Comparative Mammalian Immunology: The Evolution and Diversity of the Immune Systems of Mammals

By Ian R Tizard

Comparative Mammalian Immunology: The Evolution and Diversity of the Immune Systems of Mammals provides a review on the current knowledge of mammalian immune systems from a comparative viewpoint. This reference encompasses recent work on the immune systems of marine mammals, bats and marsupials in addition to other lesser-known species, with the immune systems of humans and laboratory mice as components of chapters on primates and rodents respectively. The book also makes use of the most recent studies on the genomic sequences of the mammals to identify both common and unique features of each mammal's immune system.

The book elucidates the complex, but coordinated and controlled series of interactions involving cells and molecules that has evolved to protect the host against disease. Mammals consist of a highly diverse group of animals in which the immune system has been subjected to a variety of selective pressures. This is reflected in differences in the organization and function of their immune systems, and is especially seen in those gene families characterized by complexity and polymorphism.

• Demonstrates multiple diverse pathways and mechanisms to optimize resistance and survival in the face of infectious diseases
• Shows the clear patterns of emergence of different immunologic traits among the diverse orders of mammals
• Reflects issues with innate or adaptive immune systems
• Serves as a comprehensive review of the current state of knowledge of the immune system of each mammalian order

• Language: English
• Publisher: Academic Press
• Release date: Feb 9, 2023
• ISBN: 9780323952200

Ian R Tizard

Ian Tizard, BVMS, BSc, PhD, DSc (Hons), DACVM, is a Diplomate of the American College of Veterinary Microbiologists and a University Distinguished Professor Emeritus of Immunology, Department of Veterinary Pathobiology, The Texas Veterinary Medical Center at Texas A &M University (TAMU), College Station, Texas, USA. Dr. Tizard earned his Bachelor of Veterinary Medicine and Surgery from the University of Edinburgh, Scotland in 1965. He then completed a Bachelor of Science in Pathology and a PhD in Immunology. After completing his studies, Dr. Tizard became a Post-Doctoral Fellow at the University of Guelph, where he remained on as a professor until 1982 when he moved to TAMU. Dr. Tizard wrote the first standardized textbook on Veterinary Immunology in 1977. This text, now in its 10th edition, is used worldwide, and has played a major role in establishing Immunology among the key disciplines of Veterinary Science.

Book preview

Section 1

Mammalian immunology

Outline

Chapter 1 The evolution of the mammals and their immune systems

Chapter 2 The evolution of viviparity

Chapter 3 The evolution and role of lactation

Chapter 4 Endothermy and immunity

Chapter 5 The microbiota–immune system relationship

Chapter 6 Innate immunity: basic features

Chapter 7 The mammalian major histocompatibility complex

Chapter 8 T Cells and their receptors

Chapter 9 Mammalian B cells

Chapter 10 Mammalian innate lymphoid cells

Chapter 11 The mammalian lymphoid system

Chapter 1

The evolution of the mammals and their immune systems

Abstract

Every mammal that has ever lived has had to fight off pathogens and parasites while at the same time, controlling the microbial commensals living on the body surfaces. To do this they employ both innate and adaptive immune processes. Each species has had to face different microbial challenges based on their environment, diet, lifestyle, whether solitary or social, as well as climatic and other challenges. For over 200 million years mammals have diversified their immune systems. Modern-day descendants have inherited these unique ancestral traits. As a result, mammals currently possess immune systems that agree on basic details but can differ widely in the details. The three major supraordinal clades of the mammals exemplify these differences. This chapter reviews the phylogeny of the major mammalian clades to provide a basis for understanding the differences in the immune systems discussed in later chapters.

Keywords

Synapsids; monotremes; prototheria; Eutheria; K-Pg event; short-fuse model; amniotes

Every multicellular organism must be able to defend itself against invasion and exploitation by microorganisms. Even the lowliest invertebrate needs a defense system. The existence, and indeed dominance of microbes have been a feature of life since the earliest times. As vertebrates evolved, they too had to maintain their integrity by excluding microbial invaders. The earliest mammals could not have survived without an effective immune system. Immunity and resistance to microbial pathogens have always been a key part of the evolutionary process. This must inevitably have involved not only constitutive defenses, the production of molecules and cells whose role was to simply kill invaders, but it also has involved induced defenses whose function is to respond to infection by rapidly counter-attacking and destroying any invaders.

Every mammal ever born would have to be able to defend itself against microbial invasion if it were to survive and reproduce. Thus the evolution of immunity is as much a part of mammalian living systems as the evolution of the skeleton or the cardiovascular system. This would also have been a relatively complex process since microbial threats are also constantly evolving. No doubt innumerable arms races between invader and host have occurred in the past. The immune systems of today represent the current state of these races—but the process continues; bacteria and viruses attack, and mammals evolve to counter them [1]. Resistance and counter-resistance fuel these races in which each protagonist may gain a temporary advantage that is then countered by a move by the other. The net result is a constant pressure on the invader and defender to adapt. In the case of mammals, this also requires perpetual positive selection of key defensive pathways. This constant struggle for survival is the basis of the Red Queen concept -the need to run constantly to stay in the same place!

1.1 Amniotes

Amniotes are vertebrates that produce a membrane called the amnion, that surrounds and protects their developing embryos. As a result, they do not require an intermediate larval stage nor do they need to lay their eggs in water. The amnion serves to retain water while still allowing oxygen transfer and hence respiration. As a result, amniote embryos can develop either in eggs laid on land or even within the mother. This differentiates them from the preamniotes such as the fish and amphibians. The evolution of the amnion facilitated the movement of vertebrates from water to land. The first amniotes emerged around 350 million years ago (mya) during the Carboniferous period. As a result of their ability to grow and survive out of the water, the amniotes became, and remain the predominant land vertebrates. The amnion itself consists of several different membranes, including the amniotic sac that surrounds the developing fetus in the placental (Eutherian) mammals, as well as the chorion and allantois. The early amniotes also developed a leathery porous eggshell that permitted their eggs to be much larger than those of fish or amphibians. The development of a large yolk sac also permitted the developing fetus to grow to a larger size and develop fully before hatching. This in turn, also resulted in the evolution of much larger animals.

As the early amniotes evolved, their fossilized skeletal remains show that they diverged into two main lines. The earliest amniotes, the anapsids, lacked an otic notch at the back margins of the skull since, not being aquatic, they no longer needed a spiracle. One branch subsequently developed a single opening (temporal fenestra) behind each eye. These animals are classified as synapsids, and they eventually gave rise to the mammals. The other branch developed two such openings and are classified as diapsids or sauropsids (Fig. 1.1). The sauropsids eventually gave rise to the reptiles, dinosaurs, and birds.

