Search Results for: ACE2

Du som följt mina inlägg om corona / Covid-19 (https://4health.se/?s=corona) har förstått att det finns ett enzym som heter ACE2 som viruset SARS-CoV-2 använder sig av för att infektera våra celler. ACE2 står för angiotensin-converting enzyme och är det nya Coronavirusets inkörsport in i våra celler.

Det nya Coronaviruset behöver alltså ACE2 som inkörsport när det ska ta sig in i cellerna. Det är nämligen så virus fungerar, de “kidnappar” våra celler och förökar sig där inne. De nya viruskopiorna släpps fria i blodet och hittar nya celler som de kan invadera och replikera sig inuti.

När coronaviruset ska försöka få fäste så binder det till ACE2-enzym som finns på ytan av bland annat lungceller (det finns alltså även hos andra typer av celler). En helt ny studie visar tex att viruset kan ta sig in i tarmens celler och direkt föröka sig där.

Att detta enzym (ACE2) inte är färdigutvecklat hos barn tror man är anledningen till att barn sällan blir smittade och inte blir lika sjuka. Omvänt så är ju män värre drabbade än kvinnor av Covid-19. Män och personer med hjärt-kärlsjukdom och diabetes har högre nivåer av ACE2, vilket skulle kunna vara en av förklaringarna till att de blir mer sjuka.

Detta är också anledningen till att det inte bara är lungor, utan även andra organ som direkt drabbas av sars-cov-2, det nya coronaviruset. Alla celler där ACE2 sitter fast i cellmembranet riskerar att bli invaderade. Viruset förökar sig därför i bland annat njurar och blodkärl, vilket är en förklaring till att vissa covid-19-patienter drabbas av skador på flera organ än lungorna.

Förutom på lungornas celler så finns ACE2 i tunntarmen (japp magproblem har vi ju sett hos ungefär en tredjedel med Covid-19), hjärnan (man har nu sett en del fall med hallucinationer), blodkärl, njurar (vi ser skador på både njurar och blodkärl). Dock har vi faktiskt inte så mycket ACE2 i näsans celler, vilket kan var anledningen till att en del testar negativt med tester i näsan (nose swabs) trots att de är sjuka.

Vidare så är detta anledningen till att när man nu forskar och försöker framställa läkemedel mot det nya Coronaviruset, så gör man det med hjälp av en kopia av ACE2. Dessa kopior drar till sig viruset och binder fast det utan att det kunde börja göra kopior av sig självt inne i själva cellerna.

En del immunstimulerande preparat kan stimulera just ACE2 eller ACE2-receptorer. Det finns alltså de som tror att ämnen som stimulerar ACE2 också kan öka risken att infekteras av det nya coronaviruset. Men det vetenskapliga stödet för att så skulle var fallet är inte tillräckligt starkt. 

Jag har i ett antal inlägg diskuterat kring huruvida man bör använda ACE2-höjande preparat och tillskott eller ej, med tanke på om detta skulle kunna förenkla coronavirusets invadering av våra celler. Detta gäller alltså tillskott som A- och D-vitamin, kurkumin/gurkmeja och en rad andra immunstimulerande preparat. Men frågan är om det inte är så att dessa näringsämnen istället ökar fritt cirkulerande ACE2 och därmed snarare “lurar bort” viruset från cellerna – på liknande sätt som man tänker sig att läkemedel mot Covid-19 ska göra.

Vi måste antagligen skilja på ACE2 som sitter i cellmembranen och fungerar som inkörsportar för viruset, och på fritt cirkulerande ACE2 i vårt blod (på bilden här kallat soluble ACE2).

Saker som kan höja fritt cirkulerande ACE2 är bl.a. A-vitamin och D-vitamin (finns i naturlig balans i fiskleverolja och lever) , gurkmeja/ kurkumin, sömn/melatonin och träning. Men detta gäller de flesta immunstimulerande tillskott såsom propolis, echinacea etc. Det kan alltså vara så att dessa gör nytta för att undvika även Covid-19, trots att de stimulerar ACE2.

