COVID-19 and autoimmune diseases

Authors: Yu Liu,aAmr H. Sawalha,b and Qianjin Lua,cAuthor information Copyright and License information Disclaimer This article has been cited by other articles in PMC.

Abstract

Purpose of review

The aim of this study was to evaluate the relationship between infection with SARS-CoV-2 and autoimmunity.

Recent findings

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome (SARS) associated coronavirus 2 (SARS-CoV-2). Although most of the infected individuals are asymptomatic, a proportion of patients with COVID-19 develop severe disease with multiple organ injuries. Evidence suggests that some medications used to treat autoimmune rheumatologic diseases might have therapeutic effect in patients with severe COVID-19 infections, drawing attention to the relationship between COVID-19 and autoimmune diseases. COVID-19 shares similarities with autoimmune diseases in clinical manifestations, immune responses and pathogenic mechanisms. Robust immune reactions participate in the pathogenesis of both disease conditions. Autoantibodies as a hallmark of autoimmune diseases can also be detected in COVID-19 patients. Moreover, some patients have been reported to develop autoimmune diseases, such as Guillain–Barré syndrome or systemic lupus erythematosus, after COVID-19 infection. It is speculated that SARS-CoV-2 can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells. The infection risk and prognosis of COVID-19 in patients with autoimmune diseases remains controversial, but patient adherence to medication regimens to prevent autoimmune disease flares is strongly recommended.

Summary

We present a review of the association between COVID-19 and autoimmune diseases, focusing on similarities in immune responses, cross-reactivity of SARS-CoV-2, the development of autoimmune diseases in COVID-19 patients and the risk of COVID-19 infection in patients with preexisting autoimmune conditions.

INTRODUCTION

Since December 2019, a novel infection named coronavirus disease 2019 (COVID-19) broke out in Wuhan, China, and has been sweeping across the globe. COVID-19 was officially declared a pandemic by WHO on 11 March 2020 [1]. The disease is caused by a newly identified strain of severe acute respiratory syndrome (SARS) associated coronavirus, which was named SARS-CoV-2 after SARS-CoV that caused the epidemic of SARS in 2002 [2].

SARS-CoV-2 belongs to the coronavirus family, which are enveloped viruses with a spherical morphology and a single-stranded RNA (ssRNA) genome [3]. The spike glycoproteins (S protein) cross through the peplos of the virus and form a crown-like surface [4]. Through the receptor binding domain (RBD) located in the S1 subunit of the S protein, the virus can ligate to the host cell receptor angiotensin-converting enzyme 2 (ACE2) and invade into the cell [57].

In many cases, hosts infected by SARS-CoV-2 present with flu-like symptoms, such as fever, fatigue and dry cough. Headache, myalgia, sore throat, nausea and diarrhoea can also be seen in patients with COVID-19 [8,9]. Shortness of breath and hypoxemia occur in severe cases. In critical cases, the disease progresses rapidly and patients can develop septic shock and multiorgan dysfunction [10]. As such, COVID-19 can be a systemic disease affecting multiple organ systems, including the skin, kidneys, respiratory system, cardiovascular system, digestive system, nervous system and haematological system [11]. The dysregulated immune response and increased pro-inflammatory cytokines induced by SARS-CoV-2 contribute to the disease pathogenesis and organ damage, which brought attention to immune-regulatory therapy in the treatment of COVID-19 [12]. Medications used to treat autoimmune diseases are widely used in critical cases of COVID-19 [13]. Further, some autoantibodies can be detected in patients with COVID-19 [14]. These observations suggest that examining pathways known to contribute to the pathogenesis of autoimmunity might provide clues to better understand and treat COVID-19. 

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880581/

Trained Innate Immunity, Epigenetics, and Covid-19

Authors: Alberto Mantovani, M.D., and Mihai G. Netea, M.D.

Innate immunity is mediated by different cell types and cell-associated or fluid-phase pattern-recognition molecules and plays a key role in tissue repair and resistance against pathogens.1 Exposure to selected vaccines, such as bacille Calmette–Guérin (BCG) or microbial components, can increase the baseline tone of innate immunity and trigger pathogen-agnostic antimicrobial resistance (known as trained innate immunity). Such training is directly relevant to resistance against infectious diseases, including Covid-19. A recent study by de Laval et al.2 pinpoints a driver of durable innate immune memory conferred by myeloid cells (monocytes, macrophages, and neutrophils).

