how do antimalarial drugs work for lupus?

Antimalarial drugs can treat autoimmune diseases, such as lupus, Sjogren's, and rheumatoid arthritis...
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Here's how! (described in easy to understand language)

Malaria organism attaching to a red blood cell to infect. Photo by NIAID: https://www.flickr.com/photos/54591706@N02/34034143483

“How do medicines used to treat malaria also work for autoimmune diseases like lupus?”

Antimalarial drugs, such as hydroxychloroquine (Plaquenil), chloroquine, and quinacrine, are some of the most common medicines used to treat autoimmune disorders, especially lupus (SLE) and Sjogren's. 

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To answer this question, you need to understand how the immune system works. One of the key things in the immune system is antigen presentation (figure 30.1A). Antigens are proteins that cause the immune system to make antibodies directed toward those specific antigens for protection. For example, let us say you are infected with parvovirus, which can cause a cold-like illness and sometimes even rash, joint pain, and even a lupus-like illness. The immune system “sees” the proteins (which act as antigens) on this virus, recognizes that they do not belong to the body, and launches an all-out war against the virus. It does this by making antibodies that can attach to the parvovirus antigens, which in turn identifies the virus invaders as the “bad guys.” Subsequently, this alerts other white blood cells of the immune system to attack the virus. The immune system has now learned that parvovirus is a “bad guy.” It is now able to produce these antibodies that recognize parvovirus for the rest of your life. Suppose you are infected by parvovirus ever again. Your immune system’s white blood cells can attack the virus so that you do not get sick from it ever again.

Hydroxychloroquine changes the acidity inside the portions of immune cells that recycle antigen proteins

So now, let us go a little deeper into how the body makes these antibodies in the first place, focusing on a concept called antigen processing (figure 30.1A). This is a very technical discussion that can be skipped by many people reading this book. However, it can be interesting for the person who wants to know more about how anti-malarial medicines work. Macrophages are white blood cells that are responsible for identifying foreign antigens for the immune system. You can think of them as the frontline soldiers that come into contact first with any unusual antigen proteins such as viruses and bacteria invading the body.

Macrophages are often also called “antigen-presenting cells” in immunology. In lupus, where the immune system starts to attack parts of the body itself, the antigens it thinks are foreign are actually antigen proteins naturally occurring in the body. When the macrophages see these antigens (such as proteins from skin cells), they engulf them into little bubbles called vacuoles (follow along in figure 30.1A). The vacuoles break down (or digest) these antigen proteins into numerous smaller components and reassemble them into structures that are then attached to the outside of the macrophage cell surface. The macrophages then show these antigens (antigen presentation) to other white blood cells of the immune system (especially T-cells) so that they can recognize them as being “bad” proteins. This causes other white blood cells (called B-cells) to start making antibodies directed against these antigen proteins. However, in lupus, these antigen proteins that end up being attacked belong to the person’s own body. The antibodies produced to attack the body’s own antigens are called “auto-antibodies.” 

A well-known example in systemic lupus erythematosus (SLE) is when ultraviolet (UV) light can damage skin cells. These can then release their inner contents, such as the nucleus and its own DNA, into the surrounding tissues and bloodstream.  The lupus immune system can then make anti-DNA autoantibodies that attach to the person’s own DNA from the skin cells (thinking that the DNA is a foreign attacker). This combination of the DNA protein antigen bound to the anti-DNA antibody is called an “immune complex.” These immune complexes can then travel throughout the body, depositing in other tissues where the lupus immune system can cause inflammation and damage. An important example of this is the kidneys. These immune complexes can contribute to kidney inflammation (lupus nephritis). This illustrates how UV light exposure can cause a lupus rash in the area of exposure and in distant parts of the body, like the kidneys. 

For this antigen presentation to occur, the macrophages’ vacuoles must have a low pH level (in other words, they must be acidic). Otherwise, the enzymes of the vacuoles that are responsible for processing the antigens will not work. The anti-malarial medicines (such as hydroxychloroquine, Plaquenil) enter the macrophages and subsequently concentrate inside these vacuoles. The anti-malarials have a higher pH level and cause the vacuoles to develop a higher pH level (figure 30.1B). The vacuole enzymes only work under precise pH conditions. This higher pH level in the vacuoles prevents the macrophages’ digesting enzymes from breaking down the antigens to present the T-cells. Therefore, the T-cells cannot “see” these antigens and do not signal the B-cells to make the lupus autoantibodies. Therefore, the anti-malarial medicine calms down the immune system of the person who has lupus. Interestingly, though, it does not actually cause overt immunosuppression. In other words, the immune system can still function normally in different areas and still protects the person from infections and cancer.
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Why hydroxychloroquine is not a cure for autoimmune diseases-

After reading the above, one may think it sounds like a cure! It stops autoantibody formation; therefore, it should control lupus completely!

