Cytokine
GM-CSF
Histamine
TGF-Beta
IL-10
CXCL8
(IL-8)
IL-1
TNF-alpha
IL-6
Source
Macrophages, Mast cells,
Th17 cells
Mast cells, Basophils
Tregs (Tr1, Th3 cell
subsets), Th9 cells, many
other cell types
Th2 cells,
Activity
Induce proliferation neutrophils and other granulocytes in
bone marrow “replenishes neutrophils”
Increases vascular permeability, separation of endothelial cells
(responsible for hives), and pain and itching
Inhibits growth, differentiation, and function of a number of
cell types including T and B cells and macrophages.
Involved in the polarization of subsets of T help cell subsets.
High amounts in alimentary canal cell milieu.
Th2 cells: IL-10 enhances proliferation of B cells and stimulates
IgA secretion. Also, inhibits Th1 cells.
Tregs and Th9: IL-10 has anti-inflammatory effect.
Chemotactic factor: recruits neutrophils, basophils, T cells to
site of infection.
Th9 cells, Tregs (and Tr1)
Macrophages, Mast cells
Th17 cells
Activity
1.Activates vascular endothelium.
2. Activates lymphocytes
3. Local tissue destruction
4. Increases access of effector cells.
Systemic effects: Fever, production IL-6
1.Activates vascular endothelium.
2. Increases vascular permeability which increases entry of IgG, complement, and
lymphocytes into tissues.
3. Increased fluid drainage to lymph nodes.
Systemic effects: Fever and Increases risk of shock
1.Lymphocyte activation
2. Increased antibody production
System effects: Fever and Induces liver to synthesize acute-phase proteins,
mannose-binding lectin, and amyloid protein
Th17 cells are a lineage of CD4+ effector T helper cells that produce Interleukin-17 (IL-17). Th17 cells are
part of the adaptive immune response mounted against fungal and bacterial infections, but may also
contribute to the pathogenesis of autoimmune diseases.
In mice, Th17 cells develop from naïve CD4+ T cells in the presence of TGF-Beta, IL-6, and IL-23. IL-23
regulates the establishment and clonal expansion of Th17 cells. Th17 cells produce CXCL8 (IL-8) to
recruit neutrophils. Also, produce CM-CSF to replenish neutrophils from bone marrow. IL-17 activates
macrophages to produce IL-1 exacerbating the immune response. Th17 cells also secrete IL-21 which
activates NK cells and CD8+ T cells (cytotoxic T cells) which may have an antiviral effect.
While these cytokines play a central role in eliminating harmful microbes, persistent secretion of Th17
cytokines promotes chronic inflammation and tissue destruction characteristic of autoimmune diseases.
For these reasons, factors involved in Th17 differentiation, or those that inhibit Th17 function, may
serve as potential targets for preventing the pathogenesis of a variety of autoimmune conditions,
including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disorders.
Th9 cells are a subpopulation of T-helper cells, characterized to be involved in allergic diseases and
resistance against intestinal nematodes (helminths). TGF-β reprograms Th2 T-helper cells to lose their
characteristic profile of IL-17 secretion and switch to IL-9 secretion. Differentiation of Th9 cells can be
obtained by a combination of TGF-β and IL-4. Th9 cells have a rapid IL-9 induced inflammatory response
which is short and IL-9 rapidly disappears. During this short IL-9 induced inflammatory phase mast cells
are recruited, IgE is produced by B cells, and Th17 cells are promoted. IL-9 also induced Treg cells and
both Treg cells and IL-10 suppress the immune response.
Regulatory T cells (Tregs) are another major CD4+ T-cell subset negatively regulates T-cell response and
plays a critically important role (in animal models) in peripheral tolerance by limited autoimmune T-cell
activity. Regulatory T cells (Treg cells) can inhibit the proliferation of other T-cell populations. They
express on their surface CD4 as well as CD25 (the α chain of the IL-2 receptor). However, Treg cells are
more definitely identified by their expression of the master transcriptional regulator, FoxP3, the
expression of which is necessary and sufficient to induce differentiation to the Treg lineage. TGF-Beta
induces expression of FoxP3.
“Natural” Treg cells develop in the thymus. Most thymocytes that express receptors with high affinity
for self-antigen die via negative selection. However, a small fraction appear to commit to the regulatory
T-cell lineage and leave the thymus to patrol the body and thwart autoimmune reactions.
