Unlocking the relationship between autoimmunity and long-term infection

Researchers from The Australian National University have discovered the gene, called Zeb2, that proliferates in autoimmunity diseases like the painful and debilitating inflammations of lupus, rheumatoid arthritis, Crohn’s disease and ulcerative colitis.

Zeb2 controls the immune system’s Atypical B cells (ABCs).

The discovery was made in a slightly off-beat way — by giving mice malaria.

Around 10% of the global human population, and uncounted pets, suffer Auto Immune Diseases, with about 13% of women and 7% of men affected. And the numbers are rising.

Having an autoimmune disease means your immune system no longer recognises your body as ‘self’ and starts to attack your tissues and organs. Causes are unclear, but thought to be genetic or epigenetic, that is, environmental stressors (e.g. age, infections, smoking, nutrition, pollution) that affect the way genes work.

Finding Zeb2 could lead to a better understanding of autoimmune diseases and to more effective treatments.   

The study continued Post-Doctoral Fellow Dr Xin Gao’s PhD research at The John Curtin School of Medical Research at ANU. Gao uses mouse malaria models to better understand how Atypical B cells (ABCs) interact with other parts of the immune system to fight infection.

What are B cells?

Our B cells, also called B lymphocytes, protect us against all kinds of infections, says Gao.  Originating in the bone marrow, circulating in the blood and lymph, they produce antibodies that recognise, and neutralise antigens in the blood — anything ‘non-self’, from outside the body, living or otherwise.  Antigens include substances, usually proteins, found on parasites, bacteria, viruses, fungi or pollen, as well as non-living chemicals such as drugs and poisons.

This is where mosquitos and mouse malaria parasite models come in — to better understand why ABCs are so prolific in patients with autoimune diseases. The same ABCs that cause inflammation in autoimmune diseases also proliferate in malaria, but in this case, they reduce the spread of the antigens, that is, the parasites. Same cells and mechanisms, but different outcomes, and because mouse malaria models are well established, they’re a useful way to explore the mystery.

Genetic Switches

Researchers compared the responses of mice to malaria, in strains of animals with and without the capacity to make ABCs in response to the infection.  The gene for ABC production was identified as ‘Zeb2’, and switched off in half the test mice using Crisper Cas9’s molecular scissors.

Two mouse malaria species were used — Plasmodium berghei, and Plasmodium chabaudi, both harmless to humans. Mouse malaria shows the same cycles and effects in rodents as it does in humans.

Two sets of experiments were carried out. Firstly, irradiated parasites were injected into strains of mice with or without Zeb2. The parasite was dead so the malaria couldn’t spread throughout the body, meaning this was an immunisation — a small dose of antigen designed to prime the immune system against further attack. But the ABCs showed similar responses in both mouse strains, suggesting that “they didn’t have an obvious function in that situation”, says, Gao.

The second set, where mice were infected with live malaria, produced a very different result. ABCs reacted, helping to sustain the antibody response in the mice with the Zeb2 gene[IM1] , stopping parasite division and their spread in the blood, controlling the infection. Those without Zeb2 did not fare so well.

Blocking ABCs

So, ABCs are important in the immune response and the Zeb2 gene has a major role in their formation, says Gao.

The ABCs of the Zeb2 mice were responding to antigens, in this case, successive waves of malaria parasites infecting the blood. And that’s the key, says Professor Ian Cockburn, also of ANU’s John Curtin School of Medical Research, and Gao’s supervisor. “The ability to ultimately control the parasites and get the infection under control is what’s important. These ABCs are critical for sustaining an immune response in a situation where infection is ongoing.”

The researchers have shown that ABCs have a role in controlling mouse malaria, and it is possible that the same could be true for strains infecting humans. But there is a long way to go to make that call.  The work was more about understanding how ABCs work, in general, than investigating their use in the treatment of malaria, says Cockburn.

“The relationship between auto immunity and long-term infection is that your antigen’s the thing that’s stimulating the immune system and is hanging around for a long period of time,” says Cockburn. “In infection, the ABCs respond to that and that’s a good thing. In autoimmunity, these things are responding and actually contributing to the pathology of the autoimmunity.”

“So, in terms of implications for human health,  it’s probably more about trying to block ABCs in auto immunity. Knowing that Zeb2 is a critical molecule in autoimmunity means you might wish to develop a drug to block Zeb2 and pathways downstream of autoimmunity.”

“Autoimmune models are probably the next step in the research,” says Cockburn, “One could look at drug screens to inhibit ABC formation.”

The quest for better autoimmunity treatments

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