Figure 1.1 The structural features of the skull that define sauropsids and synapsids. The synapsids are considered the earliest precursors of what eventually became the mammals. There is no consensus on the functions of these fenestra in the skull. It is generally believed however, that they provided attachment sites for jaw muscles. The synapsids also progressively developed differentiated teeth such as the canines and molars rather than the relatively uniform teeth of amphibians.

1.2 The origins of the mammals

The synapsids are a class of amniotes that possess a single temporal opening (fenestra) on the side of the skull and a bony arch under each eye. These structures are located in the area where the jaw muscles attach. This distinctive feature of their skulls evolved around 320–305 mya during the late Carboniferous period. The synapsids are a distinctly different evolutionary branch from the reptiles (although superficially somewhat similar) and are much more closely related to living mammals [2]. The synapsids have subsequently been classified into a primitive subclass, the pelycosaurs, and an advanced subclass, the therapsids. The pelycosaurs were lizard-like animals with a sprawling gait and none have survived to the present. The therapsids, on the other hand, as proto-mammals, gradually underwent changes in their pelvis and limb bones and developed an upright gait. This would have enabled them to run faster and be more maneuverable. Modern monotremes such as the duckbilled platypus still retain the sprawling gait.

The advanced synapsids, the therapsids first emerged about 310 mya during the Middle Permian period and evolved into a diverse array of shapes, sizes, and lifestyles (Fig. 1.2). They included both large and small herbivores as well as carnivores. They were the dominant land vertebrates at that time but were largely wiped out by the Permian-Triassic mass extinction event that occurred around 252 mya. The predominant surviving synapsids are known as cynodonts. The cynodonts in general became progressively smaller and more mammal-like during the Triassic period and remained relatively small during the Jurassic and Cretaceous periods. The earliest cynodont fossils are dated from the late Permian about 257 mya and are ancestral to modern mammals [3].

Figure 1.2 The geologic time scales and the timing of the progressive emergence of the proto-mammals.

The synapsids, in addition, to the characteristic single temporal fenestra on the sides of their skulls progressively developed other anatomical features that we associate with mammals. For example, the earliest synapsids had a bone at the back of the skull called the quadrate that formed a joint with the lower jaw, called the articular. As the synapsids evolved, the quadrate and articular were replaced by two other bones, called the squamosal and the dentary. Instead of having multiple jawbones characteristic of reptiles, the cynodonts progressively relied on a single mandible (dentary). The remaining quadrate and articular bones progressively decreased in size and eventually either disappeared or migrated to the ear where they developed into two of the bony ossicles within the middle ear, the malleus, and incus. The stimuli for these structural changes are unclear. They may have improved hearing or even permitted an increase in brain size. Synapsids also developed differentiated teeth. Instead of a mouth full of almost identical teeth, they eventually developed a consistent tooth pattern with paired canines on the upper jaw and differentiated cheek teeth. This restructuring of the jaw and a diversified dentition would have increased their effectiveness as predators. The therapsids also gradually developed a bony palate that eventually separated the oral from the nasal cavities and permitted much higher respiratory rates. This would also have facilitated chewing rather than requiring their prey to be ingested whole. (They could still breathe even when their mouth was full!) The secondary palate would also have been necessary for suckling. These early synapsids also developed a relatively large brain that filled the endocranium.

At some stage, some of the synapsids developed hair. It is unclear when this might have occurred since soft tissues such as skin and hair are rarely preserved as fossils. At least one beaver-like fossil from the middle Jurassic period shows unambiguous hair impressions [4]. There is also evidence of the presence of pre-mammalian therapsid hair in coprolites (fossil feces) dated to the Upper Permian (before 250 mya) [5]. It is suggested that fur may have developed at a time when dinosaurs dominated the globe and in response, mammals became small and nocturnal. As a result, they would have benefited from the additional layer of insulation [6]. Likewise, it is not known when the ability to secrete nutritional milk arose.

1.3 Mammalian phylogeny

Despite the dominance of the dinosaurs, the mammalian clade progressively developed during the Mesozoic era that followed the massive extinction event that occurred at the Permian/Triassic (P-Tr) boundary about 252 mya. This event has been described as a greenhouse with lethal temperatures [7]. (The P-Tr event was likely due to massive volcanic activity causing a spike in carbon dioxide levels resulting in lethal global warming). Over the 200 million years of the Mesozoic era, the earth’s climate was generally warm and there was little ice cover. However, local climatic changes may have been triggered by the break-up of the megacontinent, Pangaea into Laurasia and Gondwana around 190 mya. This was followed by the progressive fragmentation of the southern continents between 140 and 80 mya. Thus Gondwana broke up into the continents of Australasia, South America, and the Antarctic. North America separated from Laurasia at about 80 mya. North and South America eventually rejoined much more recently in the Cenozoic era about 2.7 mya.

During millions of years of keeping a low profile, throughout the Mesozoic era, the early cynodonts prospered. They became more diverse and abundant. Initially, they were predominantly small insectivores and carnivores. Their trend towards differentiated teeth with canines probably permitted rapid capture and crushing of arthropods. As their size decreased, to maintain endothermy, it became necessary to develop thermal insulation such as hair in addition, to maintaining precise temperature control. Sensitive hearing and an acute sense of smell were also vital for survival. Thus middle ear bones developed. Likewise increased olfactory lobe size resulted in increased brain size. This problem and its solution have been called the nocturnal bottleneck [8].

The nocturnal bottleneck hypothesis suggests that the early Eutherian mammals faced severe competition from large aggressive diurnal dinosaurs. The dinosaurs, being largely ectothermic would have generally restricted their activities to the daytime hours when they were warmed by the sun. The mammals, placed under severe pressure by these aggressive predators, would only have survived by becoming nocturnal. However, this change would have stimulated the development of endothermy [9]. As a result, these early mammals became less dependent on solar heating or environmental temperature. This nocturnal lifestyle would likely also have resulted in significant changes in visual acuity.

It is perhaps no coincidence that nocturnality is widespread in modern mammals, the most obvious case being the bats. It is suggested that the bats may have evolved from a nocturnal ancestor that had emerged before the K-Pg event. Like other placental mammals, they probably took advantage of the elimination of competition from the diurnal dinosaurs to diversify and expand their ranges.

The first major evolutionary divergence from the main mammalian line was the emergence of the subclass Prototheria, the Monotremes. The egg-laying Monotremes that currently consist of the echidnas and the platypus survive only in Australia and New Guinea. They probably had a last common ancestor with the therian mammals about 220–200 mya during the Triassic period [10]. The echidnas probably diverged from the platypus lineage much more recently, about 19–48 mya. Like the synapsids, monotremes retain a single orifice through which they defecate, urinate, and reproduce. They lay leathery, uncalcified eggs. They feed their young with milk secreted from glands in modified skin patches on their bellies.