Animal studies show that members of the FoxP3+ T reg population inhibit the development of
autoimmune disease such as experimentally induced inflammatory bowel disease and diabetes.
Possible mechanisms of Treg activity:
1. Cytokine inhibition. Tregs secrete several cytokines, including IL-10 and TGF-Beta which bind
receptors on activated T cells and reduce signaling activity.
2. Inhibition of antigen presenting cells. Tregs can interact directly with MHC Class II expressing
antigen-presenting cells and inhibit their maturation, leaving them less able to activate T cells.
3. Cytotoxicity. Tregs can also display cytotoxic function and kill cells by secreting perforin and
granzyme.
Type 1 regulatory T (Tr1) cells are an inducible subset of regulatory T cells that play a pivotal role in
promoting and maintaining tolerance. The main mechanisms by which Tr1 cells control immune
responses are the secretion of high levels of IL-10. To date NO defined cell surface signature has been
identified for Tr1 cells so they do not express FoxP3 or CD25.
Th3 cells are involved in mucosal immunity and protecting mucosal surfaces in the gut from
nonpathogenic non-self antigens. They mediate this non-inflammatory environment by secreting TGFbeta. TGF-beta promotes the class switch to low concentrations of IgA which is noninflammatory. IgA
does not usually activate the complement system and is not involved with phagocytosis. Th3 inhibits Th1
and Th2 cells.
CENTRAL TOLERANCE
T cells are selected for survival much more rigorously than B cells. They undergo both positive and
negative selection to produce T cells that recognize self- major histocompatibility complex (MHC)
molecules but do not recognize self-peptides. T cell tolerance is induced in the thymus.
Positive selection occurs in the thymic cortex. This process is primarily mediated by thymic epithelial
cells, which are rich in surface MHC molecules. If a maturing T cell is able to bind to a surface MHC
molecule in the thymus it is saved from programmed cell death; those cells failing to recognize MHC on
thymic epithelial cells die. Thus, positive selection ensures that T cells only recognize antigen in
association with MHC. During positive selection T cells are transformed into either CD4+CD8- or
CD8+CD4- T cells depending on whether they recognize MHC II or MHC I, respectively.
T cells may also undergo negative selection in a process analogous to the induction of self-tolerance in B
cells. This occurs in the thymus by epithelial cells which display "self" antigens to developing T-cells and
signal those "self-reactive" T-cells to die via programed cell death (apoptosis) and thereby deleted from
the T cell repertoire.
Regulatory T cells are another group of T cells maturing in the thymus, they are also involved with
immune regulation but are not directly involved in central tolerance.
Peripheral tolerance is immunological tolerance developed after T and B cells mature and enter the
periphery. These include the suppression of autoreactive cells by 'regulatory' T cells and the generation
of hyporesponsiveness (anergy) in lymphocytes which encounter antigen in the absence of the costimulatory signals that accompany inflammation, or in the presence of co-inhibitory signals.
1. A dendritic cell or macrophage picks up an antigen and displays this via MHC class II to a Treg
cell. Because there is no co-stimulatory signal “cytokine” (like a toll-like receptor induced costim
signal) then the Treg shuts down the APC (dendritic or macrophage).
2. T cell suppression (Antigen specific shut down): A T cell and a T reg recognized the same antigen
and are next to each other. Their TCRs are similar enough to recognize the same antigen. The
Treg then inhibits the T cell next to it via IL-10 or CTLA.
ACUTE INFLAMMATION - Inflammation is a vascular response to injury.
A. Processes
1. Exudation of fluid from vessels
2. Attraction of leukocytes to the injury. Leukocytes engulf and destroy bacteria, tissue debris,
and other particulate material.
3. Activation of chemical mediators.
4. Proteolytic degradation of extracellular debris.
5. Restoration of injured tissue to its normal structure and function. This is limited by the
extent of tissue destruction and by the regenerative capacity of the specific tissue.
B. Cardinal signs
1. Rubor (redness caused by dilation of vessels)
2. Dolor (pain due to increased pressure exerted by the accumulation of interstitial fluid and to
mediators such as bradykinin)
3. Calor (heat caused by increased blood flow)
4. Tumor (swelling due to an extravascular accumulation of fluid)
5. Functio laesa (loss of function)
A. Adhesion molecules – plan an important role in acute inflammation.
1. Selectins
a. These molecules are induced by the cytokines interleukin-1 (IL-1) and tumor
necrosis factor (TNF).
b. L-selectins are expressed on neutrophils and bind to endothelial mucin-like
molecules such as GlyCam-1.
c. E- and P-selectins are expressed on endothelial cells and bind to oligosaccharides
such as sialyl-Lewis X on the surface of leukocytes. P-selectins, stored in endothelial
Weiberl-Palade bodies and platelet alpha granules, relocated to the plasma
membrane after stimulation by mediators such as histamine and thrombin.
