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IMMUNOLOGY
(mainly
from wikipedia)
Adaptive
immunity
Protection that
arises by an immune response, including humoral immunity producing
antibodies and cellular immunity.
Agonist
An agonist is a
substance that binds to a specific receptor and triggers a response in
the cell. It mimics the action of an endogenous ligand (such as hormone
or neurotransmitter) that binds to the same receptor.
Alloreactive
Response
Cytotoxic T cells
of various specificities within a host immune system recognise and
trigger an immunological response against a cell exhibiting an HLA
class I molecule which is of a different allotype from the HLA class I
molecules of the host cells.
Antagonostic
A substance which
binds to a receptor but does not activate the effector system
associated with that receptor.
Antigen
(Ag)
Anything causing
an immune response, usually foreign material but may be body's own
tissues.
Autoimmunity
A failure of
tolerance, the immune system reacts to self.
Chemokines
Molecules released
by pathogens and infected tissues to attract cells of the immune system.
Cytokines
Signaling
molecules released by one cell to cause a response in another.
Signaling is extremely important in body's immune response.
Histamine
Histamine is a
biogenic amine involved in local immune responses as well as regulating
physiological function in the gut and acting as a neurotransmitter. New
evidence also indicates that histamine plays an important role in
chemotaxis of white blood cells.
Immune
system (IS)
Cells
in bone marrow, thymus, and the lymphatic system of ducts and
nodes, spleen, and blood that function to protect the body.
Innate
immunity
Protection that is
always present. Includes phagocytic (cells that eat other cells)
macrophages and dendritic cells.
Kinin
A kinin is any of
various structurally related polypeptides, such as bradykinin and
kallikrein. They are members of the autacoid family. They act locally
to induce vasodilation and contraction of smooth muscle.
Pathogen
Any disease
causing micro-organism.
Tolerance
Non-reactivity of
the immune system, usually refers to "self" but may include foreign
tissue in organ transplants.
Vaccination
Vaccination is the
administration of antigenic material to produce immunity to a disease.
Abbreviations
Ab, Antibodies
Ag, Antigen
APC, antigen-presenting
cell;
ASM cells, airway smooth muscle cells
β-Rag DKO, IL-2 receptor
β chain (IL-2Rβ)-/-Rag2-/-DKO
BD, blood dendritic cells
BM, blood monocytes
BMDC, bone marrow-derived cell
CD4, cluster of
differentiation 4
CD8, cluster of
differentiation 8
CDR1, first
complementarity-determining region
CDR2, second
complementarity-determining region
CDR3, third
complementarity-determining region
CTL, Cytotoxic T cells, Tc , T-Killer
cell or killer T cell
DC, dendritic cell
DKO, double knockout
γc-Rag DKO, cytokine
receptor common γ chain (γc)-/-Rag2-/-DKO
GABA, γ-aminobutyric
acid
GALT, gut-associated
lymphoid tissue
gEC, gastric epithelial
cell
gLP, gastric lamina
propria
HLA, Human Leukocyte
Antigen
i.d., intradermally
i.v., intravenously
IL-2, Interleukin-2
ILF, isolated lymphoid
follicle
LAM,
lymphangioleiomyomatosis
LD, lung dendritic cells
LP, lamina propria
MC1R, melanocortin-1
receptor
MHC, Major Histocompatibility Complex
mLN, mesenteric lymph
node
MLRQ, mitochondrial
respiratory protein complex
MPC, Mononuclear phagocytic cells
NK, natural killer
NMDA,
N-methyl-D-aspartic acid
OVA, ovalbumin
PI3K, phosphotidylinositol 3-kinase
signaling pathway
PKA, Protein kinase A
PKB, Protein kinase B
PKC, Protein kinase C
pMHC, self peptide–major
histocompatibility complex antigen
PPs, Peyer’s patches
RSV, respiratory
syncitial virus
RTE, recent thymic emigrants
RTKs, activated receptor
protein-tyrosine kinases
S6K1, p70S6 kinase, downstream
effector of PI3K
SED,subepithelial dome
SP-A, Surfactant protein A - collectin
(collagen-like lectin) family
SP-D, Surfactant protein D - collectin
(collagen-like lectin) family
TCR, T cell receptors
Tc, Cytotoxic T cells, CTL, T-Killer
cell or killer T cell
Th, Helper T cells
TSC2, tumor suppressor
gene tuberous sclerosis complex 2
