All of the other cells have an accessory function: activation of lymphocytes, phagocytosis/antigen clearance, secretion of cytokines.
MONOCYTES AND MACROPHAGES
also called mononuclear cells
Monocytes circulate in the blood and lymph (represent 5-8% of WBCs in the blood)
From monocyte ------> macrophage
This transition occurs as the monocytes enter the tissues.
Changes which occur during this transition:
Cells enlarge [5-10x]
intracellular organelles increase in number and complexity
cells acquire increased phagocytic ability
secretion of many soluble factors
Macrophages play the following important roles:
1) phagocytosis
2) antimicrobial activity
3) antigen presentation
4) secretion of soluble factors
Macrophages are activated by a variety of stimuli in the course of an immune response. Phagocyotosis itself is an initial activating stimulus. Macrophages are further activated by cytokines secreted by T helper cells [IFN-gamma], by mediators of the inflammatory response and by various microbial products.
PHAGOCYTOSIS
The process of phagocytosis involves:
chemotaxis
extension of pseudopodia
formation of a phagosome
fusion with lysosome---->phagolysosome
[lysosome contains hydrogen peroxide, oxygen free radicals, peroxidase, lysozyme, hydrolytic enzymes]
elimination of digested components via exocytosis
Antimicrobial Activity
Following phagocytosis, microorganisms are killed by both oxygen dependent and oxygen independent mechanisms.
Oxygen Dependent
Respiratory burst involves the activation of a membrane-bound oxidase that catalyzes the reduction of oxygen to superoxide anion (O2-) which is extremely toxic.
The O2- also generates other powerful oxidizing agents:
hydroxyl radicals (OH')
singlet oxygen (O2)
hydrogen peroxide (H2O2)
Macrophages activated with LPS or other microbial products together with IFN-gamma also express high levels of enzyme= nitric oxide synthestase
This enzyme oxidizes L-arginine to yield citruline and nitric oxide (NO)
NO is a very potent toxic agent. When it combines with the superoxide anion O2- it is even more toxic. Nitric Oxide-mediated killing may be more important than respiratory burst in the destruction of intracellular pathogens.
Oxygen Independent
-Lysozyme
-Other Hydrolytic enzymes
-Defensins [ cysteine-rich cationic peptides - circularize due to the presence of 3 intramolecular disulfide bonds- Form ion-permeable channels in bacterial and mammalian cell membranes
-tumor necrosis factor alpha
(produced by activated macrophages - cytotoxic affect on some cell types)
Secretion of Cytokines
IL-1 - multiple effects (activation of TH cells, affects vascular endothelial cells thus influencing inflammatory response, affects the thermoregulatory center in the hypothalamus leading to fever.
tumor necrosis factor alpha (kills a variety of cells)
IL-12
plus a large # of cytokines which play a role in hematopoiesis [IL-6, GM-CSF, G-CSF, M-CSF]
Other soluble factors
several of the complement proteins
various hydrolytic enzymes
Macrophages possess in their membrane, receptors for certain classes of antibody (Fc receptors), receptors for complement components (CRs). Allowing for opsonization.
GRANULOCYTIC CELLS
(large leucocytes which contain cytoplasmic granules)
Neutrophils, Eosinophils, Basophils (Mast Cells)
Neutrophil - 50-70% of circulating WBC
If higher numbers, a good sign of bacterial infection.
Sometimes called PMN (polymorphonuclear) cell because of multi-lobed nucleus.
The fine granules stain poorly with acidic and basic dyes....thus the name- neutrophil.
These granules fuse with phagosome to destroy internalized bacteria
Primary granules - electron dense and contain bactericidal enzymes such as lysozyme and myeloperoxidase; neutral proteases (i.e. elastase); and acid hydrolases (B-glucoronidase and cathepsin B.
Secondary granules - not electron dense
contain lysozyme, collagenase and lactoferrin
Oxygen dependent and Oxygen independent mechanisms are used to kill internalized microorganisms.
Neutrophils are more likely than macrophages to kill ingested microorganisms. Neutrophils also exhibit a larger respiratory burst than macrophages and consequently are able to generate more reactive oxygen intermediates. In addition, neutrophils express higher levels of defensins.
The neutrophil is a phagocytic cell, particularly important in the phagocytosis of bacteria. However, these cells DO NOT function as APCs.
