Immunological memory

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Immunological memory is the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. Generally, they are secondary, tertiary and other subsequent immune responses to the same antigen. The adaptive immune system and antigen-specific receptor generation (TCR, antibodies) are responsible for adaptive immune memory.[ citation needed ]

Contents

After the inflammatory immune response to danger-associated antigen, some of the antigen-specific T cells and B cells persist in the body and become long-living memory T and B cells. After the second encounter with the same antigen, they recognize the antigen and mount a faster and more robust response. Immunological memory is the basis of vaccination. [1] [2] Emerging resources show that even the innate immune system can initiate a more efficient immune response and pathogen elimination after the previous stimulation with a pathogen, respectively with PAMPs or DAMPs. Innate immune memory (also called trained immunity) is neither antigen-specific nor dependent on gene rearrangement, but the different response is caused by changes in epigenetic programming and shifts in cellular metabolism. Innate immune memory was observed in invertebrates as well as in vertebrates. [3] [4]

Adaptive immune memory

The time course of an immune response. The formation of immunological memory causes a later reinfection to lead to a rapid increase in antibody production and effector T cell activity. The later infections can be mild or even unapparent. Immune response2.svg
The time course of an immune response. The formation of immunological memory causes a later reinfection to lead to a rapid increase in antibody production and effector T cell activity. The later infections can be mild or even unapparent.

Development of adaptive immune memory

Immunological memory occurs after a primary immune response against the antigen. Immunological memory is thus created by each individual, after a previous initial exposure, to a potentially dangerous agent. The course of secondary immune response is similar to primary immune response. After the memory B cell recognizes the antigen it presents the peptide: MHC II complex to nearby effector T cells. That leads to activation of these cells and rapid proliferation of cells. After the primary immune response has disappeared, the effector cells of the immune response are eliminated. [5]

However, antibodies that were previously created in the body remain and represent the humoral component of immunological memory and comprise an important defensive mechanism in subsequent infections. In addition to the formed antibodies in the body there remains a small number of memory T and B cells that make up the cellular component of the immunological memory. They stay in blood circulation in a resting state and at the subsequent encounter with the same antigen these cells are able to respond immediately and eliminate the antigen. Memory cells have a long life and last up to several decades in the body. [6] [2]

Immunity to chickenpox, measles, and some other diseases lasts a lifetime. Immunity to many diseases eventually wears off. The immune system's response to a few diseases, such as dengue, counterproductively worsens the next infection (antibody-dependent enhancement). [7]

As of 2019, researchers are still trying to find out why some vaccines produce life-long immunity, while the effectiveness of other vaccines drops to zero in less than 30 years (for mumps) or less than six months (for H3N2 influenza). [8]

Evolution of adaptive immune memory

The evolutionary invention of memory T and B cells is widespread; however, the conditions required to develop this costly adaptation are specific. First, in order to evolve immune memory the initial molecular machinery cost must be high and will demand losses in other host characteristics. Second, middling or long lived organisms have higher chance of evolving such apparatus. The cost of this adaption increases if the host has a middling lifespan as the immune memory must be effective earlier in life. [9]

Furthermore, research models show that the environment plays an essential role in the diversity of memory cells in a population. Comparing the influence of multiple infections to a specific disease as opposed to disease diversity of an environment provide evidence that memory cell pools accrue diversity based on the number of individual pathogens exposed, even at the cost of efficiency when encountering more common pathogens. Individuals living in isolated environments such as islands have a less diverse population of memory cells, which are, however, present with sturdier immune responses. That indicates that the environment plays a large role in the evolution of memory cell populations. [10]

Previously acquired immune memory can be depleted by measles in unvaccinated children, leaving them at risk of infection by other pathogens in the years after infection. [11]

Memory B cells

Memory B cells are plasma cells that are able to produce antibodies for a long time. Unlike the naive B cells involved in the primary immune response the memory B cell response is slightly different. The memory B cell has already undergone clonal expansion, differentiation and affinity maturation, so it is able to divide multiple times faster and produce antibodies with much higher affinity (especially IgG). [1]