TNF-α, tumour necrosis
factor-α
Inflammatory
Response
The inflammatory
response is a defensive action which takes into account fluids,
hormones, and cells. Some apparent symptoms relating to this response
are redness, heat, swelling, and pain. Once pathogens have seeped into
the blood stream, hostile chemicals like prostaglandins, kinins,
histamines and lymphokins cause vasodilation, a dilation of the blood
vessels, which allows blood to rush into the damaged area. This gives a
feeling of congestion in blood vessels and causes a burning sensation
and redness. These chemicals provoke clotting factors and antibodies to
amass in the area, irritating nearby nerves, giving rise to sensation
of pain. Pain is enhanced by the damaging secretion of the bacterial
toxins. Nevertheless, the hormones, in a process called chemotaxis, act
like homing signals to the defensive cells of the system, which
latently arrive on the scene to breach the pathogenic invasion. To
further help the clogging agents, nuetrophils cling to the skin surface
one after another, forming chains which seal the damaged area. One
common effect of the inflammatory response is that of pus. By releasing
lysosomal enzymes, nuetrophils kill large portions of the invading
armies but destroy themselves in the process. This mass killing of both
pathogens and cells results in a cream like fluid called pus.
Interferon (IFN-α, IFN-
ß, IFN- γ) is a family of small proteins which are manufactured by an
infected cell and helps inhibit viruses from entering other healthy
cells. Once a cell has been infected by some virus, it releases
interferon, which binds to the membranes of other immune cells, such as
phagocytes. As the interferon binds to these cells, viruses become
incapable of dividing within these cells. The three kinds of interferon
have somewhat similar effects on immune cells. In addition to their
anti-viral effects, interferon activate macrophages, natural killers,
and decrease cell division. Alpha [α] interferon is produced by
leukocytes. Beta [ß] interferon is produced by fibroblasts. Gamma [γ]
interferon is fabricated by lymphocytes.
Fever is an abnormally high increase
of body temperature in response to pathogen invasion. Body temperature
is regulated by a section of the brain called the hypothalamus. Normal
temperature is set by the hypothalamus at 37°C (98.6°F). If pathogens
should enter the body, then macrophages, which would be fighting the
invaders, secrete chemicals called pyrogens. These chemicals order the
hypothalamus to raise the body temperature; therefore, the body works
harder to meet the set temperature. This means that there will be an
increase in cell division. Not only does an increase in temperature
kill many bacteria that can't live in temperature over 37°C, but the
immune cells divide and work faster to kill the pathogens.
Natural Killers (NK) are a unique set
of cells which kill virus infested and cancer cells by a process called
lysis. This involves the use of proteins called complement. This arrow
like strand of proteins allows the natural killer to drain all the
cellular fluid in the cell. Since bacteria can replace it's membrane
just like the body can replace its skin, the natural killers'
complement has a protein called C9 which keeps the membrane hole open.
This ensures the full drainage of the cellular fluid. Mainly, lysis and
the nonspecific ability to destroy all diseased cells spontaneously
gives Natural Killers' their name.
Phagocytosis is the cellular action of
"eating". This mechanism is mostly used by immune cells called
macrophages and neutrophils to destroy pathogens and disease infested
cells. The cell grabs any bacteria or diseased cell with its flowing
extensions thus engulfing its victim. After the bacteria is ingested in
a food vacuole, a ball of highly acidic enzymes called a lysozyme,
inside the cell begins, to digest it. To further impose harm on the
surrounding pathogens, the neutrophil secretes a deadly chemical
somewhat similar to household bleach. Unfortunately, upon secreting the
chemical, the neutrophil can not live in such an environment and dies
along with the other pathogens.
