Blood, Lymphoid Tissue And Haematopoeisis Flashcards
(31 cards)
What is blood?
Blood is an opaque fluid with a viscosity greater than that of water
(mean relative viscosity 4.75 at 18°C), and a specific gravity of 1.06 at
15°C. It is bright red when oxygenated, in the systemic arteries, and dark
red to purple when deoxygenated, in systemic veins. Blood is a mixture
of a clear liquid, plasma and cellular elements.
What is plasma?
Plasma is a clear, yellowish fluid that contains many substances in solution or suspension. Plasma contains high concentrations of sodium and chloride ions, potassium, calcium, magnesium, phosphate, bicarbonate, traces of many other ions, glucose, amino acids and vitamins. It also includes high-molecular-weight plasma proteins,
e.g. clotting factors, particularly prothrombin; immunoglobulins and complement proteins involved in immunological defence; glycoproteins, lipoproteins, polypeptide and steroid hormones, and globulins
for the transport of hormones and iron.
ERYTHROCYTES
Erythrocytes (red blood cells, RBCs) account for the largest proportion of blood cells (99% of the total number).
Polycythaemia (increased red cell mass) can occur in individuals living at high altitude, or pathologically in conditions resulting in arterial hypoxia.
Each erythrocyte is a biconcave disc. Mature erythrocytes lack nuclei.
Haemoglobin
Haemoglobin (Hb) is a globular protein. It consists of globulin molecules bound to haem, an iron containing porphyrin group. The oxygen-binding power of haemoglobin is provided by the iron atoms of the haem groups, and these are maintained in the ferrous (Fe++) state.
Mutations in the haemoglobin chains can result in a range of pathologies.
Lifespan of Erythrocytes
Erythrocytes last between 100 and 120 days before being destroyed. As erythrocytes age, they become increasingly fragile, and their surface charges decrease as their content of negatively charged membrane glycoproteins diminishes. The lipid content of their membranes also reduces. Aged erythrocytes are taken up by the macrophages of the spleen and liver sinusoids.
Iron is removed from the porphyrin ring and either transported in the circulation bound to transferrin and used in the synthesis of new haemoglobin in the bone marrow, or stored in the liver as ferritin or haemosiderin.
The remainder of the haem group is converted in the liver to bilirubin and excreted in the bile. Haemoglobin that is released by destruction of erythrocytes in the body binds to haptoglobin, and is
taken up via CD163 receptors expressed on the surface of macrophages.
Neutrophil granulocytes
Neutrophil granulocytes (neutrophils) are also referred to as polymorphonuclear leukocytes (polymorphs) because of their irregularly segmented (multilobed) nuclei.
In mature neutrophils the nucleus is characteristically multilobed with up to six (usually three or four) segments joined by narrow nuclear strands; this is known as the segmented stage.
Why are neutrophils important in the defence of the body?
Neutrophils are important in the defence of the body against microorganisms. They can phagocytose microbes and small particles in the circulation and, after extravasation, they carry out similar activities in other tissues. They function effectively in relatively anaerobic conditions, relying largely on glycolytic metabolism, and they fulfil an important role in the acute inflammatory phase of tissue injury, responding to chemotaxins released by damaged tissue. Phagocytosis of cellular debris or invading microorganisms is followed by fusion of the phagocytic vacuole with granules, which results in bacterial killing and digestion. Actively phagocytic neutrophils are able to reduce oxygen enzymatically to form reactive oxygen species including superoxide radicals and hydrogen peroxide, which enhance bacterial destruction probably by activation of some of the granule contents. Neutrophils can also produce neutrophil extracellular traps (NETs), which are web-like structures composed of DNA and
proteolytic enzymes that can trap bacteria and kill them.
Eosinophils
Like other leukocytes, eosinophils are motile. When suitably stimulated, they are able to pass into the extravascular tissues from the circulation.
Eosinophil numbers rise (eosinophilia) in worm infestations and also in certain allergic disorders, and it is thought that they evolved as a primary defence against parasitic attack. They have surface receptors for IgE that bind to IgE-antigen complexes, triggering phagocytosis and release of granule contents. However, they are only weakly phagocytic and their most important function is the destruction of parasites too large to phagocytose. This antiparasitic effect is mediated via toxic molecules released from their granules. They also release histaminase, which limits the inflammatory consequences of mast cell degranulation.