We wish it were that easy. This is just one little tiny part of the immune system. There are many other sections of the immune system that are functioning abnormally in SLE. Also, hydroxychloroquine doesn't completely stop antigen processing and antibody formation. It is a weak medication. Think of it as "calming down" the process, not eliminating it entirely. And, thank goodness it doesn't! We need antigen processing to keep working so that our immune system still fights off infections, cancers, etc. The immune system continues to function well with antimalarial drugs. In fact, SLE patients who take hydroxychloroquine are less apt to get infections and cancers compared to patients who do not take it.

Also, this is not the only way that antimalarials work on the immune system. They also work in other ways. For example, we think that inhibiting part of the immune system called toll-like receptors probably plays a more critical role in how antimalarials help in treating lupus. However, delving deeper is beyond the scope of this post.

That would have to be the subject of a different (long) post. The purpose of this article was to just give one part of the story on why a medicine used to treat an infection would work for an autoimmune disease. The immune system is indeed fascinating!

electron microscope of malarial food vacuole (fv) inside the malaria parasite. This is where Plaquenil changes the pH (credit cited below)

​How hydroxychloroquine kills malaria-

A similar thing occurs in malaria. Malaria is an infection due to single-celled parasites called Plasmodium that get into humans from mosquito bites. The malaria organisms get into the red blood cells, where they ingest iron-rich hemoglobin. The malaria parasite needs to digest this hemoglobin inside vacuoles within their own bodies (similar to the macrophages of the immune system ingesting antigen proteins inside their vacuoles). The malaria organisms digest the proteins of the hemoglobin to use for food and reproduce. Just as our macrophage vacuoles need an acidic environment to digest antigen proteins, the malaria organisms also require an acidic environment to digest the hemoglobin and dispose of the waste product (the iron-rich heme portion of the hemoglobin). The anti-malarial medicine dissolves into the vacuoles of the malaria organisms and raises their pH levels. The malaria organisms are unable to digest the hemoglobin and to get rid of the heme. The heme molecules combine with the anti-malarial medicine molecules and build up inside the malaria organisms, trapped within their vacuoles. This is toxic to the malaria organisms, and they stop reproducing and hopefully die.

The bottom line is that anti-malarials appear to work by increasing the vacuoles’ pH inside malaria organisms and macrophages. These vacuoles usually ingest hemoglobin (in the case of malaria organisms) or antigen proteins (in the case of macrophages in people with lupus). When the pH is increased, these vacuoles are unable to process these components. In the case of malaria, the malaria organisms die due to the buildup of toxic waste products. In the case of lupus, the macrophages cannot process antigens properly to present them to T-cells. Therefore the immune system is calmed down so that it does not attack the body (such as the skin, joints, or kidneys) as much.
Anti-malarial drugs have other effects on the immune system. However, we will only discuss the above effect as it is simple to illustrate. 

Feel free to comment above.
Please get 2 yearly eye exams (SD-OCT and a VF 10-2) if you take Plaquenil or chloroquine.
Get 3 tests if you are Asian (add on a VF 24-2 or a VF 30-2)

The above excerpt and figure comes from "The Lupus Encyclopedia" by Johns Hopkins University Press. The language has been altered for better readability. ​

Source of electron microscope malaria parasite food vacuole: Jani D, et al. HDP-a novel heme detoxification protein from the malaria parasite. PLoS Pathog. 2008 Apr 25;4(4):e1000053. doi: 10.1371/journal.ppat.1000053. PMID: 18437218; PMCID: PMC2291572.

Author

Don Thomas, MD, author of "The Lupus Encyclopedia" and "The Lupus Secrets"

Other references:

Torigoe M, Sakata K, Ishii A, Iwata S, Nakayamada S, Tanaka Y. Hydroxychloroquine efficiently suppresses inflammatory responses of human class-switched memory B cells via Toll-like receptor 9 inhibition. Clin Immunol. 2018 Oct;195:1-7. doi: 10.1016/j.clim.2018.07.003. Epub 2018 Jul 4. PMID: 29981383.

Wang F, Muller S. Manipulating autophagic processes in autoimmune diseases: a special focus on modulating chaperone-mediated autophagy, an emerging therapeutic target. Front Immunol. 2015;6:252. Published 2015 May 19. doi:10.3389/fimmu.2015.00252​