Eutherian fetoembryonic defense system hypothesis

Last updated

The eutherian fetoembryonic defense system (eu-FEDS) is a hypothetical model describing a method by which immune systems are capable of recognizing additional states of relatedness like "own species" such as is observed in maternal immune tolerance in pregnancy. The model includes descriptions of the proposed signaling mechanism and several proposed examples of exploitation of this signaling in disease states.

Contents

Background

The concept of immunity refers to an organism's ability to respond to various foreign intrusions (as occurs in infection). A basic requirement in such a system is the ability to avoid self-harm through some mechanism of recognizing "self". In classic immunity several types of molecules label the organism's own cells as "self". Cells labelled in this manner are tolerated and not damaged by the various defense mechanisms employed to protect against infection. Dysregulation of this system is responsible for several types of disease states known collectively as autoimmune disorders.

The term Eutheria is a taxon describing placental organisms such as mammals. The sister group of Eutheria is Metatheria, which includes marsupials and their extinct relatives.

The term eu-FEDS was first described in 1997 by Gary F. Clark et al. [1] as "the human fetoembryonic defense system", and later renamed to apply more broadly to all members of the taxon Eutheria. In 1949 Frank Burnet, and later in 1953 Peter Medawar, observed that the developing fetus was, in fact, similar to a transplanted "foreign" organ, because of the father's contribution to its genome. [2] In 1960, Medawar and Burnet were awarded the Nobel Prize in part for their early contributions and discoveries related to understanding the necessity for the development of tolerance to the developing eutherian. It is now apparent that a human fetus is tolerated by its birth mother, even when it is completely unrelated. These observations were made following the introduction of modern assisted reproduction technologies involving unrelated donor eggs and the use of in vitro fertilization (IVF). [3] The eu-FEDS hypothesis was itself proposed to describe the precise immunological mechanisms that mediate protection of the developing eutherian fetus from the immune responses of its mother.

Hypothesis

The basic premise of the eu-FEDS hypothesis is that both soluble and cell surface associated glycoproteins, present in the reproductive system and expressed on gametes, suppress any potential immune responses, and inhibit rejection of the fetus. [1] The eu-FEDS model further suggests that specific carbohydrate sequences (oligosaccharides) are covalently linked to these immunosuppressive glycoproteins and act as "functional groups" that suppress the immune response. The major uterine and fetal glycoproteins that are associated with the eu-FEDS model in the human include alpha-fetoprotein, CA125, and glycodelin-A (also known as placental protein 14 (PP14)).

Normally, a low level of these glycoproteins is detected in the maternal serum during the early stages of pregnancy. It appears that the effects of these eu-FEDS associated glycoproteins are manifested only during implantation and the very early development of the embryo. In humans, the expression of such glycoproteins greatly decreases toward the end of the first trimester. Therefore, more highly targeted mechanisms of immune suppression, such as the expression of the enzyme indoleamine dioxygenase (IDO), are likely employed by the fetus during the subsequent stages of development. One potential reason for early inactivation of the system is that the immunosuppressive effect of these glycoproteins may be so complete that their continued leakage into the circulatory system could lead to a global suppression of the maternal immune response, compromising the mother's ability to carry the fetus to term.

Implications of the hypothesis

Human sperm and eggs also lack molecules for the immune recognition of "self". [4] These immune markers are also known as major histocompatibility complex (MHC) antigens or more specifically in humans as human leukocyte antigens (HLA)). [5] [6] Therefore, a major question is how are human gametes recognized by immune effector cells. Specifically, their lack of MHC recognition markers should trigger the immune system, resulting in lysis of both sperm and eggs by leukocytes known as natural killer, or NK cells. These cells target and kill other cells lacking such MHC markers, a concept known as "missing self". [7] One distinct possibility is that sperm and eggs are recognized via oligosaccharides expressed on their surfaces. For example, human gametes are coated with carbohydrate sequences that have been implicated in the suppression of NK cell mediated responses. [8]

One of the major corollaries of the eu-FEDS hypothesis is that persistent pathogens and aggressive tumor cells are able to either mimic or acquire the same carbohydrate functional groups used to suppress any immune response that could interfere with the reproductive imperative, thus enabling them to similarly resist the human immune response. [9] These pathogens include HIV-1, helminthic parasites such as schistosomes, and Helicobacter pylori, the bacterium that causes stomach ulcers.

There are some notable examples of this mimicry or acquisition of the same carbohydrate sequences implicated in this protective system by pathogens and aggressive tumor cells. The major carbohydrate sequence linked to glycodelin-A also profusely coats the surface of schistosomes. [10] The profile of the major oligosaccharides linked to CA125 and the major surface glycoprotein of HIV-1 (gp120) almost perfectly overlap. [11] More persistent pathogens linked to the eu-FEDS model may be identified as mass spectrometry methods for sequencing oligosaccharides become more sensitive.

