9.6: Subviral Entities - Biology

9.6: Subviral Entities - Biology

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9.6: Subviral Entities

In Virology

Frontiers in Virology explores all biological and molecular aspects of viruses and reports cutting-edge studies that can direct future research. Virology is a multidisciplinary research field with respect to the technologies/methodologies in use, as well as the study targets and their focuses.

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Research Topics

Morphogenesis of hepatitis B virus and its subviral envelope particles

Université François Rabelais, INSERM U 966, Tours, France.

Present address: Liver Diseases Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: [email protected]

Université François Rabelais, INSERM U 966, Tours, France.


After cell hijacking and intracellular amplification, non-lytic enveloped viruses are usually released from the infected cell by budding across internal membranes or through the plasma membrane. The enveloped human hepatitis B virus (HBV) is an example of virus using an intracellular compartment to form new virions. Four decades after its discovery, HBV is still the primary cause of death by cancer due to a viral infection worldwide. Despite numerous studies on HBV genome replication little is known about its morphogenesis process. In addition to viral neogenesis, the HBV envelope proteins have the capability without any other viral component to form empty subviral envelope particles (SVPs), which are secreted into the blood of infected patients. A better knowledge of this process may be critical for future antiviral strategies. Previous studies have speculated that the morphogenesis of HBV and its SVPs occur through the same mechanisms. However, recent data clearly suggest that two different processes, including constitutive Golgi pathway or cellular machinery that generates internal vesicles of multivesicular bodies (MVB), independently form these two viral entities.

Transmission Genetics

Monohybrid Cross and Test Cross

Mendel's cross-hybridization studies involved purebred plants that differed with regard to a single contrasting trait. Purebred, homozygous, parental stocks were crossed and the offspring of this cross are called F1 hybrids, or monohybrids. In the F1 generation, all of the hybrids resembled the parent with the dominant trait. The genotype of these monohybrid, or heterozygous, plants can be represented as genotype Aa, with the uppercase letter representing the dominant allele and the lowercase letter representing the recessive allele. The F1 hybrid plants were next self-fertilized (Aa×Aa ) and this cross is known as a monohybrid cross . In the offspring of monohybrid crosses, or F 2 generation, Mendel repeatedly observed a phenotype ratio of three plants with the dominant phenotype to one plant with the recessive phenotype (3:1 phenotype ratio) in the F2 generation. Mendel predicted that the plants with a dominant phenotype in the F2 generation were of mixed genotypes with some being homozygous dominant genotype AA and others being heterozygous genotype Aa. In order to determine the genotypes of plants with dominant phenotypes in the F2 generation Mendel devised the test cross.

The test cross takes the organism with a dominant phenotype but unknown genotype and crosses it to a homozygous recessive individual with a known genotype aa. In a test cross with a plant of genotype AA all offspring will have the dominant phenotype and will have the heterozygous genotype Aa. However, if a plant with genotype Aa is used in a test cross, then the genotypes of 50% of the offspring will have the genotype Aa and display the dominant trait. The other 50% will be display the recessive phenotype since they will have the homozygous recessive genotype aa. Mendel's test cross method is still used today in breeding procedures with plants and animals in order to determine the genotype of plants with dominant phenotypes.

Synthesis and Evaluation of Novel Anticancer Compounds Derived from the Natural Product Brevilin A

Cancer is the second leading cause of death globally, responsible for an estimated 9.6 million deaths in 2018, and this burden continues to increase. Therefore, there is a clear and urgent need for novel drugs with increased efficacy for the treatment of different cancers. Previous research has demonstrated that brevilin A (BA) exerts anticancer activity in various cancers, including human multiple myeloma, breast cancer, lung cancer, and colon carcinoma, suggesting the anticancer potential present in the chemical scaffold of BA. Here, we designed and synthesized a small library of 12 novel BA derivatives and evaluated the biological anticancer effects of the compounds in various cancer cell lines. The results of this structure-activity relationship study demonstrated that BA derivatives BA-9 and BA-10 possessed significantly improved anticancer activity toward lung, colon, and breast cancer cell lines. BA-9 and BA-10 could more effectively reduce cancer cell viability and induce DNA damage, cell-cycle arrest, and apoptosis when compared with BA. Our findings represent a significant step forward in the development of novel anticancer entities.

Copyright © 2020 American Chemical Society.

Conflict of interest statement

The authors declare no competing financial interest.


