of the immune system

CHAPTER 13 Development of the immune system



Morten Vejlsted


The adult body employs multiple layers of defence against foreign materials. These defences are derived from all three embryonic germ layers. Physical barriers, comprising intact epithelia on external and internal body surfaces (i.e. the skin and gastrointestinal tract) serve as a first layer of defence and are derived from the ectoderm and endoderm, respectively. In contrast, cells central to the second and third layers of defence, the innate (pre-existing) immunity and specific (induced/acquired) immunity systems, are derived from the mesoderm. The innate immunity system can act very rapidly but lacks any form of memory; important components of this system are the granulocytes of the myeloid cell lineage that develop from haematopoietic stem cells. The acquired or adaptive immunity system, of the lymphoid cell lineage, on the other hand has memory; cells of the lymphocyte lineage form descendants with effector as well as memory competence. Acquired immunity is dependent on microbial colonization of the gut and is therefore a postnatal phenomenon. Potential pathogen microbes in the gut and on the external body surfaces exhibit high mutation rates. In essence, acquired immunity is all about evolution of the lymphocyte cell lineage having the ability to somatically mutate surface receptors to keep up with this continual exposure to new challenges.


During intra-uterine life, the placenta largely protects the embryo and fetus from exposure to foreign pathogens (see Chapter 9). This results in newborn animals being more or less immunologically naïve – equipped with the fundamentals of the acquired immune system, but still awaiting antigen stimulation for its final development. To compensate for this, intake of antibody-laden colostrum from the mother protects the newborn passively during the first few weeks post partum,. Then, however, the newborn’s own immune system has to mature for the animal to survive. Since this is a textbook on embryology, the focus will be on intra-uterine formation of the cells and organs of the immune system. For descriptions of the post-natal maturation of the immune system and the immune response, as well as immunological specificity and memory, textbooks such as ‘Veterinary Immunology: An Introduction’ by Tizard (2008) should be consulted.



THE LYMPHOCYTES


It has been customary to begin any description of the cells of the developing immune system with a discussion of haematopoietic stem cell formation in the yolk sac. Recently, however, it has been shown that the haematopoietic potential of this yolk-sac stem cell population is limited compared to that of stem cells appearing in the intra-embryonic aorta-gonad-mesonephros (AGM) region shortly afterwards (see Chapter 12). Thus, it is now generally accepted that first the fetal liver, then the thymus and the spleen (during the hepato-lienal period), and finally the bone marrow (during the medullary period) are seeded by haematopoietic stem cells from the AGM region, eventually giving rise to the full complement of the lymphoid, erythroid and myeloid cell lineages. It is the lymphoid cell lineage that gives rise to the Natural Killer (NK) cells and B and T lymphocytes whereas the myeloid cell lineage gives rise to neutrophil, eosinophil and the basophil granulocytes.


Differentiation of lymphocytes begins in the thymus as early as during the hepato-lienal period. Later, gut-associated lymphoid tissue develops, followed by the appearance of lymph nodes, tonsils, and the spleen. With the onset of the medullary period, the bone marrow becomes a site of both haematopoiesis, including lymphopoiesis, and lymphocyte differentiation. The bone marrow, the thymus, and also the gut-associated lymphoid tissue comprise the primary lymphoid tissues, in which cells of the lymphoid cell lineage differentiate and mature. From the primary lymphoid tissues, immune-competent lymphocytes eventually reach secondary lymphoid tissues where immune responses to antigens occur in the newborn animal. Secondary lymphoid tissues include the lymph nodes, spleen, mucosa-associated lymphoid tissues (MALT) and skin associated lymphoid tissues (SALT).



Differentiation of the lymphoid cell lineages


Based on function and specific cell-surface molecules, the lymphoid cell lineage may be divided into large lymphocytes with a granular cytoplasm and small lymphocytes with almost no cytoplasm. The large granular lymphocytes are, together with the granulocytes, effector cells in the innate immune system, and are also known as Natural Killer or NK cells. The small lymphocytes comprise several sublineages, the two major ones being the T and B lymphocytes. T and B lymphocytes differ in function, depending on their various cell-surface receptors (see below). Functionally, T lymphocytes are said to mediate a cellular immune response to foreign macromolecules either directly (by killing virus-infected cells, for example) or indirectly, through activation of specialized phagocytes, including tissue macrophages. B lymphocytes, in contrast, are said to mediate a humoral immune response through their differentiation into antibody-producing plasma cells. The antibodies bind to set areas on foreign macromolecules (antigens) known as epitopes, which may be parts of cell-surface proteins, polysaccharides, or glycosaminoglycans on invading bacteria or viruses. The binding mediates phagocytosis of the intruders and this mechanism is known as opsonization. Antibodies may also activate certain serum proteins (collectively known as the complement system) thereby mediating cell lysis, or may bind to and neutralize bacterial toxins or viruses.



