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Dogan et al. Balancing immune-mediated virus clearance and overt immunopathology may be difficult in certain patients. In contrast to exacerbated T cell activation, T cell exhaustion could represent the cause of this inflammatory syndrome. Mechanisms leading to peripheral lymphopenia and severe disease remain unclear.
Three non-exclusive hypotheses have been emitted. First SARS-CoV-2 might directly infect and the destroy splenic and lymph nodes follicles, as indicated by the post mortem analysis of 6 patients. Furthermore, the increased incidence of Kawasaki disease in young children with COVID infections, even in the absence of cardiovascular predisposition, is indicative of SARS- CoV-2 vascular tropism and vascular damage.
Hence, pulmonary complications result in part from endothelitis, activation of coagulation and myeloid pathways, maybe calling for therapeutics targeting angiopoietin-2, bevacizumab, a monoclonal antibody that binds VEGF and counteracts its vessel permeabilizing effect. Recent studies revealed that emergency myelopoiesis marked by the occurrence of pre-neutrophils and immature neutrophils is correlated with the severity of the disease.
In mouse models in which coronavirus replication is increased by genetic defects in innate lines of defense such as TRIF, TLR3, TLR4, C3, NLRP3 deficiencies , increased weight loss and fatality are associated with excess recruitment of neutrophils and monocytic cells to the lung, correlating with acute respiratory distress syndrome. Neutrophils facilitate trapping and killing of pathogens through an organized cell death pathway in which decondensed chromatin and antimicrobial proteins are expelled from the cell to form Neutrophils Extracellular Traps NETs.
The first anecdotic report identified a favourable course of treatment with tocilizumab TCZ , while the first cohort study reported that 3 of the 10 treated patients died perhaps because TCZ was used in combination with methylprednisolone. This is the first cohort study reporting strong promising results.
In addition, progression to secondary haemophagocytic lymphohistiocytosis was reported for severe COVID patients presenting a cytokine release syndrome under tocilizumab treatment. While it appears clear that T lymphocyte responses can confer effective and durable protection against SARS-CoV-2, the role of humoral responses is still elusive. Paradoxically, the mortality rate associated with COVID19 is mainly the result of a dysregulated immunopathology in response to the virus rather than organ injury due to the viral replication itself.
There is an urgent need for a high dimensional and longitudinal follow-up of the underlying immunological mechanisms across the different stages of the COVID to make more rational and personalized therapeutic decision. Consortia aimed at patient stratification and appropriate clinical management are being constituted to bring together the required expertise to reach this goal in short term. Importantly, pilot and large clinical trials based on antivirals, immunostimulatory and immunosuppressive drugs are being conducted for early and late stages of COVID in hospitals of these consortia, awaiting diagnostic tools to optimally stratify patients according to their risk.
The race between viral replication and the elicitation of a productive and coordinated immune response likely necessitates drugs that operate on those sides likely as a result of off-target effects or combinatorial regimen. Medium-term goals include the development of effective vaccines against highly pathogenic CoVs. National Center for Biotechnology Information , U.
Journal List Oncoimmunology v. Published online Aug Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. In the second phase of the disease, abnormal blood parameters involved in the severity of the disease can be observed. Then,from day 9 to 12 after the onset of symptoms phase III , sudden deterioration caused by the cytokine storm syndrome and pulmonary macro and micro embolism can lead to acute respiratory distress syndrome phase IV and death.
Therapeutic strategies have been proposed for each stage of the disease. Oxygen and intensive care therapy are used in the third and fourth phases of the disease. Figure 2. Extrapulmonary manifestations are observed in one quarter to one third of hospitalized patients.
Four mechanisms are involved in the pathophysiology of multiorgan injury: i. Dysregulation of the renin-angiotensin-aldosterone system RAAS. Endothelial cell damage and thrombo-inflammation and iv. Dysregulation of the immune system and cytokine release syndrome that causes disseminated organ injuries. Histopathological analyses identified the virus in the lung, the kidney, the myocardium, the brain, and the gastro-intestinal tissues. Innate barriers to viral infection paving the way to T and B cell responses Lung parenchyma local immunity The lung is a complex organ with specialized structures to allow for adequate gas exchange.
Figure 3. Putative immune scenarios associated with protective immune responses. Bone marrow-derived monocytes and DC precursors migrate to lung and inflammatory lesions to cross-present apoptotic virally-infected epithelial cells. Bats are increasingly recognized as the natural reservoirs of viruses of public health concern. Furthermore, the unexpected high number of T cells in bats BM could suggest a role for this primary lymphoid organ in T celldevelopment. Relevant TLR signaling pathways TLR agonists and antagonists have been discussed as potential compounds with broad-spectrum therapeutic bioactivity against a number of respiratory infections in the context of antivirals and vaccine adjuvants.
T cell response against coronaviruses The significance of T cell responses to respiratory coronaviruses has been extensively reviewed. Theoretical principles A and tentative scheme B of the kinetics of virus replication and infectivity, humoral and cellular immune responses, based on previous human pandemic infections with betacoronaviruses.
T FH cells follicular helper T cells T FH cells follicular helper T cells are essential for antibody-mediated humoral immunity against various pathogens in rodents. The humoral response against coronaviruses The quality of the Ig production makes a difference for the long-term immunization against harmful viruses. Serological cross -reactivity and neutralizing antibodies The SARS-Cov2 nucleocapsid and S genes share some degrees of sequence homology with other human coronaviruses.
Vaccination Preclinical studies in rodents tested a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene into replication-competent vesicular stomatitis virus VSV -based vaccine. Monoclonal antibodies The development of antibodies protecting during Sars CoV-2 infection is an urgent public health and vaccine development issue. The wrong side of the janus face: virus-induced immunopathology Balancing immune-mediated virus clearance and overt immunopathology may be difficult in certain patients.