En del av de här sakerna, såsom kurkumin och fläder, har dessutom allmänna virushämmande egenskaper.

Jag hittade en mycket spännande artikel skriven av en läkare på det här temat (se länk nedan). Där skriver hon bl.a. att:

ACE2 has gotten a bad rap these days, I think undeservedly. Initial concerns that medicines that block Angiotensin-converting enzyme (ACE inhibitors) and angiotensin II receptor blockers (ARBs) and INCREASE circulating levels of ACE2 could potentially worsen COVID-19 have been unfounded. No worsening of outcomes has been found with patients who are on ACE inhibitors and ARBs. And a recent study showed the exact opposite – that patients with high blood pressure hospitalized with COVID-19 who were on ACE inhibitors or ARBs had a 63% LOWER mortality risk than those who were not. (2) Current recommendations from cardiologists are that if you are on an ACE inhibitor or ARB for hypertension, to stay on it if you get COVID-19. 

We need to understand the difference between:

ACE2 attached to cell membranes (aka membrane-bound ACE2 or ACE2 receptors), and

ACE2 that is floating around our blood (aka soluble or circulating serum ACE2)

We may not want more ACE2 attached to our cell membranes, as this could theoretically increase the number of entry portals for SARS-CoV-2 to enter our cells. 

BUT, we probably DO want more circulating serum ACE2. Circulating serum ACE2 may actually act as a “decoy” for SARS-CoV-2 to bind the virus BEFORE it can attach to our cells and invade. Circulating ACE2 is PROTECTIVE against lung injury, septic shock and many of the chronic conditions that increase risk of serious COVID-19 infection in the first place. 

Administering soluble ACE2 has been found to be protective in animal models of acute lung injury (ARDS) and sepsis. One mouse study (3) of acute lung injury and sepsis, that mimicked what is seen in human SARS coronavirus cases, found that lower serum ACE2 worsened acute lung injury, while higher ACE2 actually protected lungs. Another mouse study (4) of acute respiratory distress syndrome (ARDS) induced by avian influenza H5N1 (aka “bird flu”) found that ACE2 administration could improve lung function and survival rates. ACE2 inactivates Angiotensin II. Elevated serum levels of Angiotensin II were found in patients with H7N9 avian influenza, with higher levels of Angiotensin II correlating with worse disease severity and outcome. The authors speculate that treatment with soluble ACE2 could be beneficial for patients with SARS-CoV-1, which is very similar to the currently circulating SARS-CoV-2 that causes COVID-19.

And even more importantly, this study found that administering soluble human ACE2 could actually inhibit SARS-CoV-2 infections in vitro by a factor of 1,000-5,000. (5) 

Mer via https://4health.se/?s=ACE2 och https://4health.se/?s=corona

https://www.hubrecht.eu/coronavirus-sars-cov-2-infects-cells-of-the-intestine/

https://healthykidshappykids.com/2020/04/29/kawasaki-ace2-covid-19/

https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.317134

https://www.nature.com/articles/nature03712

https://www.sciencedirect.com/science/article/pii/S0092867420303998

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970173/

https://www.ahajournals.org/doi/10.1161/01.HYP.0000146400.57221.74

Jag har tagit upp hur man kan använda bl.a. glutation och NAC om man drabbas av Covid-19. Både för att aktivera immunförsvaret (rätt delar) och för att dämpa de besvär som kan uppstå tex i form av cytokinstormar. En ny vetenskaplig sammanställning betonar just rollen i att dämpa inflammationen i sjukdomens senare skede. Det är just denna överdrivna immunrespons som gör att Covid-19 kan bli farligt.

