Marsupial Immune System

Richard H Sutton, Department of Veterinary Pathology, University of Queensland, Queensland, Australia

The Marsupialia are a widely divergent mammalian order which are phylogenetically distinct from Eutheria. It is an order in which the female has two uteri and two lateral vaginae. The young are born at a very early stage of development and continue their growth while permanently attached to a teat, which is usually enclosed within a pouch or marsupium.

Many groups or families of the order have been recognized in both Australia and the Americas. Because the marsupials are born at a very early stage of growth, development in the pouch is akin to fetal in utero growth. Therefore, access to the pouch young has allowed study of many aspects of development which is not readily available in the Eutheria.

Studies of the immune system, both anatomically and physiologically, have been limited to only a few of the more than 100 known species. Much of the work has been on four species: the Virginian opossum (Didelphis virginiana), the South American short-tailed opossum (Monodelphis domestica) and two Australian species, the brush-tail possum (Trichosurus vulpécula) and the quokka (Setonix brachyurus). These are considered typical of marsupials; it is assumed, as in placental mammals, that the structure and function of the immune system are similar regardless of the species. What differences are present probably reflect different dietary habits and different evolutionary pressures within their respective environments.

The pouch young Maternal antibody

The very early developmental stage of the newborn pouch young means that they have only basic but essential physiological processes. Most eutherian newborn are immunologically competent at birth but they are antigenically inexperienced. In contrast, marsupials are not only antigenically inexperienced but also immunologically incompetent. Furthermore, they have to survive in a pouch environment which contains potential pathogens. The development of immune competence and the passive protection of maternal antibody are therefore important requirements. The various time stages relevant to immune development are shown in Table 1.

There is no passage of immunoglobulins during fetal life. This is perhaps surprising in view of their immune incompetence at birth. In Setonix, as in most of the Marsupialia, the placenta has a yolk sac (choriovitelline)-endometrial attachment; the allan-tois does not form part of the attachment. The yolk sac-uterine attachment in Setonix appears to form a complete barrier to immunoglobulins, even though they have been detected in uterine fluid.

The main exception to this type of attachment appears to be in the bandicoot (Per ameles and Isoodon spp.) where there is a true allanto-chorionic placenta in addition to the yolk sac placenta. Neonatal development is comparatively well advanced at birth in the bandicoot as compared to other marsupials. How this relates to immunoglobulin transfer is not known, but studies in placental mammals have shown that where immunoglobulin transfer between mother and fetus prior to birth does occur, there is an allanto-chorionic placenta, such as in primates, or an inverted yolk sac placentation, such as occurs in rodents. In domestic mammals with epithelio-chorionic attachment (horse, cow, pig, sheep), the

Table 1 Developmental stages in the growth and immune responsiveness of the quokka (Setonix brachysurus) and the Virginian opossum (Didelphis virginiana)

Setonix

Didelphis

Time in pouch 180 60-65

Time of initial Ig in pouch young 1-2 1-2

Period of maternal antibody transfer Pouch term (approx.)

Time of initial humoral response 10 8

Time of initial cellular response 20 12

Cervical thymus

First presence of lymphocytes 3 NA

First presence of Hassall's 10 NA

corpuscles Thoracic thymus

First presence of lymphocytes 3-5 2-4

First presence of Hassall's 60 corpuscles

Time to reach full maturity - 32

Lymph nodes

First presence of lymphocytes 5 6-7

Definitive germinal centers 80-100 65 Bone marrow

First presence of lymphocytes - 10-12

Spleen

First presence of lymphocytes - 17-22

All times expressed in days NA, not applicable.

placenta is impermeable to antibodies and where the attachment is endothelio-chorionic (car, dog), there is about 5-10% transfer of the required immunoglobulin.