Saliva in the mouth contains an enzyme
called lysozyme which kills bacteria. Any pathogen upon entering the
mouth will meet not only the sugar digesting enzyme called alamalze,
which will produce some harm, but, also lysozyme.
The nostrils lead to the lungs where
the warm environment would allow pathogens to grow. However, the mucous
covered hairs of the nose trap these invaders. If pathogens get past
the nose, then the ciliated trachea , the wind pipe, trap these
organisms and sweep them to the top of the trachea, where it is met by
the mouth.. From there, pathogens would be swallowed into the stomach .
The stomach acid, namely hydrochloric acid, kills off most, if not all
bacteria, almost immediately, far before it can get into the
bloodstream.
The skin will keep most pathogens from
entering, at least while it is healthy, because it has a very thick
layer of fat and dead skin cells which block any intruder from entering
the body. Also, it secrets acidic chemicals that kill many pathogens.
The cavities in the skin, such as nostrils and mouths, have to be
protected to keep pathogens out.
Macrophages
Macrophages (Greek: "big
eaters", from makros "large" + phagein "eat") (mø[1]) are cells within
the tissues that originate from specific white blood cells called
monocytes. Monocytes and macrophages are phagocytes, acting in both
non-specific defense (or innate immunity) as well as specific defence
(or cell-mediated immunity) of vertebrate animals. Their role is to
phagocytose (engulf and then digest) cellular debris and pathogens
either as stationary or mobile cells, and to stimulate lymphocytes and
other immune cells to respond to the pathogen.
Life cycle
When a monocyte enters
damaged tissue through the endothelium of a blood vessel (a process
known as the leukocyte adhesion cascade), it undergoes a series of
changes to become a macrophage. Monocytes are attracted to a damaged
site by chemical substances through chemotaxis, triggered by a range of
stimuli including damaged cells, pathogens, histamine released by mast
cells and basophils, and cytokines released by macrophages already at
the site. At some sites such as the testis, macrophages have been shown
to populate the organ through proliferation. Unlike short-lived
neutrophils, the life span of a macrophage ranges from months to years.
Function
Steps of a
macrophage ingesting a pathogen:
a. Ingestion through
phagocytosis, a phagosome is formed
b. The fusion of
lysosomes with the phagosome creates a phagolysosome; the pathogen is
broken down by enzymes
c. Waste material is
expelled or assimilated
Parts:
1. Pathogens
2. Phagosome
3. Lysosomes
4. Waste material
5. Cytoplasm
6. Cell membrane
Phagocytosis
One important main role
of macrophage is the removal of necrotic debris and dust in the lungs.
Removing dead cell material is important in chronic inflammation as the
early stages of inflammation are dominated by neutrophil granulocytes,
which are ingested by macrophages if they come of age.
The removal of dust and
necrotic tissue is to a greater extent handled by fixed macrophages,
which will stay at strategic locations such as the lungs, liver, neural
tissue, bone, spleen and connective tissue, ingesting foreign materials
such as dust and pathogens, calling upon wandering macrophages if
needed.
When a macrophage
ingests a pathogen, the pathogen becomes trapped in a food vacuole,
which then fuses with a lysosome. Within the lysosome, enzymes and
toxic peroxides digest the invader. However, some bacteria, such as
Mycobacterium tuberculosis, have become resistant to these methods of
digestion. Macrophages can digest more than 100 bacteria before they
finally die due to their own digestive compounds.
Role in
specific immunity
Macrophages are
versatile cells that play many roles. As scavengers, they rid the body
of worn-out cells and other debris. They are foremost among the cells
that "present" antigen; a crucial role in initiating an immune
response. As secretory cells, monocytes and macrophages are vital to
the regulation of immune responses and the development of inflammation;
they churn out an amazing array of powerful chemical substances
(monokines) including enzymes, complement proteins, and regulatory
factors such as interleukin-1. At the same time, they carry receptors
for lymphokines that allow them to be "activated" into single-minded
pursuit of microbes and tumour cells.