Immature neutrophils and the cytokine storm Recent studies revealed that emergency myelopoiesis marked by the occurrence of pre-neutrophils and immature neutrophils is correlated with the severity of the disease. Competing interests statement LZ, RD and GK are cofounders of EverImmune, a biotech company devoted to the use of commensal microbes for the treatment of cancers.
References 1. Middle East respiratory syndrome. The Lancet. Infect Dis Clin North Am. Travel Med Infect Dis. June Indian J Med Res. Infez Med. Epidemiol Infect. J Thromb Thrombolysis. July 6. Nat Rev Immunol. April March Kidney Int. Eur J Heart Fail. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun. Identification of a potential mechanism of acute kidney injury during the COVID outbreak: a study based on single-cell transcriptome analysis.
Intensive Care Med. N Engl J Med. May Profile of natural anticoagulant, coagulant factor and anti-phospholipid antibody in critically ill COVID patients. July 9. Arthritis Rheumatol. High frequency of antiphospholipid antibodies in critically ill COVID patients: a link with hypercoagulability? J Intern Med. Emerg Infect Dis. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid April; 8 :e Cold agglutinin disease and autoimmune hemolytic anemia with pulmonary embolism as a presentation of COVID infection.
Hematol Oncol Stem Cell Ther. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J Virol. Engelmann B, Massberg S.
Thrombosis as an intravascular effector of innate immunity. South China Morning Post. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in Wuhan, China. COVID consider cytokine storm syndromes and immunosuppression. Sig Transduct Target Ther. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment.
Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Three unique interstitial macrophages in the murine lung at steady state. Non-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung.
Nat Commun. Identification of a nerve-associated, lung-resident interstitial macrophage subset with distinct localization and immunoregulatory properties. Sci Immunol. Nat Med. Dynamics of human monocytes and airway macrophages during healthy aging and after transplant.
J Exp Med. Front Immunol. Lung-resident memory CD8 T cells TRM are indispensable for optimal cross-protection against pulmonary virus infection. J Leukoc Biol. Antibody-targeted vaccination to lung dendritic cells generates tissue-resident memory CD8 T cells that are highly protective against influenza virus infection. Mucosal Immunol. Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles.
J Clin Invest. Pulmonary antigen encounter regulates the establishment of tissue-resident CD8 memory T cells in the lung airways and parenchyma. Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells. Nat Immunol. Interferon and IL antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses.
Anti-severe acute respiratory syndrome coronavirus immune responses: the role played by V gamma 9V delta 2 T cells. J Infect Dis. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host. Nat Microbiol. Unlocking bat immunology: establishment of Pteropus alecto bone marrow-derived dendritic cells and macrophages.
Sci Rep. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Longitudinal alteration of circulating dendritic cell subsets and its correlation with steroid treatment in patients with severe acute respiratory syndrome. Clin Immunol. Severe acute respiratory syndrome SARS coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells.
Age-related increases in PGD 2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. Mapping the human DC lineage through the integration of high-dimensional techniques. Constitutive Siglec-1 expression confers susceptibility to HIV-1 infection of human dendritic cell precursors. Control of coronavirus infection through plasmacytoid dendritic-cell—derived type I interferon.
Systematic identification of type I and type II interferon-induced antiviral factors. Proc Nat Acad Sci. Protein Cell. Emerg Microbes Infect. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. Antiviral Res. Virus Res. Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles moscona A, editor.
Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3. Selinger M. Towards formal representation and evaluation of arguments.
Cell Host Microbe. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. Bach2 deficiency leads to spontaneous expansion of ILproducing T follicular helper cells and autoimmunity.
High secretion of interferons by human plasmacytoid dendritic cells upon recognition of middle east respiratory syndrome coronavirus perlman S, editor. Mucosal polyinosinic-polycytidylic acid improves protection elicited by replicating influenza vaccines via enhanced dendritic cell function and T cell immunity. J Immunol. PLoS Pathog. JCI Insight. Chen Y, Li L. Lancet Infect Dis. Detection of SARS coronavirus in patients with severe acute respiratory syndrome by conventional and real-time quantitative reverse transcription-PCR assays.
Clin Chem. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Phenotypic and functional characterization of the major lymphocyte populations in the fruit-eating bat Pteropus alecto. T cell-mediated immune response to respiratory coronaviruses.
Immunol Res. Middle east respiratory syndrome coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways. IFN-induced attrition of CD8 T cells in the presence or absence of cognate antigen during the early stages of viral infections. Clin Infect Dis. J Infect. T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice.
Resistance of naive mice to murine hepatitis virus strain 3 requires development of a Th1, but not a Th2, response, whereas pre-existing antibody partially protects against primary infection. Mucosal resident memory CD4 T cells in protection and immunopathology. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection.
Xu X, Gao X. Immunological responses against SARS-coronavirus infection in humans. Cell Mol Immunol. Engineering T cells specific for a dominant severe acute respiratory syndrome coronavirus CD8 T cell epitope. IFITM3 restricts the morbidity and mortality associated with influenza.
Early hypercytokinemia is associated with interferon-induced transmembrane protein-3 dysfunction and predictive of fatal H7N9 infection. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis. Human Ebola virus infection results in substantial immune activation.
Deep immune profiling of COVID patients reveals distinct immunotypes with therapeutic implications. July eabc Eosinophil numbers spike when female rats have higher estrogen levels, and surgical excision of rat ovaries results in a sharp decrease in uterine eosinophils Eosinophil-derived neurotoxin is a key protein found in eosinophil granules and has strong ribonuclease activity especially when activated by proinflammatory stimuli.
