Molecular Basis of Immune Diversity: Causes and Clinical Applications

Psomagen Blog

Immune mechanisms vary greatly, both in how immunity develops and how those mechanisms fight pathogens. These differences are what make up an organism’s immune diversity. 

By understanding immune diversity in humans, researchers can develop clinical tools to treat patients or predict disease and treatment outcomes.

In This Article:

  1. Why Is Immune Diversity Important?
    1. Limiting the spread of disease
    2. Preventing pathogenic mutations
    3. Survival of species
  2. What Causes Immune Diversity? 
    1. Germline mutations
    2. Somatic mutations
    3. Exposure to pathogens
    4. The HLA complex
  3. How NGS Improves Immune Research
  4. Clinical Applications of Immune Diversity
    1. Treatment decisions
    2. Understanding immune response
    3. Boosting the immune system
    4. Predicting survival rates
  5. The Future of Immune Diversity in Medicine

Why Is Immune Diversity Important?

Limiting the spread of disease

Research on prokaryotic bacterial and viral samples has shown that a more diverse immune environment prevents disease spread. In the study, viruses were able to spread in a culture full of just one type of bacteria. When the virus was up against multiple types of bacteria, however, it went extinct quickly. 

Preventing pathogenic mutations

When an immune system quickly kills a pathogen, it does not have time to become a more contagious or dangerous disease. In the same study above, very little viral evolution occurred in the culture with multiple types of bacteria. 

Survival of species

Immune diversity occurs on an individual level. Having a diverse population ensures there will be survivors in the event of a devastating pathogenic outbreak. 

In the endangered Wyoming toad, for example, a fungal infection severely decreased their population in the wild. Fungus-resistant Wyoming toads were then brought into captivity to breed. 

All of these fungus-resistant toads have similar immune systems. Therefore, researchers were concerned about their ability to fight off new pathogens. Researchers found that decreased diversity created a “genetic bottleneck,” leaving insufficient immune diversity for the species to fight off infection.

These findings will inform captive breeding decisions made in the future. They also provide insights into how immune diversity can protect human survival in the face of new pathogens.

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What Causes Immune Diversity?

Many molecular-level changes can impact a person’s immune diversity, including mutations, pathogen exposure, and the human leukocyte antigen (HLA) complex. Several major factors are listed below. 

Germline mutations

For decades, scientists have had two major theories about how and which mutations create immune diversity. Thoughts can be split into two major categories: germline mutations and somatic mutations.

Germline mutations occur within germ cells. These germ cells go on to become sperm and ova. These mutations can be passed on to an organism's offspring. Germline mutations impact an organism's immune traits.

For example, in 2021 researchers investigated germline variants in about 9,000 cancer patients. These variants impacted the tumor immune microenvironment, proving that some cancer response is inherited. Meaning, a person's genetic background can impact their ability to respond to cancer.

Somatic mutations

Somatic mutations occur after conception (not in reproductive cells). Somatic mutations cannot be passed to offspring. Several types of somatic mutation are listed below.

During V(D)J recombination, early stage T cells and B cells rearrange gene segments. B cells produce immunoglobulins (antibodies). T cells produce cytokines, kill target cells, activate immune cells, and remember antigens for future infections.

V(D)J recombination creates diverse sets of antibodies and T cell receptors. They are then able to recognize and bind with a wider variety of pathogens than a homogenous immune system. 

Interested in V(D)J single-cell sequencing? Take a look at our page.

In somatic hypermutation (SHM), the immune system is exposed to a new pathogen. It then diversifies B cell receptors and creates new B lymphocytes with high-affinity antibodies to combat this new microbe.

In class switch recombination, a type of SHM, B cells switch to producing different types of antibodies. The antibodies can then interact with different effector molecules on the same antigen.

Exposure to pathogens

Pathogens contribute to diversity by providing the incentive for an immune system to adapt. In a 2016 study published in PNAS, researchers argued that immunity changes are adaptations in response to a changing pathogenic environment. A pathogen that occurs frequently will prompt greater immune response and variation. A pathogen that occurs less frequently will prompt less investment in defense from the immune system. 

The HLA complex

Human leukocyte antigens (the HLA complex) impact a person’s immune response, susceptibility to disease, and even pregnancy outcomes. This is the human version of the major histocompatibility complex (MHC), which is present in many other species.