After digesting a
pathogen, a macrophage will present the antigen (a molecule, most often
a protein found on the surface of the pathogen, used by the immune
system for identification) of the pathogen to a corresponding helper T
cell. The presentation is done by integrating it into the cell membrane
and displaying it attached to a MHC class II molecule, indicating to
other white blood cells that the macrophage is not a pathogen, despite
having antigens on its surface.
Eventually the antigen
presentation results in the production of antibodies that attach to the
antigens of pathogens, making them easier for macrophages to adhere to
with their cell membrane and phagocytose. In some cases, pathogens are
very resistant to adhesion by the macrophages. Coating an antigen with
antibodies could be compared to coating something with Velcro to make
it stick to fuzzy surfaces.
The antigen presentation
on the surface of infected macrophages (in the context of MHC class II)
in a lymph node stimulates TH1 (type 1 helper T cells) to proliferate
(mainly due to IL-12 secretion from the macrophage). When a B-cell in
the lymph node recognizes the same unprocessed surface antigen on the
bacterium with its surface bound antibody, the antigen is endocytosed
and processed. The processed antigen is then presented in MHCII on the
surface of the B-cell. TH1 receptor that has proliferated recognizes
the antigen-MHCII complex (with co-stimulatory factors- CD40 and CD40L)
and causes the B-cell to produce antibodies that help opsonisation of
the antigen so that the bacteria can be better cleared by phagocytes.
Macrophages provide yet
another line of defense against tumor cells and body cells infected
with fungus or parasites. Once a T cell has recognized its particular
antigen on the surface of an aberrant cell, the T cell becomes an
activated effector cell, releasing chemical mediators known as
lymphokines that stimulate macrophages into a more aggressive form.
These activated or angry macrophages, can then engulf and digest
affected cells much more readily. The angry macrophage does not
generate a response specific for an antigen, but attacks the cells
present in the local area in which it was activated.
Fixed
macrophages
A majority of
macrophages are stationed at strategic points where microbial invasion
or accumulation of dust is likely to occur. Each type of macrophage,
determined by its location, has a specific name:
Macrophage
Name of cell Location
Dust cells/Alveolar
macrophages
pulmonary alveolus of lungs
Histiocytes
connective tissue
Kupffer
cells
liver
Microglial
cells
neural tissue
Osteoclasts
bone
Sinusoidal lining
cells
spleen
Mesangial
cells
kidney
Investigations
concerning Kupffer cells are hampered because in humans Kupffer cells
are only accessible for immunohistochemical analysis from biopsies or
autopsies. From rats and mice they are difficult to isolate and after
purification only approximately 5 million cells can be obtained from
one mouse.
Macrophages can express
paracrine functions within organs that are specific to the function of
that organ. In the testis for example, macrophages have been shown to
be able to interact with Leydig cells by secreting
25-hydroxycholesterol, an oxysterol that can be converted to
testosterone by neighbouring Leydig cells. Also, testicular macrophages
may participate in creating an immune privileged environment in the
testis, and in mediating infertility during inflammation of the testis.
Involvement
in symptoms of diseases
Due to their role in
phagocytosis, macrophages are involved in many diseases of the immune
system. For example, they participate in the formation of granulomas,
inflammatory lesions that may be caused by a large number of diseases.
Some disorders, mostly
rare, of ineffective phagocytosis and macrophage function have been
described.
Macrophages are the
predominant cells involved in creating the progressive plaque lesions
of atherosclerosis.
When fighting influenza,
macrophages are dispatched to the throat. However, until the killer T
cells for the flu virus are found, the macrophages do more damage than
help. They not only destroy throat cells infected with the flu virus
but also destroy several surrounding non-infected cells.
Macrophages also play a
role in Human Immunodeficiency Virus (HIV) infection. Like T cells,
macrophages can be infected with HIV, and even become a reservoir of
ongoing virus replication throughout the body.
Macrophages are believed
to help cancer cells proliferate as well. They are attracted to
oxygen-starved (hypoxic) tumour cells and promote chronic inflammation.
Inflammatory compounds such as Tumor necrosis factor (TNF) released by
the macrophage activates the gene switch nuclear factor-kappa B. NF-kB
then enters the nucleus of a tumour cell and turns on production of
proteins that stop apoptosis and promote cell proliferation and
inflammation.