Once neonates reach the pouch, attach to the teat, and begin to suckle, immunoglobulins are faintly detected in their serum within 24-48 h (Table 1). As in placental mammals, the transfer in the milk is confined principally to the immunoglobulin G (IgG) class, although IgA and IgE classes are probably also transferred. Some variation in the level of maternal antibody being absorbed has been noted, and with Didelphis it has been suggested that the passive transfer does not make an important contribution to the immunological status of the pouch young. More observations are needed to confirm this, but it would be surprising if Didelphis were markedly different from other species, where the level of maternal transfer is an important contributor to pouch young immunity. Antigenic stimulation of specific antibody-production in the mother is followed by a long delay before transfer of the specific antibody to the young. This may reflect the initial lgM response which does not cross the maternal milk. Absorption of antibody from maternal milk is believed to continue until the young leave the pouch (Table 1). This is in contrast to placental mammals, where, for example, maternal antibody is absorbed by the foal, calf, lamb, and piglet for about 24 h, the dog for 10-12 days, the rat for 21 days and the hedgehog for 41 days.

Pouch environment and development of immunity

The pouch normally contains a wide range of microorganisms which might be expected to be a problem for an antigenically inexperienced and immune-incompetent neonate. However, it has been shown that there is a reduction in the pouch flora of pregnant Setonix. It is not clear whether the antibacterial properties of pouch secretions are due to immunoglobulins or other substances. This 'cleansing' process allows time for the adaptation of the pouch young to its environment and the opportunity to become immune competent. In Setonix, the gut of the pouch young is first colonized at about 10 days, which is the time at which some immunocompetence is first apparent (Table 1).

The ability to develop and maintain an immune response is dependent on thymic maturation. The Marsupialia include species with thymic tissue in both intrathoracic and superficial ventral cervical locations. The cervical thymus has its origin in the cervical sinus, whereas the thoracic thymus originates in the third and fourth pharyngeal pouches. There are three distinct groupings based on thymic location, namely thoracic only, both thoracic and cervical, and cervical only. The reason for this variation is not clear. Those with two distinct glands are herbivorous, have a small number (1-4) of pouch young and a large deep pouch. These include many Australian species including Trichosurus and Setonix. Most families that have carnivorous, insectivorous or omnivorous diets have large litters, a shallow or no pouch, a short pouch term and a thoracic thymus only. All the American marsupials, including Didelpbis and Monodelphis, are in this latter group, which also includes Antechinus, Isodoon and Perameles spp. from Australia. The only family grouping with cervical thymus glands only are the wombats, Vombatus and Lasiorhinus spp.

The deep-pouched species have a rich and varied bacterial profile, whereas species with only a thoracic thymus have much less diversity in the bacterial flora in the pouch. However, it has been shown that in Setonix, the cervical gland plays a definite role in the development of immune responses. Removal of the gland does not cause a compensatory increase in the thoracic gland but removal of the cervical thymus before day 10 and total thymectomy before day 20 depresses the blood lymphocyte count and delays the onset of immune competence. Total neonatal thymectomy does not stop the subsequent development of immune competence in the adult, even though the development of other lymphoid tissues is delayed following the thymectomy. Functionally, the role of the cervical gland is probably, at least in parr, similar to that of the thoracic gland.

Thymic development in the pouch young is very-rapid and appears to correspond to the development of immune competence, which occurs very early after entering the pouch. Immune competence of Setonix appears to increase in proportion to the development of the cervical thymus, which becomes functional about 30 days before the thoracic gland and reaches full size at about the time the young leave the pouch. However in the American marsupials the thoracic-gland reaches maturity at an early age (Table 1). Whether this also applies to the bandicoots (where immunoglobulin transfer across the allantoic-chori-onic placenta may occur) or whether development of their thoracic gland is delayed is not known. The cervical gland can develop to a large size and it has been suggested that the size of the cervical thymus would be difficult to accommodate in an intrathoracic location.

In most instances, detectable antibody is present within 7 days of challenge. Challenge prior to 8-10 days of age is unlikely to elicit a response. The degree or level of antibody response appears to be dependent on the nature of the antigen. Some antigens appear to provoke an adult-like response early in life, whereas others tend to show an increasing magnitude of response in proportion to age; reaching adult levels at the time of leaving the pouch. This would suggest that there is an inverse relationship between the degree of immune response and the presence of maternally derived antibody. Similar findings to this have also been noted in various species of kangaroos (Macropus spp.).

The development of cellular immunity appears to parallel the development of humoral immunity. The results of lymphocytic stimulation tests, for example, support the conclusion that both humoral and cellular immunity develop throughout the pouch term and reach full maturity at the end of pouch life.

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