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Difficulties in paternity of seahorses: genetic metamorphoses of the immune system



In nature, it is full of mysterious phenomena and processes that cannot always be explained right away, sorting out all the components. One of these processes is pregnancy. Of course, we all know how this process begins and what is the result. However, pregnancy in humans is not the same as pregnancy in seahorses. The most obvious difference is the sex of the pregnant individual - in mates it is males. And here a number of questions arise regarding the immune system of the male, which must undergo serious metamorphoses in order not to kill future offspring, but at the same time protect the male from foreign microorganisms. A group of scientists from the Center for Ocean Research. Helmholtz (Kiel, Germany) studied the immune system of 12 species of syngnatine (needle fish) and seahorses.What changes occur in the body of future fathers during pregnancy and how can this information help people in the fight against diseases of the immune system? We learn about this from the report of scientists. Go.

Study basis


Pregnancy is the strongest natural defense of future offspring. Protection against temperature changes, from anoxia, from osmotic stress, etc. A future mother or father becomes a real safe with an integrated life support system, which requires impressive investments from them, which manifest themselves in the form of anatomical and physiological changes in their own body.

From the point of view of immunology, the most significant change is the acceptance, and not rejection, of an embryo that carries alleles (roughly speaking, genes) of not only a pregnant individual, but also the second parent. In other words, if the immune system does not rebuild, the embryo becomes a foreign body that must be destroyed. But the reconfiguration of the immune system has a downside - a decrease in protection against various pathogens.

Vertebrates have a unique variety of genesthe main histocompatibility complex * (GCHS) of grades I and II plays a key role in the process of determining β€œfriend or foe” (native cells and alien).
The main histocompatibility complex * is a part of the genome or a family of genes that are responsible for the development of immunity.
One of the forms of protection of the embryo against rejection is trophoblast - the outer layer of blastocyst cells (an early stage of embryo development), which forms the initial outer layer of the embryo shell.

The trophoblasts do not express HCH II and thus prevent the presentation of antigen to maternal T-helper ( Th * ) cells, which prevents an immune response. In addition, there is a suppression of the expression of genes of HCH I (HLA-A, -B and -D).
Th* (-) β€” T-, ( ).
These immunological adaptations are mediated by a cross-link between placental trophoblasts and uterine immune cells, in particular natural killer cells and regulatory T cells (Tregs). Tregs suppress Th1 immune responses - this is confirmed by the fact that deficiency of Tregs leads to miscarriage.

To better understand the evolution of pregnancy and the corresponding molecular interactions in the body, scientists decided to study some of the most unusual parents on the planet, namely representatives of the Syngnathiformes squad . The species in this order demonstrate a wide range of pregnancies in males: external attachment of eggs to the abdomen (in the subfamily Nerophinae ); additional external protection through skin bags (in Doryrhamphus ,Oosthethus and Solegnathiinae ); internal pregnancy (in Syngnathus ), etc. (image No. 1).


Image No. 1

In the last two births, the fertilized eggs (and then the hatched embryos) are covered and efficiently integrated by the parent tissues and supplied with nutrients, oxygen and parental immunity through the placenta-like organ.

The main theory considered in this study is the genomic modification of the adaptive immune system, which ensures the adoption of the embryo, i.e. immunological tolerance.

Research results


For the study, genetic data of 12 species of Syngnathiformes were collected . Phylogenetic analysis showed that the order Syngnathiformes is already about 80 million years old. The species included in this order showed a rather variable genome size: from 347 Mbp in Syngnathus rostellatus to 1.8 Gbp in Entelurus aequoreus (1 Mbp = 106 bp; 1 Gbp = 109 bp, where bp are paired bases * ).
Paired bases * - a pair of two nitrogenous nucleotide bases on complementary nucleic acid chains.
Curiously, species of Syngnathiformes that have no male pregnancy ( Fistularia tabacaria , Mullus surmuletus , Dactylopterus volitans , Aeoliscus strigatus and Macroramphorus scolopax ) have larger genomes than both genders with full male pregnancy (i.e., all species of Hippocampus and Syngnath ) . In contrast, the Nerophinae needle fish with external male pregnancy ( Nerophis ophidion and E. aequoreus ) have significantly larger genomes.

To compare the modifications of adaptive immunity with the stage of pregnancy, scientists analyzed a set of key genes from the collected genomes.

MCHC I and MCHC II are extremely important for the recognition of improper peptides, presenting them to CD8 + and CD4 + T cells, respectively. If the researchers' theory is correct, then all species with male pregnancy have undergone significant modifications to their adaptive immune system, characterized by losses or changes in key genes of HCHS II (image No. 2).