Myeloid cells are central players in innate immunity: they produce effector molecules and contribute to the activation, orientation, and regulation of adaptive immune responses. Diversity and plasticity are fundamental properties of myeloid cells, particularly macrophages. To some extent, these properties are imprinted through ontogenetic origin (embryonal vs. adult bone marrow), but they are also influenced by environmental cues in the tissue. Moreover, in response to microbial molecules, metabolic products, or cytokines, macrophages increase effector function (“activation”), are primed for short-term responses (“priming”), or become unresponsive (“tolerance”). Microbial components can also cause long-term imprinting (“training”) of innate immunity and myeloid-cell function (Figure 1).3 (This type of imprinting is distinct from genomic imprinting whereby methyl groups are added to DNA in or near specific genes.)

For More Information: https://www.nejm.org/doi/10.1056/NEJMcibr2011679

Good news: Mild COVID-19 induces lasting antibody protection

People who have had mild illness develop antibodyproducing cells that can last lifetime

Authors: by Tamara Bhandari•May 24, 2021

Months after recovering from mild cases of COVID-19, people still have immune cells in their body pumping out antibodies against the virus that causes COVID-19, according to a study from researchers at Washington University School of Medicine in St. Louis. Such cells could persist for a lifetime, churning out antibodies all the while.

The findings, published May 24 in the journal Nature, suggest that mild cases of COVID-19 leave those infected with lasting antibody protection and that repeated bouts of illness are likely to be uncommon.

“Last fall, there were reports that antibodies wane quickly after infection with the virus that causes COVID-19, and mainstream media interpreted that to mean that immunity was not long-lived,” said senior author Ali Ellebedy, PhD, an associate professor of pathology & immunology, of medicine and of molecular microbiology. “But that’s a misinterpretation of the data. It’s normal for antibody levels to go down after acute infection, but they don’t go down to zero; they plateau. Here, we found antibody-producing cells in people 11 months after first symptoms. These cells will live and produce antibodies for the rest of people’s lives. That’s strong evidence for long-lasting immunity.”

For More Information: https://medicine.wustl.edu/news/good-news-mild-covid-19-induces-lasting-antibody-protection/

COVID-19 Science Update released: June 4, 2021 Edition 92

Authors: From the Office of the Chief Medical Officer, CDC COVID-19 Response, and the CDC Library, Atlanta GA. Intended for use by public health professionals responding to the COVID-19 pandemic.

PEER-REVIEWED

Safety, immunogenicity, and efficacy of the BNT162b2 COVID-19 vaccine in adolescents.external icon Frenck et al. NEJM (May 27, 2021).

Key findings:

  • Vaccine efficacy was 100% (95% CI 75.3%-100%) in 12- to 15-year-olds.
    • There were no cases in the vaccinated group compared with 16 cases among the placebo group, 7 or more days after dose 2.
  • Compared with baseline, geometric mean neutralizing antibody titers were 118.3-fold higher 1 month after dose 2.
  • Vaccine reactions were mainly transient, mild to moderate, and similar to a comparator group of 16–25-year-olds.
    • Injection-site pain was reported by 79% to 86%, fatigue was reported by 60% to 66%, and headache was reported by 55% to 65% of participants (Figure).

Methods: A randomized, placebo-controlled, observer-blinded trial of Pfizer/BioNTech BNT162b2 in 2,260 adolescents 12–15 years old (1,129 received placebo). Efficacy of the vaccine was assessed based on confirmed SARS-CoV-2 infection with onset 7 or more days after dose 2. Reactogenicity events (assessed for 7 days after each dose) and unsolicited adverse events compared with 16–25 age group (n = 3,610). SARS-CoV-2 serum neutralization assays were performed. LimitationsRacial and ethnic diversity of participants 12-15 years does not reflect the general US population; short (1 month) post-vaccination safety evaluation.

Implications: Vaccination of adolescents with BNT162b2 was safe and effective. Vaccinating adolescents will broaden community protection, and it will likely facilitate reintegration into society and resumption of in-person learning.

Figure:Graphs showing systemic events with 7 days after dose 1 or dose 2 of vaccine or placeboresize iconView Larger

Note: Adapted from Frenck et al. Systemic events reported within 7 days after receiving dose 1 (top) or dose 2 (bottom) of vaccine or placebo. 1 participant in the 12-to-15-year-old group had a fever with a temperature >40°C after dose 1. From the New England Journal of Medicine, Frenck et al., Safety, immunogenicity, and efficacy of the BNT162b2 COVID-19 vaccine in adolescents. May 27, 2021, online ahead of print. Copyright © 2021 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Occurrence of severe COVID-19 in vaccinated transplant patientsexternal icon. Caillard et al. Kidney International. (May 21, 2021).

