Immunodominance

Last updated October 28, 2023

Immunodominance is the immunological phenomenon in which immune responses are mounted against only a few of the antigenic peptides out of the many produced.^[1] That is, despite multiple allelic variations of MHC molecules and multiple peptides presented on antigen presenting cells, the immune response is skewed to only specific combinations of the two.^[1] Immunodominance is evident for both antibody-mediated immunity and cell-mediated immunity.^[2]^[3] Epitopes that are not targeted or targeted to a lower degree during an immune response are known as subdominant epitopes.^[1]^[2] The impact of immunodominance is immunodomination, where immunodominant epitopes will curtail immune responses against non-dominant epitopes.^[4] Antigen-presenting cells such as dendritic cells, can have up to six different types of MHC molecules for antigen presentation.^[1] There is a potential for generation of hundreds to thousands of different peptides from the proteins of pathogens.^[1] Yet, the effector cell population that is reactive against the pathogen is dominated by cells that recognize only a certain class of MHC bound to only certain pathogen-derived peptides presented by that MHC class.^[1] Antigens from a particular pathogen can be of variable immunogenicity, with the antigen that stimulates the strongest response being the immunodominant one. The different levels of immunogenicity amongst antigens forms what is known as dominance hierarchy.^[2]

Mechanism

CTL immunodominance

The mechanisms of immunodominance are very poorly understood.^[1]^[2] What determines cytotoxic T lymphocyte (CTL) immunodominance can be a number of factors, many of which are debated.^[1] Of these, one in particular focuses on the timing of CTL clonal expansion.^[2]^[3] The dominant CTLs that arise were activated sooner so therefore proliferate faster than subdominant CTLs that were activated later, thus resulting in a greater number of CTLs for that immunodominant epitope.^[2] This can be in concordance with an additional theory which states that immunodominance may be dependent on the affinity of the T-cell receptor (TCR) to the immunodominant epitope.^[4] That is, T cells with a TCR that has high affinity for its antigen are most likely to be immunodominant.^[4] High affinity of the peptide to the TCR contributes to the T cell’s survival and proliferation, allowing for more clonal selection of the immunodominant T cells over the subdominant T cells.^[4] Immunodominant T cells also curtail subdominant T cells by outcompeting them for cytokine sources from antigen-presenting cells.^[4] This leads to a greater expansion of the T cells that recognize a high affinity epitope and is favoured since these cells are likely to clear the infection much more quickly and effectively than their subdominant counterparts. It is important to note, however, that immunodominance is a relative term. If subdominant epitopes are introduced without the dominant epitope, the immune response will be focused to that subdominant epitope.^[4] Meanwhile, if the dominant epitope is introduced with the subdominant epitope, the immune response will be directed against the dominant epitope while silencing the response against the subdominant epitope.^[4]

Antibody immunodominance

The mechanism of immunodominance in B cell activation focuses on the affinity of epitope binding to the B-cell receptor (BCR). If an epitope binds very strongly to a B cell BCR, it will then subsequently bind with high affinity to the resultant antibodies produced by that B cell upon activation. These antibodies then out-compete the BCR for the epitope, and thus that B cell lineage will be unavailable for subsequent stimulation.^[2] On the opposite end of the scale where BCRs have low affinity for the epitopes, these B cells are outcompeted for stimulation by B cells with BCRs that have higher affinities for their respective epitopes.^[2] Insufficient T cell stimulation by these B cells also leads to suppression of these B cells by the T cells.^[2] The immunodominant epitope will be a BCR that has a particular ‘goldilocks’ amount of affinity for its epitope determined by equilibrium binding affinity.^[2] This leads to initial IgM response directed at the strongly binding epitope, and the subsequent IgG response focused on the immunodominant epitope.^[2] That is, those within the ‘goldilocks zone’ for affinity will be available for subsequent T helper stimulation, allowing for class switching, affinity maturation and thus, resulting in immunodominance to that particular epitope.^[2]