Saxat ur artikeln:

“The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19

The novel COVID-19 pandemic is affecting the world’s population differently: mostly in the presence of conditions such as aging, diabetes and hypertension the virus triggers a lethal cytokine storm and patients die from acute respiratory distress syndrome, whereas in many cases the disease has a mild or even asymptomatic progression. A common denominator in all conditions associated with COVID-19 appears to be the impaired redox homeostasis responsible for reactive oxygen species (ROS) accumulation; therefore, levels of glutathione (GSH), the key anti-oxidant guardian in all tissues, could be critical in extinguishing the exacerbated inflammation that triggers organ failure in COVID-19. The present review provides a biochemical investigation of the mechanisms leading to deadly inflammation in severe COVID-19, counterbalanced by GSH. The pathways competing for GSH are described to illustrate the events concurring to cause a depletion of endogenous GSH stocks. Drawing on evidence from literature that demonstrates the reduced levels of GSH in the main conditions clinically associated with severe disease, we highlight the relevance of restoring GSH levels in the attempt to protect the most vulnerable subjects from severe symptoms of COVID-19. Finally, we discuss the current data about the feasibility of increasing GSH levels, which could be used to prevent and subdue the disease.”

“Among the many functions of GSH, some are worthy of mention in relation to their impact on the exacerbated inflammation taking place in COVID-19 and in relation to the symptoms developed in the disease.

1. GSH protects cells by neutralizing (i.e., reducing) ROS, which are key signaling molecules that play an important role in the progression of inflammatory disorders. The relationship between ROS production and proinflammatory cytokine activation is well established [22]. An enhanced ROS generation by polymorphonuclear neutrophils at the site of inflammation causes endothelial dysfunction and tissue injury [23].

2. The conjugation of GSH to xenobiotics is particularly abundant; glutathione S-transferase enzymes catalyze GSH conjugation to lipophilic xenobiotics, facilitating the excretion or further metabolism of many drugs. The conjugation process is illustrated by the metabolism of N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is a reactive metabolite formed by the action of cytochrome P450 on paracetamol (acetaminophen). Glutathione conjugates to NAPQI and the resulting product is excreted [24].

3. Many enzymes use GSH as a cofactor or substrate. For example reactions requiring GSH as a key cofactor are catalyzed by the prostaglandin H synthase, the rate-limiting enzyme in the production of prostaglandins and thromboxane [25], which are essential regulators of vascular function. Moreover, the enzyme leukotriene C(4) synthase conjugates LTA(4) with GSH to form the leukotriene LTC(4), the parent compound of the cysteinyl leukotrienes [26]; these molecules are potent mediators of airway narrowing.

4. GSH is used to synthesize S-nitrosoglutathione (GSNO), an endogenous S-nitrosothiol that plays a critical role in nitric oxide (NO) signaling and is a source of bioavailable NO. The generation of GSNO can serve as a stable NO pool which can properly transduce NO signaling [27]. NO produced by nitric oxide synthase eNOS and nNOS, in the presence of GSH, can effectively modulate vessels and neuronal functions, regulating the blood flow according to the local calcium influx.

As a consequence of the competition between these and many other GSH-consuming pathways, on one hand, the raging inflammation and oxidative stress triggered by the viral infection steals GSH from core functions such as NO-dependent vasodilatation; on the other hand, when other biochemical pathways are consuming GSH, the patient is not protected from an inflammation that can prove fatal.”

“ACE expression and activity are modulated by glutathione; in fact, the oxidized form GSSG shows an activating effect on ACE activity, whereas the reduced GSH provides an inhibitory effect [28]. Finally, the boosted ANGII production can be due to decreased ACE2 expression and activity; this is the case with coronavirus infection, which recognizes ACE2 as its extracellular binding site [29]. Compared to SARS-COV-1, SARS-CoV-2 has about 4-fold higher affinity for ACE2 [30]. Infection of cells by SARS viruses that bind ACE2 results in two effects: inhibition of ACE2 activity and decrease of ACE2 expression in infected cells”

“By reducing ROS production, GSH inhibits NF-kB activation and consequently keeps the cytokine storm under control.”

Tidigare om glutation bl.a. i podcastavsnitt om Covid-19 https://4health.se/259-dr-cecilia-furst-covid-19 och här https://4health.se/sa-kan-glutation-boosta-ditt-immunforsvar och här https://4health.se/?s=glutation och här https://4health.se/?s=corona

https://www.mdpi.com/2076-3921/9/7/624

Det är välkänt att diabetes är en riskfaktor för Covid-19, men det omvända verkar också gälla.