Differences in EDN expression have not yet been analyzed in males vs. Basophils are the rarest of the granulocytes, and study of the basophil response to coronaviruses is even more unknown than eosinophil interactions. In one study, the incubation of human basophils with mild strains of coronavirus did not cause the leukocytes to degranulate or release histamine More studies are needed, however, to establish that basophils are not involved in the coronavirus response or that there are no sex-related differences in their interactions.
Mast cells reside in the submucosal layers of the respiratory tract; although they are mainly known for their functions in allergy responses, mastocytes are also intimately involved in protection from viral invaders In fact, their roles and activation in the immune response are incredibly interesting in the context of sex bias. It seems that, although mast cells from female mice bear granules with higher enymatic activity, these cells are activated to a lesser degree via the complement system than mast cells from male mice.
This may explain the increased preponderance of lung injury in men with coronavirus infection. Even when controlling for differences in number and extent of activation, mast cells from female mice make, store, and secrete more histamine than mastocytes of male origin. Gene analysis study has shown that genes such as Tnf, Hexa , and several mcpt genes that encode these intracellular granule mediators are upregulated in female mice. Mast cells from women store this increase in protein product by increasing the packing density of granules in mast cells This set of studies was repeated in the presence of various levels of female sex hormones, as previous literature has shown that the menstrual cycle can affect properties of mast cells in rodent models.
The study found that there was no statistically significant difference in the amount of histamine that mast cells released across levels of sex hormones in male and female mice This shows that while previous studies may point to significant hormonal effects on mast cell properties, there are sex-based differences in mastocyte biology that are not attributable to hormone interaction. Mastocytes in the context of SARS-CoV infection are intimately involved with the complement system, which has significant proinflammatory responses that can result in pathological states.
In fact, coronavirus infection activates the classical, the lectin, and the alternative pathways of the complement system. Of particular interest are C3 and C5 proteins which activate mast cell degranulation in SARS to trigger a cytokine storm 19 , This cytokine storm can lead to further downstream effects such as hyperemia and vascular permeability, which can result in acute, fatal lung injury.
In a similar vein, inhibition of the complement cascade via inhibition of C3 in Minfected mice results in less recruitment of neutrophils and inflammatory monocytes to the lung tissue The conclusion that reduced activation of the complement cascade results in maintenance of healthy lung tissue correlates to the sex bias found in levels of complement proteins.
A recent study of 50, racially diverse subjects found that, compared to men, women have significantly lower levels of C4, an activator of C3. In an investigation of Caucasian populations, levels of C3, C5, C7, C8, and C9 were significantly lower in women compared to men. Also women had lower amounts of proinflammatory positive regulators of the cascade such as properdin, mannan-binding lectin MBL , and Ficolin-3 These reduced levels of complement proteins were found to control activity of the whole cascade and its terminal products for the classical, lectin, and alternative pathways that are involved in SARS infection 20 , Yet, from both studies it is justifiable to say that the female host has mechanisms to reduce proinflammatory effects even with more potent mastocytes.
In the context of SARS, these techniques may prove useful if they are an explanation for the minimized incidence of pulmonary injury. In the discussion of pDC, it was iterated that the role and clinical effects of Type I IFN are still incompletely understood and are often conflicting across various studies. For example, Type I IFN administration 6 h post-infection before viral peak in mice infected with SARS coronavirus completely protected them from clinical disease 10 , Elevated and extended exposure of the host to IFN, however, led to excessive proinflammatory pathways and pulmonary pathology.
In the same study, mice were exposed to IFN post-peak of viral titers which resulted in lethal pathology. This acute lung injury in mice and humans with SARS is characterized by the presence of IFN-stimulated inflammatory monocyte-macrophages IMM and their associated proinflammatory cytokines in bronchoalveolar lavage fluid 10 — Although women have higher activation of IFN pathways early in coronavirus infections, it is unknown if there is a difference in IFN levels between men and women after peak viral load.
It may be that early activation of antiviral pathways more effectively reduces viral load by priming the innate and adaptive immune systems. This early activation can better protect the host from the cytokine storm found mostly in males that is associated with later IFN secretion 10 , 12 , Just three days post infection, there were 2—3-fold greater numbers of these IMM IL-6 is an activator of CCL2 binding to CCR2 which promotes lymphoid and myeloid chemotaxis as well as properties of leukocyte adhesion, polarization, secretion, and survival in the immune responses 12 , Additionally, use of monoclonal antibodies has also been considered for therapy in humans.
Natural Killer NK cells are cytotoxic lymphocytes of the innate immune system that target cancerous and infected cells. There is a plethora of puzzling information about the sex bias in NK cells. Some studies have found greater numbers and activity of NK cells from male rodents compared with females 4 , Another study of healthy geriatric individuals found that while there was an initial surplus of NK cells in men less than 70 years of age, there was a steep increase and superiority in NK cell function in women over 70 years 17 , This post-menopausal finding seems to defy other studies that found a rise in NK cells during the periovulatory phase when estrogen and progesterone are increased 4 , It is possible, however, that even if estrogen derivatives increase the number of NK cells, the cytotoxic capabilities of these cells may be reduced.
In contrast, Th2 cells produce cytokines that are more anti-inflammatory and redirect focus to humoral immunity mechanisms. The homeostasis between Th1 and Th2 cells is vital for the obliteration of infectious microbes without causing pathological states in the host. The SARS coronavirus of is notable in that it exclusively produced an activation of Th1 cells and cytokines in the host.
These protein levels were elevated for at least 2 weeks after onset and were sufficient for full recovery of the host. Across several studies, induction of anti-inflammatory Th2 pathways was not necessary for host survival 30 — The novel coronavirus SARS-CoV-2, however, seems to work differently when compared to its older relative, as sufficient induction of anti-inflammatory Th2 response is necessary.