Other experimental models

Several other models have been developed that seek to address this hypothetical system for immune tolerance, including the depletion of tryptophan via the enzyme indoleamine dioxygenase (IDO) [12] and the expression of the nonclassical MHC class I molecule designated HLA-G. [13] However, genetic deletion of IDO in female mice does not lead to the rejection of their foreign fetal offspring, [14] indicating that a redundant system for the suppression of the mother's immune response exists in the uterus during pregnancy. In addition, HLA-G expresses oligosaccharides that are very different from those linked to other HLA class I molecules, [15] [16] so the possibility exists that HLA-G at the fetomaternal interface is itself employing its unusual carbohydrate sequences as functional groups to suppress the mother's immune response.

See also

Related Research Articles

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

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

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically they cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. Superantigens act by binding to the MHC proteins on antigen-presenting cells (APCs) and to the TCRs on their adjacent helper T-cells, bringing the signaling molecules together, and thus leading to the activation of the T-cells, regardless of the peptide displayed on the MHC molecule. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

<span class="mw-page-title-main">HLA-DR</span> Subclass of HLA-D antigens that consist of alpha and beta chains

HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR and peptide, generally between 9 and 30 amino acids in length, constitutes a ligand for the T-cell receptor (TCR). HLA were originally defined as cell surface antigens that mediate graft-versus-host disease. Identification of these antigens has led to greater success and longevity in organ transplant.

<span class="mw-page-title-main">HLA-DRA</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DR alpha chain is a protein that in humans is encoded by the HLA-DRA gene. HLA-DRA encodes the alpha subunit of HLA-DR. Unlike the alpha chains of other Human MHC class II molecules, the alpha subunit is practically invariable. However it can pair with, in any individual, the beta chain from 3 different DR beta loci, DRB1, and two of any DRB3, DRB4, or DRB5 alleles. Thus there is the potential that any given individual can form 4 different HLA-DR isoforms.

Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. At least 15 genes and 2 pseudogenes encoding KIR map in a 150-kb region of the leukocyte receptor complex (LRC) on human chromosome 19q13.4.

<span class="mw-page-title-main">Minor histocompatibility antigen</span>

Minor histocompatibility antigen are peptides presented on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.

<span class="mw-page-title-main">HLA-DRB3</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DRB3-1 beta chain is a protein that in humans is encoded by the HLA-DRB3 gene.

<span class="mw-page-title-main">HLA-DMB</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DM beta chain is a protein that in humans is encoded by the HLA-DMB gene.

<span class="mw-page-title-main">HLA-DMA</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DM alpha chain is a protein that in humans is encoded by the HLA-DMA gene.

<span class="mw-page-title-main">KIR2DL1</span> Protein-coding gene in the species Homo sapiens

Killer cell immunoglobulin-like receptor 2DL1 is a protein that in humans is encoded by the KIR2DL1 gene.

<span class="mw-page-title-main">KIR2DL4</span> Protein-coding gene in the species Homo sapiens

Killer cell immunoglobulin-like receptor 2DL4 is a protein that in humans is encoded by the KIR2DL4 gene.

<span class="mw-page-title-main">Pregnancy-specific beta-1-glycoprotein 1</span> Mammalian protein found in Homo sapiens

Pregnancy-specific beta-1-glycoprotein 1 (PSBG-1) also known as CD66f, is a protein that in humans is encoded by the PSG1 gene and is a member of the carcinoembryonic antigen (CEA) gene family. Pregnancy-specific glycoproteins (PSGs) are a complex consisting of carbohydrate and protein, which is present in the mammalian body specifically during pregnancy. This glycoprotein is the most abundant protein found in the maternal bloodstream during the later stages of pregnancy and it is of vital importance in fetal development. The PSG functions primarily as an immunomodulator to protect the growing fetus.

<span class="mw-page-title-main">HLA-DOA</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DO alpha chain is a protein that in humans is encoded by the HLA-DOA gene.

<span class="mw-page-title-main">HLA-DOB</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DO beta chain is a protein that in humans is encoded by the HLA-DOB gene.

<span class="mw-page-title-main">HLA-DQA2</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DQ(6) alpha chain is a protein that in humans is encoded by the HLA-DQA2 gene. Also known as HLA-DXA or DAAP-381D23.2, it is part of the human leucocyte antigen system.

<span class="mw-page-title-main">CD160</span> Protein-coding gene in the species Homo sapiens

CD160 antigen is a protein that in humans is encoded by the CD160 gene.

<span class="mw-page-title-main">HLA-DQB2</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DX beta chain is a protein that in humans is encoded by the HLA-DQB2 gene.

<span class="mw-page-title-main">CD8A</span> Protein-coding gene in the species Homo sapiens

CD8a, is a human gene.

Immune tolerance in pregnancy or maternal immune tolerance is the immune tolerance shown towards the fetus and placenta during pregnancy. This tolerance counters the immune response that would normally result in the rejection of something foreign in the body, as can happen in cases of spontaneous abortion. It is studied within the field of reproductive immunology.

CD94/NKG2 is a family of C-type lectin receptors which are expressed predominantly on the surface of NK cells and a subset of CD8+ T-lymphocyte. These receptors stimulate or inhibit cytotoxic activity of NK cells, therefore they are divided into activating and inhibitory receptors according to their function. CD94/NKG2 recognize nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse).