Scheme 1. Synthesis of BA-18

Scheme 1. Synthesis of BA-18

Scheme 2. Synthesis of BA-912

Scheme 2. Synthesis of BA-912

BA analogue series. (A) Series…

BA analogue series. (A) Series 1: derivatives with A ring modifications (B) series…


With Anni we make available to the public a text mining methodology that we have successfully applied to several tasks: retrieving associations between genes, the functional annotation of genes, the functional annotation of the nucleolar proteome and the prediction of novel nucleolar proteins [18, 21, 22]. In this report Anni was applied to two very different use cases with good results: a new hypothesis on the progression of localized prostate cancer to metastatic disease and reproduction and extension of a previously published literature-based discovery. The tool has several innovative and useful features as described below.

Anni uses a concept-based approach. Definitions for the concepts are available in the application, as well as links to external databases and ontological information such as semantic type and 'parent/child' relations. In addition, when references to concepts are identified in texts, synonymous terms are mapped to the same concept. For this process, we pursued a high level of precision through a carefully curated ontology and by applying automatic homonym disambiguation (see [19] for a system description and performance evaluation). This is especially relevant for genes, as gene terminology is rich in synonymous and ambiguous terms [47, 48] and is also an important feature of information retrieval tools like iHop [49].

Anni can compare concepts based on similarities in the documents associated with these concepts therefore, implicit relations between concepts can be found. In addition, the user has complete control over which concepts are taken into account during the comparison. Combined, these features are very useful for knowledge discovery [8]. The approach also allows concepts to be included that are very hard to find in documents, such as GO codes, which are usually described with long, systematic terms.

Anni is a highly interactive application and offers a range of options to interactively explore the implicit and explicit associations between concepts. Query and match results can be viewed in a textual representation or in a graphical form through hierachically clustered heatmap or MDS projection visualizations. In addition, the tool provides a high level of transparency, which further improves its use.

Anni is a multi-purpose text-mining tool and the modular set-up and broad range of biomedical concepts allow many more tasks than the ones presented. The broad applicability of Anni 2.0 contrasts strongly with the majority of the previously published text-mining tools as well as with the earlier version of Anni. Text-mining tools tend to focus on one application, such as knowledge discovery [11, 50] or the analysis of DNA microarray data [16, 18, 20]. Arrowsmith [11], for example, can compare two document sets to each other at a time, which is well suited for knowledge discovery, but impractical when looking for associations between a group of genes. TXTgate [20] is well suited to explore indirect associations between genes, but is not suitable for knowledge discovery purposes, as it cannot compare genes to a set of diseases or drugs. To further illustrate this point, the table in Additional data file 1 provides a comparison of Anni 2.0 to 13 previously published tools.

The Anni system has some limitations. First of all, the system works with co-occurrence based associations. These associations may not always reflect functional relations or facts. In addition, Anni relies on an ontology and automatic concept recognition in texts and neither are error free. For these reasons Anni was built to be transparent and all results can be traced back to the underlying documents. Another limitation is that only genes from mouse, rat and human are covered support for other species is in development.

In conclusion, Anni provides an innovative ontology-based interface to the literature, and builds on advanced and well evaluated text-mining technology. Anni is a highly versatile tool, applicable to a broad range of tasks. It is freely available online [51].

Let me explain!

Let’s start from 1, doubled it is 2 2 doubled is 4 4 doubled is 8 8 doubled is 16 which means 1 + 6 and that equals to 7 16 doubled is 32 resulting in 3 + 2 equals 5 (you can do 7 doubled if you want to which you would get 14 resulting in 5) 32 doubled is 64 (5 doubled is 10) resulting in total of 1 If we continue we will keep following the same pattern: 1, 2, 4, 8, 7, 5, 1, 2…

If we start from 1 in reverse we will still get the same pattern only in reverse: Half of one is 0.5 (0+5) equaling 5. Half of 5 is 2.5 (2+5) equaling 7, and so on.

As you can see there is no mention of 3, 6, and 9! It’s like they are beyond this pattern, free from it.

However, there is something strange once you start doubling them. 3 doubled is 6 6 doubled is 12 which would result in 3 in this pattern there is no mention of 9! It’s like 9 is beyond, completely free from both patterns.

But if you start doubling 9 it will always result in 9: 18, 36, 72, 144, 288, 576…


The first descriptions of the MHC were made by British immunologist Peter Gorer in 1936. [7] MHC genes were first identified in inbred mice strains. Clarence Little transplanted tumors across differing strains and found rejection of transplanted tumors according to strains of host versus donor. [8] George Snell selectively bred two mouse strains, attained a new strain nearly identical to one of the progenitor strains, but differing crucially in histocompatibility—that is, tissue compatibility upon transplantation—and thereupon identified an MHC locus. [9] Later Jean Dausset demonstrated the existence of MHC genes in humans and described the first human leucocyte antigen, the protein which we call now HLA-A2. Some years later Baruj Benacerraf showed that polymorphic MHC genes not only determine an individual’s unique constitution of antigens but also regulate the interaction among the various cells of the immunological system. These three scientists have been awarded the 1980 Nobel Prize in Physiology or Medicine [10] for their discoveries concerning “genetically determined structures on the cell surface that regulate immunological reactions”.