Image No. 2 HKGS

II invariant chain ( CD74 * ), preventing premature peptide binding of MHC II, shows divergent exon * 3 in Syngnathus and Hippocampus compared with both mammals and other bony fishes (image No. 3).
CD74 * (invariant chain) is a membrane protein involved in the functioning of the immune system.
Exon * is a portion of DNA, a copy of which is mature RNA.



Image 3

In addition, an exon 6b replacement sequence was found in the Hippocampus species, while Syngnathus showed a divergent exon compared to other fish and humans. Both exons (3 and 6b) are located in the region of the protein protruding into the endosomal * lumen.
Endosome * - a membrane intracellular organelle formed by the fusion and maturation of endocytotic vesicles.
Scientists believe that it is these processes that disrupt the functions of CD74. The most significant change in the genome of Syngnathus is the loss of a gene encoding the classical Ξ± and Ξ² chains of HCH II. The result of this is disabling the presentation of antigens to the T-cell receptor on CD4 + T-lymphocytes. This is confirmed by the loss of CD4, which ensures successful receptor binding and activation of CD4 + T lymphocytes (AICDA). The only canonical HCGS II gene remaining in the Syngnathus genomes was an autoimmune regulator that controls central tolerance when any developing T or B cells that respond to themselves are eliminated.

The totality of the data directly suggests that Syngnathus lost the MCHS II.

With hippocampusthe situation was much more complicated. Similar modifications, as in Syngnathus for the CD74 gene, were observed with respect to divergent exon 3 and replacement of exon 6b. It is important to note that no loss of HCHG II genes was observed, as in all three species of Syngnathus .

However, in Hippocampus the gene sequences of HCHS II, in particular Ξ²-copies, were very different from other functional genes of HCHS II found in species with functioning HCHS II (sea bass, salmon, etc.). Moreover, in the tertiary structure * of HCCG II Hippocampus Ξ²-genes, there are no two critical cysteine ​​bridges * , which are necessary for the formation of the peptide-binding pocket of the MHC II molecule.
* β€” , .

* .
A more thorough study of the invariant chain encoding the CD74 gene also suggests that the evolution of adaptive immunity went different ways in the two related genera Syngnathus and Hippocampus .

While the main genes of the HCHG II pathway were lost in Syngnathus , in Hippocampus they are preserved and show a clear sequence discrepancy compared to other bone fish and humans. Researchers have several possible explanations for Hippocampus HCH II .

The first is the difference in the sequences of the main HCGS II genes, unlike other fish, plus signs of positive selection may indicate that in Hippocampus the genes for HCGS II acquire additional or completely new functions.

CD74 is key to the functioning of MCHS II. Although the CD74 CLIP protein (exon 3) is usually associated with HCH II, the remaining exons of CD74 act as transfers, transporting HCH II in the loading compartment. The loss of exon 6b in the hippocampus may indicate a compromised loading process. Therefore, the HCHC II system in Hippocampus is likely to be less effective unlike other vertebrates, which may be sufficient for the development of a full pregnancy in males.

The second - GKGS II, perhaps, is not broken in terms of its functions, despite the lost and divergent exons of CD74 due to the functional restructuring of the immune system. However, this option is very unlikely, since tests in mice with transgenic expression of the shortened CD74 protein, which lacks the CLIP region (in Hippocampus, it differs from other bone fish), showed that CD74 cannot transport HCH II.

As for HCHS I, a recent study of Gadiformes (cod-shaped) showed an independent loss of HCHS II, from which a theory was proposed - gene diversification of HCHS I compensates for the loss of functional HCHS II.

To test the applicability of this theory to Syngnathidae(needle), the number of HCG I genes was estimated using the most conservative exon 4. This assessment showed that the number of these genes in all species with full pregnancy in males is higher compared to species without it: Nerophinae with external pregnancy in males - 27– 42 copies; Hippocampus and Syngnathus with full pregnancy - 20-36 and 24-44 copies; species without pregnancy males - 5-10 copies.

While all identified HCGS I sequences in Syngnathiformes are part of the U line, a separate cluster of HCGS I sequences in Syngnathid supports the potential co-evolution of HCGS I and male pregnancy.

In addition, key genes of HCHS I, such as Ξ²2-microglobulin and CD8, belonged to positive selection (when new species-beneficial genetic changes begin to develop) in the needle ones. Therefore, part of the functions goes from GKGS II to GKGS I, due to the complete loss or change of GKGS II.