Granulocyte
macrophage colony-stimulating factor (GM-CSF)
Granulocyte-macrophage
colony-stimulating factor, is a protein secreted by macrophages, T
cells, mast cells, endothelial cells and fibroblasts.
GM-CSF is a cytokine
that functions as a white blood cell growth factor. GM-CSF stimulates
stem cells to produce granulocytes (neutrophils, eosinophils, and
basophils) and monocytes. Monocytes exit the circulation and migrate
into tissue, whereupon they mature into macrophages. It is thus part of
the immune/inflammatory cascade, by which activation of a small number
of macrophages can rapidly lead to an increase in their numbers, a
process crucial for fighting infection. The active form of the protein
is found extracellularly as a homodimer.
The gene has been
localized to a cluster of related genes at chromosome region 5q31,
which is known to be associated with interstitial deletions in the 5q-
syndrome and acute myelogenous leukemia. Other genes in the cluster
include those encoding interleukins 4, 5, and 13.
Human granulocyte
macrophage colony-stimulating factor is glycosylated in its mature
form. The glycosylation sites are reported to be at amino acid residues
23 (leucine), 27 (asparagine), and 39 (glutamic acid).
Granulocyte
Colony-Stimulating Factor (G-CSF or GCSF)
Granulocyte
Colony-Stimulating Factor (G-CSF or GCSF) is a colony-stimulating
factor hormone. It is a glycoprotein, growth factor or cytokine
produced by a number of different tissues to stimulate the bone marrow
to produce granulocytes and stem cells. G-CSF then stimulates the bone
marrow to pulse them out of the marrow into the blood. It also
stimulates the survival, proliferation, differentiation, and function
of neutrophil precursors and mature neutrophils. G-CSF is also known as
Colony-Stimulating Factor 3 (CSF 3).
G-CSF is produced by
endothelium, macrophages, and a number of other immune cells. The
natural human glycoprotein exists in two forms, a 174- and
180-amino-acid-long protein of molecular weight 19,600 grams per mole.
The more-abundant and more-active 174-amino acid form has been used in
the development of pharmaceutical products by recombinant DNA (rDNA)
technology.
The G-CSF-receptor is
present on precursor cells in the bone marrow, and, in response to
stimulation by G-CSF, initiates proliferation and differentiation into
mature granulocytes.
The gene for G-CSF is
located on chromosome 17, locus q11.2-q12. Nagata et al. found that the
GCSF gene has 4 introns, and that 2 different polypeptides are
synthesized from the same gene by differential splicing of mRNA. The 2
polypeptides differ by the presence or absence of 3 amino acids.
Expression studies indicate that both have authentic GCSF activity. It
is thought that stability of the G-CSF mRNA is regulated by an RNA
element called the G-CSF factor stem-loop destabilising element.
G-CSF stimulates the
production of white blood cells (WBC). In oncology and hematology, a
recombinant form of G-CSF is used with certain cancer patients to
accelerate recovery from neutropenia after chemotherapy, allowing
higher-intensity treatment regimens. Chemotherapy can cause
myelosuppression and unacceptably low levels of white blood cells,
making patients prone to infections and sepsis. However, in a
Washington University School of Medicine study, G-CSF is shown to
lessen the density of bone tissue even while it increases the WBC count.
Interleukins
Interleukins are a group of cytokines
(secreted signaling molecules) that were first seen to be expressed by
white blood cells (leukocytes, hence the -leukin) as a means of
communication (inter-). The name is something of a relic though (the
term was coined by Dr. Paetkau, University of Victoria); it has since
been found that interleukins are produced by a wide variety of bodily
cells. The function of the immune system depends in a large part on
interleukins, and rare deficiencies of a number of them have been
described, all featuring autoimmune diseases or immune deficiency.