In contrast, the naive plasma cell is fully differentiated and cannot be further stimulated by antigen to divide or increase antibody production. Memory B cell activity in secondary lymphatic organs is highest during the first 2 weeks after infection. Subsequently, after 2 to 4 weeks its response declines. After the germinal center reaction the memory plasma cells are located in the bone marrow which is the main site of antibody production within the immunological memory. [12]

Memory T cells

Memory T cells can be both CD4+ and CD8+. These memory T cells do not require further antigen stimulation to proliferate; therefore, they do not need a signal via MHC. [13] Memory T cells can be divided into two functionally distinct groups based on the expression of the CCR7 chemokine receptor. This chemokine indicates the direction of migration into secondary lymphatic organs. Those memory T cells that do not express CCR7 (these are CCR7-) have receptors to migrate to the site of inflammation in the tissue and represent an immediate effector cell population. These cells were named memory effector T cells (TEM). After repeated stimulation they produce large amounts of IFN-γ, IL-4 and IL-5. In contrast, CCR7 + memory T cells lack proinflammatory and cytotoxic function but have receptors for lymph node migration. These cells were named central memory T cells (TCM). They effectively stimulate dendritic cells, and after repeated stimulation they are able to differentiate in CCR7- effector memory T cells. Both populations of these memory cells originate from naive T cells and remain in the body for several years after initial immunization. [14]

Experimental techniques used to study these cells include measuring antigen-stimulated cell proliferation and cytokine release, staining with peptide-MHC multimers or using an activation-induced marker (AIM) assay. [15]

Innate immune memory

Many invertebrates such as species of fresh water snails, copepod crustaceans, and tapeworms have been observed activating innate immune memory to instigate a more efficient immune response to second encounter with specific pathogens, despite missing an adaptive branch of the immune system. [3] RAG1-deficient mice without functional T and B cells were able to survive the administration of a lethal dose of Candida albicans when exposed previously to a much smaller amount, showing that vertebrates also retain this ability. [4] Despite not having the ability to manufacture antibodies like the adaptive immune system, innate immune system has immune memory properties as well. Innate immune memory (trained immunity) is defined as a long-term functional reprogramming of innate immune cells evoked by exogenous or endogenous insults and leading to an altered response towards a second challenge after returning to a non-activated state. [16]

When innate immune cells receive an activation signal; for example, through recognition of PAMPs with PRRs, they start the expression of proinflammatory genes, initiate an inflammatory response, and undergo epigenetic reprogramming. After the second stimulation, the transcription activation is faster and more robust. [17] Immunological memory was reported in monocytes, macrophages, NK cells, ILC1, ILC2, and recently in ILC3 as well, [18] [17] Concomitantly, some nonimmune cells, for example, epithelial stem cells on barrier tissues, or fibroblasts, change their epigenetic state and respond differently after priming insult. [19]

Mechanism of innate immune memory

At the steady state, unstimulated cells have reduced biosynthetic activities and more condensed chromatin with reduced gene transcription. The interaction of exogenous PAMPs (β-glucan, muramyl peptide) or endogenous DAMPs (oxidized LDL, uric acid) with PRR initiates a cellular response. Triggered Intracellular signaling cascades lead to the upregulation of metabolic pathways such as glycolysis, Krebs cycle, and fatty acid metabolism. An increase in metabolic activity provides cells with energy and building blocks, which are needed for the production of signaling molecules such as cytokines and chemokines. [17]

Signal transduction changes the epigenetic marks and increases chromatin accessibility, to allow binding of transcription factors and start transcription of genes connected with inflammation. There is an interplay between metabolism and epigenetic changes because some metabolites such as fumarate and acetyl-CoA can activate or inhibit enzymes involved in chromatin remodeling. [16] After the stimulus let up, there is no need for immune factors production, and their expression in immune cells is terminated. Several epigenetic modifications created during stimulation remain. Characteristic epigenetic rewiring in trained cells is the accumulation of H3K4me3 on immune genes promoters and the increase of H3k4me1 and H3K27ac on enhancers. Additionally, cellular metabolism does not return to the state before stimulation, and trained cells remain in a prepared state. This status can last from weeks to several months and can be transmitted into daughter cells. Secondary stimulation induces a new response, which is faster and stronger. [16] [17]

