Our body is equipped with multiple layers of defense mechanisms to shield us from a diverse range of pathogen threats.¹ The initial line of defense is the physical barrier formed by the overlapping layers of skin, providing inherent protection. Subsequently, chemical barriers, including enzymes, have the ability to eliminate numerous microbes, thereby adding an extra layer of safety.

Despite these defenses, when a pathogen manages to breach these barriers, it can pose a significant risk, leading to cell damage and, in severe cases, even cell death. Different microbes use different mechanisms to attach to the cell surface and enter its host. Thus, our body produces antibodies that block the entry of these pathogens before they can enter and infect a cell.

Antibodies are Y-shaped proteins present in both the blood and tissues, where they attach to the surface of cells. Antibodies composed of two light and two heavy chains, they feature two variable regions that confer antigen specificity. There are different types of antibodies, including IgM, IgG, IgA, IgD, and IgE, each with specific functions.

In the human body, the antibodies are produced by plasma as a part of adaptive immunity to act against foreign organisms.¹ However, their responses are regulated by a number of factors to ensure their optimal performance when needed. Therefore, with this view, understanding the regulatory mechanisms of antibody production is crucial for its clinical and biotechnology applications, such as vaccine or targeted therapy development.

In this article, we review the mechanism of antibody production, their regulatory mechanisms, and factors influencing or affecting the process.

Overview of antibody production

When a pathogen invades, the human body initiates an adaptive immune response (such as a humoral immune response) to fight against the pathogen.¹ The Antigen-Presenting Cells (APCs) transport antigens derived from the pathogen to localized regions within lymph nodes or the spleen.¹ Dendritic cells activate resting T-cells in both in vitro and in vivo conditions.²

The B-cells bind to these antigens through their receptors, known as B-cell receptors (BCR), leading to B-cell activation. The activated B-cell internalizes the antigen-BCR complex through endocytosis and breaks down the antigen into smaller fragments. The broken fragments of antigen are then loaded onto Major Histocompatibility Complex (MHC) class II molecules and presented on the B-cell surface as antigen-MHC II complex.

The T-helper cells then interact with B-cells through the antigen-MHC II complex, stimulating their differentiation into identical B-cells and plasma cells by releasing cytokines, such as IL-6 (involved in the maturation of B-cells into plasma cells).³ The plasma cells then produce antigen-specific antibodies to act against pathogens. The effector function of the antibodies includes neutralizing the actions of pathogens or flagging them for destruction through various possible mechanisms, such as opsonization, elimination through other effector cells, or complement activation.⁴

Regulatory mechanisms of antibody production

The antibody production in the human body is controlled at different levels to ensure that the body produces enough antibodies to fight off the pathogen but not so much that it causes any adverse reactions. Further, it’s also regulated to ensure that the immune system does not become overstimulated.

Antibody production is regulated by controlling the B cell activation.⁵ To activate and differentiate into plasma cells that secrete antibodies, mature B cells in peripheral lymphoid organs need two signals. An antigen-coupled B cell receptor (BCR) delivers the first signal, while the second signal is generated in a T-cell-dependent or independent manner, which regulates the production of antibodies in response to the antigen. Low-affinity antibodies are produced in response to the secretion of lipopolysaccharides and glycolipids. However, the interaction of follicular T-helper cells with the antigen enables B-cells to enter the germinal center for their differentiation into memory and plasma B-cells.

Signals from the microenvironment, including cytokines and interactions with other immune cells also guide the maturation and activation of B-cells, influencing the quantity and quality of antibodies produced.

In addition, epigenetic modifications, encompassing histone posttranslational modifications and DNA methylation, play pivotal roles in governing processes such as class switch DNA recombination (CSR), somatic hypermutation (SHM), and the differentiation process leading to the formation of plasma cells or long-lasting memory B-cells.⁶

Factors influencing antibody production

Antibody production in humans is influenced by several intrinsic and extrinsic factors, which include:

• Environmental factors: Several studies have reported that the humorous and cellular immune responses of people are influenced by the season, the environment they live in, their family size, and exposure to certain toxic chemicals.⁷ For example, it has been found that children living in rural areas show higher antibody responses to tetanus vaccines than those living in semi-urban areas.⁸ As another example, infants born in the wet season in Africa exhibit more robust CD154 vaccine responses to BCG compared to those born in the dry season.
• Genetic factors: Studies report that people of different ethnic groups living in the same locations show different immune responses to vaccination.⁹ Further, polymorphism in Toll-like receptor (TLR) genes, major histocompatibility complex (MHC) genes, and RIG-like receptor (RLR) genes also influence antibody production.⁸
• Age-related changes: Infants show lower immune response against any disease compared to adults. It demands their immunization to reduce their susceptibility to any infection. Additionally, it has been observed that with aging the immune response decreases, and there is a loss of immune memory and increased chronic inflammation in older individuals.¹⁰ The aging process has a widespread impact on humoral immunity, leading to diminished antibody affinity. This affects the adaptive immune processes involved in antibody production, such as a reduction in antibody production by plasma cells and a decrease in CD4+ T cell receptor diversity.¹⁰

Clinical implications of understanding antibody regulation

The discovery of antibodies has revolutionized the medical field.¹¹ Understanding antibody regulation has many clinical implications ranging from designing more targeted immunotherapies to vaccine development. In autoimmune disorder cases, such as Crohn’s disease or rheumatoid arthritis, monoclonal-based therapies are extremely popular. The synthetically produced antibodies bind to the inflammatory mediators such as TNF-alpha and prevent their functioning and the disease progress.

Monoclonal antibodies have been proven to be revolutionary in Cancer treatment. It plays a crucial role by leveraging the immune response to target cancerous cell lines and improve the survival chances of patients with solid or hematologic cancers. Direct-targeting antibodies that directly target immune cells and immune checkpoint antibodies that activate immune cells, eliminating cancer cells with the tumor microenvironment, are two antibodies that are clinically successful.¹²

Antibody production - Research

The field of therapeutic antibodies has experienced substantial expansion in recent years, emerging as a prominent player in the therapeutics market. For years, antibodies have been used to treat several autoimmune disorders and cancer. However, if the molecular mechanisms underlying a particular disease can be thoroughly understood, and the specific proteins or molecules implicated in the disease's development can be identified, antibodies may offer a promising and effective therapeutic avenue for intervention.¹¹

Now, new methods have been developed for discovering new antibodies for specific disease treatments - next-generation sequencing, single-cell sequencing, and high-throughput robotic screening. These advancements are bound to speed up the development of monoclonal antibodies (mAb) for pharmaceuticals and medical research.

The retrieval of antibodies from individual cells is anticipated to be a powerful technique in the future, especially when combined with advanced sequencing methods.¹¹ This approach has broad applications in diagnostics, studying how drugs act in the body and developing clinical treatments.

References

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