The Phagocyte System
Monocytes and Dendritic Cells
A. The Phagocyte System
Granulocytes. monocytes, and dendritic cells (DCs) have phagocytic capabilities (from the Greek word phagein to eat).
They all derive from blood progenitor cells: the cytokine granulocyte colony stimulating factor (G CSF) promotes the differentiation into granulocytes.
while granulocyte macrophage colony stimulating factor(GM CSF). IL 4, and tumor necrosis factoru (TNF (1) promote differentiation into monocytes and DCs.
The normal fate of Circulating monocytes (their half life in the blood is only a few hours) is to differentiate into tissue phagocytes. The macrophages remain in the tissue for the rest of their lifetime (up to years).
DCs are large. mobile cells with long cytoplasmic processes (some >10 pm). DCs are seldom found in the blood; their precursors migrate into the skin to form the Langerhans cells of the epidermis and dermal DCs. or into the lymph nodes, where they give origin to interdigitating dendritic cells (IDC) in the T cell areas and to germinal center dendritic cells (GCDC). A different lineage of DCs. called lymphoid DC or type 2 DC, differentiates from progenitor ceIls in the presence of IL 3 and the cytokine Flt3L They locate in the paracortical region of the lymph nodes. It has been suggested that they constitute the thymic DC population.
B. Mechanisms of Endocytosis
Uptake of small fluid particles (pinocytosis, from the Greek word pinein to drink) begins with the formation of membrane indentations, which is driven by a protein complex called clathrin. Clathrin coated vesicles. or coated pits," fuse with lysosomes. where the antigens are digested. In macropinocytosis.
the cell can absorb large drops up to 0.5 pm in size Water is expelled through channels, called aquapor ins, Polymerization of the cytoskeleton protein actin is needed for the formation of larger phagocytic vesicles.
Langerhans cells of the skin utilize Birbeck granules (small vesicles with a typical narrow neck) for phagocytosis.
Some bacteria (e.g., Legionella pneumophila) are inter nalized by coiling phagocytosis, whereby a cy toplasmic protrusion. called pseudopodium. spirals around the bacterium to form a "coiling" phagosome." The membranes of the pseudo podium then fuse. releasing the pathogen with in the cytoplasm.
C. Fc-Mediated Phagocytosis.
Several receptors can bind the Fc portion of immunoglobulins .
Receptors for IgG. IgA. and IgE are called FcyR, Peak, and FcaR respectively. These receptors signal through immunreceptor tyrosine based activation motifs (lTAMs), which are intracytoplasmic domains consisting of two tyrosine (Y) residues separated by 9 12 amino acids.
On ligation. the tyrosines in these lTAM domains become phosphorylated, leading to the recruitment of the tyrosine kinase Syk, which then triggers different intracellular signal cascades,
leading to transcriptional activation. cytoskeletal rearran gement, and release of inflammatory mediators. Fc~{Rll A has itself an lTAM motif in its intracellular portion. while FqRi and FeyRIH lack rTAMs in their cytoplasmic tails. They interact respectively with 7 and e transducing proteins. which contain the lTAMs needed for signal transduction.
D. Mannose Receptor
Macrophages and DCs can recognize the sugars mannose and fucose, which are present on different pathogens. through the mannose re ceptor (MR), a molecule with a long extracellu lar portion consisting of multiple (at least 8) lectin like domains. MR ligation leads to the release of cytokines, such as IL lniL 6. GM CSF. TNF a, and IL 12.
E. Complement Receptor-Mediated Phagocytosis
Serum complement proteins coat (opsonize) altered red blood cells or bacteria. The complement receptors CR1, CR3, and CR4 are present on monocytes and macrophages.
CR1 binds to the complement fractions C3b, C4b, and C3bi. CR3 and CR4 bind specifically to C3bi. Complement coated particles. such as senescent red blood cells. sink directly into the cell, almost without pseudopodia for mation. in this process, the proteins vinculin. paxillin, and F actin are involved. There is no release of proinflammatory cytokines
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