The second major divergence from the crown mammals occurred when the placental mammals, the Eutheria, diverged from the marsupials, the Metatheria. Based on molecular genetic analysis, the divergence between the placentals and metatherians likely began around 180 mya. This is much earlier than the earliest metatherian fossil (Sinodelphis in China dated to 125 mya [11] but is consistent with the earliest Eutherian fossil Juramaia dated to 160 mya and also found in China [12]).

Marsupials characteristically develop a yolk-sac placenta to feed the developing embryo in utero. They also developed a simple placenta that attaches the embryo to the uterine wall. Pregnancy is very short, and the marsupial embryo is born in a very early stage of development. As discussed in the next chapter, this short gestation period likely enables the embryo to avoid a destructive attack by the maternal immune system. The newborn marsupial climbs to a nipple within a pouch where it attaches and continues its development. Marsupials may also have a pair of epipubic bones that support the pouch as the young continues to grow. These bones are not unique to marsupials since they have been found in fossilized monotremes and Eutherians as well.

The marsupials probably originated in Gondwana but as the continents drifted apart survived and diversified in what is now South America. Some also succeeded in reaching Australasia by way of Antarctica. (Fossil marsupials have been found in Antarctica). In the absence of competition from Eutherians they prospered. Except for bats and some rodents, the placental land mammals did not reach Australasia until the first humans arrived about 50,000 years ago. Some marsupials, the opossums remained behind and survived in South America. While marsupial diversification occurred in Gondwana in the Mesozoic, the K-Pg event largely stopped this, and subsequent radiation was confined to the isolated island continents of South America and Australia where the oldest marsupial fossil is dated to 55 mya [13].

1.3.1 Modern mammals

Despite the continuing threat from the dinosaurs, the mammals survived, thrived, and continued to evolve. They remained small and insectivorous or carnivorous. Once, however, the dinosaurs had disappeared the mammals radiated explosively. There is an ongoing debate about the timing of this explosion. It should be pointed out that until recently, the appearance and stratification of fossil remains were the only methods of dating these divergences. Now, molecular genetic techniques have become available and can generate reliable molecular clocks. It is often the case however, that the results obtained by molecular methods do not agree with the fossil record. In general, molecular clocks tend to support much earlier divergence dates than does the fossil record.

1.3.2 Eutherians

Following the divergence of the marsupials, the true placental mammals, the Eutheria continued to evolve and diversify. Modern placental mammals now dominate the planet. There are estimated to be about 6100 identified extant mammalian species plus thousands of cryptic species and they are found worldwide.

The characteristic feature of the Eutherians is their mode of reproduction. Thus the Eutherian embryo attaches itself to the uterine wall using a large placenta through which the embryo receives both nutrients and oxygen. Eutherians have also succeeded in preventing immunologic rejection of the semi-allogeneic fetus and thus permit it to survive in utero until ready to take on the outside world. Eutherians have a relatively long pregnancy, and their young are often well developed at birth. This is especially obvious in the young of the large herbivores. The final stages of Eutherian development are supported by the nourishment of the newborn through milk, the defining characteristic of mammals.

Historically, the phylogeny of mammals and other vertebrates has been determined by the examination of fossilized skeletal remains and the classification of morphological characters. As a result, there was much emphasis on skeletal details such as the number of fenestra in the skull. Unfortunately, many such classification attempts have proven to have produced incorrect results. Recently however, it has proved possible to reexamine mammalian phylogeny using molecular methods. Thus phylogeny can now be inferred by comparing the large numbers of gene sequences available for extant mammals. Consequently, there has not always been complete concordance between the paleontological phylogeny and the molecular phylogeny [14]. This is especially the case with placental mammals, especially when seeking to resolve finer-scale phylogenies. Fossil formation is a relatively infrequent event. Thus a species may be around for a very long time before one of its members just happens to be fossilized and paleontologists happen to find that fossil. As a result, a wave of large-scale molecular phylogenetic studies beginning around 2000 has forced some revisions in the timing and details of the mammalian phylogenetic tree.

1.3.3 The initial branching events

There is still debate about the initial branching event, the timing, and the precise order in which these early Eutherian lineages diverged. Three models have been proposed for this process.

The long-fuse model suggests that the initial steps in this diversification occurred early in the Mesozoic around 180 mya. The short-fuse model suggests that diversification was a late event, perhaps occurring ~100 mya when dinosaurs still ruled. Both these models suggest that mammalian diversification significantly preceded their explosive growth after the K-Pg event. A third model, the explosive model suggests that the mammals started their divergence in the early Cenozoic immediately after the K-Pg event around 65 mya [15]. The long fuse model suggests that mammals diversified early but remained small and inconspicuous while the earth was dominated by large dinosaurs. The explosive model suggests that diversification and explosive growth occurred close together once the dinosaurs had been eliminated.

Molecular studies using both mitochondrial and nuclear gene sequences have tended to support the short-fuse model. Thus these have confirmed the existence of four supraordinal clades of mammals that last shared a common ancestor about 110–100 mya. Because they diverged rapidly over a very short time period (less than 10 mya) there are still disagreements regarding their precise branching order and the roots of the Eutherian family tree (Fig. 1.3) [16–18].

Figure 1.3 A classification of modern mammals and their orders. Mammalian paleontologists continue to differ regarding the precise timing of these divergences. Recent molecular dating studies have tended to push back divergence dates significantly when compared to estimates based on the fossil record.

The first major split probably occurred between the evolving mammals in the southern hemisphere and those in the north. Thus the northern group, termed the Boreoeutheria, is estimated to have diverged from the main placental line at about 105 mya. They subsequently split again into two supraordinal groups, the Laurasiatheria, and the Euarchontoglires. This divergence likely occurred around 97 mya on the northern continent of Laurasia.

The southern group is classified as the Atlantogenata. These also diverged subsequently into the Xenarthra—species classically restricted to South and Central America, and the Afrotheria, which as their name implies, consists of mammals that are almost exclusively of African origin.

While the four supraordinal clades are agreed upon, their branching order is contentious. Where and when did the initial split occur? The problem remains unresolved [19]. The most favored but somewhat contentious mammalian family tree divides the Eutheria into two major groups, the Atlantogenata (born around the Atlantic) and the Boreotheria (the northern placental mammals) [16,19]. The Atlantotheria contain the Afrotheria as well as the Xenarthra. Remember that Africa and South America were joined until between 100 and 120 mya when Pangaea broke up. However, recent analysis has failed to support this split. Current opinion based on molecular genomic data suggests that the Xenarthra and the Afrotheria are sister superorders that split from the other mammals about 105 mya (95–114) and subsequently diverged [20]. Thus Afrotheria evolved and diversified in isolation on the Afro-Arabian continent. Likewise, the Xenarthra evolved on the continent of South America after it separated from Pangaea.