Levels of these cytokines were much lower in non-ICU patients and the control group 32 , indicating that pathogenic Th1 cells correlate with the hyper-inflammatory response in SARS-CoV-2 pathogenesis. Physiologic changes within the immune system during pregnancy typically involve an attenuation of the Th1 response and a shift toward Th2 anti-inflammatory pathways 31 , This is in the interest of protecting the developing fetus from an overactive cell-mediated immune response, while simultaneously developing antibodies for passive transfer of immunity through the placenta and breast milk.
Although there may be numerous variables at play, it seems that host survival in COVID is tied to substitution of the proinflammatory Th1 for the anti-inflammatory Th2 that is dominant in gravid hosts. In coronavirus infections, IL encourages the assembly of downstream proinflammatory cytokines that result in activation of neutrophil chemokines and secretory elements that damage lung parenchyma An investigation of polymorphisms for IL genes in SARS patients showed that individuals predisposed to lower levels of IL activation had significantly increased day survival when compared with patients prone to increased IL production Th17 lymphocytes also contribute to ARDS pathogenesis by activation of IL, which seems involved in the production of mucin and fibrin-rich secretions in patients with pulmonary edema 36 , While the role of gender in relation to Th17 function in coronavirus infections has yet to be studied, there is some literature on how this cell type affects AD.
In AD that predominantly affect males, there has been significant literature on Th17 cells playing a paramount role in disease progression 37 — For example, although multiple sclerosis MS affects 2—3 times more women than men, men tend to experience more rapid and aggressive disease progression Similarly, in systemic lupus erythematosus SLE which afflicts women 9—10 times more often than men, men tend to experience more severe complications especially nephritis leading to renal failure.
This finding suggested that male sex is a crucial and inherent element of disease-induced severity related to Th17 cells. Whether this finding is applicable to host attack in the context of SARS remains to be determined. The optimal balance of these activities is different for every pathogen, but, in the context of mouse hepatitis virus MHV coronavirus, Tregs are necessary for mild disease outcomes, as their depletion results in increased mortality 40 , While studies of Treg influences and functions have been performed on several types of respiratory viruses, there is little information on their roles against human coronaviruses.
The role and activity of Treg lymphocytes, therefore, cannot yet be verified in the context of COVID, but these cells may offer a benefit by reducing excessive damage to lung parenchyma. The transcription factor Foxp3 serves not only as a marker for Treg cells, but it is also necessary for their development, maintenance, and suppressive functions 42 , Foxp3 is encoded on the X chromosome and can escape X inactivation, giving XX females higher activity of Foxp3 and Treg cells 33 , This may give women an immunosuppressive advantage in the context of coronaviruses.
Scarcity of Treg cells from loss-of-function alterations in Foxp3 lead to severe and even lethal inflammation in human and rodent models of coronavirus infection Across several studies, there are a significant portion of COVID patients who present with lymphopenia and markers of T cell exhaustion. It was found that as patients progressed from prodromal to active symptoms, their levels of PD1 and Tim3 would directly increase. In the same vein, patients in the ICU had much higher expression of these markers compared to non-ICU and control populations 44 , Consistent with previous work, these markers were significantly elevated in critically ill patients compared with those who were only mildly symptomatic with COVID Causes and effects of lymphopenia have not been thoroughly studied in SARS, and much less can be said for differences in sex.
After an initial encounter with a pathogen, antigen-specific naive CD4 and CD8 T cells clonally expand to become effector T cells, which mount a cellular and humoral response against the offending pathogen. After pathogen clearance, most effectors die by apoptosis, while some survive and persist to become long-lived memory T cells, and it is these cells that offer the host protection from subsequent encounters with the pathogen.
Memory cells also form the basis for vaccinations which elicit a similar immune response albeit at a significantly reduced magnitude without causing disease. Memory T cells are heterogeneous in phenotype, function and localization and include central memory Tcm , effector memory Tem , tissue resident memory Trm , terminally differentiated memory Temra , and other cells These antigen-specific cells are the basis of vaccine development, as they are skilled in triggering a targeted immune response upon re-exposure to an antigen.
As SARS-CoV-2 is a novel infection, development and viability of memory T cells in men and women is truly unknown, especially in the face of viral mutation. As SARS-CoV-2 is a novel infection, development and maintenance of memory T cells in men and women is truly unknown, especially in the face of viral mutation.
Antibody secretion is the primary function of B lymphocytes. As expected, IgG antibody levels were stable while IgM antibodies reached low levels within 5 weeks and became undetectable at 7 weeks This may have to do with the upregulation of IL-4, IL, and other cytokines promoting antibody class-switching at an ultra-rapid rate These interleukins are part of the Th2 pathway which is naturally enhanced in women, suggesting that there may be a physiological sex difference in antibody switching, although no known studies have been done in this specific area 32 Another study investigated IgG levels between male and female COVID patients, stratifying patients by disease severity into mild, moderate, and severe status and into early, active, and recovery phases.
While there was no significant difference in serum IgG levels across gender in mild and recovering patients, IgG levels in women were significantly elevated in the early disease phase and in severe cases This situational increase in antibody titers cannot yet be determined as helpful or harmful in SARS, but it is worth noting for future investigation. B-cell production of cytokines make these lymphocytes powerful regulators of adaptive immunity, but in many cases turn maladaptive, such as in SARS.
A series of seven case studies was recently published on B-cell immunocompromised COVID patients and sheds light on the excessive lymphocyte immune response. Disease presentation of patients with common variable immune deficiency CVID hypogammaglobulinemia were compared to patients with agammaglobulinemia AGG.
