Major histocompatibility complex

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Histocompatibility molecule
)
Major histocompatibility complex molecule
Major histocompatibility complex protein (class I) in orange and pink, with a presented peptide in red. Membrane in grey. The transmembrane and cytoplasmic domains are shown in cartoon form. (PDB: 1hsa​)
Identifiers
SymbolHLA
InterProIPR001039
Membranome63

The major histocompatibility complex (MHC) is a large

polymorphic genes that code for cell surface proteins essential for the adaptive immune system
. These cell surface proteins are called MHC molecules.

The name of this locus comes from its discovery through the study of transplanted tissue compatibility.

organ transplant, as well as one's susceptibility to autoimmune diseases
.

In a cell, protein molecules of the host's own phenotype or of other biologic entities are continually synthesized and degraded. Each MHC molecule on the cell surface displays a small peptide (a molecular fraction of a protein) called an epitope.[3] The presented self-antigens prevent an organism's immune system from targeting its own cells. The presentation of pathogen-derived proteins results in the elimination of the infected cell by the immune system.

Diversity of an individual's

gene variants are highly polymorphic (diversely varying from organism to organism within a species).[4] Sexual selection has been observed in male mice choosing to mate with females with different MHCs.[5] Also, at least for MHC I presentation, there has been evidence of antigenic peptide splicing, which can combine peptides from different proteins, vastly increasing antigen diversity.[6]

Discovery

The first descriptions of the MHC were made by British

Clarence Little transplanted tumors across different 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.

mammals. 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.

Genes

The MHC locus is present in all

base 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.[citation needed
]

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 are 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 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
heat shock proteins
buffering cells from stresses 		Various

Proteins

MHC-II

MHC class I

Main article: MHC class I

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.[citation needed
]

The first crystal structure of Class I MHC molecule, human HLA-A2, was published in 1989.

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.

Schematic view of MHC class I and MHC class II molecules

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

Main article: MHC class II

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

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,

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]

Sr.No Feature[25] Class I MHC Class II MHC
1 Constituting polypeptide chains α chain (45KDa in humans)

β2 chain (12 KDa in humans)

α chain (30–34 KDa in humans)

β chain (26–29 KDa in humans)

2 Antigen binding domain α1and α2 domains α1 and β1 domains
3 Binds protein antigens of 8–10 amino acids residues 13–18 amino acids residues
4 Peptide bending cleft Floor formed by β sheets and sides by α

helices, blocked at both the ends

Floor formed by β sheets and sides by α

helices, opened at both the ends

5 Antigenic peptide motifs

involved in binding

Anchor residues located at amino and

carbon terminal ends

Anchor residues located almost uniformly

along the peptide

6 Presents antigenic peptide to CD8+ T cells CD4+ T cells

MHC class III

Main article: MHC class III

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

TNF-α, LTA, and LTB), and heat shock proteins
.

Function

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.

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.

Antigen processing and presentation

MHC class I pathway: Proteins in the cytosol are degraded by the proteasome, liberating peptides internalized by TAP channel in the endoplasmic reticulum, there associating with MHC-I molecules freshly synthesized. MHC-I/peptide complexes enter Golgi apparatus, are glycosylated, enter secretory vesicles, fuse with the cell membrane, and externalize on the cell membrane interacting with T lymphocytes.

Peptides are processed and presented by two classical pathways:

Peptide binding for Class I and Class II MHC molecules, showing the binding of peptides between the alpha-helix walls, upon a beta-sheet base. The difference in binding positions is shown. Class I primarily makes contact with backbone residues at the Carboxy and amino terminal regions, while Class II primarily makes contacts along the length of the residue backbone. The precise location of binding residues is determined by the MHC allele.[28]
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
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 synthesized 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

T lymphocyte recognition restrictions

Main article: MHC restriction

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

three-dimensional
structure.)

In sexual mate selection

Main article: Major histocompatibility complex and sexual selection
See also: Interpersonal compatibility

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,

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] In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs like their own,[36] although with oral contraceptives, the women showed no particular preference.[37] No studies show the extent to which odor preference determines mate selection (or vice versa).