Basophil granulocytes
Their distinguishing feature is the presence of large, conspicuous basophilic granules. The nucleus is somewhat irregular or bilobed. The granules are membrane-bound vesicles, which display a variety of crystalline, lamellar and granular inclusions: they contain heparin, histamine and several other inflammatory agents, and closely
resemble those of tissue mast cells. Both basophils and mast cells have high-affinity membrane receptors for IgE and are therefore coated with IgE antibody. If this binds to its antigen it triggers degranulation of the
cells, producing vasodilation, increased vascular permeability, chemotactic stimuli for other granulocytes, and the symptoms of immediate hypersensitivity, e.g. in allergic rhinitis (hay fever). Despite these similarities, basophils and mast cells develop as separate lineages in the myeloid series, from haemopoietic stem cells in the bone marrow.
Monocytes
Monocytes are the largest of the leukocytes. Monocytes are actively phagocytic cells and contain numerous lysosomes. Phagocytosis is triggered by recognition of opsonized material, as described for neutrophils. Monocytes are highly motile.
Monocytes express class II MHC antigens and share other similarities
to tissue macrophages and dendritic cells.
Most monocytes are thought to be in transit via the blood stream from the bone marrow to the
peripheral tissues, where they give rise to macrophages and dendritic cells; different monocyte subsets may target inflamed tissues.
Lymphocytes
Blood lymphocytes are a heterogeneous collection mainly of B and T cells. About 85% of all circulating lymphocytes in normal blood are T cells. Primary immunodeficiency diseases can result from
molecular defects in T and B lymphocytes. Included with the lymphocytes, but probably constituting a separate lineage subset, are the natural killer (NK) cells.
B cells
B cells and the plasma cells that develop from them synthesize and secrete antibodies that can specifically recognize and neutralize foreign (non-self) macromolecules (antigens), and can direct various nonlymphocytic cells (e.g. neutrophils, macrophages and dendritic cells) to phagocytose pathogens.
B cells differentiate from haemopoietic stem cells in the bone marrow.
B cells develop into long-lived memory cells capable of responding to their specific antigens not only with a more rapid and higher antibody output, but also with an increased antibody affinity compared with the primary response.
Antibodies are immunoglobulins, grouped into five classes.
* Immunoglobulin G (IgG) forms the bulk of circulating antibodies.
* Immunoglobulin M (IgM) is normally synthesized early in immune responses.
* Immunoglobulin A (IgA) is present in breast milk, tears, saliva and other secretions of the alimentary tract, coupled to a secretory piece. IgA contributes to mucosal immunity.
* Immunoglobulin E (IgE is an antibody which binds to receptors on the surfaces of
mast cells, eosinophils and blood basophils).
* Immunoglobulin D (IgD is found together with IgM as a major membrane-bound immunoglobulin on
mature, immunocompetent but naïve (prior to antigen exposure B cells, acting as the cellular receptor for antigen).
T cells
There are a number of subsets of T (thymus-derived) lymphocytes, all progeny of haemopoietic stem cells in the bone marrow. They develop and mature in the thymus, and subsequently populate peripheral secondary lymphoid organs, which they constantly leave and re-enter via the circulation. As recirculating cells, their major function is immune surveillance. Their activation and subsequent proliferation and functional maturation are under the control of antigen-presenting cells. T cells undertake a wide variety of cell-mediated defensive functions that are not directly dependent on antibody activity, and which constitute the basis of cellular immunity.
T-cell responses focus on the destruction of cellular targets such as virus-infected cells, certain bacterial infections, fungi, some protozoal infections, neoplastic cells and the cells of grafts from other individuals (allografts, when the tissue antigens of the donor and recipient are not sufficiently similar). Targets may be killed directly by cytotoxic T cells, or indirectly by accessory cells (e.g. macrophages that have been recruited and activated by cytokine-secreting helper T cells). A third group, regulatory T cells, acts to regulate or limit immune responses.
Functional groups of T cells are classified according to the molecules they express on their surfaces. The majority of cytokine-secreting helper T cells express CD4, while cytotoxic T cells are characterized by CD8.
Cytotoxic T cells
Cytotoxic T lymphocytes (which express CD8 are responsible for the
direct cytotoxic killing of target cells (e.g. virus-infected cells; the
requirement for direct cell–cell contact ensures the specificity of the
response)). Recognition of antigen, presented as a peptide fragment on
MHC class I molecules, triggers the calcium-dependent release of lytic
granules by the T cell. These lysosome-like granules contain perforin
(cytolysin, which forms a pore in the target cell membrane). They also
contain several different serine protease enzymes (granzymes), which
enter the target cell via the perforin pore and induce the programmed
cell death (apoptosis) of the target.