Surprisingly, the AGG cases proved to be mild, and the patients had normal lung CT scans with no consolidation. The patients were treated in the hospital for a maximum of 3 days and went home without requiring assisted ventilation. They were in the hospital for at least two weeks and needed antiretroviral therapy ART , IL antagonists, and some required mechanical ventilation. According to the study, the difference in patient outcomes was likely due to the lack of non-Ig B cell cytokine functions, meaning that patients with AGG avoided a host-harming cytokine storm.
This cytokine activation is linked to stimulation of TLR in T-cell independent activation This process authorizes B cells to respond to activation from coronavirus-TLR7 binding by immediate expansion and differentiation without much T cell interaction. These mature and activated B cells are capable of producing IgM as well as proinflammatory cytokines, namely IL Contrary to other immune cells discussed above , it seems that B-cell-derived cytokines may be more harmful to a female host.
Women mount a stronger immune response against viral infections than men Women possess both maternal and paternal X chromosomes, which necessitates the silencing of one copy of genes in order to ensure an appropriate gene dosage. The silencing of one copy, or X chromosome inactivation XCI , leads to functional mosaicism in women with regards to X-linked genes X chromosome inactivation is cell-specific and variable among individuals, which causes some cells to express the maternal chromosomal copy and others to express the paternal copy.
In turn, this leads to a diversity of possible immune responses in females, which provides women with a wider variety of tools with which to fight pathogens Skewed inactivation patterns may additionally offer a protective effect by silencing immunodeficiency-causing mutations Furthermore, X-chromosome skewing may preferentially express beneficial alleles, leading to a larger proportion of cells producing functionally advantageous gene products X chromosome inactivation is particularly relevant to discussion of the SARS-CoV-2 immune response, as the X chromosome encodes for several genes involved in both adaptive and innate immunity, including those involved in the TLR pathway Cellular mosaicism suggests that women may be better equipped to respond to immune challenges, particularly viral infections such as SARS-CoV Evidence shows that XCI escape commonly occurs in female lymphocytes, which display atypical heterochromatic modification and tend to reactivate the inactivated X chromosome Xi The XCI escape of genes involved in the immune system may further contribute to an immunologic advantage in women.
The gene for TLR7 is located at Xp When stimulated by TLR7, biallelic B cells were 2. Increased class switching suggests that women and KS males may have enhanced humoral immune response due to TLR7 overexpression. Estrogen levels likely contribute to the sex-based difference in TLR7 signaling, as immune cells from both men and women have been shown to increase TLR7 expression post-exposure to estradiol treatment 60 , As a result, inclusion of genotypically diverse individuals may lend additional insights into the impact of XCI escape on TLR7 gene dosing.
As a result, XCI escape may be correlated with increased TLR7 signaling and more vigorous immune response to viral infections. CXorf21 is located at gene locus Xp While its exact function is presently unknown, its overexpression in female APC suggests that CXorf21 may cooperate with TLR7 to contribute to the heightened antiviral response in women The gene locus for CD40L has been identified as Xq CD40L functions in several aspects of the adaptive immune response, including T-cell differentiation, immunoglobulin class switching, and formation of long-lived plasma cells and memory B cells A comparison of antigen presenting cells APCs from TS women, KS men, and individuals with typical karyotype found that cells from typical women expressed significantly more CD40L than those from typical men or TS women Klinefelter Syndrome men yielded similar results to women possessing an XX karyotype, suggesting that XCI escape may confer an advantage against viral infections by increasing CD40L expression.
Increased CD40L in individuals with an additional chromosome may cause greater T- and B-cell activation, leading to better ability to fight off viral infection. Mannose-binding lectin was found to be depleted in patients with SARS-CoV, suggesting that the complement system may aid in the response to coronavirus infection C4, which is located at the MHC, is of particular interest because of observed differences between sexes C4 protein is more abundant in the cerebrospinal fluid and plasma of men compared to women, with a greater difference observed in men and women of childbearing age 20—50 years.
Moreover, mutation in the C4 gene affects disease risk differently in men and women. Moreover, the sex-based difference in disease incidence mirrors that of C4 protein levels and is most noticeable between men and women aged 20— As a result, the discrepancy in disease rates may be attributed to variable effects of C4 between men and women. Human leukocyte antigen enables differentiation between host cells and pathogens through antigen presentation to the T-cell receptor TCR.
As MHC binding is required for effective T-cell activity, this finding is consistent with the observation that men are biased toward infections and non-reproductive system cancers hypoactive T-cell response while women are biased toward autoimmune disorders hyperactive T-cell response. For instance, incontinentia pigmenti, caused by mutations in NEMO, causes lethality in men but has variable presentation in women. Skewed X-inactivation favoring the wildtype allele has been observed in heterozygous women, which supports the notion that X inactivation may confer a protective advantage against immunodeficiency disorders Moreover, men with KS have been observed to escape lethality from incontinentia pigmenti FoxP3 has been mapped to locus Xp Because FoxP3 does not undergo skewed X inactivation, heterozygous women express both mutant and wildtype FoxP3 alleles equally However, women heterozygous for mutant FoxP3 exhibit normal lymphocyte levels and normal immune response to infection.
The participation of FoxP3 in positive feedback loops, in which FoxP3 protein further stimulates transcription of the FoxP3 gene, indicates that one functional copy of the gene may be sufficient to maintain appropriate levels of FoxP3 As FoxP3 is critical to Treg-mediated immunosuppression, the protective effect of mosaicism implies an immunologic advantage for women at a population level As a result, the ability to curb excessive activity by cytotoxic neutrophils, macrophages, and other immune cells may decrease risk of fatality from SARS-CoV and other coronaviruses Although Tregs may offer benefit by reducing excessive tissue damage, they may also dampen the immune system and limit ability to clear an infection, indicating the need to strike a balance between the two.