1.3.4 The Xenarthra

The Xenarthra are of South American origin and consist of very specialized mammals classified into the Cingulata (armadillos) and the Pilosa (anteaters and sloths). While most are restricted to continental South America, the nine-banded armadillo has reached North America but only after the formation of the isthmus of Panama about 2.7 mya.

1.3.5 The Afrotheria

Some of the major areas of a dispute relate to the very top level of division of the tree. In 1945 the famed paleontologist George Gaylord Simpson published The Principles of classification and a classification of Mammals [21]. This classic work has largely withstood the test of time. Simpson’s work had however, a fairly obvious weak link. He was unclear about the relationships of the unique African mammals such as the elephants, manatees, and aardvarks. As a result, Simpson lumped these into a group he called the Afrotheria. Molecular data now suggests that Simpson’s Afrotheria contained several groups of mammals that are only distantly related. Thus these include the African insectivores (Afroinsectiphilia), and the elephant shrews (Macroscelidea) more related to the Glires. There is however, both molecular and fossil agreement that the Paenungulata, the hyraxes, elephants, and sirenians are closely related. The Afrotheria in the broad sense contains the Tubulidentata (aardvarks); the Afrosoricida (the golden moles and tenrecs); the Macroscelidea (the elephant shrews); the Hyracoidea (hyraxes); the Sirenia (manatees and dugongs); and the Proboscidea (elephants). The last three are related and are therefore grouped into a single clade, the Paenungulata.

1.3.6 The Laurasiatheria

The Laurasiatheria contain diverse Eutherian orders including the Carnivora (dogs, cats, bears as well as the marine pinnipeds), the Chiroptera (bats); the Cetartiodactyla (cows, pigs, and whales), the Pholidota (pangolins), the Perissodactyla (horses and rhinoceroses) and the Eulipotyphla (shrews and hedgehogs).

1.3.7 The Euarchontoglires

The Euarchontoglires also include a diverse variety of mammals including the primates (both humans and monkeys); the Scandentia (tree shrews) and the Dermoptera (colugos). They also include the Glires (rabbits and rodents).

1.3.8 After the K-Pg event

Another, much more famous, extinction event occurred at the end of the Mesozoic era called the Cretaceous-Paleogene (K-Pg) event. This occurred around 66.5 mya and resulted in the extinction of the dinosaurs (This is also called the Cretaceous-Tertiary event). The K-Pg event was triggered by a massive asteroid strike in what is now the Yucatan peninsula in Mexico [22]. The phylogenetic tree is further confused by the mass extinctions that occurred after the K-Pg event, the extinction of the dinosaurs, and the subsequent rapid diversification of the mammals. Thus unlike the dinosaurs, small mammals survived the K-Pg event and subsequently prospered. (Fig. 1.4).

Figure 1.4 The current consensus on the Eutherian superorders, their classification and origins. This classification will be used throughout this text.

The Eutherian mammals did not expand their numbers significantly until after the K-Pg event. The recent molecular phylogenetic studies have indicated, however, that the initial diversification of the Eutherians began late in the Cretaceous period 100–70 mya. but that the extant modern families developed in the late Eocene and early Miocene epochs of the Cenozoic following the K-Pg event. The greatest diversification of the placentals occurred in the early Cenozoic epoch. This idea is supported by both the long- and short-fuse models [23]. The fossil evidence on the other hand suggests that these families first appeared later in the Cenozoic. Very few mammal fossils are found before the extinction of the dinosaurs and evidence suggests that their greatest expansion occurred after that event. The explosive model suggests that all the diversion occurred within a very short time after the K-Pg event, but this would require improbably high mutation rates and is thus considered unlikely.

1.4 The evolution of mammalian immunity

It is important not to anthropomorphize the role of the immune system. We humans put much emphasis on our need for a long healthy lifespan and freedom from lethal infections. We place much emphasis on the role of the immune system as a defense system. This is of course vitally important. In the absence of such defenses, we would simply be eaten alive. However, given that evolution is all about relative breeding success, it must be emphasized that the immune system is optimized not for long life and good health but simply for sufficient longevity and health to ensure breeding success and the raising of the young. This requires not only defeating aggressive pathogens but also reaching optimal accommodation with the body’s commensals to everyone’s benefit. Commensals and many parasites can be tolerated as long as they do not endanger the success of the species. These needs, while broadly similar between mammalian species are as diverse as the biology of the mammals themselves. A successful mouse may have very different immune requirements than a successful cow or dolphin.

Animal hosts with long generation times such as the large mammals, necessarily evolve at slower rates than either short-lived mammals, or most importantly, potential pathogens. This results in asymmetric warfare. Thus even in the presence of lethal infections, several generations may have to pass before sufficiently protective genetic changes can develop in mammalian species. Temporary setbacks are common—humans call them pandemics. The signatures of these events can be detected in their genomes. Different mammalian species have different susceptibilities to specific pathogens so that the outcome of an infection in one species may not be the same in another species. In some cases, mammals, both domestic and wild, may serve as reservoir hosts for parasites or pathogens. Such reservoir species may have taken millions of years to adapt to the infection and so become carriers.

In general, animals use two types of the immune system to control microbial invaders. One depends on identifying the characteristic molecules expressed by or in the invaders. These molecular patterns include the cell wall structures of bacteria and the unique nucleic acid sequences of viruses. These unique features are recognized by specialized pattern recognition receptors and so stimulate innate immunity—rapid reflexive stereotypic responses such as inflammation. Innate immune mechanisms evolved early in the evolutionary process. Thus they are critical to the survival of invertebrates. However, they play an important defensive role and as a result, have been maintained, refined, and continue to play a key role in the defense of even the most advanced vertebrates including the mammals.

The second type of immune system, the adaptive immune system, depends upon the use of specialized receptors to identify specific pathogens. Generated by somatic mutation and other mechanisms, these adaptive receptors can bind and respond specifically to each of the enormous diversity of molecules, especially the proteins, that make up bacteria, viruses, and protozoa. As a result, they too are enormously diverse. Some of these specific receptors can bind to the unique structures (antigens) found on the surface of invading microorganisms. As a result, they enable the body to recognize an enormous diversity of foreign antigens and trigger defensive immune responses to an enormous diversity of invaders. This adaptive response first evolved in the jawless vertebrates but has proven so successful that all subsequent animal life forms, especially all the vertebrates, use it as their main means of defense.

Just as throughout millions of years, mammalian shapes, behaviors, diets, and sizes evolved constantly to adapt to their environment, exploit food resources, reproduce successfully, and avoid being eaten by macropredators. So too they were obliged to adapt to the constant pressure placed upon them by the bacteria, viruses, fungi, and protozoa inhabiting their bodies as well as the microbial environment in which they lived. This microbial environment would have varied based on local environmental conditions such as temperature and humidity, based on food sources such as plants or meat, and based on behavior patterns such as a solitary lifestyle or living in densely populated herds or colonies. Each of these factors would have provided mammals with different pressures to evolve mechanisms that maximize survival and reproduction, successfully raise offspring, or find sufficient food in the face of constant microbial and parasite challenges. Presumably many extinct mammals failed to adapt successfully to microbial challenges and are now extinct. (See Chapter 4 for a discussion on dinosaurs and their fungal difficulties.) The extant mammals however, clearly had ancestors that adapted successfully and so survived in a microbial world.

