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. [1] For example, the BCG vaccine leads to a reduction in childhood mortality caused by unrelated infectious agents. [2] The term "innate immune memory" is sometimes used as a synonym for the term trained immunity [3] [4] which was first coined by Mihai Netea in 2011. [5] 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. [6] [7] 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 (which may last up to a lifetime), and is usually unspecific because there is no production of specific antibodies/receptors. [8] 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. [9] The BRACE trial is currently assessing if BCG vaccination can reduce the impact of COVID-19 in healthcare workers. [10] Other vaccines are also thought to induce immune training such as the DTPw vaccine. [11]
Trained immunity is thought to be largely mediated by functional reprogramming of myeloid cells. [1] One of the first described adaptive changes in macrophages were associated with lipopolysaccharide tolerance, which resulted in the silencing of inflammatory genes. [12] Similarly, Candida albicans and fungal β-glucan trigger changes in monocyte histone methylation, this functional reprogramming eventually provides protection against reinfection. [13] Also, a non-specific manner of protection in training with different microbial ligands was showed, for example treatment with fungal β-glucan induced protection against Staphylococcus aureus infection [14] or CpG oligodeoxynucleotide training protecting against infectious with Escherichia coli . [15]
Evidence of trained immunity is found mainly at monocytes/macrophages and NK cells and, less at γδ T cells and innate lymphoid cells. [16]
Monocytes/macrophages can undergo epigenetic modifications after a ligation of their pattern recognition receptors (PRRs). This ligation prepares these cells for a second encounter with the training pathogen. [16] The secondary response may be heightened not only against the training pathogen, but also against different pathogens whose antigens are recognized by the same PRRs. This effect has been observed when stimulating cells by β-glucan, Candida Albicans, or by vaccination against tuberculosis with a vaccine containing BCG. [17] [7] Monocytes are very short-lived cells; however, the heightened secondary response can be spotted even several months after the primary stimulation. This shows that the immune memory is created at the level of progenitor cells, but so far it is not known how this memory is achieved. [7] Though the epigenetic modification is beneficial to the innate immune system response, it can impair macrophage resolution pathways- promoting unfavorable tissue remodeling at the inflammatory site. [18] Additionally, dendritic cells isolated from mice exposed to Cryptococcus neoformans, manifested an immunological memory response, associated with a strong interferon-γ production after C. neoformans reinfection. [19]
Trained immunity can shift macrophages toward a pro-inflammatory glycolytic M1 phenotype by an Akt/mTor HIF1𝛼 dependent pathway, away from the M2 phenotype in which macrophages maintain the Krebs cycle and oxidative phosphorylation [20] [21]
This article may require cleanup to meet Wikipedia's quality standards. The specific problem is: citation; too heavy focus on specific people.(December 2020) |
The trained immunity involving NK cells looks more like classic immunological memory, because there is development of at least partially-specific clones of NK cells. These cells have receptors on their surface against the antigens with which they came in contact during the first stimulation. [8] For example, after the encounter with cytomegalovirus, certain clones of NK cells (those that have a Ly49H receptor on their surface) expand and then show signs of immunological memory. [22] Reinfection of memory NK cells in mouse led to an enhanced cytokine production by Ly49H receptor with a more specific response to pathogen. [23] In human NK cells, this is mediated by NKG2C a receptor with a similar function as mouse Ly49H. [24] NK cells are known for their memory specific to different pathogens. The first descriptions of NK memory-like phenotype were made on mouse models with murine cytomegalovirus infections. [25] Other viral infections such as Herpes Simplex Virus [26] or Influenza Virus [27] also induce memory or memory-like responses. Memory or memory-like phenotype can be caused by bacterial phatogens, for example Mycobacterium tuberculosis, [28] or eukaryotic pathogens, for example Toxoplasma gondii. [29]
Another resident cell group 1 innate lymphoid cells (ILC1s) were discovered in liver, which expand after the infection with murine cytomegalovirus and which have manifest transcriptional, phenotypical and epigenetic changes. For the induction of ILC1s, pro-inflammatory cytokine and antigen specificity are critical. [30] Lung specific ILC2 showed memory-like phenotype after allergen exposure [31]
Trained immunity relies on epigenetic reprogramming which leads to a stronger and rapid response to recurrent triggers. There are multiple potential epigenetic mechanisms such as changes in chromatin accessibility, DNA methylation or histone modifications. Long non-coding RNAs (lncRNAs) are also critical to epigenetic reprogramming, such as their role in the assignment of H3K4me3 markers to genome which modulates gene expression. [32] Additionally, transcription factors, including STAT4 [33] and RUNX family transcription factors [34] play a role in the introduction of histone modifications. Cell metabolism is a crucial mediator of trained immunity, for example monocytes trained with β-glucan had an increased aerobic glycolysis. Additionally, priming with β-glucan resulted in epigenetic upregulation of genes involved in glycolysis 1 week later. [35] Subsequently, a cross-talk between glycolysis, glutaminolysis and cholesterol synthesis pathways was demonstrated as essential for trained immunity – β-glucan-triggered monocytes. In addition, accumulation of fumarate, caused by glutamine addition into tricarboxylic acid cycle, led to epigenetic reprogramming similar to β-glucan treatment [36]
The immune system is a network of biological processes 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.