It is also worth noting that any pregnancy is associated with certain physiological changes. In the case of needle ones, a change in hemoglobin genes is observed, which contributes to better oxygen transfer during pregnancy in males. Firstly, all needle ones lost the hemoglobin alpha 6 gene. Secondly, the species with complete pregnancy in males ( Syngnathus and Hippocampus ) also lost alpha 5. However, this loss was compensated by the acquired alpha 1 and alpha 2 gene.

The next stage of the study was to find the answer to the question - is there a certain compatibility of genes and physiological processes during female and male pregnancy for the evolution of immunological tolerance. For this, an analysis of the patterns of gene expression in the tissues of the brood sac of S. typhle was performed.

Two groups of males took part in the analysis: with an undeveloped and with a fully developed brood sac. All differentially expressed genes were searched for potential functions using homology, i.e. by comparing the described functions during pregnancy in female mammals (lizard of the species Chalcides ocellatus or ocular chalcid ) and in male pregnancy ( S. scovelli and Hippocampus abdominalis ).

A total of 141 genes were found, which one way or another differed during male pregnancy in S. typhle and S. scovelli . The direction of expression in differentially expressed genes correlated between S. typhle and S. scovelli , implying that the increase or decrease in regulation during pregnancy was basically the same in both needle species. In particular, this was manifested in four genes with the most pronounced increase in regulation during pregnancy (MYOC, HCEA, LS-12, APOA1) and for two genes that showed a decrease in regulation during pregnancy (STX2 and MSXC).

It was found that 116 genes involved in important processes during pregnancy in humans were differentially expressed during male pregnancy in S. typhle . These genes were involved in the degradation of the corpus luteum, the transport of parent-embryo substances, the development of the placenta, the growth of the embryo, etc. (image No. 4).


Image No. 4

In other words, it cannot be said that males during pregnancy are transformed into females at the genetic level. However, their genetic set undergoes certain changes, i.e. there is a mixed set of genes and similar physiological pathways for the interaction of molecules.


Image No. 5

The final stage of the study was the study of changes in the expression of immune genes that accompany the modification of HCHS II and the expansion of the repertoire of the HCHS gene I.

Together, the observed changes in gene expression during male pregnancy contribute to immunological tolerance during pregnancy, which is evident from the gene repertoire.

In particular, changes in the expression of pro-inflammatory Th1 and anti-inflammatory Th2 responses and the simultaneous suppression of HCH I during pregnancy in males that resemble changes in expression during mammalian pregnancy have been identified. There was also a suppression of the formation and proliferation of lymphocytes due to the suppression of CHIA and MEF2C proteins, activation of GIMAP4 (enhances apoptosis of lymphocytes) and due to increased regulation of the transcriptional repressor PRDM1 (which promotes placental growth and morphogenesis).

In accordance with the transition from Th1 to Th2 immune responses during pregnancy in mammals, the CEBPB protein, which represses Th1 but facilitates the Th2 immune response, was elevated during pregnancy of males in needles.

In late pregnancy, the GPR97 and MFNG genes (both responsible for B-cell differentiation) underwent downregulation along with the NFATC4 and HAVCR1 genes, which are involved in T-cell maturation.

By analogy with human pregnancy, CASP3 modifies HCHS I to maintain immunological tolerance, therefore, in male needle-based CASP3 was increased during pregnancy.

For a more detailed acquaintance with the nuances of the study, I recommend that you look into the report of scientists and additional materials to it.

Epilogue


In this study, scientists showed that seahorses and other species with male pregnancy underwent tremendous changes in their immune system, losing one of its most important elements - HCH II. In addition to this loss, there is a decrease in the activity of the second element - MHC I, which is observed during pregnancy in female mammals.

As the scientists themselves say, such a change may seem insignificant, but such a radical genetic metamorphosis is comparable to the discovery of a new species.

Studying pregnancy in male seahorses not only helps to better understand these creatures, but helps to expand our knowledge in the field of immunology. For example, genes lost during the evolution of needles encode molecular pathways that are attacked by the human immunodeficiency virus.

Scientists say that needlepoints that can survive without such important components of immunity can be an excellent research model. Indeed, an understanding of the genetic changes associated with the formation of immune tolerance during needle pregnancy can help in understanding the mechanisms of development of immune diseases in humans.

Friday off-top:

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Off Top 2.0:

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Thank you for your attention, stay curious and have a great weekend everyone, guys! :)

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