Why do our immune systems vary so much?

Produced by: Science Popularization China

Author: Li Juan

Producer: China Science Expo

We all know that when faced with the same virus infection, different people are affected differently. Some people will produce antibodies to eliminate the virus calmly, while others will be deeply affected by the violent immune response and even develop into patients who need intensive care. This difference is closely related to the state of the individual's immune system , such as the differences in the activity and proliferation capacity of various immune cells.

Indeed, people's immune systems show great differences in fighting pathogens or detecting cancerous cells, which is what we often call "resistance". So, what factors cause differences in individual or group immune systems?

Environment and genetics jointly drive immune differences

Simply put, environmental and genetic factors jointly shape the diversity of the human immune system.

Figure 1 Diversity of human immune status

(Image source: Chinese translation from reference [1])

The first is the impact of environmental factors on the diversity of our immune system.

Our daily living habits or the environment we live in, such as diet, smoking, local climate, air quality, history of bacterial and viral infections, vaccination history, and the status of symbiotic flora in the body, all constitute environmental exposure.

Another important driving factor is genetic factors .

Genetic factors refer to the fact that genes related to immunity will mutate during the long process of human evolution. After accumulation from generation to generation , diverse immune systems have been formed in different races or individuals.

Environmental exposure and immune diversity

There are many ways of environmental exposure. Next, we will discuss their impact on immune diversity from the aspects of diet, pollution, flora, and history of viral infection.

Diet: Adequate nutrition is essential for healthy immune function. Especially for children, severe nutritional deficiencies can lead to immune deficiency. Some studies have shown that diet may indirectly affect immune response through changes in microbiota, weight and other factors . For example, a high-salt diet or a high-fat diet will affect normal immune function to some extent.

Pollution: Food pollution and industrial chemical pollution in life can also affect the immune system. Clinical data have confirmed that air pollution and industrial chemical accidents are associated with inflammatory diseases. Another strong evidence is smoking. Smoking can cause inflammation and induce changes in the autoimmune state. Smokers have lower overall levels of serum immunoglobulins and reduced functional activity of natural killer cells (one of the immune cells).

Microbiota: Whether it is the microbial flora in the environment or the intestinal flora in the body, we cannot see them with the naked eye, but they play an important role in shaping the human immune system. For example, the farm living environment in early life has a protective effect on the onset of asthma; the connection between intestinal flora and disease has also attracted much attention. The regulation of the immune system by intestinal flora is one of the recent hot research topics. However, some scholars believe that the diversity of the microbiota may be largely a "bystander correlation", which occurs simultaneously with the immune system's response to pathogenic factors. In other words, changes in the intestinal flora may be the result of the integration of multiple influencing factors, and it is the link between direct pathogenic factors and changes in the immune system.

History of viral infections: Humans have co-evolved with viruses for thousands of years, during which some viruses have integrated into our genomes and others have established lifelong chronic infections. Can you believe it? Extensive serological analyses have shown that at any given time, a person carries antibodies to about 10 different viruses. Humans are constantly reinfected with low-virulence viruses, which can induce immune responses and also cause adaptive changes in the proportion and function of immune cells. Therefore, viruses participate in shaping the diversity of herd immunity at both the genetic and acquired adaptive levels.

Genetic and immune diversity

Genetic variation is an important driver of immune diversity. Now, a combination of modern technologies allows us to better understand the genetic basis of human immune diversity.

During the long process of evolution and migration, the mixing of ancestry between early Eurasians and now-extinct archaic humans (such as Neanderthals or Denisovans), or between modern human groups, produced favorable genetic traits that can cope with pathogen pressure.

The study in the figure below (Figure 2) selected 175 healthy people of African or European descent. The study found that in the gene regulatory response to anti-bacterial infection, about 9.3% of macrophage-expressed genes showed differences related to ancestral descent. Among them, African descent showed stronger inflammatory responses and less intracellular bacterial proliferation. Researchers believe that a large part of the differences in population immunity caused by natural selection is controlled by genetic genes.

Figure 2 Role of African and European genetic ancestry in primary macrophage responses to live bacterial infection

(Image source: Chinese translation from reference [4])

Genetic studies of transitions in major human lifestyles (e.g., from hunting and gathering to farming) and past epidemic histories can also provide important information about changes in human immune function or immune diversity.

Classic examples are genetic variants that reduce the risk of malaria that have emerged in malaria-endemic areas and alleles that confer protection against African trypanosomiasis that have emerged in African populations.

Other recent studies have shown that genes related to autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, and ulcerative colitis) have very significant expression differences among populations. The incidence or severity of autoimmune diseases is very different between African Americans and European Americans. This also clearly shows the association between genetic characteristics from ancestors and differences in immune response.