Evolutionary diversity

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.[38] The most diverse loci, namely HLA-A, HLA-B, and HLA-C, have roughly 6000, 7200, and 5800 known alleles, respectively.[39] 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[40] 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.[41] Genetic drift is also a major driving force in some species.[42][43] It is possible that the combined effects of some or all of these factors cause the genetic diversity.[44]

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.[45][46] 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),[47] Eurasian beaver (Castor fiber),[48] and giant panda (Ailuropoda melanoleuca).[49] 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.[50] 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.[51] 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.[51][52][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.[53]

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

Trichoplax adhaerens.[55]

In transplant rejection

In a transplant procedure, as of an organ or

cytotoxic T lymphocytes (CTLs).[56]

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, triplets, or higher order multiple births, 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[57][58] and MHC class II[59] were observed.

HLA biology

Codominant expression of HLA genes
Main article: Human leukocyte antigen

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-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.[60] 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.[61]

See also

Notes and references

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  3. ^ Kimball JW (11 February 2011). "Histocompatibility Molecules". Kimball's Biology Pages. Archived from the original on 4 February 2016.
  4. ^ Janeway Jr CA, Travers P, Walport M, et al. (2001). "The major histocompatibility complex and its functions". Immunobiology: The Immune System in Health and Disease (5th ed.). New York: Garland Science.
  5. PMID 1032893
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  6. S2CID 33796351
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  7. S2CID 28211127
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  8. ^ Little CC 1941, "The genetics of tumor transplantation", pp 279–309, in Biology of the Laboratory Mouse, ed by Snell GD, New York: Dover.
  9. PMID 14840651
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  10. ^ "The Nobel Prize in Physiology or Medicine 1980". 10 October 1980. The Nobel Assembly of Karolinska Institutet has decided today to award the Nobel Prize in Physiology or Medicine for 1980 jointly to Baruj Benacerraf, Jean Dausset and George Snell
  11. ^
    S2CID 186243515
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  12. S2CID 4387040
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  13. PMID 16435885
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  14. ^ "IPD-MHC Database". EMBL-EBI.
  15. S2CID 41765680
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  16. ^ "The International ImMunoGeneTics Information System". Archived from the original on 2012-07-17. Retrieved 2020-03-11.
  17. PMID 2038058
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  18. S2CID 4267617
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  19. S2CID 24591879
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  20. ^
    PMID 25888517
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  21. PMID 21900604
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  22. S2CID 53110357
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  23. PMID 24279922
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  24. PMID 33126081
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  25. OCLC 276274663
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  26. ISBN 978-1-4292-0211-4
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  27. S2CID 234948691
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  28. ^ Murphy (2012). "Antigen recognition by T cells". Janeway's Immunobiology (8th ed.). Garland Science. pp. 138–153.
  29. S2CID 15621496
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  30. PMID 9421795
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  31. PMID 9326314
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  32. PMID 18787687
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  33. PMID 20442868
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  34. doi:10.2478/s11535-010-0020-6
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  35. S2CID 34971350
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  36. S2CID 8568275
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  37. ^ Bryner J (12 August 2008). "The pill makes women pick bad mates". Live Science. Future US Inc.
  38. PMID 32375397
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  39. ^ "HLA Alleles Numbers". hla.alleles.org.
  40. PMID 18986972
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  41. PMID 30703088
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  42. PMID 24937211
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  43. PMID 28806900
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  44. PMID 29773018
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  45. PMID 16242022
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  46. PMID 31380027
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  47. PMID 21183613
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  48. S2CID 22260395
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  49. PMID 17555583
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  50. PMID 17911263
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  51. ^
    S2CID 5725603
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  52. S2CID 36838421
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  53. PMID 31027287
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  54. S2CID 29886370
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  55. PMID 25114105
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  56. ISBN 978-1-4160-4688-2
    .
  57. S2CID 21437633
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  58. PMID 15707666
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  59. PMID 11535641
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  60. ISBN 978-1-4160-4688-2
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Bibliography

External links
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