References

  1. 1 2 Clark, G. F.; Dell, A.; Morris, H. R.; Patankar, M. S.; Easton, R. L. (2001). "The species recognition system: a new corollary for the human fetoembryonic defense system hypothesis". Cells Tissues Organs. 168 (1–2): 113–21. doi:10.1159/000016812. PMID   11114593.
  2. ↑ Medawar, P. (1953). "Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates". Symp. Soc. Exp. Biol. VII: 320–338.
  3. ↑ Leeton, J.; Trounson, A.; Wood, C. (1984). "The use of donor eggs and embryos in the management of human infertility". The Australian and New Zealand Journal of Obstetrics and Gynaecology. 24 (4): 265–70. doi:10.1111/j.1479-828X.1984.tb01508.x. PMID   6398696.
  4. ↑ Hutter, H.; Dohr, G. (1998). "HLA expression on immature and mature human germ cells". J. Reprod. Immunol. 38 (2): 101–22. doi:10.1016/S0165-0378(98)00032-1. PMID   9730286.
  5. ↑ Burnet, F. M. (1960). "Immunological recognition of self". Science. 133: 307–311. doi:10.1126/science.133.3449.307. PMID   13689158.
  6. ↑ Desoye, G.; Dohr, G. A.; Ziegler, A. (1991). "Expression of human major histocompatibility (MHC) antigens on germ cells and early preimplantation embryos". Lab. Invest. 64 (3): 306–12. PMID   2002651.
  7. ↑ Ljunggren, H. G.; Karre, K. (1990). "In search of "missing self"? MHC class I molecules and NK cell recognition". Immunol. Today. 11 (7): 237–244. doi:10.1016/0167-5699(90)90097-S. PMID   2201309.
  8. ↑ Patankar, M. S.; Ozgur, K.; Oehninger, S.; Dell, A.; Morris, H.; Seppala, M.; Clark, G. F. (1997). "Expression of glycans linked to natural killer cell inhibition on the human zona pellucida". Mol. Hum. Reprod. 3 (6): 501–5. doi: 10.1093/molehr/3.6.501 . PMID   9239739.
  9. ↑ Clark, G. F.; Dell, A.; Morris, H. R.; Patankar, M.; Oehninger, S.; Seppala, M. (1997). "Viewing AIDS from a glycobiological perspective: potential linkages to the human fetoembryonic defense system hypothesis". Mol. Hum. Reprod. 3 (1): 5–13. doi: 10.1093/molehr/3.1.5 . PMID   9239703.
  10. ↑ Dell, A.; Morris, H. R.; Easton, R. L.; Panico, M.; Patankar, M.; Oehniger, S.; Koistinen, R.; Koistinen, H.; Seppala, M.; et al. (1995). "Structural analysis of the oligosaccharides derived from glycodelin, a human glycoprotein with potent immunosuppressive and contraceptive activities". J. Biol. Chem. 270 (41): 24116–26. doi: 10.1074/jbc.270.41.24116 . PMID   7592613.
  11. ↑ Wong, N. K.; Easton, R. L.; Panico, M.; Sutton-Smith, M.; Morrison, J. C.; Lattanzio, F. A.; Morris, H. R.; Clark, G. F.; Dell, A.; et al. (2003). "Characterization of the oligosaccharides associated with the human ovarian tumor marker CA125". J. Biol. Chem. 278 (31): 28619–28634. doi: 10.1074/jbc.M302741200 . PMID   12734200.
  12. ↑ Munn, D. H.; Zhou, M.; Attwood, J. T.; Bondarev, I.; Conway, S. J.; Marshall, B.; Brown, C.; Mellor, A. L. (1998). "Prevention of allogeneic fetal rejection by tryptophan catabolism". Science. 281 (5380): 1191–3. doi:10.1126/science.281.5380.1191. PMID   9712583.
  13. ↑ Hunt, J. S. (2006). "Stranger in a strange land". Immunol. Rev. 213: 36–47. doi:10.1111/j.1600-065X.2006.00436.x. PMC   1637092 . PMID   16972895.
  14. ↑ Baban, B.; Chandler, P.; McCool, D.; Marshall, B.; Munn, D. H.; Mellor, A. L. (2004). "Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific". J. Reprod. Immunol. 61 (2): 67–77. doi:10.1016/j.jri.2003.11.003. PMID   15063630.
  15. ↑ McMaster, M.; Zhou, Y.; Shorter, S.; Kapasi, K.; Geraghty, D.; Lim, K. H.; Fisher, S. (1998). "HLA-G isoforms produced by placental cytotrophoblasts and found in amniotic fluid are due to unusual glycosylation". J. Immunol. 160 (12): 5922–8. PMID   9637505.
  16. ↑ Barber, L. D.; Patel, T. P.; Percival, L.; Gumperz, J. E.; Lanier, L. L.; Phillips, J. H.; Bigge, J. C.; Wormwald, M. R.; Parekh, R. B.; et al. (1996). "Unusual uniformity of the N-linked oligosaccharides of HLA-A, -B, and -C glycoproteins". J. Immunol. 156 (9): 3275–84. PMID   8617950.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.