The first fully sequenced and annotated MHC was published for humans in 1999 by a consortium of sequencing centers from the UK, USA and Japan in Nature. [11] It was a "virtual MHC" since it was a mosaic from different individuals. A much shorter MHC locus from chickens was published in the same issue of Nature. [12] Many other species have been sequenced and the evolution of the MHC was studied, e.g. in the gray short-tailed opossum (Monodelphis domestica), a marsupial, MHC spans 3.95 Mb, yielding 114 genes, 87 shared with humans. [13] Marsupial MHC genotypic variation lies between eutherian mammals and birds, taken as the minimal MHC encoding, but is closer in organization to that of nonmammals. The IPD-MHC Database [14] was created which provides a centralised repository for sequences of the Major Histocompatibility Complex (MHC) from a number of different species. The database contains 77 species for the release from 2019-12-19.

The MHC locus is present in all jawed vertebrates, it is assumed to have arisen about 450 million years ago. [15] Despite the difference in the number of genes included in the MHC of different species, the overall organization of the locus is rather similar. Usual MHC contains about a hundred genes and pseudogenes, not all of them are involved in immunity. In humans, the MHC region occurs on chromosome 6, between the flanking genetic markers MOG and COL11A2 (from 6p22.1 to 6p21.3 about 29Mb to 33Mb on the hg38 assembly), and contains 224 genes spanning 3.6 megabase pairs (3 600 000 bases). [11] About half have known immune functions. The human MHC is also called the HLA (human leukocyte antigen) complex (often just the HLA). Similarly, there is SLA (Swine leukocyte antigens), BoLA (Bovine leukocyte antigens), DLA for dogs, etc. However, historically, the MHC in mice is called the Histocompatibility system 2 or just the H-2, in rats - RT1, and in chicken - B-locus.

The MHC gene family is divided into three subgroups: MHC class I, MHC class II, and MHC class III. Among all those genes present in MHC, there are two types of genes coding for the proteins MHC class I molecules and MHC class II molecules that directly involved in the antigen presentation. These genes are highly polymorphic, 19031 alleles of class I HLA, and 7183 of class II HLA are deposited for human in the IMGT database. [16]

Class Encoding Expression
I (1) peptide-binding proteins, which select short sequences of amino acids for antigen presentation, as well as (2) molecules aiding antigen-processing (such as TAP and tapasin). One chain, called α, whose ligands are the CD8 receptor—borne notably by cytotoxic T cells—and inhibitory receptors borne by NK cells
II (1) peptide-binding proteins and (2) proteins assisting antigen loading onto MHC class II's peptide-binding proteins (such as MHC II DM, MHC II DQ, MHC II DR, and MHC II DP). Two chains, called α & β, whose ligands are the CD4 receptors borne by helper T cells.
III Other immune proteins, outside antigen processing and presentation, such as components of the complement cascade (e.g., C2, C4, factor B), the cytokines of immune signaling (e.g., TNF-α), and heat shock proteins buffering cells from stresses Various

MHC class I Edit

MHC class I molecules are expressed in all nucleated cells and also in platelets—in essence all cells but red blood cells. It presents epitopes to killer T cells, also called cytotoxic T lymphocytes (CTLs). A CTL expresses CD8 receptors, in addition to T-cell receptors (TCR)s. When a CTL's CD8 receptor docks to a MHC class I molecule, if the CTL's TCR fits the epitope within the MHC class I molecule, the CTL triggers the cell to undergo programmed cell death by apoptosis. Thus, MHC class I helps mediate cellular immunity, a primary means to address intracellular pathogens, such as viruses and some bacteria, including bacterial L forms, bacterial genus Mycoplasma, and bacterial genus Rickettsia. In humans, MHC class I comprises HLA-A, HLA-B, and HLA-C molecules.

The first crystal structure of Class I MHC molecule, human HLA-A2, was published in 1989. [17] The structure revealed that MHC-I molecules are heterodimers, they have polymorphic heavy α-subunit whose gene occurs inside the MHC locus and small invariant β2 microglobulin subunit whose gene is located usually outside of it. Polymorphic heavy chain of MHC-I molecule contains N-terminal extra-cellular region composed by three domains, α1, α2, and α3, transmembrane helix to hold MHC-I molecule on the cell surface and short cytoplasmic tail. Two domains, α1 and α2 form deep peptide-binding groove between two long α-helices and the floor of the groove formed by eight β-strands. Immunoglobulin-like domain α3 involved in the interaction with CD8 co-receptor. β2 microglobulin provides stability of the complex and participates in the recognition of peptide-MHC class I complex by CD8 co-receptor. [18] The peptide is non-covalently bound to MHC-I, it is held by the several pockets on the floor of the peptide-binding groove. Amino acid side-chains that are most polymorphic in human alleles fill up the central and widest portion of the binding groove, while conserved side-chains are clustered at the narrower ends of the groove.