Helper T cells
Helper T cells (which express CD4) are characterized by the secretion of cytokines. Two major populations have been identified according to the range of cytokines produced. Th1 helper T cells typically secrete
interleukin (IL-2, tumour necrosis factor alpha (TNF-α and interferon gamma (IFN-γ)), while Th2 cells produce cytokines such as IL-4, IL-5 and IL-13. These two CD4-expressing populations are termed ‘helper’ T cells because one aspect of their function is to stimulate the proliferation and maturation of B lymphocytes and cytotoxic T lymphocytes (mediated via cytokines such as IL-4, IL-2 and IFN-γ), thus enabling and enhancing the immune responses mediated by those cells.
Natural killer (NK) cells
Natural killer (NK) cells have functional similarities to cytotoxic T cells but they lack other typical lymphocyte features and do not express antigen-specific receptors. These contain the protein perforin, which is capable of inserting holes in the plasma membranes of target cells, and granzymes, which trigger subsequent
target cell death by apoptosis. NK cells are activated to kill target cells. They can recognize and kill antibody-coated target cells via a mechanism termed antibody-dependent cell-mediated cytotoxicity. They also have receptors that inhibit NK destructive activity when they recognize MHC class I on normal cells. When NK cells detect the loss or downregulation of MHC class I antigens on certain virus-infected cells and some tumour cells, they activate
apoptosis-inducing mechanisms that enable them to attack these abnormal cells, albeit relatively non-specifically.
PLATELETS
Blood platelets, also known as thrombocytes, are relatively small in blood. In freshly harvested blood samples
they readily adhere to each other and to all available surfaces, unless the blood is treated with citrate or other substances that reduce the availability of calcium ions. Platelets are anucleate cell fragments, derived from megakaryocytes in the bone marrow. They are surrounded by a plasma membrane with a thick glycoprotein coat, which is responsible for their adhesive properties.
Platelets play an important role in haemostasis. When a blood vessel is damaged, platelets become activated, evert their membrane invaginations to form lamellipodia and filopodia, and aggregate at the site of
injury, plugging the wound. They adhere to each other (agglutination) and to other tissues. Adhesion is a function of the thick platelet coat and is promoted by the release of adenosine diphosphate (ADP) and calcium ions from the platelets in response to vessel injury. The contents of released α granules, together with factors released from the damaged tissues, initiate a complex sequence of chemical reactions in the blood plasma, which leads to the precipitation of insoluble fibrin filaments in a three-dimensional meshwork, the fibrin clot. More platelets attach to the clot, inserting extensions of their surfaces, filopodia, deep into the spaces between the fibrin filaments, to which they adhere strongly. The platelets then contract (clot retraction) by actin–myosin interactions within their cytoplasm, and this concentrates the fibrin clot and pulls the walls of the blood vessel together, which limits
any further leakage of blood. After repair of the vessel wall, which may be promoted by the mitogenic activity of PDGF, the clot is dissolved by enzymes such as plasmin. Plasmin is formed by plasminogen activators
in the plasma, probably assisted by lysosomal enzymes derived from the λ granules of platelets. Platelets typically circulate for 10 days before they are removed, mainly by splenic macrophages.
LYMPH NODES
Lymph nodes are encapsulated centres of antigen presentation and lymphocyte activation, differentiation and proliferation, which are facilitated by complex trafficking of cells and lymphatic flow through the structure. They generate mature, antigen-primed B and T cells, and filter particles, including microbes, from the lymph
by the action of numerous phagocytic macrophages. Lymph nodes are particularly numerous in the
neck, mediastinum, posterior abdominal wall, abdominal mesenteries, pelvis and proximal regions of the limbs (axillary and inguinal lymph nodes).
Lymphatic and vascular supply
Lymph nodes are permeated by channels through which lymph percolates after its entry from the afferent vessels. The conduit system consists of collagen fibres and associated fibrils surrounded by fibroblast reticular cells, forming a sponge-like reticulum that provides not only spaces for the lymphocytes but also a system for the transport of antigen and signalling molecules (such as chemokines) that control the highly dynamic movement and interaction of the immune cells. Dendritic cells can reach inside the conduits to sample antigen, and then present it to immune cells.
