The system is usefully divided into the innate and specific responses, although there is considerable interaction between these components.
This comprises the elements of the immune system that can mount a non-specific, ‘immediate’ response. These are directly activated by infectious agents, inflammation or tumours. The innate response has the advantage of speed, but lacks specificity, and may cause host tissue damage. The main components are:
1 Phagocytes (neutrophils, monocytes and macrophages)
2 Other inflammatory cells
4 Acute phase reactants such as fibronectin, C-reactive protein
The neutrophil (polymorphonuclear, or PMN cell) is the most specialized microbicidal phagocyte. The human body contains over lOll cells/kg, most of which are in the bone marrow. These cells are released in large numbers during acute infection, and new cells are produced by the action of granulocyte and granulocyte-macrophage colony stimulating factors (G-CSF and GM-CSF, to cause the characteristic neutrophil leukcocytosis.
In premature infants, or others with poorly functioning bone marrow, storage pool exhaustion can occur and results in peripheral blood neutropenia during severe infections.
Microbicidal function of neutrophils
RECRUITMENT. Powerful chemoattractants (chemicals which attract phagocytes) are released at sites of infection or inflammation. The main ones are the complement activation products CSa and C3a and the macrophage-derived leukotriene B.. These substances cause migration of neutrophils to the site by two mechanisms:
1 Up-regulation of adhesion molecules on neutrophils, which increases margination and adhesion of neutrophils to the vascular endothelium.
2 Stimulating neutrophil chemotaxis (movement towards the stimulus). Cells pass between endothelial cells into the tissues by diapedesis.
PHAGOCYTOSIS AND INTRACELLULAR KILLING.
Phagocytosis occurs by the formation of pseudopodia around the organism or particle to be ingested. Due to the fluidity of the cell membrane, the tips eventually fuse to form a membrane-bound vesicle. The phagosome fuses with the neutrophil cytoplasmic granules to form a phagolysosome. Within this localized environment killing occurs. There are two major mechanisms:
1 02-dependent response or respiratory burst, in which there is production of reactive oxygen metabolites, such as hydrogen peroxide, hydroxyl radicals and singlet oxygen, via the reduction of oxygen by an NADPH oxidase 2 02-independent response, due to the toxic action of preformed cationic proteins and enzymes contained within the neutrophil cytoplasmic granules Ingestion and killing of organisms is much more effective if the particle is first coated or opsonized (‘made ready to eat’) with specific antibody and complement. This is because neutrohils have Fe receptors (FcR) for immunoglobulin, and complement receptors (CR), which bind to the coated particle. Binding of the receptors:
• Increases the force of adhesion between particle and phagocyte
• Causes transduction of intracellular signals and activation of the cell to increased phagocytic and killing activity.
The role of antibody in this situation demonstrates the interaction of the innate and specific immune responses. Neutrophils can only ingest particles smaller than themselves and are therefore mainly active against extracellular infections, particularly bacteria and fungi. They provide the major immune response protecting the blood and viscera from these types of organisms.
These cells comprise up to 5% of white blood cells in healthy individuals and appear to be used selectively for fighting parasitic (particularly nematode) infections. They have low-affinity surface receptors for IgE. Unlike neutrophils, they do not appear to be phagocytic, but they contain many large granules, which are cytotoxic when released onto the surface of organisms.
MAJOR BASIC PROTEIN (MBP) is the major protein component of eosinophil granules and directly damages helminths, producing ballooning and detachment of the tegumental membrane.
EOSINOPHIL CATIONIC PROTEIN (ECP) is present in the matrix of eosinophil granules and its deposition has been seen in the kidneys of patients with renal disease, certain types of myocardial infarction and allergic gastroenteritis. It is highly toxic to parasites, being eight to ten times more active than MBP, producing complete fragmentation and disruption of the organisms. ECP is a potent neurotoxin.
EOSINOPHIL-DERIVED NEUROTOXIN (EDN) IS released from the matrix of eosinophil granules and can damage myelinated neurones in experimental animals.
EOSINOPHIL PEROXIDASE (EPO) is localized in the granule matrix of the eosinophil and in combination with a halide and hydrogen peroxide can kill bacteria,helminths and tumour cells; it inactivates leukotrienes C. and D. and causes mast cell degranulation. Eosinophils also participate in immediate hypersensitivity reactions.
8asophils and mast cells
Mast cells consist of at least two distinct populations, which are distinguished by their enzymic content. The T mast cells contain trypsin alone and were formerly termed mucosal mast cells owing to their location near mucosal surfaces. The TC mast cells contain both trypsin and chymotrypsin and were formerly described as connective tissue mast cells, owing to their location. The TC mast cells contain more histamine, which is released following stimulation with basic amines. Conversely, only T mast cells contain cytoplasmic IgE.
Basophils and the morphologically similar mast cells make up only a very small proportion of the granulocytic white blood cell population. Basophils are involved in inflammation although their role is rather obscure. The cytoplasmic granules of basophils and mast cells contains histamine and other vasoactive amines. These cells also bear high affinity IgE Fc receptors and participate in immediate hypersensitivity reactions.
Complement is involved in the eradication of organisms and immune complexes, as well as inflammation and immunoregulation. The complement system comprises a series of at least 20 serum glycoproteins that are activated in a cascade sequence, with proenzymes that undergo sequential proteolytic cleavage, similar to the coagulation pathway.
Two pathways of activation exist, termed the classical and alternative pathways. These converge in the activation of C3, both forming individual C3 convertases.
This leads into the final common pathway with the assembly of C5-C9 into the membrane attack complex (MAC), which forms a ‘doughnut-like’ transmembrane channel leading to cell lysis by osmotic shock. Activation of the classical pathway Activation of the classical pathway is calcium and magnesium dependent and occurs by the binding of Cl q (a subcomponent of the Cl molecule) with:
• IgG-containing antigen-antibody immune complexes
Activation of the alternative pathway The main components of this pathway are:
• Factor B
• Factor D
In the presence of factor D, factor B is cleaved (to Bb) and combines with C3b to form the alternative pathway C3 convertase, C3bBb. This convertase is stabilized by properdin. The alternative pathway is continually turning over a a low rate. This is markedly accelerated by alternative pathway activators which provide a ‘protected’ site for the C3bBb convertase, by enhancing the binding of properdin and preventing degradation of the complex.
Activators of the alternative pathway include:
• Yeast cell walls
• Endotoxin (Gram-negative bacterial cell walls)
• C3 nephritic factor (an autoantibody that stabilizes the
convertase), found in patients with mernbrano-proliferative glomerulonephritis.