Classical MHC molecules present epitopes to the TCRs of CD8+ T lymphocytes. Nonclassical molecules (MHC class IB) exhibit limited polymorphism, expression patterns, and presented antigens this group is subdivided into a group encoded within MHC loci (e.g., HLA-E, -F, -G), as well as those not (e.g., stress ligands such as ULBPs, Rae1, and H60) the antigen/ligand for many of these molecules remain unknown, but they can interact with each of CD8+ T cells, NKT cells, and NK cells. The evolutionary oldest nonclassical MHC class I lineage in human was deduced to be the lineage that includes the CD1 and PROCR (alias EPCR) molecules, and this lineage may have been established before the origin of tetrapod species. [19] However, the only nonclassical MHC class I lineage for which evidence exists that it was established before the evolutionary separation of Actinopterygii (ray-finned fish) and Sarcopterygii (lobe-finned fish plus tetrapods) is lineage Z of which members are found, together in each species with classical MHC class I, in lungfish and throughout ray-finned fishes [20] why the Z lineage was well conserved in ray-finned fish but lost in tetrapods is not understood.

MHC Class II Edit

MHC class II can be conditionally expressed by all cell types, but normally occurs only on "professional" antigen-presenting cells (APCs): macrophages, B cells, and especially dendritic cells (DCs). An APC takes up an antigenic protein, performs antigen processing, and returns a molecular fraction of it—a fraction termed the epitope—and displays it on the APC's surface coupled within an MHC class II molecule (antigen presentation). On the cell's surface, the epitope can be recognized by immunologic structures like T-cell receptors (TCRs). The molecular region which binds to the epitope is the paratope.

On surfaces of helper T cells are CD4 receptors, as well as TCRs. When a naive helper T cell's CD4 molecule docks to an APC's MHC class II molecule, its TCR can meet and bind the epitope coupled within the MHC class II. This event primes the naive T cell. According to the local milieu, that is, the balance of cytokines secreted by APCs in the microenvironment, the naive helper T cell (Th0) polarizes into either a memory Th cell or an effector Th cell of phenotype either type 1 (Th1), type 2 (Th2), type 17 (Th17), or regulatory/suppressor (Treg), as so far identified, the Th cell's terminal differentiation.

MHC class II thus mediates immunization to—or, if APCs polarize Th0 cells principally to Treg cells, immune tolerance of—an antigen. The polarization during primary exposure to an antigen is key in determining a number of chronic diseases, such as inflammatory bowel diseases and asthma, by skewing the immune response that memory Th cells coordinate when their memory recall is triggered upon secondary exposure to similar antigens. B cells express MHC class II to present antigens to Th0, but when their B cell receptors bind matching epitopes, interactions which are not mediated by MHC, these activated B cells secrete soluble immunoglobulins: antibody molecules mediating humoral immunity.

Class II MHC molecules are also heterodimers, genes for both α and β subunits are polymorphic and located within MHC class II subregion. Peptide-binding groove of MHC-II molecules is forms by N-terminal domains of both subunits of the heterodimer, α1 and β1, unlike MHC-I molecules, where two domains of the same chain are involved. In addition, both subunits of MHC-II contain transmembrane helix and immunoglobulin domains α2 or β2 that can be recognized by CD4 co-receptors. [21] In this way MHC molecules chaperone which type of lymphocytes may bind to the given antigen with high affinity, since different lymphocytes express different T-Cell Receptor (TCR) co-receptors.

MHC class II molecules in humans have five to six isotypes. Classical molecules present peptides to CD4+ lymphocytes. Nonclassical molecules, accessories, with intracellular functions, are not exposed on cell membranes, but in internal membranes, assisting with the loading of antigenic peptides onto classic MHC class II molecules. The important nonclassical MHC class II molecule DM is only found from the evolutionary level of lungfish, [22] although also in more primitive fishes both classical and nonclassical MHC class II are found. [23] [24]

β2 chain (12 KDa in humans)

β chain (26-29 KDa in humans)

helices, blocked at both the ends

helices, opened at both the ends

Class III Edit

Class III molecules have physiologic roles unlike classes I and II, but are encoded between them in the short arm of human chromosome 6. Class III molecules include several secreted proteins with immune functions: components of the complement system (such as C2, C4, and B factor), cytokines (such as TNF-α, LTA, and LTB), and heat shock proteins.