Interactions with commensals and pathogens are one of the dominant factors shaping mammalian evolution. The body must not only counter potential pathogens by the use of an effective immune system, but it must also balance the aggressive elimination of potential pathogens with the compromises necessary to maintain an incredibly useful commensal gut and body surface microbiota.

Life-history patterns are shaped in many ways by the risks and benefits conferred by the immune system [24]. In the presence of aggressive parasites and pathogens, immunity will be one of the most important determinants of survival and reproductive success. Nevertheless, immunological defenses are costly to maintain and operate. Immunity requires the allocation of precious nutrient calories, and in effect competes with other critical systems as well as growth, reproduction, and temperature. It is reasonable to assume therefore that the investments made in the immune systems are the minimal commensurate with success. Success can be measured by survival and successful reproduction.

As mentioned, the major components of the innate and adaptive immune systems had evolved and matured well before the emergence of mammals. Key antigen recognition molecules such as the toll-like receptors, major histocompatibility complex gene products, B cell antigen receptors, and T cell antigen receptors as well as a multitude of cytokines, both regulatory and effector, were present and functional in the earliest mammals. The earliest synapsids had T and B cells and made antibodies. During ongoing mammalian evolution, however, the system required to be tweaked. Numerous minor adjustments resulted in improved survival and reproductive effort in the successful species. Some components were not found to be beneficial and as a result, suffered a loss of function.

While numerous environmental and climatic factors must have resulted in mass extinctions, so too would infectious diseases. It is possible to discern traces of these past disease events in the genomes of modern mammals. One of the most obvious methods is the evidence for positive selection in the genes of the immune system. Host defense mechanisms are under very strong selective pressure and must evolve rapidly. The negative selection caused by infectious agents is not subtle. In situations where a species population density is sufficiently high, epizootics can result in mass die-off that wipes out huge numbers of a species in a very short space of time [25]. Thus in 2015 a mass die-off killed >200,000 Saiga antelope (Saiga tatarica) in Kazakhstan. Caused by hemorrhagic septicemia due to Pasteurella multocida, it is estimated that 88% of the saiga in Central Kazakhstan died [25]. Presumably, however, the surviving 12% had an immunogenetic background that enabled them to survive the epizootic and provide the breeding population for future generations of antelope. This was not the first mass die-off suffered by this species. While such die-offs may not necessarily result in total species extinction, they can massively alter the genetic structure of a population and so can have long-term consequences as well. By reducing the population density of a species to a level insufficient to maintain disease transmission they will also tend to reduce their impact significantly until the organisms can no longer sustain themselves. Thus infectious agents go extinct too.

A related issue relates to herd behavior. Thus the aggregation of a single species into large shoals, flocks, or herds, is an effective mechanism of defense against macropredators. On the other hand, these aggregates greatly increase the potential for infectious disease spread. Thus members become much more susceptible to micropredation by invading bacteria and viruses.

Behavioral changes would also have required changes in immune system components to offset inadvertent adverse consequences. For example, the development of a carnivorous diet in predators would have introduced parasites into the intestinal tract. Social behavior such as the avoidance of sick congeners also plays a role in disease resistance [26]. The development of a large body mass would have made available a larger number of cells to attack invaders and may thus have improved survivability in the face of infectious disease challenges. This too may have contributed to the development of a K survival strategy dependent upon a long life span within a stable environment. While premature death is the ultimate negative selection pressure, diseases need not be immediately lethal to have a negative effect. Mate selection in many mammals is also based on the appearance of good health and fitness. This is not merely visual but also odor-based [26]. Appearance does however, signal resistance to parasites and perhaps other infections. These disease impacts are especially important in closed systems such as islands or specialized environments.

It should also be noted that infectious agents and parasites can result in either the direct death of an animal or indirect death through predation. There are many examples, (discussed in Chapter 19), where predators selectively hunt and kill sick prey. They are easier to catch. Thus innate immune responses resulting in sickness may be effectively lethal in prey species that can neither run nor hide. This places major selective pressure on the appearance of good health. Sickness (or its appearance) is to be avoided at all costs. The flood of cytokines induced during an innate response has the potential to itself cause sickness and death [27]. The elimination of gastrointestinal parasites has the potential to cause debilitating diarrhea. Thus there is pressure on the immune system to eliminate invading pathogens without triggering sickness behaviors. This results in a tendency to use adaptive immunity whenever possible. It also means that a balance must be achieved between eliminating pathogens and the costs needed to do this. Partial elimination of parasites may be sufficient in the trade-off between immunity and health. Additionally, mammals (and birds) go to great lengths to avoid any appearance of weakness, especially in the presence of potential predators. Wild mammals may look very healthy but this may hide underlying disease or inapparent weakness. As noted later in this text, the white blood cell counts of wild mammals are consistently greater than those of their captive or domestic counterparts simply because of the relatively high background levels of infections or parasitic infestations in the wild.

It must not be forgotten that pathogens evolve too so that life is a constant battle between the innovative methods adopted by parasites to avoid immune elimination and the adaptability of the innate and adaptive immune systems to counter such attacks [28]. Studies on the differences in gene content between the early mammalian lineages such as opossums, and much more recent species such as humans have identified major changes in the genes associated with innate immunity. The most significant of these influence natural killer cells and their receptors (Chapter 10) [29].

One of the major reasons why the immune system is so complex is the need for flexibility. The diversity of potential pathogens requires an equally diverse defensive system. Different pathogens invade by different routes and cause disease and damage by multiple pathways. Thus the immune system is required to be flexible. It needs to mount inflammatory responses against tissue invaders. It needs to make antibodies against extracellular bacteria. It needs to mount cell-mediated immune responses against intracellular viruses and bacteria. In other words, the immune system has to be flexible and very adaptable. It achieves this by the use of multiple polymorphic gene families that can recognize the invader and select an appropriate defensive strategy. A mistake in selecting the correct response can be the difference between life and premature death. Millions of years of constant selective pressure, an eternal arms race, means that the defenses are highly effective most of the time. But the race never ends and there is also a continuous selection for the ability to effectively invade new, susceptible hosts. The pathogens never rest, but then neither does the immune system [30].

As a result of all these pressures, it is not surprising that immune system genes are among those that show the most evidence of positive selection [31]. When mammalian genomes are analyzed using sequence-based data for evidence of clusters of positively selected sites, two systems stand out—the immune system and metabolic enzymes [31].