While Tregs may be less important in acute viral infections requiring an aggressive immune response, the disease characteristics for SARS-CoV-2 suggest that Tregs may play a crucial role in the antiviral response. Cellular mosaicism and the resulting improvement in genetic diversity may allow women to strike this balance more easily. Given that women have two copies of the X chromosome, and that some of these genes may escape X-inactivation, this may help to explain the sex bias in immune responses.
Additionally, it has been found that miRNA that are evolutionarily conserved are more often implicated in disease states 85 , and male-specific miRNA evolve more quickly than female miRNA 84 and therefore are less conserved. Following the binding, the miRNA can either inhibit translation and decrease viral infectivity or it can stabilize the RNA and effectively increase translation.
Together, these contribute to viral evasion of the immune response. Sex hormones are an important biological factor contributing to the gender-bias in the immune response, and can influence outcomes of disease severity in infections and autoimmunity 4 , 88 — In general, estrogens are considered immuno-stimulatory and activate both the innate and adaptive immune responses and therefore women are able to clear pathogens more efficiently than men, whereas testosterone is immuno-suppressive, which may underlie the higher susceptibility and severity of infectious diseases in men 4.
On the other hand, the stronger immune response in women is thought to underlie the disproportionately high prevalence of AD in women over men. Sex hormones control both cellular and humoral components of the immune response and thus determine the sex-bias in susceptibility, manifestations and clinical outcomes in infections, AD and malignancies 4 , Sex hormones bind these receptors and trigger intracellular signaling cascades to regulate gene and protein expression to influence development, maturation, activation, and function of innate and adaptive immune cells during homoestasis and the immune response to infections.
Better understanding of the factors that control the immune response in a sex-specific manner is therefore crucial to not only understanding disease pathogenesis but also guiding treatment and prevention strategies and a first step toward personalized medicine.
The sex-biased factors that impact immunity have developmental origins beginning in utero , infancy and childhood For example, placental hormones help shape fetal and neonatal immunity, and some of these influences are retained through adulthood. Estrogen and progesterone are important in alveolarization and surfactant production respectively. For some infections and AD, these differences in susceptibility and severity are retained through adulthood but may change or even reverse for some allergy-related conditions and AD.
Studies on the role of sex hormones in immune cells range from ex vivo cultures of human or mouse cells, or in vivo supplementation in mice after gonadectomy, including those assessing mice with genetic deletions of sex hormone receptors. Given the wide variations in human versus rodents in vitro versus in vivo systems, epidemiological studies have shown that there is not a universal paradigm regarding the role of gender or sex hormones on the immune response to respiratory viruses.
It is hypothesized that the disease outcomes are ultimately a combination of the magnitude of the immune response and degree of host tissue damage 92 , There is a male bias when a weaker immune response contributes to damage, while a female bias may occur due to a stronger immune response that causes damage. Estrogen-ER signaling regulates innate myeloid cells including pDCs, monocytes, neutrophils, and lymphoid cells, including innate lymphoid cells ILC Estrogens contribute to delayed neutrophil apoptosis and can modulate chemotaxis and NO production in vitro.
The lung-resident alveolar macrophages are important in respiratory infections and produce type I IFN for viral clearance. These findings imply that wherein estrogen and ERa enhance while AR may dampen the type 2 responses important for lung tissue repair post-viral infections.
While these cells predominantly express AR, there is tissue specific regulation by sex hormones and estrogen-ER signaling promoted uterine over lung ILC2. Elevated numbers in IAV infections may provide superior tissue repair, however their plasticity to convert to ILC-1 like cells and IFN-g production may make them more pathogenic and contribute to immunopathology In general, estrogens are immune-stimulatory and are known to be involved in T-cell development, activation, differentiation and function 4.
Estrogen-ER signaling was shown to be necessary for normal thymic size and development, and furthermore estrogen is known to promote extrathymic T-cell differentiation in the liver. Its role in T-cell homeostasis with respect to cell survival and proliferation is complex and varies depending on cell type, context, and concentration, where physiologic doses of estradiol suppress apoptosis whereas pharmacologic doses suppress proliferation in cancer cells.
Estrogen controls cell metabolism and genes involved in metabolic activity important to stimulate T-cell differentiation and stimulate mitochondrial function. Estrogen is known to suppress IL-2 cytokine production in human T cells 94 and rat splenocytes.
Accordingly, lower IL-2 levels are observed during the luteal phase of the menstrual cycle in healthy young women and thought to contribute to the observed increase in pre-menstrual infections. CD4 T follicular helper Tfh cells are crucial for providing cognate help to B cells and promote class switching and somatic hypermutation to produce antibodies.
Estrogen was shown to promote the expression of Calcineurin and CD40L in human T cells 95 , molecules important for help to B cells in the antibody response. T cells traffic within the body to peripheral tissue sites of infection and migrate across chemokine gradients via chemokine receptors expressed on their surface.
Estrogen promotes both chemokines as well as chemokine receptor expression as evidenced by ex vivo and in vivo studies in mice 4. Estrogens also enhance CD8 T-cell activity and suppress Th17 immune responses. The role of Tregs in response to viral infections is complex.
Estrogen increases FoxP3 levels and Tregs in vitro and correlations have been observed in vivo. In women with recurrent spontaneous abortions RSA , lower Treg levels were found in both follicular and luteal phases and in postmenopausal women. The suppressive capacity of these Tregs was also lower in case of RSA.