I UK är ungefär 25% av de som behöver sjukhusvård för Covid-19 diabetiker. Men det verkar också vara så att Covid-19 kan skada de insulinproducerande cellerna, så att man kan utveckla diabetes av virusinfektionen.

Många som anländer till sjukhus med svår Covid-19 har skyhöga blodsockernivåer. En antydan om att insulinmekanismen inte fungerar som den ska. För en del av dessa blir tillståndet kroniskt.

Forskning har visat att ACE-2, proteinet/ receptorn som Sars-Cov-2 binder till när det kommer in i den mänskliga cellen, inte bara finns i lungorna. ACE2 finns också i organ och vävnader som är involverade i glukosmetabolismen – såsom bukspottkörteln, tunntarmen, fettvävnaden, levern och njurarna. Experter tror att viruset kan orsaka flera olika och komplexa dysfunktioner av glukosmetabolism genom att komma in i dessa vävnader. Och därmed leda till diabetes.

Men det behövs betydligt mer forskning för att nå ett avgörande svar kring detta. En global databas, CoviDiab Registry-projektet, inrättades i början av juni för att samla information om Covid-19-patienter med höga blodsockernivåer.

Mer via https://4health.se/?s=corona

Not only may diabetes make a coronavirus infection worse, but Covid-19 may also trigger the onset of the chronic condition in some people, emerging evidence suggests. 

It is well known that underlying health issues increase the likelihood of severe illness or death after contracting the coronavirus. 

In the first two months of the UK’s outbreak, roughly 25 per cent of people hospitalised with Covid-19 with already had diabetes, suggesting that the risk of severe illness among diabetics was four times higher than for the general population. 

But Paul Zimmet, a professor of diabetes at Monash University in Melbourne, told Nature that “two pandemics could be clashing”, with Covid-19 also damaging the cells responsible for producing the hormone insulin. 

He said that dozens of patients suffering from severe Covid-19 have arrived at hospital with very high blood sugar levels – a sign that the body is not producing enough of the hormone. 

A handful of these patients have gone on to rapidly develop the chronic condition, where the body produces either no insulin at all, or not enough to work effectively. 

The theory has some precedent as other viruses are known to precipitate autoimmune diseases, including type 1 diabetes. A paper published in Acta Diabetologica journal in 2009 found that damage to the body caused by Sars, a close cousin of the virus that causes Covid-19, triggered the onset of diabetes in some patients.

More recently, an experimental study in miniature lab-grown pancreases published in the Lancet last week concluded that a Covid-19 infection “could induce new onset diabetes” by damaging the cells responsible for control blood sugar levels. 

The findings have not been confirmed in humans and it is unclear whether Covid-19 plays a direct role in the reduced production of insulin.

But on June 12, a group of 17 leading diabetes experts wrote a letter published in the New England Journal of Medicine warning that new-onset diabetes is being observed in some patients who have tested positive for the Covid-19. 

Research has shown that ACE-2, the protein that Sars-Cov-2 binds to as it enters the human cell, is not only located in the lungs. It is also in organs and tissues that are involved in glucose metabolism – such as the pancreas, the small intestine, the fat tissue, the liver and the kidney.

Experts believe that by entering these tissues, the virus may cause multiple and complex dysfunctions of glucose metabolism, triggering diabetes. 

But there are warnings that considerably more research is needed to reach a conclusive answer. Experts hope for clarity in the coming months after a global database, dubbed the CoviDiab Registry project was established in early June to collect information on Covid-19 patients with high blood-sugar levels. 