B. Vasoactive changes
1. These changes begin with a brief period of vasoconstriction, followed shortly by dilation of
arterioles, capillaries, and postcapillary venules.
2. The resultant marked increase in blood flow to the affected area is clinically manifest by
redness and increased warmth of the affected area.
C. Increased capillary permeability
1. This results in leakage of proteinaceous fluid, which causes edema.
2. Causes include endothelial changes that vary from contraction of endothelial cell in post
capillary venules, with widening of interendothelial gaps, to major endothelial damage
involving arterioles, capillaries, and venules.
D. Types of inflammatory cells
1. Neutrophils are the most prominent inflammatory cells in the foci of acute inflammation
during the first 24hours. Important causes of neutrophilia (increased neutrophils in the
peripheral blood) include bacterial infections and other causes of acute inflammation, such
as infarction. The early release of neutrophils into the peripheral blood in acute
inflammation is from the bone marrow postmitotic reserve pool. There is often an increase
in the proportion of less mature cells such as band neutrophils.
2. After 2-3 days, neutrophils are replaced mainly by monocytes-macrophages, which are
capable of engulfing larger particles, are longer-lived, and are capable of dividing and
proliferating within the inflamed tissue.
3. Lymphocytes are the most prominent inflammatory cells in many viral infections and along
with monocytes-macrophages and plasma cells, are the most prominent cells in chronic
inflammation.
4. Eosinophils are the predominant inflammatory cells in allergic reactions and parasitic
infestations. The most important causes of eosinophilia include allergies such as asthma,
hay fever, and gives and also parasitic infections.
5. Mast cells and basophils are sources of histamine.
Exogenous and endogenous mediates of acute inflammation
These mediators influence chemotaxis, vasomotor phenomena, vascular permeability, pain, and
other aspects of the inflammatory process.
E. Exogenous mediates are the most often of microbial origin (e.g., formylated peptides of Escherichia
coli, which are chemotactic for neutrophils.
F. Endogenous mediators are of host origin.
1. Vasoactive amines
a. Histamine mediates the increase in capillary permeability associated with the
contraction of endothelial cells in postcapillary venules that occurs with mild injuries.
i. Histamine is liberated from basophils, mast cells, and platelets.
ii. Basophils and mast cells. Histamine is liberated by degranulation triggered
by the following stimuli:
 Binding of specific antigen to basophil and mast cell membranebound IgE (complement is not involved)
 Binding of complement fragments C3a and C5a, anaphylatoxins, to
specific cell-surface receptors on basophils and mast cells (specific
antigen and IgE antibodies are not involved)
 Physical stimuli such as heat and cold
 Cytokine IL-1
 Factors from neutrophils, monocytes, and platelets
iii. Platelets. Histamine is liberated from platelets by platelet aggregation and
the release reaction, which can be triggered by endothelial injury and
thrombosis or platelet-activating favor (PAF).
iv. Serotonin (5-hydroxytryptamine) - acts similarly to histamine.
2. The Kinin system. The kinin system is initiated by activated Hageman factor (factor XIIa).
Factor XIIa also activates the intrinsic pathway of coagulation and the plasminogen
(fibrinolytic) system. Activation of the system in turn activates the complement cascade.
Thus, factor XIIa links the kinin, coagulation, plasminogen, and complement systems.
a. This system converts prekallikrein to kallikrein (a chemotactic factor).
b. The results in the cleavage, by kallikrein, of high-molecular weight kininogen to
bradykinin, which is a peptide that is a nine aminoacid in length that mediates
vascular permeability, arteriolar dilation and pain.
3. Complement system. The complement system consists of a group of plasma proteins that
participate in immune lysis of cells and play a significant role inflammation.
a. C3a and C5a (anaphylatoxins) mediate degranulation of basophils and mast cells with
the release of histamine. C5a is a chemotactic, mediates the release of histamine
from platelet-dense granules, induces expression of leukocyte adhesion molecules,
and activates the lipoxygenase pathway of arachidonic acid metabolism.
b. C3b is an opsonin
c. C5b-9, the membrane attack complex, is a lytic agent for bacteria and other cells.