“Genes Protect, Genes Attack: Decoding Immunogenic Responses to Activate Community Defenses”

by Jonalyn Jame Catedrilla (Polyplex)

With the COVID-19 pandemic taking up the world by storm, there is a need to identify genes that play a role in the immunogenic responses of a population, especially the Filipinos, against SARS-CoV-2 infection. As GeneSoc conducts this year’s Genetics Week, we look through the lenses of immunogenetics in its continuing relevance to the world’s current health situation.

Thanks to a functional immune system, the body can feel less agony from infections. Different substances from the environment predispose an organism to favorable or unfavorable response, but the body has an efficient mechanism to identify what remains in the body. Environmental or genetic factors can influence this mechanism. Before the age of medicine and epidemiology, ancient people believed that diseases are punishment befallen from the gods. They commended those who did not contract the disease for having “the favors of the gods.” In 430 B.C. Thucydides deducted through observations that those who experienced the disease and recovered did not have it a second time. The discussion about human immunity started since then and centuries after, a lot of discoveries led to the elucidation of treatments to different diseases.

Genetic principle of diverse antibodies

Antibodies are proteins encoded by genes that protect the body from pathogens. Pre-immune antibody repertoire is a mechanism in which humans produce several varying antibody molecules, even without the simulation of antigen. A specific antibody can interact with a variety of related antigen-binding sites, but have different antigenic determinants. Antibodies produced will interact with antigen-binding sites, even with low affinity. After simultaneous interaction of the antibodies and the antigen-binding site, B cells can further make antibodies with higher affinity to bind to the antigen. We know this process as affinity maturation. Thus, antibodies continuously increase its ability to recognize and eradicate pathogens. 

Major Histocompatibility Complex

Major histocompatibility complex (MHC) molecules bind peptide fragments of pathogens and transport them to the cell surface for T cells to recognize it. The activation of macrophages and B cells eradicate pathogens, along with infected cells.. Macrophages kill bacteria in the intracellular environment and B cells produce the antibodies that will neutralize or eliminate pathogens in the extracellular environment. Mutated pathogens unrecognized by the MHC molecule can be detrimental to an organism’s health. MHC has two mechanisms which makes it impossible for most pathogens to avoid immune response. MHC is polygenic, meaning there are distinct classes of MHC genes that persist. Each MHC class, MHC Class I and Class II, have a distinct set of MHC molecules that has a specific binding system with different ranges of peptides. MHC is also highly polymorphic. There are several variants of each gene within an entire population, thus it can interact and eradicate a lot of different pathogens.

Peter Gorer first described Matching of Histocompatibility and further investigated it by George Snell and his colleagues. The results of the investigation yield a safer and more efficient organ transplant, hence providing a higher chance of survival of the patient. The MHCs in humans are the human leukocyte antigens (HLA), which have a vital role in rejection or acceptance of organs. Mismatched alleles of HLA of donor and recipient can cause the rejection of organ transplant.

Gene for T-cell receptor

T cell receptors eradicate infected cells and pathogens existing inside the body, but tumors are exceptionally a challenge for T cells to recognize. Cancer cells can make themselves invisible wherein they build their own microenvironment that suppress activity, migration, and survival of T cells. Today’s advancement in biotechnology makes it possible to counter this problem. Health researchers may obtain and modify T cells from the patients, particularly the coding genes for receptors that recognize antigens of cancer cells. Additional genes play a role in resisting immunosuppression to prolong survival and facilitate T cells in penetrating in tumors. Genetic modification can make it possible to eradicate persistent cancer cells in the body.

Immunogenetics in Vaccines

Immunogenetics aid in development, and delivery of Vaccine in humans by understanding the genetic variation that influences adaptive and innate response of the immune system towards vaccines. This can provide information initial identification of adverse effects of vaccines in a specific patient. Vaccine developers should develop a vaccine relative to a patient’s genomic information and immune phenotype, by also integrating precision medicine in oncology and other fields. In a study in 2014, they observed that haplotypes in the cytokines interleukin (IL)-1 gene complex and IL8 gene play a role in fever that some patients experience after receiving a smallpox vaccine. Presence of haplotype in the IL4 gene shows significant correlation to lower chances of having fever after receiving a vaccine among vaccine naïve individuals. Haplotypes in IL-1 gene complex, IL8 and IL4 can predict if the patient will develop fever after vaccination for smallpox.

Immunogenetics amid Worldwide COVID-19 Outbreak

Applying these concepts in SARS-CoV-2 infection, the current literature on twin studies tells us how a population’s susceptibility to infection and outcome once COVID-19 symptoms manifest is heritable. Immunogeneticists also observed a variation in susceptibility of individuals in a population caused by polymorphisms in the human HLA gene, which emerged from the selective pressure caused by infectious diseases. Gene polymorphisms in the tumor necrosis factor (TNF), IL-6, and IL-1β, causing a cytokine “storm” in the overproduction of such gene products as a response to the infection, link themselves in a population’s susceptibility on severe deterioration, multiorgan failure, and death caused by SARS-CoV-2 infection. Even though the current understanding of the immunogenetics of humans against SARS-CoV-2 is incomplete, the information we have is invaluable towards vaccine and drug development.

The genes and environmental factors come hand in hand in strengthening or weakening the body’s immune response. Genes produce the needed materials for the immune system to be possible. Other organisms may be more vulnerable than others because of their genetic make-up. Biotechnological advancements today have made it possible to manipulate genes in the body to make it more robust and decrease the mortality rate of humans. Along with the genes, the environment and the lifestyle of the individual also affect the efficiency of the immune system.  Even with the existence of a systematic protection from diseases, individuals take care of the overall condition of their well-being.