Afferent lymphatic vessels enter at many points on the periphery, branch to form a dense intracapsular plexus, and then open into the subcapsular sinus, a cavity that is peripheral to the whole cortex except at the hilum . Numerous radial cortical sinuses lead from the subcapsular sinus to the medulla, where they coalesce as larger
medullary sinuses. The latter become confluent at the hilum with the efferent vessel that drains the node. All of these spaces are lined by a continuous endothelium and traversed by fine reticular fibres.
Cells and cellular zones of lymph nodes
Although most of the cells in a lymph node are B and T lymphocytes, their distribution is not homogeneous. In the cortex, cells are densely packed and in the outer cortical area they form lymphoid follicles or nodules, which are populated mainly by B cells and specialized follicular dendritic cells (FDCs). A primary follicle is uniformly populated by small, quiescent lymphocytes, whereas a secondary follicle has a germinal centre, composed mainly of antigenstimulated B cells, which are larger, less deeply staining and more rapidly dividing than those at its periphery.
The role of the germinal centre is to provide a microenvironment that allows the affinity maturation of the B-cell response, so that as the immune response progresses, the affinity or strength with which antibodies bind their antigen increases. In the ‘dark zone’, the B cells (centroblasts) undergo rapid proliferation, which is associated with hypermutation of their antibody molecules. They then move into the ‘light zone’ (as centrocytes), where they can interact with the FDCs, which carry intact unprocessed antigen on their surface in the form of
immune complexes.
T cells are also present, helping the survival of the B cells and inducing class switching. Macrophages in the germinal centre phagocytose apoptotic lymphocytes (e.g. those B cells that die as part of the process of affinity maturation), and consequently macrophage cytoplasm becomes filled with engulfed lipid and nuclear debris
forming sparkling intracellular inclusions (leading to the term tingible body macrophage).
The mantle zone is produced as surrounding cells are marginalized by the rapidly growing germinal centre. It is populated by cells similar to those found in primary follicles: mainly quiescent B cells
with condensed heterochromatic nuclei and little cytoplasm, a few helper T cells, FDCs and macrophages. After numerous mitotic divisions the selected B cells give rise to small lymphocytes, some of which become memory B cells and leave the lymph node to join the recirculating pool, while others leave to mature as antibody-secreting plasma cells either in the lymph node medulla or in peripheral tissues.
The deep cortex or paracortex lies between the cortical follicles and the medulla, and is populated mainly by T cells, which are not organized into follicles. Both CD4 and CD8 T-cell subsets are present.
BONE MARROW
Bone marrow is a soft pulpy tissue that is found in the marrow cavities of all bones and even in the larger Haversian canals of lamellar bone. It differs in composition in different bones and at different ages, and occurs in two forms: yellow and red marrow. In old age the marrow of the cranial bones undergoes degeneration and is then termed gelatinous marrow.
Yellow marrow
Yellow marrow consists of a framework of connective tissue that supports numerous blood vessels and cells, most of which are adipocytes.
Red marrow
Red marrow is found throughout the skeleton in the fetus and during the first years of life. After about the fifth year the red marrow, which represents actively haemopoietic tissue, is gradually replaced in the long bones by yellow marrow. By 20–25 years of age, red marrow persists only in the vertebrae, sternum, ribs, clavicles, scapulae, pelvis and cranial bones, and in the proximal ends of the femur and humerus.
Red bone marrow consists of a network of loose connective tissue, the stroma, which supports clusters of haemopoietic cells (haemopoietic cords or islands and a rich vascular supply in which large, thin-walled sinusoids are the main feature). The vascular supply is derived from the nutrient artery to the bone. Lymphatic vessels are absent from bone marrow.
Marrow thus consists of vascular and extravascular compartments, both enclosed within a bony framework from which they are separated by a thin layer of endosteal cells.
Stroma
Stroma is composed of a delicate network of fine type III collagen (reticulin fibres secreted by highly branched, specialized fibroblast-like cells (reticular cells derived from embryonic mesenchyme). When haemopoiesis stops, as occurs in most limb bones in adult life, these cells (or closely related cells become distended with lipid droplets and fill the marrow with yellow fatty tissue (yellow marrow). If there is a later demand for haemopoiesis, the stellate stromal cells reappear. The stroma also contains numerous macrophages attached to extracellular
matrix fibres. These cells actively phagocytose cellular debris created by haemopoietic development, especially the extruded nuclei of erythroblasts, remnants of megakaryocytes and cells that have failed the
B-lymphocyte selection process. Stromal cells play a major role in the control of haemopoietic cell differentiation, proliferation and maturation.