Estrogen promotes B-cell homeostasis, activation, maturation, and differentiation and enhances immunoglobulin production 4. These properties make women and female mice able to mount greater magnitudes of neutralizing antibody responses to infections and thus contribute to protection against respiratory viral infections including the SARS-CoV infections. Estrogen administration led to increased marginal zone B cells in the spleen and in transgenic mice led to elevated anti-dsDNA antibodies.
Estrogen promoted the expansion of high-affinity antibody-producing B cells and also promoted survival by increasing expression of the Bcl-2 anti-apoptotic molecule Immune cells express PR and AR, and progesterone, androgen, and testosterone in particular are considered immuno-suppressive and may counteract the effects of estrogens, contributing to the observed increased susceptibility to the SARS-CoV-2 and disease in men 98 — Androgen receptor-deficient mice exhibit reduced numbers of neutrophils and accordingly increased susceptibility of male mice to SARS-CoV infection correlated with accumulation of neutrophils in the lung.
Progesterone reduces T-cell proliferation and T-cell-dependent antibody responses in human peripheral blood and cell line or mouse studies. Its effects on B cells included reduced class switch recombination and reduced T cell dependent antibody production. Normal testosterone levels are associated with normal respiratory capacity, whereas plasma testosterone levels decline in men with increasing age with observed associations between an increase of pro-inflammatory states and decline in testosterone in aging men.
On the other hand, high androgen levels may promote or contribute to infection because AR mediated transcription of TMPRSS2 protease which is important for viral entry into host cells. A proposed androgen sensitivity model provides a link between increased disease severity in men and the role of androgens in COVID Androgen sensitivity is primarily determined by genetic variants of the AR. While men are generally predisposed to these effects due to higher testosterone levels compared to women, individuals with hyperandrogenism and other conditions may similarly be impacted.
For example, women with hirsutism and polycystic ovarian syndrome PCOS , as well as women taking progesterone-based birth control, may be at greater risk for more severe COVID symptoms Markers of androgen sensitivity such as PCOS, androgenetic alopecia, and prostatic hyperplasia may thus be used as clinical signs of vulnerability. In this pandemic, men are more acutely ill and exhibit higher death rates with disproportionately higher numbers in ICU and requiring ventilators compared to women.
Even pregnant women had lower rates and less severe disease and complications than men. Estrogen and progesterone levels rise exponentially during pregnancy, causing a shift in the immune response, and this may underlie the observed protective effects. The importance of these female sex hormones in the immune response to infections has triggered two clinical trials with sex hormone administration to patients with COVID Half will receive a single-use transdermal estradiol patch for 7 days, and the other half will serve as a control group and receive standard of care.
The second, smaller randomized controlled trial with 40 male patients at Cedars-Sinai hospital in Los Angeles will administer progesterone in an effort to suppress the overactive immune response and mitigate immunopathology. Inpatients with mild to moderate disease will be included and half will receive progesterone mg subcutaneous twice daily for 5 days, and the other half is a control group.
Since progesterone is immune-suppressive and diminishes the proinflammatory response, this trial is intended to determine whether progesterone treatment can reduce the incidence of cytokine storm and related immunopathology leading to ARDS. It is well-known that the commensal bacteria in the GI tract impact the immune response. Some possible mechanisms involve microbiota affecting and regulating cytokine production , while others involve microbiota modulation of the production of mucous and antiviral defensins and ROS In regard to viral infections, however, some microbiota elicit protective effects, while others serve as a route of viral entry and infection.
For example, the Lactobacillus genus prevents murine norovirus replication in vitro , and there is in vivo evidence that this genus is decreased in a mouse that is affected by norovirus. In response to Influenza and WNV, gut microbiota secrete IgA and upregulate TLR-7 in the respiratory mucosa in order to promote activation of important components of antiviral immunity—cytotoxic T lymphocytes, Th1 cells, and inflammasomes.
It is therefore possible that there is an interaction between these bacteria and the virus, though the exact relationship is unknown. One possible mechanism is that, similarly to the human norovirus, the normally commensal bacteria are harboring the virus and are producing a cytokine response that is inappropriate for the response to the infection. This ultimately would result in dysbiosis and a worse outcome for the patient.
Alternatively, a relationship between ACE-2 and the gut microbiome may play a role in the immune response. This protein is critical for the transportation of tryptophan across the epithelium, which then normally increases the production of antimicrobial peptides that affect the composition of the microbiome Lack of this peptide production would likely result in dysbiosis and an impaired immune response.
Recently, it has been noted that sex hormones have a large effect on the microbiome. Particularly, higher levels of systemic estrogen, like those seen in women, are positively associated with the richness and diversity of the fecal microbiome Additionally, germ-free female mice have higher baseline antibody levels than germ-free male mice Taken together, these studies suggest that female sex hormones, particularly estrogen, have a pro-inflammatory effect 4 that promotes a more robust response to infection.
In addition to lacking the stimulatory effects of estrogen, men also produce androgens that seem to have a protective mechanism against the immune response. Furthermore, the testosterone surge at puberty in male mice dampens B- and T-cell development Commensal bacteria in the gastrointestinal tract have a role in regulation of testosterone levels An in vivo study found that the number of species in microbiomes of mice was not significantly different during the pre-pubescent stage but was significantly different following puberty This suggests that hormone changes during puberty drive changes in the microbiome.
Further, the microbiome elevates androgens to a level that confers protection from type 1 diabetes in mice , , which illustrates the synergistic effect of the male hormones and the microbiome. While this is thought to be a major factor in the protection against autoimmunity, it is also reasonable to think that the immune response may be dampened below the level that is needed for a strong response to pathogens.
Overall, these findings suggest that the microbiome is an important biological factor in the sex-bias in response to infection and may be involved in the SARS-CoV-2 responses. This binding leads to the subsequent downregulation of ACE2, which is considered to be protective against lung injury.