A number of substances produced during an inflammatory response recruit neutrophils to a site of inflammation. Neutrophils are the 1st cells to arrive.
Eosinophil(represent 1-3% of circulating WBCs)
Possess a bi-lobed nucleus and a heavily granulated cytoplasm.
Granules stain orange/red with the acidic dye Eosin Y.
Phagocytic but DO NOT act as APCs.
The major role of the eosinophil is believed to be against parasites, particularly parasitic worms.
Eosinophils kill by ADCC [antibody dependent cell-mediated cytotoxicity] by binding to parasite - specific Ig E via cell surface FcRs.
When eosinophils bind to IgE on the surface of a worm, the cell is triggered to degranulate. The contents of the granules cause damage to the worm's tegument.
Basophil - <1% of circulaing WBC
Lobed nucleus--more variable, large coarse granules stain blue with basic dye methylene blue.
Basophils are not phagocytic.
They play a major role in the allergic response when they release their granules (containing histamine, serotonin, prostaglandin, etc).
Basophils also bear Fc receptors for IgE. When an individual is exposed to an allergen, allergen specific IgE is produced. This IgE binds to the surface of basophils [in the sensitization phase of the allergic response]. Upon re-exposure to the allergen, the allergen binds to IgE on the surface of basophils resulting in degranulation.
Mast cells
Mast cells are released from the bone marrow as undifferentiated precursor cells and do not differentiate until they enter the tissues (skin, connective tissue, mucosal epithelium, etc.)
Morphology and function similar to circulating basophils.
Mast cells bear Fc receptors for IgE and contain large numbers of cytoplasmic granules which also play a very important role in the allergic response.
Dendritic Cells
Cells which are covered with a maze of long membrane processes resembling dendrites of nerve cells. These cells function as antigen presenting cells. They have high levels of Class II MHC molecules and the co-stimulatory molecule known as B7. They capture antigen in the tissues and migrate to various lymphoid organs where they present the antigen to T helper lymphocytes.
They are termed:
Langerhan cells in skin
Veiled cells in lymph
Interdigitating dendritic cells in T cell areas of secondary lymphoid tissue and thymic medulla
Interstitial dendritic cells populate most organs (e.g. heart, lungs, liver, kidney, GI tract)
Follicular dendritic cells- do not express MHC class II and do not present antigen to Th cells. Exclusive location in lymphoid follicles, B cell rich areas of lymph node. Express high levels of membrane receptors for antibody and complement. Binding of immune complexes to these cells is thought to facilitate B cell activation. Complexes are retained for very long periods of time. Role in MEMORY B cell development??
LYMPHOCYTES
Leucocytes which are responsible for the specific immune response.
Represent 20-40% of circulating WBC in blood - 99% of cells in lymph
Lymphocytes circulate in the blood and lymph but can also enter the tissues.
Broadly divided into T lymphocytes and B lymphocytes and null cells.
All three are small, motile, nonphagocytic cells which cannot be distinguished from each other morphologically.
B and T lymphocytes which have not interacted with antigen are said to be resting [virgin or naive] lymphocytes. These cells have little visible cytoplasm around their nucleus. Once stimulated with antigen (and appropriate cytokine/cellular signals) the cell progresses through the cell cycle and enlarges into a blast cell. Lymphoblasts further differentiate into effector cells or memory cells. [Plasma cells, Th cells, Tcytotoxic cells].
The memory cells are long-lived cells that reside in the Go phase of the cell cycle until activated by a secondary encounter with antigen.
Different lineages or different maturational stages of lymphocytes can be distinguished by their expression of membrane molecules recognized by particular monoclonal antibodies. Molecules recognized are referred to as CD molecules (now well over 100) Cluster of Differentiation (CD)
Null cells
Small group of peripheral blood lymphocytes
Fail to express membrane molecules Ig or TcR or typical CD molecules.
One functional population of these cells are the NK cells (natural killer cells).
These cells are large, granular, and represent 5-10% of the peripheral blood lymphocytes. NK cells kill tumor cells or virally-infected cells by direct membrane contact or through antibody-dependent cell-mediated cytotoxicity.
Megakaryocyte
Giant polyploid cells.
Nucleus undergoes multiple mitotic divisions with no cytoplasmic divisions.
Megakaryocytes give rise to platelets when fragments or pieces of cytoplasm break or "bleb" off of the cell body. Platelets are involved in the blood clotting process.
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