Some of these immune system components are largely predictable such as the class II molecules of the major histocompatibility complex that determine which foreign antigens can or cannot induce an immune response. Likewise, CD1a molecules are required for a mammal to respond to lipid-based antigens. Other positively selected sites include components of the innate immune system such as complement components 1a, 5, and 8α. Another such component is TLR4, the toll-like receptor that binds bacterial lipopolysaccharides [31]. These rapidly evolving gene clusters can change even in the absence of gene duplication.

If we examine their place in mammalian phylogeny, we can see that most domestic animal species are relatively closely related. Even domestic pets such as dogs and cats are more closely related to farm animal species than to primates. Likewise, laboratory animals tend to cluster in a separate groups. It is unsurprising, therefore that significant differences exist among the immune systems of species of interest to veterinarians and researchers. It is also clear that if we are to understand the significance of these differences and how they evolved, we must examine the immune systems of other, unrelated mammal species as well.

References

1. Sironi M, Cagliani R, Forni D, Clerici M. Evolutionary insights into host-pathogen interactions from mammalian sequence data. Nature. 2015;16:224–236.

2. Angielczyk KD. Dimetrodon is not a dinosaur: using tree thinking to understand the ancient relatives of mammals and their evolution. Evo Edu Outreach. 2009;2:257–271.

3. Botha J, Abdala F, Smith R. The oldest cynodont: new clues on the origin and early diversification of the Cynodontia. Zool J Linn Soc. 2007;149:477–492.

4. Ji Q, Luo Z-X, Yuan C-X, Tabrum AR, et al. A swimming mammaliaform from the middle Jurassic and ecomorphological diversification of early mammals. Science. 2006;311:1123–1127.

5. Bajdek P, Qvarnstrom M, Owocki K, Sulej T, et al. Microbiota and food residues including possible evidence of pre-mammalian hair in Upper Permian coprolites from Russia. Lethaia. 2016;49:455–477.

6. Ruben JA, Jones TD. Selective factors associated with the origin of fur and feathers. Am Zool. 2000;40(4):585–596.

7. Sun Y, Joachimski MM, Wighall PB, Yan C, Chen Y. Lethally hot temperatures during the early Triassic greenhouse. Science. 2010;338:366–370.

8. Gerkema MP, Davies WIL, Foster RG, Menaker M, Hut RA. The nocturnal bottleneck and the evolution of activity patterns in mammals. Proc R Soc B 2013; https://doi.org/10.1098/rspb.2013.0508.

9. Clark A, Portner H-O. Temperature, metabolic power and the evolution of endothermy. Biol Rev. 2010;85:703–727.

10. Messer M, Weiss AS, Shaw DC, Westerman M. Evolution of the monotremes: phylogenetic relationship to marsupials and Eutherians, and estimation of divergence dates based on a-lactalbumin amino acid sequences. J Mammal Evol. 1998;5(1):95–105.

11. Luo ZX, Wible JR, Yuan CX. An early cretaceous tribosphenic mammal and metatherian evolution. Science. 2003;302:1934-140.

12. Luo ZX, Yuan CX, Meng QJ, Ji Q. A Jurassic Eutherian mammal and divergence of marsupials and placentals. Nature. 2011;476:442–445.

13. Archer M, Flannery TF, Ritchie A, Molnar RE. First Mesozoic mammal from Australia, an early Cretaceous monotreme. Nature. 1985;318:363–366.

14. Novacek MJ. Mammalian phylogeny: shaking the tree. Nature. 1992;356:121–125.

15. Archibald JD, Deutchmann DH. Quantitative analysis of the timing of the origin and diversification of extant placental orders. J Mammal Evol. 2001;8:107–124.

16. Foley NM, Springer MS, Teeling EC. Mammal madness: is the mammal tree of life not yet resolved?. Proc R Soc B 2016; https://doi.org/10.1098/rstb.2015.0140.

17. O’Leary MA, Bloch JI, Flynn JJ, Gaudin TJ, et al. The placental mammal ancestor and the post-K-Pg radiation of placentals. Science. 2013;339:662–667.

18. Murphy WJ, Foley NM, Bredemeyer KR, Gatesy J, Springer MS. Phylogenomics and the genetic architecture of the placental mammal radiation. Ann Rev Anim Biosci 2021; https://doi.org/10.1146/annurev-animal-061220-023149.

19. Prasad AB, Allard MW, Green (ED). Confirming the phylogeny of mammals by use of large comparative sequence data sets. Mol Biol Evol. 2008;25(9):1795–1808.

20. Murphy WJ, Pringle TH, Crider TA, Springer MS, Miller W. Using genomic data to unravel the root of the placental mammal phylogeny. Genome Res 2007; https://doi.org/10.1101/gr.5918807.

21. Simpson GG. The principles of classification and a classification of the mammals. Bull Amer Mus Nast Hist. 1945;85:1–350.

22. Schulte P, et al. The Chicxulub asteroid impact and mass extinction at the Cretaceous Paleogene boundary. Science. 2010;327:1214-8.

23. Meredith RW, Janecka JE, Gatesy J, Ryder OA, et al. Impacts of the cretaceous terrestrial revolution and KPg extinction on mammal diversification. Science. 2011;334:521–524.

24. Lochmiller RL, Deerenberg C. Trade-offs in evolutionary immunology: just what is the cost of immunity?. Oikos. 2000;88:87–98.

25. Fereidouni S, Freimanis GL, Orynbayev M, Ribeca P, et al. Mass die-off of Saiga antelopes, Kazakhstan, 2015. Emerg Inf Dis. 2019;25(6):1169–1176.

26. Tizard IR, Skow L. The olfactory system The immune sensing arm of the immune system. Anim Hlth Res Revs. 2021;22(1):14–25.

27. Graham AL, Schrom EC, Metcalf JE. The evolution of powerful yet perilous immune systems. Trends Immunol 2022; https://doi.org/10.1016/j.it.2021.12.002.

28. Loker ES. Macroevolutionary immunology: a role for immunology in the diversification of animal life. Front Immunol 2012; https://doi.org/10.3389/fimmu.2012.00025.

29. Dunwell TL, Paps J, Holland PWH. Novel and divergent genes in the evolution of placental mammals. Proc Roy Soc B 2017; https://doi.org/10.1098/rspb.2017.1357.

30. Liston A, Humblet-Baron S, Duffy D, Goris A. Human immune diversity: from evolution to modernity. Nat Immunol. 2021;22:1479–1489.

31. Slodkowicz G, Goldman N. Integrated structural and evolutionary analysis reveals common mechanisms underlying adaptive evolution on mammals. Proc Natl Acad Sci USA. 2020;117(11):5977–5986.