“As has been stated, we’ve not encountered a virus like Sars-CoV2 before for the breadth of disease it causes,” Prof James Hildreth, president of Meharry Medical College, said. “Now evidence [is] accumulating that Covid-19 virus may cause diabetes. Clearly suggests that people who are pre-diabetic or diabetic should definitely avoid Covid-19 infection.”

https://www.nature.com/articles/d41586-020-01891-8

https://www.sciencedirect.com/science/article/abs/pii/S2213858720301522

https://www.telegraph.co.uk/global-health/science-and-disease/covid-19-may-trigger-diabetes-growing-body-evidence-suggests/

Det är vid det här laget väl känt att män generellt drabbas mer och hårdare än kvinnor av det nya coronaviruset. Fler män blir svårt sjuka, fler män vårdas på IVA och fler män dör med covid-19. I Sverige har 800 fler män dött i covid-19 än kvinnor, trots att fler kvinnor testat positivt för sjukdomen. Om man tittar globalt så är risken för att dö med covid-19 ungefär 1,7 gånger högre för män än för kvinnor. I en ny artikel i Science sammanfattar forskare den kunskap och de teorier som finns hittills om vad det här kan bero på – och många teorier handlar om att det är skillnader i kvinnors och mäns immunförsvar som ligger bakom.

Jag har skrivit om det i tidigare inlägg, bl.a. en del här https://4health.se/hur-hart-vi-drabbas-av-corona-beror-pa-genetiska-skillnader-i-olika-varldsdelar-befolkningar och här https://4health.se/?s=män+drabbas . Läs gärna också om skillnaderna mellan kvinnors och mäns immunsystem: https://4health.se/skillnader-mellan-det-manliga-och-det-kvinnliga-immunsystemet-forklarar-skillnader-i-sjukdomar

Det finns flera skillnader mellan mäns och kvinnors immunförsvar. En sak är att de åldras olika. Hos båda könen försvagas immunförsvaret med åldern, framförallt efter 60 år. Men den försvagningen är kraftigare hos män och sker normalt 5-6 år tidigare än hos kvinnor. Det gör att män, särskilt då äldre män, har svårare att kontrollera virusinfektioner.

Men män har också generellt ett sämre immunförsvar än kvinnor och i alla åldersgrupper över 30 år ser man att män drabbas hårdare och är överrepresenterade när det gäller döda med covid-19. Till och med mer än vid många andra infektioner.

Dessutom finns viktiga immunrelaterade gener på X-kromosomen.

I möss har man sett att receptorn som SARS-Cov2-viruset binder till (ACE2) kan regleras av könshormonet östrogen. Det skulle kunna förklara ytterligare en skillnad i hur man reagerar på infektionen.

Forskarna reflekterar också kring andra kända skillnader mellan män och kvinnors immunsystem, såsom “females generally mount a more robust immune response to vaccines, such as influenza vaccines. However, the heightened immune responses in females can also lead to detrimental immunopathology in infections” Jag reflekterar här över kvinnor som utvecklar långtidssymtom efter covid, samt utvecklar autoimmuna sjukdomar efter infektion generellt.

Läs mer om skillnaderna i immunsystemet i nedan text ur artikeln.

Mer via https://4health.se/?s=corona

Ur artikeln:

“the risk of death in males is ∼1.7 times higher than in females (1). Aging is strongly associated with higher risk of death in both sexes, but at all ages above 30 years, males have a significantly higher mortality risk, rendering older males the most vulnerable group (1). Sex differences are intertwined with differences in gender roles socially and with behavioral factors, which also influence COVID-19 incidence and outcomes. However, there are also possible biological mechanisms of male sex bias that affect the severity of COVID-19, particularly with respect to immune responses.”

“male sex is more often associated with lower immune responses and higher susceptibility and/or vulnerability to infections in animals. This is generally also the case in humans (2): Male patients have higher viral loads for hepatitis B virus (HBV) and HIV (2). Conversely, females generally mount a more robust immune response to vaccines, such as influenza vaccines. However, the heightened immune responses in females can also lead to detrimental immunopathology in infections”