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could cause serious problems to the health of the host organism if not cleared from the body. There are two distinct aspects of the immune response, the innate and the adaptive, which work together to protect against pathogens. The innate branch—the body's first reaction to an invader—is known to be a non-specific and quick response to any sort of pathogen. Components of the innate immune response include physical barriers like the skin and mucous membranes, immune cells such as neutrophils, macrophages, and monocytes, and soluble factors including cytokines and complement. On the other hand, the adaptive branch is the body's immune response which is catered against specific antigens and thus, it takes longer to activate the components involved. The adaptive branch include cells such as dendritic cells, T cell, and B cells as well as antibodies—also known as immunoglobulins—which directly interact with antigen and are a very important component for a strong response against an invader.
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.
The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.
Neuroimmunology is a field combining neuroscience, the study of the nervous system, and immunology, the study of the immune system. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, homeostasis, and response to injuries. A long-term goal of this rapidly developing research area is to further develop our understanding of the pathology of certain neurological diseases, some of which have no clear etiology. In doing so, neuroimmunology contributes to development of new pharmacological treatments for several neurological conditions. Many types of interactions involve both the nervous and immune systems including the physiological functioning of the two systems in health and disease, malfunction of either and or both systems that leads to disorders, and the physical, chemical, and environmental stressors that affect the two systems on a daily basis.
Chemokine ligands 4 previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the CCL4 gene. CCL4 belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the chromosome 17 was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.
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."
Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).
C-type lectin domain family 7 member A or Dectin-1 is a protein that in humans is encoded by the CLEC7A gene. CLEC7A is a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. The encoded glycoprotein is a small type II membrane receptor with an extracellular C-type lectin-like domain fold and a cytoplasmic domain with a partial immunoreceptor tyrosine-based activation motif. It functions as a pattern-recognition receptor for a variety of β-1,3-linked and β-1,6-linked glucans from fungi and plants, and in this way plays a role in innate immune response. Expression is found on myeloid dendritic cells, monocytes, macrophages and B cells. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. This gene is closely linked to other CTL/CTLD superfamily members on chromosome 12p13 in the natural killer gene complex region.
Macrophage receptor with collagenous structure (MARCO) is a protein that in humans is encoded by the MARCO gene. MARCO is a class A scavenger receptor that is found on particular subsets of macrophages. Scavenger receptors are pattern recognition receptors (PRRs) found most commonly on immune cells. Their defining feature is that they bind to polyanions and modified forms of a type of cholesterol called low-density lipoprotein (LDL). MARCO is able to bind and phagocytose these ligands and pathogen-associated molecular patterns (PAMPs), leading to the clearance of pathogens and cell signaling events that lead to inflammation. As part of the innate immune system, MARCO clears, or scavenges, pathogens, which leads to inflammatory responses. The scavenger receptor cysteine-rich (SRCR) domain at the end of the extracellular side of MARCO binds ligands to activate the subsequent immune responses. MARCO expression on macrophages has been associated with tumor development and also with Alzheimer's disease, via decreased responses of cells when ligands bind to MARCO.
Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.
Jos W.M. van der Meer is emeritus professor and former chairman at the department of internal medicine of the Radboud University Nijmegen Medical Centre in Nijmegen, Netherlands. He is a member of the Royal Netherlands Academy of Arts and Sciences, of which he was vice president and chairman of the division of natural sciences (2006-2012). He is a member of Academia Europaea. Between 2014 and 2016 he was president of European Academies Science Advisory Council (EASAC). He performs research on cytokines and host defence, chronic fatigue syndrome and hyper-immunoglobulinemia D syndrome (HIDS). He is also active in graphic art and makes cartoons, for example for the Dutch science journal Mediator.
The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage.
Non-specific effects of vaccines are effects which go beyond the specific protective effects against the targeted diseases. Non-specific effects can be strongly beneficial by increasing protection against non-targeted infections. This has been shown with two live attenuated vaccines, BCG vaccine and measles vaccine, through multiple randomized controlled trials. Theoretically, non-specific effects of vaccines may be detrimental, increasing overall mortality despite providing protection against the target diseases. Although observational studies suggest that diphtheria-tetanus-pertussis vaccine (DTP) may be detrimental, these studies are at high risk of bias and have failed to replicate when conducted by independent groups.
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, these are secondary, tertiary and other subsequent immune responses to the same antigen. The adaptive immune system and antigen-specific receptor generation are responsible for adaptive immune memory. 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. 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 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.
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.
Mihai G. Netea is a Romanian Dutch physician and professor at Radboud University Nijmegen, specialized in infectious disease, immunology, and global health.
Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. They are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.