Implications

Having the immune response focused on a specific immunodominant epitope is useful because it allows the strongest immune response against a certain pathogen to dominate, thus eliminating the pathogen fast and effectively.^[4] However, it can also cause a hindrance because of potential pathogen escape.^[4] In the case of HIV, immunodominance can be unfavourable because of the high mutation rate of HIV.^[1] The immunodominant epitope can be mutated in the virus, thus allowing HIV to avoid the adaptive immune response when reintroduced from latency.^[1] This is why the disease perpetuates, as the virus mutates to avoid the antibodies and T cells specific for the immunodominant epitope that is no longer expressed by the virus.^[1] Immunodominance can also have implications in cancer immunotherapy. Similar to HIV-escape, cancer can escape the immune system’s detection by antigenic variation.^[4] As the immunodominant epitope is mutated and/or lost in the cancer, the immune response no longer has Immunodominance also has implications in vaccine development. Immunodominant epitopes vary from person to person.^[5] This phenomenon is due to the variability of HLA types, which make up the MHC molecules that present the immunodominant epitopes.^[5] Therefore, people with different alleles may respond to different epitopes of the same pathogen. With vaccine development particularly for subunit-based and recombinant vaccines, this may lead to some individuals which have different HLA haplotype to not respond while others do.^[5]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response.

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. Additionally, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the 'B' stands for bursa and not bone marrow as commonly believed.

A cytotoxic T cell (also known as T_C, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8⁺ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

The T helper cells (T_h cells), also known as CD4⁺ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4⁺ cells are mature T_h cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4⁺ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<span class="mw-page-title-main">Superantigen</span> Antigen which strongly activates the immune system

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically they cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage of antigen presentation pathways. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens, or from phagocytosed pathogens ; subsequent presentation of these antigens on class I or class II major histocompatibility complex (MHC) molecules is dependent on which pathway is used. Both MHC class I and II are required to bind antigens before they are stably expressed on a cell surface. MHC I antigen presentation typically involves the endogenous pathway of antigen processing, and MHC II antigen presentation involves the exogenous pathway of antigen processing. Cross-presentation involves parts of the exogenous and the endogenous pathways but ultimately involves the latter portion of the endogenous pathway.

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on platelets, but not on red blood cells. Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway.

Original antigenic sin, also known as antigenic imprinting, the Hoskins effect, or immunological imprinting, is the propensity of the immune system to preferentially use immunological memory based on a previous infection when a second slightly different version of that foreign pathogen is encountered. This leaves the immune system "trapped" by the first response it has made to each antigen, and unable to mount potentially more effective responses during subsequent infections. Antibodies or T-cells induced during infections with the first variant of the pathogen are subject to repertoire freeze, a form of original antigenic sin.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

Molecular mimicry is defined as the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the prevalence of several peptide sequences which can be both foreign and self in nature, a single antibody or TCR can be activated by just a few crucial residues which stresses the importance of structural homology in the theory of molecular mimicry. Upon the activation of B or T cells, it is believed that these "peptide mimic" specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity). Molecular mimicry is a phenomenon that has been just recently discovered as one of several ways in which autoimmunity can be evoked. A molecular mimicking event is, however, more than an epiphenomenon despite its low statistical probability of occurring and these events have serious implications in the onset of many human autoimmune disorders.

Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.

Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple clones of B cell.

The Streptamer technology allows the reversible isolation and staining of antigen-specific T cells. This technology combines a current T cell isolation method with the Strep-tag technology. In principle, the T cells are separated by establishing a specific interaction between the T cell of interest and a molecule that is conjugated to a marker, which enables the isolation. The reversibility of this interaction and the low temperatures at which it is performed allows for the isolation and characterization of functional T cells. Because T cells remain phenotypically and functionally indistinguishable from untreated cells, this method offers modern strategies in clinical and basic T cell research.

Peptide-based synthetic vaccines are subunit vaccines made from peptides. The peptides mimic the epitopes of the antigen that triggers direct or potent immune responses. Peptide vaccines can not only induce protection against infectious pathogens and non-infectious diseases but also be utilized as therapeutic cancer vaccines, where peptides from tumor-associated antigens are used to induce an effective anti-tumor T-cell response.

