From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Macrophages, Part 2
Note: non-commercial reproduction.
Archive-Number: 5824
Organization: UCLA, Computer Science Department
Date: Fri, 31 Jul 92 11:10:18 PDT

Macrophages Part 2

This is the second post on the effector cells of DTH Type IV: the 
Macrophage.  Antigen presenting cells of DTH Type IV have been 
previously discussed.

The first post concerned microbial parasites that infect macrophages.  
This post discusses macrophage destruction of these parasites.

The following is from Chapter 1 titled "The biology of the macrophage" 
by M.J. Auger and J.A. Ross from The Macrophage edited by C.E. Lewis and 
J.O'D. McGee, IRL Press at Oxford University Press 1992.

This is new series on the natural immune system and includes The 
Macrophage and The Natural Killer Cell.

The mononuclears phagocyte system is as follows:

Bone Marrow: Monoblasts differentiates into Promonocytes which 
differentiate into Monocytes.

Blood: Monocytes 

Tissues: Macrophages 
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Page 31-33

10 Macrophage functions
10.1 Phagocytosis and destruction of micro-organisms
10.1.1. Recognition and phagocytosis

"Mononuclear phagocytes and neutrophils provide a defence against 
microbial invasion.  The neutrophil, in general, is a more efficient 
phagocyte, except when the particle is large in relation to the cell or 
when the particle load is great.  Under these circumstances mononuclear 
phagocytes are more effective than neutrophils.  Macrophages thus 
represent a major defence against invasion of the host by a wide variety 
of micro-organisms, including bacteria, viruses, fungi, and protozoa.  
Macrophages move toward the microbial particles guided by a gradient of 
chemotactic molecules emanating from them.  Engulfment then occurs,
beginning with the macrophage advancing pseudopodia over regions of the 
micro-organism that express recognition molecules, opsonins, which bind 
to specific sites on both invading micro-organisms and macrophages.  
Opsonins are of various types, but those most studied are IgG and 
fragments of the third component of complement.  Receptors that bind 
specifically to the Fc domain of various subclasses of IgG and to 
several isotypes of C3 are present on the macrophage surface.  Many 
micro-organisms are capable of activating the complement cascade and 
generating complement fragments that coat the organism and opsonize it.  
Furthermore, the macrophage itself is an important source of complement 
components and macrophage-derived complement factors can opsonize micro-
organisms for subsequent destruction in the absence of other sources.  
After binding with the appropriate ligand, initiation of the process of 
internalization and microbial destruction occurs.  Adsorption can also 
occur without opsonization if the micro-organisms possess surface 
determinants that can be recognized directly by the macrophage; an 
example is the interaction of the macrophage mannose-fucose receptor 
with carbohydrate residues.

The protrusive pseudopodial movement underlying phagocytosis represents 
events within only a localized region of membrane and peripheral 
cytoplasm.  Granule movements then become prominent at the base of the 
forming phagocytic vacuole and exocytosis of granule contents into the 
phagosomal vacuole is thought to occur.  The pseudopodial actin 
cytoskeleton plays a major role in phagocytosis."

...

"Although many micro-organisms are phagocytosed and destroyed with 
comparable ease by macrophages, there are certain pathogens that 
parasitize macrophages and replicate within them.  When the macrophage 
is activated, these intracellular pathogens may be inhibited or 
destroyed.  Listeria, Salmonella, Brucella, Mycobacteria, Chlamydia, 
Rickettsia, Leishmania, Toxoplasma, Trypanosoma, and Legionella 
pneumophilia have been found capable of invading and inhabiting non-
activated macrophages.  Mycobacterium tuberculosis may release certain 
substances, such as sulpholipids, that interfere with fusion of primary 
lysosomes with phagosomes and thereby avoid exposure to the lysosomal 
enzymes of the macrophage.  Leishmania and Mycobacterium lepraemurium 
survive within secondary lysosomes despite exposure to lysosomals 
enzymes; this may be due to the resistance of the microbial cell wall to 
the macrophages' degradative enzymes.  The human immunodeficiency virus 
(HIV) has also been shown to infect and replicate within monocytes and 
macrophages.  Infection with HIV occurs by binding of the virus to the 
CD4 molecule which, as mentioned previously, is present at a low density 
on monocytes and macrophages."

10.1.2  Microbicidal mechanisms

"The production and intracellular release of reactive oxygen 
intermediate species are a major microbicidal mechanism employed by 
monocytes and macrophages.  As monocytes mature into macrophages there 
is evidence of decreased microbicidal activity.  This may be due to a 
reduction in the respiratory burst or by the decreased content of 
granule peroxidase as monocytes mature into macrophages.  In addition to 
oxygen-dependent cytotoxic systems, phagocytes are equipped with oxygen-
independent means of killing micro-organisms.  A variety of granule-
associated proteins in macrophages have been shown to possess 
antimicrobial activity.  These include elastase, collagenases, lipases, 
deoxyribonucleases, polysaccharidases, sulphateses, phosphatases, and 
the defensins.

...

"Mononuclear phagocytes are also capable of interferon production, which 
may aid in protection against viral infection.  Monocyte cationic 
proteins, other than peroxidase, have been shown to have fungicidal 
activity.  Macrophages activated by cytokines, such as IFN-gamma, TNF-
alpha, or IL-1, have greater microbicidal capacities than non-activated 
cells.

"There are differences in the mechanisms by which blood monocytes and 
tissue macrophages kill some microbes.  For example, human monocytes 
kill Candida albicans readily, whereas macrophages do not.  Macrophages 
will, however, kill Candida pseudotropicalis as this organism does not 
required peroxidase activity in order to be destroyed.

"The relatively long lifespan of the macrophage and its sustained 
biosynthetic capacity permit the continued production of antimicrobial 
proteins and continued microbicidal activity."
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