People with systemic lupus erythematosus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Often the symptoms come and go in episodes called flares. In lupus, the immune system goes haywire and produces antibodies that are directed against the body itself.
The immune system can produce many types of antibodies, directed against infectious viruses (good) or against human proteins as in lupus (harmful). Each antibody-secreting cell carries a DNA rearrangement that reflects the makeup of its antibody product. Scientists can use the DNA to identify and track that cell, like reading a bar code on an item in a supermarket.
Iñaki Sanz, MD is a Georgia Research Alliance Eminent Scholar, director of the Lowance Center for Human Immunology and head of the Rheumatology division in the Department of Medicine.
Postdoc Chris Tipton, GRA Eminent Scholar Iñaki Sanz and colleagues at Emory have been using these DNA bar codes to investigate some fundamental questions about lupus: where do the autoantibody-producing cells come from? Are they all the same?
Their findings were published in Nature Immunology in May, and a News and Views commentary on the paper calls it “a quantum advance in the understanding of the origin of the autoreactive B cells.†It’s an example of how next-generation sequencing technology is deepening our understanding of autoimmune diseases.
The Emory team obtained blood samples from eight patients experiencing lupus flares and compared them to eight healthy people who had recently been vaccinated against influenza or tetanus.
When the immune system is responding to something it’s seen before, like when someone receives a booster vaccine, the bar codes of the antibody-producing cells look quite similar to each other. A set of just a few antibody-producing cells multiply and expand, making what looks like clones. In contrast, the researchers found that in lupus, many different cells are producing antibodies. Some of the expanded sets of cells are producing antibodies against infectious agents.
“We expected to see an expansion of the cells that produce autoantibodies, but instead we saw a very broad expansion of cells with all types of specificities,†Tipton says.
To use a Star Wars analogy: a booster vaccine response looks like the Clone Wars (oligoclonal — only a few kinds of monsters), but a lupus flare looks like a visit to Mos Eisley cantina (polyclonal — many monsters).
This is a difference from the autoantibody-producing cells found in multiple sclerosis, which attack a limited set of proteins found in the nervous system.
Many auto-reactive antibodies found in the blood of lupus patients have been well characterized already. These antibodies often recognize DNA or abundant housekeeping proteins such as histones, ribosomes, DNA repair enzymes or splicing factors. Tipton and his colleagues followed one type of antibody against DNA, which is connected to the antibody gene segment Vh4-34. They write:
Our results demonstrated that circulating ASCs [antibody-secreting cells] present during SLE flares were highly polyclonal and did not recognize predominantly the most prevalent lupus antigens. However, this polyclonal repertoire was punctuated by the expansion of complex clones expressing mainly disease-specific VH4-34-encoded autoantibodies.
A recent PLOS One paper from Patrick Wilson and Rafi Ahmed shows that lupus patients have anti-influenza antibodies with higher binding affinity and neutralization capacity than those from controls.
Another key finding of the Nature Immunology paper was that some of the autoantibody-producing cells grow out of a pool of “activated naïve†B cells. This is a paradoxical term, since once B cells are activated, they are not naïve anymore. But it refers to the molecules seen on the cells’ surfaces.
In a booster vaccine response, the few clones that expand are already highly trained; they have undergone a process of hypermutation that fine-tunes the antibodies that they produce. In lupus, the activated naïve cells are, in effect, untrained; they jump into producing antibodies without mutations.
Lipton’s team detected some hints that these activated naïve cells may be persisting in the body for several months. What the researchers are investigating now more closely is the relationship between the auto-antibody producing cells from one flare to the next. They are obtaining samples from lupus patients over time, while experiencing a flare and also at times when symptoms are less intense. Also, investigations of bone marrow cells are in progress, Tipton says.
While the researchers did not directly investigate the effects of lupus drugs such as belimumab (FDA-approved) and epratuzumab (still in clinical trials), they say their findings add some clinically-relevant context, because those drugs seem to preferentially target “activated naïve†B cells.
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