Key findings:

  • 55 solid organ transplant recipients developed COVID-19 after receiving 2 doses of mRNA vaccine.
    • Symptoms began a median of 22 days after the second vaccine dose (Figure).
    • 15 cases required hospitalization; of these, 6 were admitted to an intensive care unit, and 3 died.
  • Of 25 patients with post-vaccination serology, 24 were antibody negative; 1 was antibody positive but had low titers.

For More Information: https://www.cdc.gov/library/covid19/06042021_covidupdate.html

Pros and Cons of Adenovirus-Based SARS-CoV-2 Vaccines

Authors: Eric J. Kremer1,∗

Main Text

Most of us might be surprised by the rudimentary scientific rationale prevalent in the field of vaccine research just 50 years ago. For over a century after Louis Pasteur’s vaccine against rabies, approaches usually consisted of inactivating a virus, injecting it, and seeing if it protected the host. Unlike today, interactions between vaccinologists and immunologists to improve vaccine efficacy were marginal.

With the rise of molecular biology, vaccine designs became more nuanced and the use of viral vectors emerged. An example is the evolution and checkered history of vaccines based on adenoviruses (Ads). Live Ad types 4 (Ad4) and 7 (Ad7) have been used in North American military recruits since the 1950s to prevent severe respiratory illness.1 Similarly, dogs in western countries are vaccinated with an attenuated canine Ad type 2 (CAV-2) to prevent infection of the more virulent CAV-1.

Many of the first replication-defective Ad “vectors” in the early 1980s were vaccines. The original Ad vaccine design was relatively simple: delete a region of the viral genome that the virus needs to propagate, provide these functions via transcomplementing cells (e.g., Frank Graham’s 293 cells) so that one could grow the vaccine, and then insert into the virus genome an expression cassette encoding the targeted epitopes.

Fast forward to 2020. The SARS-CoV-2 pandemic may be headed toward historic proportions—although still far from the 1918 Spanish flu (50 million deaths) and AIDS (35 million deaths)—inflicting havoc on families, communities, and economies and overwhelming health care facilities. Clearly, we need a vaccine. Are Ad-based vaccines targeting the SARS-CoV-2 spike and capsid proteins our best bet? After almost 70 years of working with Ads, their biochemical properties are well characterized: Ads are simple to make (in ∼2 weeks a graduate student could generate enough of a novel Ad vaccine to treat a thousand mice and dozens of monkeys), easy to purify to high titer, genetically stable, easily stockpiled, relatively inexpensive, and can be delivered via aerosol, oral, intradermal, and intramuscular routes. The aerosol route is particularly relevant when targeting a respiratory virus because inducing protective immune responses that home to the tissue where infections will occur is strategically important. It is also worth noting that Ad-based vaccines tend to induce B cell and T cell responses.

Hundreds of millions of euros, dollars, and yen have been invested in advancing Ad-based vaccines. These advances include production and purification methods, genetic incorporation of epitopes into the capsid so that mononuclear phagocytes present these antigens via major histocompatibility complex (MHC) class I and II pathways, cloaking the capsid with polymers/shields or using Ad types with a lower level of seroprevalence to prevent neutralization by antibodies (NAbs) to common types found in many individuals, retargeting the vector to professional antigen-presenting cells, using helper-dependent vectors (so that the vector-infected cell only expresses the target epitopes and not Ad antigens), and single-cycle replication of vaccines to produce massive amounts of antigens. Each tweak, alone or in combination with others, has improved vaccine efficacy in preclinical trials.

As SARS-CoV-2 became a pandemic, it is astonishing that, in the case of the Ad-based vaccine frontrunners, little has changed from the basic design of 40 years ago. Some used the well-trodden path of an Ad5-based vaccine, while others switched to human (e.g., Ad26) or simian (monkey and gorilla) Ads that have low seroprevalence in Europe and North America (but not necessarily in Africa or Asia).2 Conceptually, Ad type switching to avoid NAbs is at least 30 years old. The advent of simian Ad vaccines was not developed following a rigorous testing of all of the >200 different Ad types but was most likely the result of intellectual property issues and the ability to produce simian Ads in good manufacturing practice (GMP)-compliant cells. One presumes that subsequent rounds of Ad-based coronavirus disease 2019 (COVID-19) vaccine candidates will be more sophisticated.