When responding to a disease, the HLA complex encodes protein and carbohydrate molecules. These glycoproteins attach to antigens and present them to T cells, which can then destroy the cell. This is seen in MHC class I genes (mainly fighting viruses and cancer cells) and class II genes (mainly fighting bacteria and other foreign entities). 

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How NGS Improves Immune Research

In the past, Sanger sequencing was commonly used to estimate the complexity of B cell and T cell repertoires. This technique has a relatively low throughput, and does not adequately represent the entire scope of lymphocyte diversity.

Using high-throughput sequencing technologies, researchers can study diversity more directly in B and T cell receptors. Choosing the correct high-throughput sequencing platform is important, because there are many options for read length and depth. Understanding what the data output will be ensures that researchers encounter lower error rates. It has proven useful in both single-cell sequencing and bulk sequencing analyses.

It also helps to capture the correct information from complex repertoires. Bioinformatics tools like IMGT/V-QUEST, IgBLAST, or IHMMune-align are used to process and interpret data findings. An extensive list of immune bioinformatic tools can be found at

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Clinical Applications of Immune Diversity

Treatment decisions

A patient’s lymphocyte receptor repertoire can help determine their disease risk, options for treatment, and likelihood of treatment success. 

A 2015 study successfully correlated B and T cell repertoire data and individuals’ health. Researchers used machine learning to identify organ transplant recipients, cancer patients, and subjects with healthy immune systems. They believe this model opens the door for individualized vaccine profiling and early disease detection. 

Understanding immune response

Immune diversity also provides insights into adaptive immune response. A study published in PLOS ONE analyzed blood samples from 10 patients who’d had their kidneys removed for medical reasons. This included cancerous tumors, contracted or swollen kidneys, etc. Specific characteristics varied depending on each patient’s condition, but B and T cells in the blood indicated clonal expansion in the kidneys. 

Kidney cancer is difficult to detect in patients who are not high-risk. There is no routine screening on the market for people considered low-risk. Researchers in this study believe that clonotypes that are very common in the kidneys and less common in the blood probably came from antigens in the kidney. This suggests that blood testing could provide insights during screening, patient treatment, or in a disease’s natural progression.

Boosting the immune system

Immune response and sequencing technology are paving the way for big discoveries in immuno-oncology, as exemplified by recent CAR-T therapy approvals. Especially in cancer research, immunotherapy is an increasingly popular area of study. 

Researchers can use a patient's immune response to control and even eliminate cancerous cells. "Natural killer cells" (NK cells) are lymphocytes that can respond to tumor growth. By modifying these cells, researchers have successfully treated cancerous tumors.

In one study on leukemia and lymphoma, CAR-NK cells were administered to 11 patients. All patients had cancer recurrence or resistance to other treatments. Of these 11, eight had a positive response. Seven achieved complete remission.

Predicting survival rates

T cell levels may also be directly related to cancer survival rates. For example, inhibiting the protein receptor CTLA-4 is an effective way to combat prostate cancer and melanoma. However, these drugs can significantly lower the frequency of T cell clones. Patients with lower T cell levels after treatment have a lower survival rate than patients whose T cell levels remain relatively constant. 

Researchers have used these insights to develop combination immunotherapies. In metastatic melanoma, for example, cytokines that activate and boost T cells have been approved for therapeutic use. When partnered with an antibody that blocks CTLA-4, this combination therapy significantly decreases tumor growth. 

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The Future of Immune Diversity in Medicine

Understanding immune diversity has opened the door to precision treatments for disease. Immune profiles are used to identify biomarkers that can be used in the therapeutic development and clinical treatment process. With lymphocyte analysis, we can use immunity insights for early detection, monitoring of disease progression, determining prognosis, choosing therapeutic agents.

In many instances, research is ongoing. A 2021 review of immune-regulated inflammatory diseases (IMIDs) is a good example of this. IMIDs include diseases like asthma, rheumatoid arthritis, psoriasis, and dermatitis. These diseases are incurable, and can't always be managed. Even if inflammation is controlled, pain often persists.

Looking to the future, the review indicates a need to understand how to restore the immune system to regularity. They argue for the investigation of certain genes. They also point to T cells and dendritic cells as major areas of exploration.

This review is a good indication of the work that must still be done. There are certainly many diseases for which further research is needed. In the near future, these developments may be available as treatment options at point-of-care.

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