagocytosis of damaged pneumocytes and viral particles Similar results have been published in a study conducted by Shan et al.

The results were spotted with chest radiographs and histopathological results. The collective response of macrophages, neutrophils, and monocytes induces excessive production of cytokines, mucus, and antibodies, which overfill the alveoli and block the gaseous exchange, leading to the death of the patient due to respiratory failure Figure 4 Novel coronavirus SARS-CoV-2 transmitting from person to person requires host alveolar type-2 pneumocytes to complete its life cycle.

Numerous ACE-2 receptors on the apical side of the type-2 pneumocytes provide an interface for viral entry. SARS-CoV-2 brings forward its spike protein for attachment with ACE-2 receptors. Its spike protein is a trimeric protein that has a furin protease cleavage site. Intracellular serine protease TMPRSST serves this function and causes the cleavage and activation of spike proteins.

Upon activation, the S1 subunit of the spike protein binds to ACE-2 receptors, and the S2 subunit initiates fusion with the plasma membrane of type-2pneumocytes.

Once in the host cells, SARS-CoV-2uses host ribosomes to synthesize its structural proteins and genomic virions. Upon completion of its life cycle, the progeny virus bursts the cell and is ready to transmit the infection in healthy individuals The host immune system starts its function once the infection is complete.

Interestingly, different responses from the host immune system have been observed in COVID patients, depending on the severity of pneumonia In mildly infected patients, only a small elevation in IgG and IgM antibodies and fewer cytokines are observed, which impart protection to the lungs.

Moderate cases of COVID have a higher level of antibody-secreting cells, macrophages, neutrophils, along with a high level of cytokines. From the reported data of COVID patients, it is tough to understand whether how the host immune system acts is pivotal.

This is simply due to the dual behavior of the immune system. It acts as a hero within limits but turns into a villain whenever there is an excess of a particular cytokine. Another reason for this type of behavior could be the specific type of organ or tissue or cells. Since lung alveoli, the site of gaseous exchange, are made of a single layer of type-1 and type-2 pneumocytes, injury to single cells means losing a large surface area.

Overactivation of inflammatory markers can overstimulate the immune system, which could damage and reduce this surface area through its phagocytotic action. This is why NK cells and T cells remain inactive in mild and moderate COVID patients In most instances, patients die of respiratory failure One way to control the hyperactive immune response is to use anti-inflammatory drugs Something can be achieved by controlling specific cytokines, i.

Excessive phagocytosis by the NK cells and CTL in severely infected patients can be managed by regulating the NKG2 receptors on these cells. Low NKG2 expression on NK cells and CTL makes them more active, while high expression makes them less involved and less phagocytic Figure 5. Therefore, by working at various immune checkpoints through innovative in vitro disease models, a physician can reduce the mortality associated with the SARS-CoV-2 virus 6 , The current review provides a detailed study of the COVID viral life cycle and host immune response, which may give a new direction to researchers in developing various treatment strategies to overcome the infection caused by the novel coronavirus.

LS contributed to the generation of the hypothesis and manuscript writing. SB, MG, and NV helped create the scientific illustration.

MNA and AS checked the whole manuscript for grammar and plagiarism errors. GK and MS perceived the idea, designed and supervised the whole study, and prepared and proofread the final manuscript.

All authors contributed to the article and approved the submitted version. The authors declare that the review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We are grateful to the Pharmaceutical Sciences Department, Assam University and School of Medical and Allied Sciences, KR Mangalam University, Gurgaon India , where the work was carried out.

ARDS, Acute respiratory distress syndrome; SARS-CoV-1, Severe acute respiratory syndrome coronavirus-1; COVID, Coronavirus disease ; MERS: Middle East respiratory syndrome; 5.

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