Should we go “all in” on an Ad-based vaccine against SARS-CoV-2? The first issue is safety. There are few drugs or biologicals that do not have side effects or cause adverse reactions. Weighing the advantages versus disadvantages during the current pandemic can be idiosyncratic, and the strength of the reasoning varies by population, culture, religious beliefs, and bizarrely (for those of us outside the USA) even political affiliation. Current criteria limit the window to identify adverse reactions to 2 months. In addition to swelling and pain at the injection site, common to some vaccines, Ad-based vaccine adverse effects include fever, pneumonia, diarrhea, transient neutropenia and lymphopenia, fatigue, labored breathing, headaches, liver damage, and fasting hyperglycaemia. Rare but grave adverse reactions include neuropathies such as Bell’s palsy, Guillain-Barré syndrome, gait disturbance, and transverse myelitis, an inflammatory condition in the spinal cord.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546260/

COVID-19 survivors may possess wide-ranging resistance to the disease

Authors: Rajee Suri rajee.suri@emory.edu

Recovered COVID-19 patients retain broad and effective longer-term immunity to the disease, suggests a recent Emory University study, which is the most comprehensive of its kind so far. The findings have implications for expanding understanding about human immune memory as well as future vaccine development for coronaviruses.

The longitudinal study, published recently on Cell Reports Medicine, looked at 254 patients with mostly mild to moderate symptoms of SARS-CoV-2 infection over a period for more than eight months (250 days) and found that their immune response to the virus remained durable and strong.

Emory Vaccine Center director Rafi Ahmed, PhD, and a lead author on the paper, says the findings are reassuring, especially given early reports during the pandemic that protective neutralizing antibodies did not last in COVID-19 patients.

“The study serves as a framework to define and predict long-lived immunity to SARS-CoV-2 after natural infection. We also saw indications in this phase that natural immunity could continue to persist,” Ahmed says. The research team will continue to evaluate this cohort over the next few years.

Researchers found that not only did the immune response increase with disease severity, but also with each decade of age regardless of disease severity, suggesting that there are additional unknown factors influencing age-related differences in COVID-19 responses. 

In following the patients for months, researchers got a more nuanced view of how the immune system responds to COVID-19 infection. The picture that emerges indicates that the body’s defense shield not only produces an array of neutralizing antibodies but activates certain T and B cells to establish immune memory, offering more sustained defenses against reinfection.

“We saw that antibody responses, especially IgG antibodies, were not only durable in the vast majority of patients but decayed at a slower rate than previously estimated, which suggests that patients are generating longer-lived plasma cells that can neutralize the SARS-CoV-2 spike protein.”

For More Information: https://news.emory.edu/stories/2021/07/covid_survivors_resistance/index.html

Adaptive immunity to SARS-CoV-2 and COVID-19

Authors: Alessandro Sette1,2 and Shane Crotty1,2,∗

Abstract

The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections and in vaccines, and thus it is critical to directly study adaptive immunity to SARS-CoV-2 to understand COVID-19. Knowledge is now available on relationships between antigen-specific immune responses and SARS-CoV-2 infection. Although more studies are needed, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19. The specific functions and kinetics of these adaptive immune responses are discussed, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.

Introduction

Coronavirus disease 2019 (COVID-19), caused by the novel human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Hu et al., 2020), is a serious disease that has resulted in widespread global morbidity and mortality. Our understanding of SARS-CoV-2 and COVID-19 has rapidly evolved during 2020. As of December 2020, the United States has experienced >300,000 deaths, winter cases are rising exceptionally fast, and the first interim phase 3 vaccine trial results have been reported. The scientific advances in understanding SARS-CoV-2 and COVID-19 have been extraordinarily rapid and broad, by any metric, which is an amazing testament to the commitment, creativity, collaboration, and expertise of the international scientific community, both in academia and industry, under extremely challenging conditions. This article will review our current understanding of the immunology of COVID-19, with a primary focus on adaptive immunity.