Function Edit

MHC is the tissue-antigen that allows the immune system (more specifically T cells) to bind to, recognize, and tolerate itself (autorecognition). MHC is also the chaperone for intracellular peptides that are complexed with MHCs and presented to T cell receptors (TCRs) as potential foreign antigens. MHC interacts with TCR and its co-receptors to optimize binding conditions for the TCR-antigen interaction, in terms of antigen binding affinity and specificity, and signal transduction effectiveness.

Essentially, the MHC-peptide complex is a complex of auto-antigen/allo-antigen. Upon binding, T cells should in principle tolerate the auto-antigen, but activate when exposed to the allo-antigen. Disease states occur when this principle is disrupted.

Antigen presentation: MHC molecules bind to both T cell receptor and CD4/CD8 co-receptors on T lymphocytes, and the antigen epitope held in the peptide-binding groove of the MHC molecule interacts with the variable Ig-Like domain of the TCR to trigger T-cell activation [26]

Autoimmune reaction: Having some MHC molecules increases the risk of autoimmune diseases more than having others. HLA-B27 is an example. It is unclear how exactly having the HLA-B27 tissue type increases the risk of ankylosing spondylitis and other associated inflammatory diseases, but mechanisms involving aberrant antigen presentation or T cell activation have been hypothesized.

Tissue allorecognition: MHC molecules in complex with peptide epitopes are essentially ligands for TCRs. T cells become activated by binding to the peptide-binding grooves of any MHC molecule that they were not trained to recognize during positive selection in the thymus.

Peptides are processed and presented by two classical pathways:

  • In MHC class II, phagocytes such as macrophages and immature dendritic cells take up entities by phagocytosis into phagosomes—though B cells exhibit the more general endocytosis into endosomes—which fuse with lysosomes whose acidic enzymes cleave the uptaken protein into many different peptides. Via physicochemical dynamics in molecular interaction with the particular MHC class II variants borne by the host, encoded in the host's genome, a particular peptide exhibits immunodominance and loads onto MHC class II molecules. These are trafficked to and externalized on the cell surface. [27]
  • In MHC class I, any nucleated cell normally presents cytosolic peptides, mostly self peptides derived from protein turnover and defective ribosomal products. During viral infection, intracellular microorganism infection, or cancerous transformation, such proteins degraded in the proteosome are as well loaded onto MHC class I molecules and displayed on the cell surface. T lymphocytes can detect a peptide displayed at 0.1%-1% of the MHC molecules.
Table 2. Characteristics of the antigen processing pathways
Characteristic MHC-I pathway MHC-II pathway
Composition of the stable peptide-MHC complex Polymorphic chain α and β2 microglobulin, peptide bound to α chain Polymorphic chains α and β, peptide binds to both
Types of antigen-presenting cells (APC) All nucleated cells Dendritic cells, mononuclear phagocytes, B lymphocytes, some endothelial cells, epithelium of thymus
T lymphocytes able to respond Cytotoxic T lymphocytes (CD8+) Helper T lymphocytes (CD4+)
Origin of antigenic proteins cytosolic proteins (mostly synthetized by the cell may also enter from the extracellular medium via phagosomes) Proteins present in endosomes or lysosomes (mostly internalized from extracellular medium)
Enzymes responsible for peptide generation Cytosolic proteasome Proteases from endosomes and lysosomes (for instance, cathepsin)
Location of loading the peptide on the MHC molecule Endoplasmic reticulum Specialized vesicular compartment
Molecules implicated in transporting the peptides and loading them on the MHC molecules TAP (transporter associated with antigen processing) DM, invariant chain

In their development in the thymus, T lymphocytes are selected to recognize MHC molecules of the host, but not recognize other self antigens. Following selection, each T lymphocyte shows dual specificity: The TCR recognizes self MHC, but only non-self antigens.

MHC restriction occurs during lymphocyte development in the thymus through a process known as positive selection. T cells that do not receive a positive survival signal — mediated mainly by thymic epithelial cells presenting self peptides bound to MHC molecules — to their TCR undergo apoptosis. Positive selection ensures that mature T cells can functionally recognize MHC molecules in the periphery (i.e. elsewhere in the body).

The TCRs of T lymphocytes recognise only sequential epitopes, also called linear epitopes, of only peptides and only if coupled within an MHC molecule. (Antibody molecules secreted by activated B cells, though, recognize diverse epitopes—peptide, lipid, carbohydrate, and nucleic acid—and recognize conformational epitopes, which have three-dimensional structure.)

