Oddly, about 20% of the B cells in our bodies are autoreactive. They target antigens belonging to our own tissues \u2014 not by design, but due to the random way B-cell diversity comes about: through sloppy replication, apparently engineered by evolution to ensure diversification. Fortunately, these B cells are typically in a dopey state of inertia, and they pretty much leave our tissues alone.<\/p>\n
But at times, somnolent autoreactive B cells become activated, take aim at our own tissues and instigate one of the disorders collectively called autoimmunity. Some awakened autoreactive B cells crank out antibodies that bind to proteins and DNA inside the nuclei of our cells. Such activated \u201cantinuclear antibodies\u201d \u2014 the hallmark of lupus \u2014 trigger damage to tissues randomly distributed throughout the body, because virtually all our body\u2019s cells have nuclei.<\/p>\n
The vast majority of EBV-infected people (most of us, that is) have no idea they\u2019re still sheltering a virus and never get lupus. But essentially everyone with lupus is EBV-infected, studies have shown. An EBV-lupus connection has been long suspected but never nailed down until now.<\/p>\n
The antinuclear B cell gets ornery<\/p>\n
Although latent EBV is ubiquitous in the sense that almost everybody carries it, it resides in only a tiny fraction of any given person\u2019s B cells. As a result, until the new study, it was virtually impossible for existing methods to identify infected B cells and distinguish them from uninfected ones. But Robinson and his colleagues developed an extremely high-precision sequencing system that enabled them to do this. They found that fewer than 1 in 10,000 of a typical EBV-infected but otherwise healthy individual\u2019s B cells are hosting a dormant EBV viral genome.<\/p>\n
Employing their new EBV-infected-B-cell-identifying technology along with bioinformatics and cell-culture experimentation, the researchers found out how such small numbers of infected cells can cause a powerful immune attack on one\u2019s own tissues. In lupus patients, the fraction of EBV-infected B cells rises to about 1 in 400 \u2014 a 25-fold difference.<\/p>\n
It\u2019s known that the latent EBV, despite its near-total inactivity, nonetheless occasionally nudges the B cell it\u2019s been snoozing in to produce a single viral protein, EBNA2. The researchers showed that this protein acts as a molecular switch \u2014 in geneticists\u2019 language a \u201ctranscription factor\u201d \u2014 activating a battery of genes in the B cell\u2019s genome that had previously been at rest. At least two of the human genes switched on by EBNA2 are recipes for proteins that are, themselves, transcription factors that turn on a variety of other pro-inflammatory human genes.<\/p>\n
The net effect of all these genetic fireworks is that the B cell becomes highly inflammatory: It dons its \u201cprofessional antigen-presenting cell\u201d uniform and starts stimulating other immune cells (called helper T cells) that happen to share a predilection for targeting cell-nuclear components. These helper T cells enlist multitudes of other antinuclear B cells as well as antinuclear killer T cells, vicious attack dogs of the immune system.<\/p>\n
When that militia bulks up, it doesn\u2019t matter whether any of the newly recruited antinuclear B cells are EBV-infected or not. (The vast majority of them aren\u2019t.) If there are enough of them, the result is a bout of lupus.<\/p>\n
What comes next?<\/p>\n
Robinson said he suspects that this cascade of EBV-generated self-targeting B-cell activation might extend beyond lupus to other autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and Crohn\u2019s disease, where hints of EBV-initiated EBNA2 activity have been observed.<\/p>\n
The million-dollar question: If about 95% of us are walking around with latent EBV in our B cells, why do some of us, but not all of us, get autoimmunity? Robinson speculates that perhaps only certain EBV strains spur the transformation of infected B cells into antigen-presenting \u201cdriver\u201d cells that broadly activate huge numbers of antinuclear B cells.<\/p>\n
Many companies are working on an EBV vaccine, and clinical trials of such a vaccine are underway. But that vaccine would have to be given soon after birth, Robinson noted, as such vaccines are unable to rid an already-infected person of the virus.<\/p>\n
Stanford University\u2019s Office of Technology Licensing has filed a provisional patent application on intellectual property associated with the study\u2019s findings and technologies used to obtain them. Robinson, Younis and a third study co-author, Mahesh Pandit, PhD, a postdoctoral scholar in immunology and rheumatology, are named inventors on the application. They are co-founders and stockholders of a company, EBVio Inc., a company exploring <\/b>an experimental lupus treatment, ultradeep B-cell depletion. This procedure involves total annihilation of all circulating B cells, which are replaced over the following few months by new, EBV-free B cells born continually in the bone marrow. Robinson is also a director of EBVio Inc. and a co-founder and shareholder of Flatiron Bio, LLC.<\/p>\n
Researchers from the U.S. Department of Veterans Affairs Medical Center, Cincinnati; the University of Massachusetts School of Medicine; the University of Oklahoma Health Sciences Center; and Rockefeller University contributed to the work.<\/p>\n
The study was funded by the National Institutes of Health (grants R01AR078268, R01AI173189-01, PATHO-PH2-SUB_17_23 and R01AI024717), the VA Palo Alto Health Care System, the Lupus Research Alliance and the Brennan Family.<\/p>\n","protected":false},"excerpt":{"rendered":"Oddly, about 20% of the B cells in our bodies are autoreactive. They target antigens belonging to our…\n","protected":false},"author":3,"featured_media":375199,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11],"tags":[210,95796,27678,3740,57005,57006,67,132,68],"class_list":{"0":"post-375198","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-health","8":"tag-health","9":"tag-immunology","10":"tag-lupus","11":"tag-medical-research","12":"tag-send-to-ucomms","13":"tag-stanford-school-of-medicine","14":"tag-united-states","15":"tag-unitedstates","16":"tag-us"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@us\/115540666931624400","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/375198","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/comments?post=375198"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/375198\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media\/375199"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media?parent=375198"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/categories?post=375198"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/tags?post=375198"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}