Hey there! Last podcast I mentioned the “theory of autoimmunity” and the range of immunosuppressive treatments that have stemmed from its promotion. I stated that the theory needs to be re-evaluated to account for the discovery of the human microbiome. Today I will go into even more detail on why that’s the case.

First, let’s talk about how the theory of autoimmunity gained popularity and widespread acceptance in the first place. Around the turn of the century, scientists began detecting Y-shaped molecules called antibodies in patients with a range of “acute” infectious diseases: diphtheria, tuberculosis, polio and pneumonia among others. Researchers (like the famous immunologist Paul Ehrlich) soon realized that these antibodies play a key role in helping the human immune system correctly target the bacterial and viral pathogens driving these and related diseases. They came up with a model of antibody activity that still largely holds up today. It contends that:

1. Antibodies are released by B cells and T cells of the human immune system in response to an infectious threat: most commonly a bacterial or viral pathogen
2. Antibodies target/neutralize these pathogens by recognizing the shape/size of unique protein molecules on the pathogen’s surface. These pathogen proteins are called “antigens.”
3. When a human antibody correctly recognizes a pathogen antigen, the two molecules bind together. This “tags” the antigen and associated pathogen for further attack by other cells of the immune system (like white blood cells).
4. The immune system begins to rapidly produce or “clone” more versions of the antibody that correctly “tagged” the pathogen. As more and more copies of this antibody pour into human blood/tissue, the immune system increasingly recognizes and kills the pathogen.

Today, almost every infectious disease is tied to antibody production. For example, when you get the flu, your immune system releases a range of antibodies in response to the flu virus. If all goes well, the antibody that best “tags” the virus’ specific antigens is “cloned.” More copies of this targeted antibody enter your bloodstream and the recovery process begins.

These same antibodies form the basis of the flu vaccine and related vaccines. In simple terms, a vaccine is made by taking an antibody already known to target a specific pathogen antigen – and injecting a small amount of this antibody into a patient. This “prepares” the patient’s immune system for the pathogen. Then, if the patient becomes infected at a later date, the immune system already knows exactly what antibody it should “clone” and rapidly release. The pathogen can then be neutralized and killed before it has a chance to spread.

OK. But what does this have to do with the theory of autoimmunity? In the 1930s-40s, researchers/doctors began to detect antibodies in patients with a range of chronic inflammatory conditions like lupus, rheumatoid arthritis, and multiple sclerosis. The natural next step would have been to search for chronic human pathogens whose presence could be tied to these antibodies. However, at the time (as described in my previous podcast), the human body was incorrectly believed to be largely sterile.

This confused many research teams working on the topic. How could they explain the presence of these antibodies when there were apparently no persistent microbes in the human body? They were forced to come up with their best guess as to what could be going on. They settled on a new concept that forms of the backbone of the theory of autoimmunity: the “autoantibody.” AKA, they postulated that in patients with these chronic inflammatory conditions, the immune system had somehow “broken down” or “gone crazy.” This confused immune system could then generate antibodies against antigens associated with the body’s own tissues. They named these hypothetical “self-targeting” antibodies “autoantibodies.”

At first the theory of autoimmunity and the idea that “autoantibodies” could exist met with resistance. Paul Ehrlich, the famous immunologist who had helped characterize antibodies in the first place, was particularly vocal. He wrote papers condemning the theory and coined the term “horror autotoxicus” to best counter it. Horror autotoxicus contends that the immune system has innate protection mechanisms that simply do not allow it to turn “against itself.”

But the scientific community wanted a consensus on the topic and needed simple guidelines on chronic inflammatory disease that could be given to doctors. Large conferences began to promote the theory of autoimmunity and detractors were increasingly pushed to the fringe. By the 1950s the theory started to be included in medical textbooks. Soon a growing number of “autoantibodies” were tied to different chronic inflammatory conditions. For example, patients with lupus test positive for an “autoantibody” that was named ANA. Rheumatoid arthritis was officially diagnosed if the “autoantibody” rheumatoid factor (RF) showed up on blood tests.

But a major question remained: if the theory of autoimmunity is correct, then what causes the immune system to fail so dramatically that it turns against the body’s own tissues? A number of theories attempting to explain this dilemma have been proposed over the years, none of which has been proven. One involves infection and is still frequently referenced today: the “pathogen/trigger” theory. It contends that certain well-characterized pathogens may infect a patient. Something about this temporary infection goes wrong and “triggers” the immune system to misfire and induce “autoimmunity.” The pathogen itself is somehow killed, but the immune system never recovers and the patient develops a full-fledged “autoimmune” disease.

The “pathogen/trigger” theory might have held more weight if the human microbiome had not been discovered around 2005. As described here, the discovery occurred when research teams started using new molecular tools to search for human microbes. The results of these new analyses were astounding: entire ecosystems of microbes were identified in the human body that had been missed by previous laboratory testing methods. Today we understand that trillions of microbes live in and on us – from the moment we are conceived in the womb until the day we die. These vast microbiome communities persist in every human body site – from the brain, to the liver, to the lungs and beyond.

This means that there are actually thousands, if not more, microbes/pathogens in the human body that could be tied to “autoantibody” release in patients with chronic disease. In other words, “autoantibodies” may just be regular antibodies created in response to pathogens that our testing methods were previously unable to detect. So, for example, when the “autoantibody” ANA is identified in patients with lupus, it could simply indicate that an unidentified pathogen plays a role in driving the lupus disease process. Also, it’s more likely that “autoantibodies” are created in response to chronic, persistent human pathogens than a temporary pathogen that the immune system somehow kills (as postulated by the “pathogen/trigger” theory.)