MHC molecules enable immune system surveillance of the population of protein molecules in a host cell, and greater MHC diversity permits greater diversity of antigen presentation. In 1976, Yamazaki et al demonstrated a sexual selection mate choice by male mice for females of a different MHC. Similar results have been obtained with fish. [29] Some data find lower rates of early pregnancy loss in human couples of dissimilar MHC genes. [30]

MHC may be related to mate choice in some human populations, a theory that found support by studies by Ober and colleagues in 1997, [31] as well as by Chaix and colleagues in 2008. [32] However, the latter findings have been controversial. [33] If it exists, the phenomenon might be mediated by olfaction, as MHC phenotype appears strongly involved in the strength and pleasantness of perceived odour of compounds from sweat. Fatty acid esters—such as methyl undecanoate, methyl decanoate, methyl nonanoate, methyl octanoate, and methyl hexanoate—show strong connection to MHC. [34]

In 1995, Claus Wedekind found that in a group of female college students who smelled T-shirts worn by male students for two nights (without deodorant, cologne, or scented soaps), by far most women chose shirts worn by men of dissimilar MHCs, a preference reversed if the women were on oral contraceptives. [35] Results of a 2002 experiment likewise suggest HLA-associated odors influence odor preference and may mediate social cues. [36] In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs like their own, [37] although with oral contraceptives, the women showed no particular preference. [38] No studies show the extent to which odor preference determines mate selection (or vice versa).

Most mammals have MHC variants similar to those of humans, who bear great allelic diversity, especially among the nine classical genes—seemingly due largely to gene duplication—though human MHC regions have many pseudogenes. [39] The most diverse loci, namely HLA-A, HLA-B, and HLA-C, have roughly 6000, 7200, and 5800 known alleles, respectively. [40] Many HLA alleles are ancient, sometimes of closer homology to a chimpanzee MHC alleles than to some other human alleles of the same gene.

MHC allelic diversity has challenged evolutionary biologists for explanation. Most posit balancing selection (see polymorphism (biology)), which is any natural selection process whereby no single allele is absolutely most fit, such as frequency-dependent selection [41] and heterozygote advantage. Pathogenic coevolution, as a type of balancing selection, posits that common alleles are under greatest pathogenic pressure, driving positive selection of uncommon alleles—moving targets, so to say, for pathogens. As pathogenic pressure on the previously common alleles decreases, their frequency in the population stabilizes, and remain circulating in a large population. [42] Genetic drift is also a major driving force in some species. [43] [44] It is possible that the combined effects of some or all of these factors cause the genetic diversity. [45]

MHC diversity has also been suggested as a possible indicator for conservation, because large, stable populations tend to display greater MHC diversity, than smaller, isolated populations. [46] [47] Small, fragmented populations that have experienced a population bottleneck typically have lower MHC diversity. For example, relatively low MHC diversity has been observed in the cheetah (Acinonyx jubatus), [48] Eurasian beaver (Castor fiber), [49] and giant panda (Ailuropoda melanoleuca). [50] In 2007 low MHC diversity was attributed a role in disease susceptibility in the Tasmanian devil (Sarcophilus harrisii), native to the isolated island of Tasmania, such that an antigen of a transmissible tumor, involved in devil facial tumour disease, appears to be recognized as a self antigen. [51] To offset inbreeding, efforts to sustain genetic diversity in populations of endangered species and of captive animals have been suggested.

In ray-finned fish like rainbow trout, allelic polymorphism in MHC class II is reminiscent of that in mammals and predominantly maps to the peptide binding groove. [52] However, in MHC class I of many teleost fishes, the allelic polymorphism is much more extreme than in mammals in the sense that the sequence identity levels between alleles can be very low and the variation extends far beyond the peptide binding groove. [52] [53] [20] It has been speculated that this type of MHC class I allelic variation contributes to allograft rejection, which may be especially important in fish to avoid grafting of cancer cells through their mucosal skin. [54]

The MHC locus (6p21.3) has 3 other paralogous loci in the human genome, namely 19pl3.1, 9q33-q34, and 1q21-q25. It is believed that the loci arouse from the two-round duplications in vertebrates of a single ProtoMHC locus, and the new domain organizations of the MHC genes were a result of later cis-duplication and exon shuffling in a process termed "the MHC Big Bang." [55] Genes in this locus are apparently linked to intracellular intrinsic immunity in the basal Metazoan Trichoplax adhaerens. [56]

In a transplant procedure, as of an organ or stem cells, MHC molecules themselves act as antigens and can provoke immune response in the recipient, thus causing transplant rejection. MHC molecules were identified and named after their role in transplant rejection between mice of different strains, though it took over 20 years to clarify MHC's role in presenting peptide antigens to cytotoxic T lymphocytes (CTLs). [57]