Immunomics is the study of immune system regulation and response to pathogens using genome-wide approaches. With the rise of genomic and proteomic technologies, scientists have been able to visualize biological networks and infer interrelationships between genes and/or proteins; recently, these technologies have been used to help better understand how the immune system functions and how it is regulated. Two thirds of the genome is active in one or more immune cell types and less than 1% of genes are uniquely expressed in a given type of cell. Therefore, it is critical that the expression patterns of these immune cell types be deciphered in the context of a network, and not as an individual, so that their roles be correctly characterized and related to one another. Defects of the immune system such as autoimmune diseases, immunodeficiency, and malignancies can benefit from genomic insights on pathological processes. For example, analyzing the systematic variation of gene expression can relate these patterns with specific diseases and gene networks important for immune functions.

Immunology is the study of the immune system during health and disease. Below is a list of immunology-related articles.

References

1 2 3 4 5 6 7 8 9 10 11 Akram, A.; R. D. Inman (2012). "Immunodominance: A pivotal principle in host response to viral infections". Clinical Immunology. 143 (2): 99–115. doi:10.1016/j.clim.2012.01.015. PMID 22391152.
1 2 3 4 5 6 7 8 9 10 11 12 Frank, S. A. (2002). Immunology and Evolution of Infectious Disease. Princeton, NJ: Princeton University Press. pp. 73–89.
1 2 Kastenmuller, W.; Gasteiger, G.; Gronau, J. H.; Baier, R.; Ljapoci, R.; Busch, D. H.; Drexler, I. (2007). "Cross-competition of CD8+ T cells shapes the immunodomiance hierarchy during boost vaccination". Journal of Experimental Medicine. 204 (9): 2187–2198. doi:10.1084/jem.20070489. PMC 2118691 . PMID 17709425.
1 2 3 4 5 6 7 8 9 10 Perrault, C. (2011). Experimental and Applied Immunotherapy. New York, NY: Humana Press. pp. 195–206.
1 2 3 Betts, M. R.; Casazza, J. P.; Patterson, B. A.; Waldrop, S.; Trigona, W.; Fu, T.; Kern, F.; Picker, L. J.; Koup, R. A. (2000). "Putative immunodominant human immunodeficiency virus-specific CD8+ T-cell responses cannot be predicted by major histocompatibility complex class I haplotype". Journal of Virology. 74 (19): 9144–51. doi:10.1128/JVI.74.19.9144-9151.2000. PMC 102113 . PMID 10982361.

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[Akram-1] 1 2 3 4 5 6 7 8 9 10 11 Akram, A.; R. D. Inman (2012). "Immunodominance: A pivotal principle in host response to viral infections". Clinical Immunology. 143 (2): 99–115. doi:10.1016/j.clim.2012.01.015. PMID 22391152.

[Frank-2] 1 2 3 4 5 6 7 8 9 10 11 12 Frank, S. A. (2002). Immunology and Evolution of Infectious Disease. Princeton, NJ: Princeton University Press. pp. 73–89.

[Kast-3] 1 2 Kastenmuller, W.; Gasteiger, G.; Gronau, J. H.; Baier, R.; Ljapoci, R.; Busch, D. H.; Drexler, I. (2007). "Cross-competition of CD8+ T cells shapes the immunodomiance hierarchy during boost vaccination". Journal of Experimental Medicine. 204 (9): 2187–2198. doi:10.1084/jem.20070489. PMC 2118691 . PMID 17709425.

[Per-4] 1 2 3 4 5 6 7 8 9 10 Perrault, C. (2011). Experimental and Applied Immunotherapy. New York, NY: Humana Press. pp. 195–206.

[Betts-5] 1 2 3 Betts, M. R.; Casazza, J. P.; Patterson, B. A.; Waldrop, S.; Trigona, W.; Fu, T.; Kern, F.; Picker, L. J.; Koup, R. A. (2000). "Putative immunodominant human immunodeficiency virus-specific CD8+ T-cell responses cannot be predicted by major histocompatibility complex class I haplotype". Journal of Virology. 74 (19): 9144–51. doi:10.1128/JVI.74.19.9144-9151.2000. PMC 102113 . PMID 10982361.

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