Stimulation of AGTR1a receptor by angiotensin II leads to endothelial cell permeability which may explain the increase in pulmonary pathology with decreasing levels of expressed ACE2. The location of ACE2 on the X chromosome suggests possible genetic influence in the elevated male mortality rate. For example, mutations in ACE2 in one cell line may alter the catalytic site and lead to divergent viral susceptibilities between cell populations decreasing peak viral load Substitutions in these amino acids, among other mutations, may alter binding affinity between the RBD and receptor, limiting the ability of the virus to enter the cell and propagate.
Variable expression of ACE2 may also influence patient outcomes. Viral entry into a cell causes downregulation of ACE2, which may be detrimental in patients already deficient in ACE2 ACE2 downregulation leads to pulmonary edema, alveolus hyalinization, and leukocyte accumulation. Cecal ligation and perforation of ACE2 knockout mice has also been shown to increase lung failure and tissue damage, indicating that ACE2 may confer a protective role in microbial infection Gene dosage, however, likely does not contribute to the sex-based difference in SARS-CoV-2 response, as evidence suggests that sexual dimorphism in ACE2 expression persists in renal tissue but not cardiac or pulmonary tissue under non-pathological conditions Moreover, changes in chromosome dosage was not observed to affect ACE2 expression in mice that had undergone gonadorectomy.
This finding implies possible hormonal but not chromosomal effects in ACE2 expression levels. Despite limited evidence supporting the effect of chromosome dosage in the increased male mortality rate, cellular mosaicism in women may offer protection against immune deficiency. As a result, the effect of detrimental mutations to ACE2 may be more pronounced in men than women, altering the clinical course in male versus female patient populations. The ACE2 receptor is expressed in the type II pneumocytes of the lungs and also in other tissues, including the heart, tubular epithelial cells in kidneys, testis, adipose tissue, and the enterocytes in the gastrointestinal tract and vascular endothelial cells A recent study evaluated ACE2 expression in older men and women with heart failure and found in two independent cohorts that circulating plasma concentrations of ACE2 were higher in men than in women This may reflect differences in tissues from men versus women.
Two studies utilized systems biology approaches of meta-analysis, co-expression and network analysis to draw information on the expression, regulation and gender bias of ACE2 receptor expression. The highest levels of ACE2 expression were found in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, medium levels in the lungs, colon, liver, bladder, and adrenal gland, and lowest in blood, spleen, bone marrow, brain, blood vessels, and muscle.
While they did not find a significant difference in gene expression between men and women, ACE2 expression in the lungs was positively correlated with immune signatures in men and negatively in women. In addition the HPA database showed high levels of both ACE2 gene and protein in the gastrointestinal tract duodenum, small intestine, colon, and rectum , kidney, gallbladder, and male tissues testis and seminal vesicle. Taken together these data suggest that the differential host immune responses may underlie the gender-bias of the remarkably distinct clinical outcomes.
The other study of patients with severe COVID who had comorbidities evaluated data from over lung transcriptome samples and found that ACE2 was highly expressed in these patients, compared to controls. Suggesting epigenetic regulation of ACE2 in the human lung. ACE2 is known to be expressed in Leydig cells of both mice and humans, albeit testosterone-independent, and is thought to contribute to steroid synthesis , It is also expressed in ovarian granulosa cells and its levels increase in correlation with increasing LH levels.
In addition to expression in the gonads, ACE2 expression and activity is influenced by sex hormones in adipose tissue, myocardium, and kidneys. Higher ACE and ACE2 activity and cardiac hypertrophy was found in male rats compared to female rats which was reduced after orchiectomy, while ovariectomy elevated ACE2 and hypertrophy in females In female mice, HFD increased adipose tissue ACE2 which was reversed by ovariectomy implying that estrogen increases ACE2 expression and activity in adipose tissue and kidneys.
Importantly, ovariectomy or treatment with an ER antagonist in SARS-CoV infected female mice increased the mortality rate therefore, suggesting a protective effect for the ER signaling pathway in mice 3. While sex hormones influence ACE2 expression and activity to influence outcomes in obesity, hypertension, and related comorbidities, thus influencing COVID outcomes, the effect of COVID on male sex hormones has been recently explored. Given that the ACE2 receptor is expressed in the testes, a study from Hubei province of China reports that the COVID impacts male gonadal function and observed alterations in hormone levels.
They studied 81 men with COVID and found that serum luteinizing hormone LH levels were increased while the ratio of testosterone to LH and the ratio of follicle stimulating hormone FSH to LH were significantly lower compared with age-matched healthy men Recent reports of increased frequency of venous thromboembolism, associated with worse outcomes in patients with COVID warrant caution in treatment with testosterone, specifically in hypogonadal men with greater genetic predisposition.
Besides its role in infection immunity, sex is equally important in the immune response to vaccines , Women not only mount stronger antibody and T-cell responses to vaccinations than men, but also suffer more adverse events. Yet there is a serious lack of attention to gender in vaccine trials. This leads to inappropriate dosage of vaccines as evidenced by the fact that the same magnitude of protective immunity is achieved by half the dose of seasonal influenza vaccine in women compared to men.
Likewise, these gender-blind vaccination strategies lead to increased adverse effects in women. Increased hospitalizations and mortality have been observed in female infants and girls following DPT, measles and oral polio vaccinations Sex-based biological factors include differences across the immune system within innate immunity, antibody responses and T cell responses. Genetics, sex hormones, epigenetic factors, nutrition, and the microbiome are important biological contributors to these sex-based differences.
Vaccine-related research and clinical trials, including those currently underway for COVID, must thus include sex as a key variable when measuring and reporting outcomes of immunogenicity and reactogenicity.