Each human cell expresses six MHC class I alleles (one HLA-A, -B, and -C allele from each parent) and six to eight MHC class II alleles (one HLA-DP and -DQ, and one or two HLA-DR from each parent, and combinations of these). The MHC variation in the human population is high, at least 350 alleles for HLA-A genes, 620 alleles for HLA-B, 400 alleles for DR, and 90 alleles for DQ. Any two individuals who are not identical twins will express differing MHC molecules. All MHC molecules can mediate transplant rejection, but HLA-C and HLA-DP, showing low polymorphism, seem least important. [ clarification needed ]

When maturing in the thymus, T lymphocytes are selected for their TCR incapacity to recognize self antigens, yet T lymphocytes can react against the donor MHC's peptide-binding groove, the variable region of MHC holding the presented antigen's epitope for recognition by TCR, the matching paratope. T lymphocytes of the recipient take the incompatible peptide-binding groove as nonself antigen. [ clarification needed ]

Transplant rejection has various types known to be mediated by MHC (HLA):

  • Hyperacute rejection occurs when, before the transplantation, the recipient has preformed anti-HLA antibodies, perhaps by previous blood transfusions (donor tissue that includes lymphocytes expressing HLA molecules), by anti-HLA generated during pregnancy (directed at the father's HLA displayed by the fetus), or by previous transplantation
  • Acute cellular rejection occurs when the recipient's T lymphocytes are activated by the donor tissue, causing damage via mechanisms such as direct cytotoxicity from CD8 cells.
  • Acute humoral rejection and chronic disfunction occurs when the recipient's anti-HLA antibodies form directed at HLA molecules present on endothelial cells of the transplanted tissue.

In all of the above situations, immunity is directed at the transplanted organ, sustaining lesions. A cross-reaction test between potential donor cells and recipient serum seeks to detect presence of preformed anti-HLA antibodies in the potential recipient that recognize donor HLA molecules, so as to prevent hyperacute rejection. In normal circumstances, compatibility between HLA-A, -B, and -DR molecules is assessed. The higher the number of incompatibilities, the lower the five-year survival rate. Global databases of donor information enhance the search for compatible donors.

The involvement in allogeneic transplant rejection appears to be an ancient feature of MHC molecules, because also in fish associations between transplant rejections and (mis-)matching of MHC class I [58] [59] and MHC class II [60] were observed.

Human MHC class I and II are also called human leukocyte antigen (HLA). To clarify the usage, some of the biomedical literature uses HLA to refer specifically to the HLA protein molecules and reserves MHC for the region of the genome that encodes for this molecule, but this is not a consistent convention.

The most studied HLA genes are the nine classical MHC genes: HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. In humans, the MHC gene cluster is divided into three regions: classes I, II, and III. The A, B and C genes belong to MHC class I, whereas the six D genes belong to class II.

MHC alleles are expressed in codominant fashion. [61] This means the alleles (variants) inherited from both parents are expressed equally:

  • Each person carries 2 alleles of each of the 3 class-I genes, (HLA-A, HLA-B and HLA-C), and so can express six different types of MHC-I (see figure).
  • In the class-II locus, each person inherits a pair of HLA-DP genes (DPA1 and DPB1, which encode α and β chains), a couple of genes HLA-DQ (DQA1 and DQB1, for α and β chains), one gene HLA-DRα (DRA1), and one or more genes HLA-DRβ (DRB1 and DRB3, -4 or -5). That means that one heterozygous individual can inherit six or eight functioning class-II alleles, three or more from each parent. The role of DQA2 or DQB2 is not verified. The DRB2, DRB6, DRB7, DRB8 and DRB9 are pseudogenes.

The set of alleles that is present in each chromosome is called the MHC haplotype. In humans, each HLA allele is named with a number. For instance, for a given individual, his haplotype might be HLA-A2, HLA-B5, HLA-DR3, etc. Each heterozygous individual will have two MHC haplotypes, one each from the paternal and maternal chromosomes.

The MHC genes are highly polymorphic many different alleles exist in the different individuals inside a population. The polymorphism is so high, in a mixed population (nonendogamic), no two individuals have exactly the same set of MHC molecules, with the exception of identical twins.

The polymorphic regions in each allele are located in the region for peptide contact. Of all the peptides that could be displayed by MHC, only a subset will bind strongly enough to any given HLA allele, so by carrying two alleles for each gene, each encoding specificity for unique antigens, a much larger set of peptides can be presented.

