Research-COVID-19: Emory University Study Shows That Human Host Immune Cell Activation In Severe COVID-19 Emulates Lupus Or SLE
: Researchers from Emory University-Altlanta in a new study observing immune cell behavior in COVID-19 patients have discovered that in severe cases of COVID-19, an exuberant activation of immune cells resembling acute flares of systemic lupus erythematosus (SLE), an autoimmune disease is witnessed.
The research findings could lead to new diagnostic tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not.
These findings also may begin to explain why some individuals infected with SARS-CoV-2 produce abundant antibodies against the SARS-CoV-2 coronavirus, yet still experience poor outcomes.
The stud team performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations.
More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multi-organ failure and death.
These study findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19.
The study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling
The study findings were published in the journal: Nature Immunology. https://www.nature.com/articles/s41590-020-00814-z
The research results converge with recent study findings by other research teams, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained.
The study team from Emory observed that B cell activation is moving ahead along an "extrafollicular" pathway outside germinal centers, looking similar to what they had observed in systemic lupus erythematosus or SLE.
It is important to note that the B cells represent a library of blueprints for antibodies, which the immune system can tap to fight infection. In severe COVID-19, the immune system is, in effect, pulling library books off the shelves and throwing them into a disorganized heap.
Prior to the starts of the COVID-19 crisis, co-senior and corresponding author Dr Ignacio Inaki Sanz, MD and his lab were focused on studying SLE and how the disease perturbs the development of B cells.
Dr Sanz is currently the head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Co-senior author Dr Frances Eun-Hyung Lee, MD is associate professor of medicine and director of Emory's Asthma/Allergy Immunology progra
The study’s co-first authors are Dr Matthew Woodruff, Ph.D., an instructor in Sanz's lab, and Dr Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital.
Dr Sanz told Thailand Medical News, "We came in pretty unbiased. It was not until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE."
It has been observed that in individuals with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of "autoantibodies" that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.
As to whether or not severe COVID-19 leads to autoantibody production with clinical consequences is currently under investigation by the Emory University study team.
The study team notes that other investigators have observed autoantibodies in the acute phase of the disease, and it will be important to understand whether long-term autoimmune responses may be related to the fatigue, joint pain and other symptoms experienced by some survivors.
Dr Sanz stressed, "It's an important question that we need to address through careful long-term follow-up. Not all severe infections do this. Sepsis doesn't look like this."
Interestingly In lupus, extrafollicular B cell responses are characteristic of African-American patients with severe disease, he adds. In the new study, the majority of patients with severe infection were African-American.
Also it will be important to understand how underlying conditions and health-related disparities drive the intensity and quality of B cell responses in both autoimmune diseases and COVID-19, the study team said.
The research compared 10 critically ill COVID-19 patients (4 of whom died) admitted to intensive care units at Emory hospitals to 7 people with COVID-19 who were treated as outpatients and 37 healthy controls.
Individuals in the critically ill group tended to have higher levels of antibody-secreting cells early on their infection. In addition, the B cells and the antibodies they made displayed characteristics suggesting that the cells were being activated in an extrafollicular pathway.
Significantly and in particular, the cells underwent fewer mutations in their antibody genes than seen in a focused immune response, which is typically honed within germinal centers.
Dr Ramonell noted that the patients studied were treated early during the COVID-19 pandemic. It was before the widespread introduction of the anti-inflammatory corticosteroid dexamethasone, which has been shown to reduce mortality.
The study team's findings could inform the debate about which COVID-19 patients should be given immunomodulatory treatments, such as dexamethasone or anti-IL-6 drugs. Patients with a greater expansion of B cells undergoing extrafollicular activation also had higher levels of inflammatory cytokines, such as IL-6.
To date certain COVID-19 patients have been given drugs that push back against IL-6, but results have been mixed in clinical trials.
The study team says that patients with markers of unregulated immune responses may be appropriate candidates for treatment with anti-inflammatory drugs that target the corresponding pathways.
In addition, immunological features could also be modified by the timing of sampling and by the use of immunomodulatory therapies.
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