“The physiological response to virus infection is initiated when virus replication is detected by pattern recognition receptors. This leads to two antiviral programs by the infected cells: (i) cellular antiviral defense programs mediated by type I and type III interferons (IFNs) to limit viral replication and spread, and (ii) cytokine and chemokine production to recruit and coordinate immune cells, such as monocytes and neutrophils that can phagocytose and eliminate infected cells. Notably, COVID-19 is characterized by strong innate immune cytokine and chemokine responses despite the disproportionately low antiviral defense signature mediated by IFNs (3). Patients with severe COVID-19 exhibit high serum concentrations of proinflammatory cytokines and chemokines, with particularly high concentrations of interleukin-6 (IL-6) and the inflammasome-associated cytokines IL-1β and IL-18 (4). Exacerbated systemic inflammation is associated with extensive pulmonary pathology, including massive infiltration of monocytes and neutrophils. Increased neutrophil count is associated with poor clinical outcome (5). The robust induction of these inflammatory cytokines and cells may be a compensatory response to the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evade IFN responses, which necessitates the engagement of IFN-independent defense mechanisms (6).

The plasma concentrations of several key innate immune cytokines and chemokines, such as IL-8 and IL-18, are increased in male patients compared with female patients in the early phase of COVID-19. Conversely, female patients have higher plasma concentrations of type I IFN (IFNα) over the disease course (7). Notably, autoantibodies that inhibit type I IFN signaling have been reported in a subset of severely ill patients, the majority (94%) of whom were older males (8). By contrast, T cell activation at the early phase of SARS-CoV-2 infection is robust even in older female patients, whereas male patients have a significant decline with age. Male patients with poor T cell activation at the early phase of disease onset have worse COVID-19 outcomes, whereas no such difference is observed in female patients (7).

What could be the potential underlying mechanism of this sex dimorphism in immune response? One culprit is the sex chromosomes: A substantial number of important immune-related genes are encoded on the X chromosome. Although one of the two copies of the X chromosome in females is usually epigenetically silenced [X chromosome inactivation (XCI)], some critical immune-related genes, including Toll-like receptor 7 [TLR7, whose viral RNA sensing elicits strong type I IFN production in its major producer, plasmacytoid dendritic cells (pDCs)], can escape from XCI in some proportion of cells. This makes the population “mosaic” for biallelic expression, which leads to higher gross expression of some immune-related genes in females (9). Human pDCs have also been reported to have higher expression of interferon regulatory factor 5 (IRF5) in females. Higher expression of these genes leads to more robust type I IFN responses in females, and this is one of the potential mechanisms involved in females’ enhanced protection against viral infections, including COVID-19 (1, 2).

Sex has a major impact on immune cell transcriptomes; immune cells or even the immune system are differentially affected by aging, depending on sex. Aging induces a decline in the proportion of naïve T cells that is more prominent in males, and B cells decline after age 65 only in males (10). Males have abrupt and drastic changes in the epigenetic landscape of their immune cells between ages 62 and 64, and subsequently males exhibit an accelerated immunosenescence phenotype that is characterized by enhanced innate proinflammatory gene expression and lower gene expression related to adaptive immunity, which could potentially predispose older males to hyperinflammation and poor adaptive immune responses.

By contrast, major changes in the epigenetic landscape of immune cells occur in females 5 to 6 years later than in males, with this gap largely corresponding to the life span differences between sexes (10). It is notable that females generally mount more pronounced cytokine responses in viral infections, although this is not the case with COVID-19. Instead, males have higher plasma concentrations of innate proinflammatory cytokines such as IL-8 and IL-18 (7). This could be because patients who have severe disease are generally of older age, and the background transcriptomic and epigenetic sex differences in immune cells in these older individuals are possibly amplified and more explicitly manifested in the context of SARS-CoV-2 infection (see the figure).