The possibility that “autoantibodies” are created in response to microbiome pathogens rather than “self” is strongly supported by the fact that “new” bacteria, viruses and other microbes continue to be identified in the human body. For example, Stanford researcher Stephen Quake recently detected thousands of never-before identified bacteria and viruses in human tissue/blood. In fact, 99% of the microbes he identified were previously unknown to science.

Also, for decades, “autoantibodies” have been regularly detected in patients with no signs of autoimmune disease that are instead suffering from an infection. For example, high levels of “autoantibodies” like rheumatoid factor, ANA (and others like ASCA, annexin-V and Anti-PL) have been identified in patients with bacterial, viral, and parasitic infections ranging from hepatitis A/B to Q fever to Rickettsia.

A more recent study by researchers at Yale came to a similar conclusion. The team studied E. gallinarum, a bacteria they identified in the human gut, liver, spleen and lymph nodes. In models of genetically susceptible mice, the researchers found that E. gallinarum initiated the production of “autoantibodies,” activated T cells, and inflammation. Moreover, this “autoantibody” production stopped when they suppressed E. gallinarum’s growth with the antibiotic vancomycin and/or with a vaccine against the microbe. The team also identified E. gallanarum in the livers of patients with “autoimmune disease”, but not in healthy controls. One media headline on the study read: “The enemy within: Gut bacteria drive autoimmune disease.”

Research by Stanford’s Mark Davis supports the findings. Davis and team used a new testing method to obtain T cell sequences from the tissues/blood of patients with colon cancer, MS, Lyme disease, and ME/CFS. In all four diseases, they found that the T cells were activated and “cloned’ in a manner not observed in healthy subjects. According to the theory of autoimmunity, these cloned T cells would indicate “autoantibody” production. But Davis suggested that associated antibodies are likely formed “originally against some pathogen peptide.” This definitely makes sense since since, especially in Lyme disease, we know pathogens drive the disease process.

Interesting right!? But at this point I should bring up an important concern. Some researchers are still convinced that “autoantibodies” can target human tissue. If this is the case, the situation can easily be explained by a concept called “molecular mimicry.” Molecular mimicry refers to the fact that pathogen proteins and human proteins are often very similar in size and shape. This means that an antibody created in response to a pathogen protein/antigen might accidentally target a similarly structured human protein/antigen. This “collateral damage” could result in an inflammatory response towards that human tissue.

Think of molecular mimicry this way: Let’s say you’re a solider in an army. You and your fellow soldiers all have red uniforms, blonde hair, and stand about 6 feet tall. You confront the enemy on a battlefield only to realize that their soldiers also have red uniforms, blonde hair and are about 6 feet tall! Even though their red uniforms are shaped somewhat differently than your own, at a certain distance the shape becomes blurred. This means that when the battle begins, you have trouble telling who’s on your side and who’s the enemy. Occasionally you end up accidentally shooting a member of your own army. These two armies can be compared to similarly shaped pathogen antigens and human antigens that might generate “collateral damage” in “autoimmune disease.”

Ample research supports this “molecular mimicry” model. For example, one research team found that B cells infected with Epstein Barr Virus secrete antibodies that also react with human antigens like albumin, renin, and thyroglobulin. Another Canadian research team found that proteins created by the hepatitis C virus had a high level of structural similarity with ~20,000 human proteins. Researchers in India identified tens of thousands of possible interactions between proteins created by Salmonella, E.coli, Yersinia, and similarly shaped human proteins.

All this research strongly suggests that in 2018 we no longer need the theory of autoimmunity. It seems Paul Ehrlich was right a century ago when he argued for “horror autotaxicus.” In patients with a range of chronic conditions, activated B cells, T cells and the antibodies they produce are likely targeting newly discovered human pathogens rather than “self.” This means the concept of the “autoantibody” is incorrect. In lieu of “autoimmunity,” we should focus on better characterizing pathogens in the microbiome and better studying their activity and survival mechanisms. For example, Mark Davis is planning to further study the activated T cells in his samples. He hopes to correlate the T cell activity with the presence of specific pathogens (and the antibodies created in response to their presence). Excellent, excellent idea!

At this point you might say: “Aw, well it looks like theory of autoimmunity will die over time, no huge rush.” But unfortunately the situation is very urgent. That’s because a large chunk of the pharmaceutical industry is focused on creating drugs based on the theory of autoimmunity. These drugs shut down extremely important parts of the human immune system in an effort to stop “autoantibody” production and related inflammation. In fact, these immunosuppressive drugs are the top-selling medicines in the world, generating billions of dollars of revenue each year.

If “autoantibodies” are created in response to pathogens rather than “self”, these drugs are actually hurting the long-term health and microbiome balance/health of patients with “autoimmune disease.” This is almost certainly why patients taking immunosuppressive drugs tend to get sicker over time, to the point where they often fall ill with a second or third inflammatory condition while taking the medications. In fact, rampant use of immunosuppressant drugs is likely a primary factor driving the current epidemic of chronic disease (the incidence of nearly every “autoimmune condition” is on the rise).

That means we stand at a crossroads. This paper published just last year describes an entire new generation of immunosuppressive drugs currently being developed by pharmaceutical companies. Some of these new drugs appear to shut down the human immune system even more profoundly than the ones prescribed today.

OR, we can move in a new direction of drug/treatment discovery. We can ditch the theory of autoimmunity and instead develop treatments that SUPPORT the human immune system. And/or treatments that better target key pathogens and, in turn, promote balance, health and diversity of the human microbiome. Then, maybe…just maybe we can create a future where new treatments target the ROOT CAUSE of human inflammatory disease instead of just palliating symptoms. And then maybe…just maybe a growing number of patients with chronic inflammatory disease could reach a state of actual recovery and remission.