Chapter 2

The evolution of viviparity

Abstract

A key feature of most mammals is viviparity. As mammals evolved, they were obliged to develop processes that prevented immunological rejection of the fetus by the mother. The fetus and the mother are immunologically incompatible. As a consequence, viviparous mammals must possess active immunosuppressive mechanisms that will prevent immunological rejection. The development of viviparity did not evolve in a single step. Monotremes lay eggs. In marsupials, pregnancies are very short so the developing young have to be raised in a pouch. In Eutherian mammals, multiple immunosuppressive mechanisms are required to ensure fetal survival. These include the loss of MHC antigen expression as well as the use of regulatory uterine natural killer cells and Treg cells. Numerous other mechanisms are employed to ensure fetal tolerance throughout pregnancy and prevent maternal sensitization.

Keywords

Placenta; trophoblast; uterine NK cells; fetal tolerance; regulatory T cells; blocking antibodies; colostrum

The development of the embryo in the eggs of fish, amphibians, reptiles, and birds is limited since it depends entirely on the availability of nutritional reserves stored within the egg itself. The development of viviparity and lactation, therefore, opened up two other avenues through which the developing embryo and newborn could receive nutrition – through the placenta and the mammary glands. The major nutritional components of egg yolks, such as proteins, lipids, calcium, and phosphorus are transported to the yolk by a family of proteins called vitellogenins. The developing embryo in ovo can receive no other nutritional support. In contrast, Eutherian mammals no longer need vitellogenins. The vascularized chorioallantoic placenta can support the nutritional needs of the developing fetus while milk provides essential nutrients to the newly born [1]. As a result, the three ancestral vitellogenin genes were progressively pseudogenized in mammals before 30–70 mya. The only exceptions to this are the egg-laying monotremes that still retain a single functional vitellogenin gene. Conversely, caseins that have a similar nutritional function, probably appeared in the milk of the common mammalian ancestor about 200–310 mya.

2.1 The evolution of the placenta

All mammals except the monotremes rely on a placenta to support fetal growth within the uterus. In Eutherians, the placenta is the sole route by which nutrients and oxygen can reach the fetus while carbon dioxide and other waste products are removed. The placenta is thus a key feature of therian reproduction. The placenta enables mammals to both protect the developing fetus while supporting its growth and development for as long as possible. As mammals have evolved, the placenta has been subjected to selective pressure and multiple different morphological types of placenta have evolved, suggesting convergent evolution. Thus an organ with great morphological variation plays the same functional role across multiple mammalian orders.

Mammalian placentas presumably evolved between 300 and 150 mya with the rise of the monotremes and the appearance of the first Metatherians and Eutherians. The development of viviparity was not however a simple single step. Too many changes are required to turn an egg-laying synapsid into a fully viviparous Eutherian. The evolution of viviparity must have involved progressive adaptations of preexisting precursor genes, causing gradual alterations in regulatory pathways and modifying many different proteins to permit their expression in the primordial placenta and uterus. A lot of things had to come together in the correct order for viviparity to succeed. Changes in uterine physiology would have had to occur together with changes in immune regulation. It would not have been a rapid conversion process. On the other hand, viviparity resulted in an enormous improvement in neonatal survival over oviparity, especially in the presence of hungry dinosaurs.

Although all mammalian placentae have similar functions, they differ in both gross and microscopic structures. These differences play a significant role in both the development of maternal immune tolerance to what is essentially a semiallogeneic parasite and also in the way by which maternal immunity can be transferred to her offspring in the form of immunoglobulins.

Depending upon the species, the placenta attaches to and then invades the uterine decidua. This is the specialized uterine mucosa [2]. Since the placenta is derived from the developing fetus and obtains half of its genetic material from the father it should be regarded as foreign by the maternal immune system and rejected in the same way that a foreign organ graft is rejected. The fact that it is not rejected is a remarkable feature of the mammalian immune and reproductive systems.

2.1.1 Monotremes

When birds lay eggs, the fertilized ovum is encased within the eggshell within a few hours of fertilization so that almost all bird development occurs within the fully formed shell. In effect, the developing embryo in the form of a fertile egg is expelled from the uterus almost immediately after it forms. Monotremes such as the platypus and echidnas do things differently. The egg is retained within the uterus for around 15–20 days in the echidna before being laid and incubated outside the body. About two-thirds of the embryologic development occurs within the egg which is very small by Eutherian standards. However, monotreme eggs still contain considerable quantities of yolk compared to marsupials and Eutherians. The developing embryo is also fed by endometrial glandular secretions. These nutrients are absorbed by the yolk sac through the permeable eggshell membrane. Thus the yolk sac functions, in effect, as a placenta. It consists of a vascularized trilaminar yolk membrane. This membrane is both porous and elastic and will stretch as the developing embryo grows. The process of feeding on maternal secretions is called matrotrophy. It has been argued that the monotreme yolk sac may be considered to be a form of placenta even though it is transient. Thus it comes into contact with the eggshell and nutrients can therefore pass from the endometrium, through the porous shell to the yolk. Yolk sacs also serve as early, temporary placentas in embryonic rodents and humans (Fig. 2.1).

Figure 2.1 The embryonic membranes of a developing mammalian embryo. Both the yolk sac and the chorioallantois have the potential to absorb nutrients and so serve as placentas (red arrows). The yolk sac is important in monotremes and serves as temporary placenta early in marsupial, rodent and human pregnancies.

2.1.2 Marsupials

Marsupials possess noninvasive epitheliochorial placentas. Their placentas are however short-lived, and so marsupials give birth to relatively underdeveloped young [3]. The developing marsupial embryo is first enclosed by a zona pellucida, a mucoid coat, and a shell membrane. The shell membrane is secreted by the epithelial cells at the utero-tubal junction. It consists of a glycoprotein, CP4, that has significant homology to α-enolase and τ-crystallin [4]. The shell membrane persists until the blastocyst stage. Eventually, however, the shell membrane breaks down and the embryo hatches between 65% and 85% of the way through gestation. (Unlike monotremes where the shell membrane persists until after birth). This event occurs at about 18–22 days gestation in the tammar wallaby (Notamacropus eugenii), a species in which the entire gestation period is 27 days. The breakdown of the shell membrane triggers an inflammatory response at the fetal-maternal interface and this response may serve as the initiating stimulus for triggering birth [5]. The marsupial oocyte also contains considerably more yolk than that of Eutherians. This yolk is required to support the earliest stages of embryonic development. As the embryo develops, most of the marsupial yolk sac remains outside and is not absorbed into the embryonic mesoderm [6]. The external yolk sac forms a transient placenta during the early post-implantation period following the rupture of the shell membrane [7]. This is a non-invasive placenta derived from the fusion of the yolk sac and the chorion. An area of syncytium forms where the placenta comes into contact with maternal blood vessels. This placenta can absorb nutrients from both the uterine glands as well as from the maternal bloodstream [3].