The immune system is broadly divided into the innate immune system and the adaptive immune system. Although the adaptive and innate immune systems are linked in important and powerful ways, they each consist of different cell types with different jobs. The adaptive immune system consists of three major cell types: B cells, CD4+ T cells, and CD8+ T cells (Figure 1 ). B cells produce antibodies. CD4+ T cells possess a range of helper and effector functionalities. CD8+ T cells kill infected cells. Given that adaptive immune responses are important for the control and clearance of almost all viral infections that cause disease in humans, and adaptive immune responses and immune memory are central to the success of all vaccines, it is critical to understand adaptive responses to SARS-CoV-2.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803150/

COVID-19 Makes B Cells Forget, but T Cells Remember

Authors: Pablo F Cañete 1Carola G Vinuesa 2

Abstract

Understanding which arms of the immune response are responsible for protection against SARS-CoV-2 infection is key to predicting long-term immunity and to inform vaccine design. Two studies in this issue of Cell collectively suggest that, although SARS-CoV-2 infection may blunt long-lived antibody responses, immune memory might still be achieved through virus-specific memory T cells.

For More Information: https://pubmed.ncbi.nlm.nih.gov/32976799/

Dr. Makary Says Natural Immunity Is More Effective Than Vaccine Immunity

Dr. Marty Makary, a professor at John Hopkins School of Medicine, during an appearance on The Vince Coglianese Show, said individuals formerly infected with COVID-19 are seven times more likely then vaccinated people to fight off the virus.

“It appears that natural immunity is better against the Delta variant. When you get infected with COVID, your body’s immune system develops antibodies to the entire surface of the virus,” Makary said. “Not just the slight protein that the vaccines gives you, but the entire surface. And so you get a more diverse antibody portfolio in your system.”

Makary said data from Israel revealed that natural immunity appears to be 6.7x more effective than being vaccinated when it comes to fighting off COVID-19.

For More Information: https://dailycaller.com/2021/08/04/dr-makary-natural-immunity-covid-19-vaccine/

Complement control for COVID-19

Authors: Markus Bosmann1,2,3,4,*

The complement system is an integral part of innate immune defense. It consists of about 50 proteins in plasma, on cell surfaces, and inside host cells. The traditional view is that complement proteins guard the local extracellular spaces and systemic bloodstream against invading pathogens. Loss-of-function mutations resulting in terminal complement pathway deficiencies are associated with a 10,000-fold higher risk for life-threatening meningococcal infections in humans. Surprisingly, the complement system is redundant for defense against most pathogens except encapsulated bacteria. Recent concepts embrace the view that complement factors mediate functions inside cells either directly or through surface receptors. Complement activity fine-tunes homeostasis, metabolism, and biogenesis. On the other hand, uncontrolled complement activation causes disease and can even worsen the outcome of infections. Toxic complement effectors mediate tissue destruction and organ injury during inflammatory diseases. Acute respiratory distress syndrome (ARDS) and sepsis are frequent and severe complications of acute infections and notorious for excessive complement consumption. The three pathways of complement activation are designed for immune sensing of nonself surfaces and foreign antigens. The mannose-binding lectin (MBL)/ficolin pathway starts with soluble pathogen pattern recognition receptors as sensors for foreign carbohydrate motifs (Fig. 1). The alternative pathway is fueled by a spontaneous “smoldering” hydrolysis of C3 targeting all surfaces, unless these surfaces present complement inhibitory proteins (CD46, CD55, and CD59) as a protective self-signal. This C3 “tick-over” is sustained by the high concentrations of C3 in plasma (1 to 2 g/liter), the highest level of all complement factors. The classical pathway is initiated by antigen-antibody complexes that are recognized by the multimeric C1 complex. As a safeguard, IgG antibodies bound in clusters or pentameric IgM are required to surpass the activation threshold. All complement pathways converge on C3 convertase complexes leading to C3 cleavage into the larger C3b and the smaller anaphylactic C3a peptides. C3b is essential for the formation of C5 convertase for cleavage of C5 into C5b and the anaphylatoxin C5a. C5b is the starting point of the pore-forming membrane attack complex (MAC) consisting of C5b-C9 with a channel diameter of ~100 Å. The C3/C5 hub represents a gigantic amplification loop. The alternative C3bBb convertase (half-life of ~3 min) cleaves additional C3, resulting in more C3bBb and so on and so forth. This enzymatic chain reaction can deposit millions of C3b molecules on target surfaces in a few seconds. It is no surprise that such explosive events need to be tightly regulated to maintain the delicate balance of effective and justified pathogen attack, while avoiding damage of innocent bystander cells.

For More Information: https://immunology.sciencemag.org/content/6/59/eabj1014.full