ASU study explores components of the immune system

Unless you’re an identical twin, you probably aren’t often mistaken for someone else. Likewise, our own sense of self, distinct from all other humans, is deeply rooted from early childhood.

The immune system, however, faces much greater challenges in distinguishing self from non-self. If this complex surveillance network fails to identify a foreign intruder, such as a bacterium or virus, the result can be serious, uncontrolled disease.

Under certain circumstances, however, the immune system can become overly vigilant, identifying our own tissues as foreign and targeting them for destruction, resulting in autoimmune disease. Autoimmune responses are also associated with some cancers.

In a new study, Joshua LaBaer, ​​a researcher at Arizona State University, and his colleagues explore components of the immune system known as autoantibodies. While they have been implicated as central players in a range of serious autoimmune diseases, the study observes that autoantibodies are also present in healthy individuals.

This fact may make the diagnostic use of autoantibodies as sentinels of autoimmune diseases more difficult, hence the importance of such investigations.

Greater awareness of the ubiquity and role of autoantibodies in human health and disease could ultimately contribute to the design of better diagnostics and therapeutics for a range of diseases.

Historically, we were looking for autoantibodies present only in disease, but we were always intrigued because our healthy controls always had autoantibodies as well. So we decided to see if any of these “healthy autoantibodies” were common in healthy people and sure enough a lot of them were. Knowing these will help us avoid confusion in future studies.”


Joshua LaBaer, ​​Researcher, Arizona State University

Dr. LaBaer is the executive director of ASU’s Biodesign Institute as well as the director of the Biodesign Virginia G. Piper Center for Personalized Diagnostics.

The research results appear in the current issue of the journal Cell reports.

Biological Civil War

Autoimmune diseases are a widespread phenomenon, affecting approximately 23 million Americans. Researchers have identified more than 80 autoimmune diseases, including common conditions like type 1 diabetes, lupus, multiple sclerosis and rheumatoid arthritis, as well as more obscure conditions, which often prove difficult to diagnose correctly. Nearly 80% of autoimmune diseases occur in women, for reasons researchers are still trying to understand.

Science has a lot to learn about the underlying mechanisms responsible for autoimmune reactions. Often these diseases occur as a result of infections. Two main components of the so-called adaptive immune system also play an important role in autoimmunity. These are the white blood cells or lymphocytes, called T cells and B cells. Lymphocytes are crucial for the maintenance of health and are essential for survival. These sentinels, constantly patrolling the bloodstream, are alerted by the presence of foreign entities called antigens.

T cells protect against infection by pathogens like bacteria, viruses and fungi. They can also attack and destroy cancer cells. B cells secrete proteins called antibodies that disrupt interactions or target infected cells so that other cells can come and destroy them. Antibodies work by binding to pathogens or foreign substances, including toxins, and neutralizing their harmful effects. If an antibody binds to a virus, for example, it can prevent the intruder from entering a normal cell to cause an infection. B cells can also recruit other specialized immune cells to migrate to the sites of infected cells and help destroy them.

The immune system’s defensive arsenal is extremely sensitive to foreign proteins, peptides, enzyme complexes, RNA and DNA. When these are encountered, B lymphocytes can spring into action, producing antibodies against these foreign entities.

Mutinous Immunity

The immune system, however, faces a formidable challenge. B and T cells must be able to precisely target threats to the body while remaining harmless to host cells and tissues. Immune cells are not born with this knowledge, they learn it within weeks, receiving training in a kind of biological classroom, where they undergo two rounds of careful screening.

B and T cells that successfully emerge from their workouts exhibit two types of immune tolerance, central immune tolerance, which develops in the bone marrow, and peripheral immune tolerance, which matures in the lymph nodes.

After their formation, cells with immune tolerance, a kind of non-aggression pact with healthy tissues, are kept in the body for future use. Immune cells that emerge from their formation and present a risk of autoimmunity are sequestered or destroyed.

Yet sometimes pathogens or cancers can produce antigens that are so similar in sequence or structure to features found in normal body tissues that host tissues are mistaken for disease antigens and targeted by antibodies. . These characteristics are called autoantigens and the antibodies produced to target them are called autoantibodies.

The mistargeting of autoantigens due to their similarities to disease antigens is known as molecular mimicry and is implicated in many autoimmune diseases, from rheumatoid arthritis to multiple sclerosis.

Scavenger hunt for antibodies

New study explores common autoantibodies; those that occur in healthy individuals. Although these common autoantibodies do not appear to cause disease, they nevertheless appear in up to 40% of those tested. It is likely that at least some of these common autoantibodies have been mistakenly identified as pathological antibodies.

The researchers performed a meta-analysis of 9 data sets. The tool of choice for exploring common autoantibodies is a device known as a protein chip. Here, thousands of individual proteins are attached to a glass slide. When a blood sample is spread over the microarray, antibodies (in this case, autoantibodies) bind to specific protein antigens.

The DNA chips were subjected to two rounds of screening. In the first round, 182 blood samples from healthy individuals were tested against 7,653 human proteins. In the second round, 90 blood samples were tested against 1,666 human proteins. The experiments identified a total of 77 common autoantibodies.

Blood samples were taken from healthy individuals of both sexes, aged from infancy to 84 years old. The results showed that the number of autoantibodies increased from birth until adolescence and then leveled off. Moreover, the number of autoantibodies detected was the same regardless of gender, a surprising result given the large disparity between men and women in the prevalence of autoimmune diseases.

Another underlying puzzle is why common autoantibodies do not produce autoimmune disease. Although these antibodies seem to have escaped the screening process leading to immune tolerance, their presence in the body remains benign. Autoimmune pathology is thought to require autoantibodies to bind and form complexes with autoantigens, which can be blocked in the case of common autoantibodies.

Future research promises to reveal many more secrets about the nature of autoantibodies. The current study looked at less than half of all human proteins. Most likely, other common autoantibodies remain to be discovered.

Source:

Journal reference:

Shome, M. et al. (2022) Serum autoantibodies reveal that healthy individuals share common autoantibodies. Cell reports. doi.org/10.1016/j.celrep.2022.110873.

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