Interleukin-1 (IL-1) is one of the
first cytokines ever described. Its initial discovery was as a factor
that could induce fever, control lymphocytes, increase the number of
bone marrow cells and cause degeneration of bone joints. At this time,
IL-1 was known under several other names including endogenous pyrogen,
lymphocyte activating factor, haemopoetin-1 and mononuclear cell
factor, amongst others. It was around 1984-1985 when scientists
confirmed that IL-1 was actually composed of two distinct proteins, now
called IL-1α and IL-1β. The original members of the IL-1 superfamily
are IL-1α, IL-1β, and the IL-1 Receptor antagonist (IL-1RA). IL-1α and
-β are pro-inflammatory cytokines involved in immune defense against
infection. The
IL-1RA is a molecule that competes for receptor binding with IL-1α and
IL-1β, blocking their role in immune activation. Recent years have seen the addition of
other molecules to the IL-1 superfamily including IL-18 and six more
genes with structural homology to IL-1α, IL-1β or IL-1RA. These latter
six members are named IL1F5, IL1F6, IL1F7, IL1F8, IL1F9, and IL1F10. In
accord, IL-1α, IL-1β, and IL-1RA have been renamed IL-1F1, IL-1F2, and
IL-1F3, respectively. A further putative member of the IL-1 family has
been recently described that is called IL-33 or IL-1F11, although this
name is not officially accepted in the HGNC gene family nomenclature
database.
Interleukin-2 (IL-2) is an
interleukin, a type of cytokine immune system signaling molecule, that
is instrumental in the body's natural response to microbial infection
and in discriminating between foreign (non-self) and self. IL-2
mediates its effects by binding to IL-2 receptors, which are expressed
by lymphocytes, the cells that are responsible for immunity.
Interleukin-2 (IL-2) belongs to a family of cytokines, which includes
IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through a receptor
complex consisting of IL-2 specific IL-2 receptor alpha (CD25), IL-2
receptor beta (CD122) and a common gamma chain (γc), which is shared by
all members of this family of cytokines. Binding of IL-2 activates the
Ras/MAPK, JAK/Stat and PI 3-kinase/Akt signaling modules.
Interleukin 6 (IL-6) also referred to
as interferon-β2, 26-kDa protein, and B cell stimulatory factor 2 is a
cytokine whose actions include a stimulation of immunoglobulin
synthesis, enhancement of B cell growth, and modulation of acute phase
protein synthesis by hepatocytes. Synthesis of IL-6 is stimulated by
interleukin 1 (IL-1), tumor necrosis factor (TNF), or platelet-derived
growth factor.
Role of
cyclic AMP (cAMP)-dependent signal transduction pathway in IL-6 gene
expression: Several
activators of adenylate cyclase, including prostaglandin El, forskolin,
and cholera toxin, as well as the phosphodiesterase inhibitor
isobutylmethylxanthine and the cAMP analog dibutyryl cAMP, shared the
ability to cause a dramatic and sustained increase in IL-6 mRNA levels
in human FS-4 fibroblasts.
A list of interleukins
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Name
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Source
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Target receptors
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Target cells
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Function
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co-stimulation
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maturation &
proliferation
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activation
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stimulates growth and
differentiation of T cell response. Can be used in immunotherapy to
treat cancer or suppressed for transplant patients.
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mast cells
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proliferation and
differentiation, IgG1 and IgE synthesis.
Important role in allergic response (IgE)
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proliferation
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production
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differentiation, IgA production
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plasma cells
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differentiation
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involved in B, T, and
NK cell survival, development, and homeostasis, ↑proinflammatory
cytokines
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cytokine production
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B cells
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activation
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Stimulation
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TH2-cells, B cells,
macrophages
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T cells and certain
malignant B cells
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activated B cells
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controls the growth
and proliferation of B cells, inhibits Ig
secretion
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mononuclear
phagocytes (and some other cells), especially macrophages following
infection by virus(es)
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T cells, activated B
cells
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lymphocytes,
epithelial cells, eosinophils, CD8+ T cells
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CD4+ T cells
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subsets of T cells
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epithelium,
endothelium, other
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macrophages
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Th1 cells, NK cells
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Induces production of
IFNγ, ↑ NK cell
activity
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Plays a role in
immune defense against viruses
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Plays a role in host
defenses against microbes
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