On the other hand, inside a population, the presence of many different alleles ensures there will always be an individual with a specific MHC molecule able to load the correct peptide to recognize a specific microbe. The evolution of the MHC polymorphism ensures that a population will not succumb to a new pathogen or a mutated one, because at least some individuals will be able to develop an adequate immune response to win over the pathogen. The variations in the MHC molecules (responsible for the polymorphism) are the result of the inheritance of different MHC molecules, and they are not induced by recombination, as it is the case for the antigen receptors.

Because of the high levels of allelic diversity found within its genes, MHC has also attracted the attention of many evolutionary biologists. [62]

9.6: Subviral Entities - Biology

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Chapter Summary

Cells communicate by both inter- and intracellular signaling. Signaling cells secrete ligands that bind to target cells and initiate a chain of events within the target cell. The four categories of signaling in multicellular organisms are paracrine signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions. Paracrine signaling takes place over short distances. Endocrine signals are carried long distances through the bloodstream by hormones, and autocrine signals are received by the same cell that sent the signal or other nearby cells of the same kind. Gap junctions allow small molecules, including signaling molecules, to flow between neighboring cells.

Internal receptors are found in the cell cytoplasm. Here, they bind ligand molecules that cross the plasma membrane these receptor-ligand complexes move to the nucleus and interact directly with cellular DNA. Cell-surface receptors transmit a signal from outside the cell to the cytoplasm. Ion channel-linked receptors, when bound to their ligands, form a pore through the plasma membrane through which certain ions can pass. G-protein-linked receptors interact with a G-protein on the cytoplasmic side of the plasma membrane, promoting the exchange of bound GDP for GTP and interacting with other enzymes or ion channels to transmit a signal. Enzyme-linked receptors transmit a signal from outside the cell to an intracellular domain of a membrane-bound enzyme. Ligand binding causes activation of the enzyme. Small hydrophobic ligands (like steroids) are able to penetrate the plasma membrane and bind to internal receptors. Water-soluble hydrophilic ligands are unable to pass through the membrane instead, they bind to cell-surface receptors, which transmit the signal to the inside of the cell.

9.2 Propagation of the Signal

Ligand binding to the receptor allows for signal transduction through the cell. The chain of events that conveys the signal through the cell is called a signaling pathway or cascade. Signaling pathways are often very complex because of the interplay between different proteins. A major component of cell signaling cascades is the phosphorylation of molecules by enzymes known as kinases. Phosphorylation adds a phosphate group to serine, threonine, and tyrosine residues in a protein, changing their shapes, and activating or inactivating the protein. Small molecules like nucleotides can also be phosphorylated. Second messengers are small, non-protein molecules that are used to transmit a signal within a cell. Some examples of second messengers are calcium ions (Ca 2+ ), cyclic AMP (cAMP), diacylglycerol (DAG), and inositol triphosphate (IP3).

9.3 Response to the Signal

The initiation of a signaling pathway is a response to external stimuli. This response can take many different forms, including protein synthesis, a change in the cell’s metabolism, cell growth, or even cell death. Many pathways influence the cell by initiating gene expression, and the methods utilized are quite numerous. Some pathways activate enzymes that interact with DNA transcription factors. Others modify proteins and induce them to change their location in the cell. Depending on the status of the organism, cells can respond by storing energy as glycogen or fat, or making it available in the form of glucose. A signal transduction pathway allows muscle cells to respond to immediate requirements for energy in the form of glucose. Cell growth is almost always stimulated by external signals called growth factors. Uncontrolled cell growth leads to cancer, and mutations in the genes encoding protein components of signaling pathways are often found in tumor cells. Programmed cell death, or apoptosis, is important for removing damaged or unnecessary cells. The use of cellular signaling to organize the dismantling of a cell ensures that harmful molecules from the cytoplasm are not released into the spaces between cells, as they are in uncontrolled death, necrosis. Apoptosis also ensures the efficient recycling of the components of the dead cell. Termination of the cellular signaling cascade is very important so that the response to a signal is appropriate in both timing and intensity. Degradation of signaling molecules and dephosphorylation of phosphorylated intermediates of the pathway by phosphatases are two ways to terminate signals within the cell.

9.4 Signaling in Single-Celled Organisms

Yeasts and multicellular organisms have similar signaling mechanisms. Yeasts use cell-surface receptors and signaling cascades to communicate information on mating with other yeast cells. The signaling molecule secreted by yeasts is called mating factor.

Bacterial signaling is called quorum sensing. Bacteria secrete signaling molecules called autoinducers that are either small, hydrophobic molecules or peptide-based signals. The hydrophobic autoinducers, such as AHL, bind transcription factors and directly affect gene expression. The peptide-based molecules bind kinases and initiate signaling cascades in the cells.

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