Evolution of innate immune memory

Immune memory brings a major evolutionary advantage when the organism faces repeated infections. Inflammation is very costly, and increased effectivity of response accelerates pathogen elimination and prevents damage to the host's own tissue. Classical adaptive immune memory evolved in jawed vertebrates and in jawless fish (lamprey), which is approximately just 1% of living organisms. Some form of immune memory is, therefore, reported in other species. In plants and invertebrates, faster kinetics, increased magnitude of immune response and an improved survival rate can be seem after secondary infection encounters. Immune memory is common for the vast majority of biodiversity on earth. [20]

It has been proposed that immune memory in innate and adaptive immunity represents an evolutionary continuum in which a more robust immune response evolved first, mediated by epigenetic reprogramming. In contrast, specificity through antigen-specific receptors evolved later in some vertebrates. [21]

See also

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.

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Immunology</span> Branch of medicine studying the immune system

Immunology is a branch of biology and medicine that covers the study of immune systems in all organisms.

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

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. In addition, 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.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th 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 Th 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.

In biology, immunity is the state of being insusceptible or resistant to a noxious agent or process, especially a pathogen or infectious disease. Immunity may occur naturally or be produced by prior exposure or immunization.

Humoral immunity is the aspect of immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Humoral immunity is named so because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Humoral immunity is also referred to as antibody-mediated immunity.

<span class="mw-page-title-main">Cell-mediated immunity</span> Immune response that does not involve antibodies

Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

<span class="mw-page-title-main">Memory B cell</span> Cell of the adaptive immune system

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

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.

Immunopathology is a branch of medicine that deals with immune responses associated with disease. It includes the study of the pathology of an organism, organ system, or disease with respect to the immune system, immunity, and immune responses. In biology, it refers to damage caused to an organism by its own immune response, as a result of an infection. It could be due to mismatch between pathogen and host species, and often occurs when an animal pathogen infects a human.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. The word "adjuvant" comes from the Latin word adiuvare, meaning to help or aid. "An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens."

Priming is the first contact that antigen-specific T helper cell precursors have with an antigen. It is essential to the T helper cells' subsequent interaction with B cells to produce antibodies. Priming of antigen-specific naive lymphocytes occurs when antigen is presented to them in immunogenic form. Subsequently, the primed cells will differentiate either into effector cells or into memory cells that can mount stronger and faster response to second and upcoming immune challenges. T and B cell priming occurs in the secondary lymphoid organs.

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, intracellular bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.

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.

<span class="mw-page-title-main">Adaptive NK cell</span> Specialized subtype of cytotoxic lymphocyte

An adaptive natural killer (NK) cell or memory-like NK cell is a specialized natural killer cell that has the potential to form immunological memory. They can be distinguished from cytotoxic NK (cNK) cells by their receptor expression profile and epigenome. Adaptive NK cells are so named for properties which they share with the adaptive immune system. Though adaptive NK cells do not possess antigen specificity, they exhibit dynamic expansions of defined cell subsets, increased proliferation and long-term persistence for up to 3 months in vivo, high IFN-γ production, potent cytotoxic activity upon ex vivo restimulation, and protective memory responses.

Trained immunity is a long-term functional modification of cells in the innate immune system which leads to an altered response to a second unrelated challenge. For example, the BCG vaccine leads to a reduction in childhood mortality caused by unrelated infectious agents. The term "innate immune memory" is sometimes used as a synonym for the term trained immunity which was first coined by Mihai Netea in 2011. The term "trained immunity" is relatively new – immunological memory has previously been considered only as a part of adaptive immunity – and refers only to changes in innate immune memory of vertebrates. This type of immunity is thought to be largely mediated by epigenetic modifications. The changes to the innate immune response may last up to several months, in contrast to the classical immunological memory, and is usually unspecific because there is no production of specific antibodies/receptors. Trained immunity has been suggested to possess a transgenerational effect, for example the children of mothers who had also received vaccination against BCG had a lower mortality rate than children of unvaccinated mothers. The BRACE trial is currently assessing if BCG vaccination can reduce the impact of COVID-19 in healthcare workers. Other vaccines are also thought to induce immune training such as the DTPw vaccine.

<span class="mw-page-title-main">Mihai Netea</span>

Mihai G. Netea is a Romanian Dutch physician and professor at Radboud University Nijmegen, specialized in infectious disease, immunology, and global health.

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