The other important biological factors are sex hormones. In a mouse model of SARS-CoV infection, higher mortality in male mice was observed and was attributed to the protective roles of the female sex hormone estrogen (1). Studies using various cell types and animal models have shown that the expression of angiotensin-converting enzyme 2 (ACE2), the host cell entry receptor for SARS-CoV-2, is modulated by estrogen (1). This likely occurs through transcriptional regulation by estrogen receptor signaling, although the detailed molecular mechanisms are yet to be identified and the consequences of the type of ACE2 modulation (up- or down-regulation) could be cell type– and context-dependent. Estrogen receptors are widely expressed by many cell types, including immune cells, and estrogen is a critical regulator of gene expression and functions in innate immune cells, including monocytes, macrophages, and dendritic cells, as well as in lymphocytes such as T helper 1/2 (T_H1/2) cells, regulatory T cells (T_regs), and B cells. One of the major forms of estrogen, estradiol, has been shown to dampen the production of excessive innate inflammatory cytokines by monocytes and macrophages (1). Menopause is an independent risk factor for female patients, and concentrations of estradiol and anti-Müllerian hormone, which is produced by cells in developing follicles and is an endocrine marker for oocytes remaining in the ovaries (ovarian reserve), are inversely correlated with COVID-19 severity (11). Conversely, androgen-deprivation therapies for prostate cancer have been reported to reduce the risk for SARS-CoV-2 infection (12). Like estrogen receptors, androgen receptors are expressed widely among immune cells, regulating the transcription of various genes, and the outcome of their signaling has been shown to be generally immunosuppressive (1).

Despite the emerging understanding of sex differences of immune responses in COVID-19, many questions remain. Sex is not binary, and little is known regarding immune responses to viral infections, including COVID-19, in individuals with disorders of sex development (DSD) or transgender individuals. DSD describes congenital conditions in which the development of chromosomal, gonadal, and anatomical sex is atypical. For example, Klinefelter syndrome (also known as 47, XXY) results in phenotypes such as gynecomastia (enlarged breast tissue in males) and small testes with hypogonadism. This condition accompanies a series of comorbidities, in particular a high frequency of autoimmune diseases, such as systemic lupus erythematosus (SLE). The prevalence of SLE among Klinefelter syndrome patients is higher by a factor of 14 than among 46, XY males; this is comparable to its prevalence among 46, XX females, which suggests a gene dosage effect of the X chromosome (13). Additionally, transgender is a collective term encompassing those whose gender identities or gender roles differ from those typically associated with the sex they were assigned at birth. Little is known about the immune responses in these individuals, some of whom are undergoing gender reassignment hormone therapies. It is possible that DSD and transgender individuals mount distinct immune responses to viral infection in general and also in COVID-19.

Sex differences in immunity also have implications for responses to SARS-CoV-2 vaccination or reinfection. Analysis of convalescent plasma showed that male sex, older age, and hospitalization for COVID-19 were associated with greater SARS-CoV-2 antibody titers (14). This could be related to increased disease severity in this demographic of patients, with increased viral load driving more B cell activation and antibody production. Alternatively, higher amounts of antiviral antibodies could be due to compensatory increases in antibody production due to suboptimal qualities of antibodies generated in older males, which are unable to neutralize the virus effectively. Antibodies with suboptimal neutralizing ability have the capacity to promote viral invasion into host cells such as macrophages [called antibody-dependent enhancement (ADE)]. However, there has been no clear evidence of ADE in COVID-19. With other viral infections, fatal diseases in dengue virus infection (dengue hemorrhagic fever and dengue shock syndrome) have been associated with ADE. Upon secondary infection with a virus of a serotype different from that of the primary infection, the fatalities from these severe diseases were primarily seen in adult females despite the male dominance in dengue hemorrhagic fever prevalence (15). The mechanism remains unknown but may be due to heightened inflammation in females, leading to capillary permeability.

It is important that studies of COVID-19 patients report results in a sex-disaggregated manner, not only to elucidate differential disease pathogenesis, but also to enable a deeper understanding of this disease and the eventual development of better treatment and preventive strategies. It should be standard practice to collect and report sex-disaggregated data for this and for all infectious disease and vaccine studies in the future.”

https://science.sciencemag.org/content/371/6527/347

https://www.dn.se/vetenskap/forskare-nya-teorier-om-varfor-man-drabbas-hardare-av-covid-19/

https://sverigesradio.se/artikel/7652493