The increasingly important role of nutrition through the placental route followed by the complex and prolonged lactation period reduced the need for yolk sac nutrition. As a result, in most mammals, the yolk sac placenta becomes vestigial after the first trimester except in rodents and rabbits [8]. In lagomorphs, rodents, some insectivores, and some Chiroptera the embryonic hemisphere of the yolk sac remains attached to the mesoderm. In most other Eutherians the entire yolk sac is invaded by embryonic mesoderm so that it is completely interiorized in the developing embryo.

2.1.3 Eutherians

Eutherian mammals have a placenta derived not from the yolk sac, but from the other two fetal membranes the chorion and allantois. This chorioallantoic placenta is fed by umbilical arteries that spread across the placenta to form a dense blood supply. In some species and individuals, the placenta may be divided into lobes. Once attached to the uterine wall, it consists of the combined endometrium and the trophectoderm.

2.1.3.1 Shapes and contact areas

Mammalian placentas, while sharing a common basic structure, vary greatly in their gross morphology and the nature of the contact area with maternal tissue. Some species such as horses and pigs have a large area of contact between almost the entire chorioallantois and the entire uterine epithelium. This will usually develop folds and villi and is termed a diffuse type of placenta. Other species have a zonary placenta in which the placenta forms a band of tissue that encircles the fetus. There is an interdigitating contact zone around the chorionic sac. These zonary placentas are found in the Carnivora including dogs, cats, bears, and pinnipeds as well as in some herbivores such as elephants.

Some placentas have multiple discrete areas of attachment with the endometrium and are classified as multicotyledonary. The interplacental areas in these cases are smooth and relatively avascular. The fetal components of these attachment points are called cotyledons. The endometrial contact sites are called caruncles while the complete complex is termed a placentome. The number of placentomes can range from 100 to 120 in sheep to four in deer. This type of placentation is a feature of ruminants.

Finally, some placentas may consist of one or two relatively simple large circular attachment sites. These are a feature of primates, rabbits, and rodents and are called discoid or bidiscoid placentas. In humans, the placenta forms once the developing blastocyst is embedded into the endometrial lining of the uterus. The outer cell layer of the blastocyst eventually differentiates into the trophoblast, the outer cell layer of the placenta. The fetal blood vessels come close to, but do not connect with the maternal blood vessels. This enables the effective transfer of oxygen, and nutrients to the fetus while waste products such as urates and creatinine can diffuse into the maternal circulation.

2.1.3.2 Histologic classification

Eutherian placentas differ in the number of cell layers that persist between the fetal and maternal circulations. This has significant immunological consequences. For example, both the chorioallantoic placenta and the uterine endometrium each have a surface structure that initially consists of three tissue layers. A layer of epithelial cells on the surface, underneath which are layers of connective tissue, and finally a layer of endothelial cells lining blood vessel walls. Depending upon which tissue layers are lost, three major types of placenta develop in mammals (Fig. 2.2). These differ in the precise relationship between the uterine wall and the placental tissues. They are classified as epitheliochorial, endotheliochorial, and hemochorial. It is debatable which of these three was the ancestral form of placenta

Figure 2.2 The three major structural types of placenta. Epitheliochorial placentas completely block maternal antibody transfer. Hemochorial placentas permit the effective transfer of IgG across the placenta to the fetus. Endotheliochorial placentas vary in their ability to permit IgG transfer depending on the species involved. In some species such as the elephant large quantities of immunoglobulins can pass through. In others, such as cats, very little immunoglobulin can pass.

2.1.4 Epitheliochorial placentas

Epitheliochorial placentas are the most superficial type of placenta since there is a minimal invasion of the maternal tissues and the uterine epithelium remains intact. In this case, all the cell layers are retained on both the fetal and maternal sides so that the epithelial cells of the fetal placenta are in close contact with the epithelial cells of the uterus. Apart from local angiogenesis resulting in increased vascularity there are minimal changes in the endometrium. Placental trophoblast cells may attach to and even fuse with maternal epithelial cells but there is no invasion of the uterus by the trophoblast. The fetal and maternal tissues interdigitate to maximize the area of contact between them. The maternal and fetal blood systems remain separated by two layers of epithelial cells and the connective tissue layers in addition to the vascular endothelia. This type of placenta is found in marsupials, horses, whales, and ruminants. It has also evolved separately in strepsirrhine primates (lemurs, bushbabies, and lorises). Many of these species tend to have singleton pregnancies although others such as pigs have large litters. Pigs have a diffuse epitheliochorial placenta. Pregnancy tends to be long, and newborns tend to be well developed (precocial).

In the case of the ruminant placentomes, the trophoblast may fuse to a limited extent with the maternal epithelium, so it is classified as a synepitheliochorial placenta. The chorionic cells fuse with the epithelial cells to form hybrid multinucleated fetomaternal cells. There is no immunoglobulin transfer across this type of placenta and as a result, the newborn is completely dependent on receiving immunoglobulins through their mother’s colostrum immediately after birth.

2.1.5 Endotheliochorial placentas

In an endotheliochorial placenta, the maternal uterine epithelium and its outer connective tissue layers are degraded after implantation so that the invasive trophoblast comes into direct contact with the uterine mesenchyme and endothelial cells of the maternal blood vessels. These invasive trophoblast cells include cytotrophoblasts and syncytiotrophoblasts. In effect, the fetal blood vessels in these cases are now in contact with the maternal blood vessels. The blood systems are only separated by a single layer of epithelial cells in addition to the blood vessel walls. This is a feature of placentas in the Carnivora such as cats and mink. Dogs have a zonary endotheliochorial placenta. This type of placentation is found in all four of the supraordinal mammalian clades Euarchoglires, Laurasiatherians, Xenarthra, and Afrotheria. Because of their close association with maternal tissues, this type of placenta must be significantly immunosuppressive to prevent a maternal immunological attack on the fetal cells [9].

Some carnivore placentas also possess placental hematomas or (hematophagous organs) [10]. In such cases, the fetal phagocytes digest any maternal blood cells that leak from the blood vessels. It is suggested that this is a mechanism by which the developing fetus can acquire iron. These hematomas are a feature of placentas in most carnivores, elephants, and some bats but not in hyaenas [11].

2.1.6 Hemochorial placentas

In a hemochorial placenta, the organ grows in such a way that by the end of the first trimester of pregnancy the invasive fetal trophoblast penetrates deep into the uterine wall and disrupts the uterine vascular endothelial cells and even the media of the uterine spiral arteries. As a result, there is fetal and maternal remodeling of the spiral arteries so that the placenta is bathed in oxygenated maternal blood. This remodeling involves dilatation of these arteries. This both reduces local blood pressure and maximizes the volume of blood bathing the intervillous space of the placenta [2]. The trophoblast cells erode all the maternal tissues including the uterine vascular epithelium so that the fetal chorionic epithelium is in direct contact with the maternal blood. As a result, only a single layer of epithelium, connective tissue, and fetal endothelium separate the blood