The T lymphocyte


As outlined above, T lymphocytes differentiate from common haematopoietic stem cells initially formed in the AGM region. From there, a small population seeds the Thymus (hence the name) early in fetal development. In the thymus, progenitor T lymphocytes proliferate, mature and form cells each of which is committed to recognizing a single epitope on either self- or non-self antigens. The basis of this specificity lies in the T cell receptor (TCR). Each mature T lymphocyte carries only one type of TCR on its cell surface (around 105 of that particular type per cell). The thymus harbours a huge number of clones, i.e. individual T lymphocyte populations, and all T lymphocytes within a clone share the same TCR characteristics.


In contrast to antibodies, the TCR only recognizes epitopes associated with major histocompatibility complex (MHC) molecules. These are special types of cell-surface molecules and are sites for presentation of an animal’s own or foreign epitopes. There are two classes of MHC molecules: MHC class I molecules, expressed by all nucleated cells except nerve cells; and MHC class II molecules, expressed on special antigen-presenting cells and on B lymphocytes. CD4 and CD8 are other types of cell-surface molecules, defined and grouped through the use of specific antibodies (CD is an acronym for ‘Cluster Defined’). During maturation in the thymus, clones of T lymphocytes differentiate into either CD4-expressing T helper lymphocytes (Th cells) or CD8-expressing cytotoxic lymphocytes (Tc cells). CD4-expressing Th cells only recognize epitopes presented by MHC class II molecules. Such epitopes are presented by antigen-presenting cells or B lymphocytes, which characteristically present epitopes that are parts of exogenous peptides from foreign particles or from pathogens that have invaded the organism and been subjected to endocytosis. CD8-expressing Tc cells, on the other hand, only recognize epitopes presented by MHC class I molecules; these are characteristically endogenous, reflecting peptides synthesized within the cell. Virus-infected cells or tumour cells for example, in which protein synthesis is altered, may be recognized in this way by Tc cells through presentation of these epitopes of ‘non-self’ proteins by MHC class I molecules.


During the maturation of the T lymphocytes in the thymus, about 98% of the cells are eliminated through the process of apoptosis. This elimination includes two selection rounds, the first ensuring that only those T lymphocytes that recognize MHC molecules survive, and the second making sure that all T lymphocytes recognizing ‘self’ epitopes are eliminated. Before their maturation, the T lymphocytes express neither CD4 nor CD8. These immature T lymphocytes are mainly located in the subcapsular thymic areas where the surrounding reticular cells are rich in both MHC class I and MHC class II molecules. During maturation, T lymphocytes move into deeper parts of the cortex, where expression of both CD4 and CD8 is initiated. The consequent ‘double positive’ T lymphocytes, i.e. those expressing both CD4 and CD8, then undergo an initial, or positive selection in which their TCRs are tested against the MHC molecules on surrounding reticular cells. Only T lymphocytes recognizing ‘self’ MHC molecules will survive this process. The positive selection forms the basis of the MHC restriction that results in T lymphocyte acceptance of ‘self’ MHC molecules only. The selected T lymphocytes then move deeper into the thymus where, upon reaching the cortico-medullary junction, the selected ‘double positive’ T lymphocytes undergo the second, or negative selection for ‘self’ reactivity. This results in the elimination of T lymphocytes carrying TCRs recognizing epitopes of ‘self’ antigens. In this way, ‘self’ is accepted, forming the basis of immunological tolerance.


One problem inherent to these selections is that during the positive selection, T lymphocytes recognizing ‘self’ MHC molecules are selected for, whereas during the negative selection, T lymphocytes recognizing ‘self’ MHC, and other, molecules are selected against. The reason for this paradoxical process, which would ultimately leave no surviving T lymphocytes, is still an enigma. One favoured hypothesis to explain the contradiction is that the positive selection results in populations of T lymphocytes with receptors having a range of affinities, from low to high, for ‘self’ MHC molecules. Through the negative selection, T-lymphocytes with high affinity receptors are weeded out while those with low affinity survive. Thus, instead of using an ‘either/or’ criterion, the second, negative selection occurs according to ‘more or less’ guidelines.


Only T lymphocytes that have survived both positive and negative selection move into the medulla, and then as either CD4-positive, MHC class II-restricted T helper (Th) lymphocytes or CD8-positive, MHC class I-restricted cytotoxic (Tc) lymphocytes. The end result is a selection for TCRs (on either Th or Tc cells) specifically recognizing a combination of ‘self’ MHC molecules and foreign or altered epitopes. The T lymphocytes, however, are functionally naïve when they leave the thymus. Subsequently, they circulate in the blood, lymphatic tissues, and lymph to perform what may be termed ‘immunological surveillance’. Only upon TCR recognition of foreign or altered epitopes presented by the MHC class I or II molecules will the T lymphocytes undergo final differentiation, perform their role in the cellular immune response, and establish memory.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on of the immune system

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