In addition to the above-mentioned environmental and genetic factors, age and gender are also important internal factors that drive immune diversity.

Age and immune diversity

Age is one of the strongest drivers of immune diversity. A common example is that young children and the elderly are more susceptible to illness than teenagers and the middle-aged.

In the early stages of life, the first line of defense against invading pathogens is the innate immune system , which involves cells such as neutrophils, monocytes, macrophages, and dendritic cells. At birth, our innate immune system is immature, probably because the fetus needs to adapt to the environment in the mother's womb and avoid a lot of stress during development. This is also the reason why newborns, especially premature babies, are more susceptible to bacterial and viral infections.

As we age, the human immune system will gradually change, such as decreased activity of hematopoietic stem cells, thymic degeneration, weakened antiviral response, changes in the differentiation of immune cell lineages, white blood cell depletion, and an increasing risk of genetic mutations.

Therefore, as the immune system gradually ages , the elderly's ability to resist infectious diseases will also decline. Some abnormal immune responses will aggravate inflammation and may also lead to other diseases. In addition, immune aging can also cause latent viruses to become active , such as the well-known varicella-zoster virus, whose activity may cause shingles and chronic neuralgia.

Figure 3 This figure is based on data from seasonal or pandemic influenza, showing the differences in the strength of a woman's immune system's response to infection at seven stages of her life. (a) Seven life stages of women. (b) Curve of deaths per thousand people in seasonal or pandemic influenza. (c) Changes in the strength of the immune response to influenza.

(Image source: Chinese translation from reference [5])

Scientists still have a lot of work to do to understand how the composition and function of the immune system changes throughout a person's life, but it is clear that age is an important factor when we talk about human immune diversity.

Gender and immune diversity

Gender is also a driver of differences in immune system function.

Multiple studies have shown that men and women differ greatly in their immune responses, making them more susceptible to autoimmune diseases, malignancies, and infectious diseases, and affecting vaccination outcomes.

For example, 80% of autoimmune diseases occur in women; the risk of death from malignant tumors in men is almost twice that of women; the antibody response of women to seasonal influenza vaccines is at least twice that of men...

Immune differences between genders are reflected in many aspects, such as the number and activity of immune cells, cytokines, and levels of basic immunoglobulins (Figure 4).

Figure 4 Differences and changes in the immune systems of human males and females during life.

(Image source: Chinese translation from reference [6])

These differences are the result of the combined effects of genetics, hormones and the environment , and change with age. Current research focuses on the two areas of sex chromosome genes and sex hormones.

In terms of sex chromosome genes, we already know that there are a large number of immune-related genes on the X chromosome, which can explain many sex-related immune differences.

In terms of sex hormones, sex hormones (estrogen, progesterone and androgen) play the role of immune response regulators. In addition, steroid hormone receptors (a protein that exists on the target cells of hormones and can specifically bind to hormones) are present on many different immune cell types (including NK cells, macrophages, dendritic cells and T cells). The density, distribution and type of these receptors are also the reasons for the differences in immune function between men and women.

Which factor has a greater impact, environment or genetics?

After understanding the impact of environment and genetics on the diversity of the immune system, you may ask, which type of factors contributes more to immune diversity?

By comparing various indicators of immunity in identical twins (who share almost all genes) and fraternal twins (who share about half of their genes), the researchers found that many important differences in the human immune system are driven by non-heritable environmental factors, and this difference increases with age. The researchers believe that a healthy human immune system will continue to adapt to changes in environmental factors such as pathogens, intestinal flora, and nutrients, thereby masking the influence of genetic factors.

If innate immunity is viewed separately from adaptive immunity, the study found that individual adaptive immune cell parameters are mainly driven by environmental exposure, while innate immune cell parameters are more affected by genetic variation (Figure 5).

Figure 5 Sources of diversity in individual immune systems. Various factors have different effects on adaptive and innate immunity.

Image source: Chinese version adapted from reference [9]

Conclusion

In summary, the human immune system components and functions are dynamic. Some scholars have compared them to sensory systems because they all need to respond to internal and external stimuli. Clarifying how the above driving factors interact and shape an individual's immune system is a major topic in immunology research.

Understanding individual differences in the immune system and their health impacts can help determine whether a person is susceptible to immune-related diseases or their risk factor for infectious diseases.

Nowadays, with the help of immunological analysis technology and whole genome technology, it is very convenient to obtain immune component information from human blood or lymph nodes. However, there are still many unknowns in analyzing the causal mechanisms of immune system diversity, and we are waiting for more discoveries.

Editor: Guo Yaxin

References

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