Download Inflammation and immunity

Inflammation and immunity
NR Webster PhD FRCA FRCP
HF Galley PhD FIMLS
The inflammatory response
Key points
The main features of the inflammatory
response are:
HF Galley PhD FIMLS
Academic Unit of Anaesthesia and
Intensive Care, Institute of Medical
Sciences, University of Aberdeen,
Foresterhill, Aberdeen AB25 2ZD
Humans must defend themselves against
viruses, bacteria, fungi, protozoa, parasites
and tumour cells as well as physical, chemical
or traumatic damage – inflammation is the
body’s reaction to such an event. The body
must also respond to injury by healing and
repairing the damaged tissue. Many effector
mechanisms capable of defending the body
against such antigens and agents have developed and these are mediated by soluble molecules or by cells of the immune system. Three
major events occur during this response: (i) an
increased blood supply to the tissue; (ii)
increased capillary permeability caused by
retraction of the endothelial cells; and (iii)
leucocytes migrate out of the capillaries into
the surrounding tissues.
The virulence of micro-organisms and the
induction of inflammation depend on their
ability to replicate in the body and to destroy
cellular structures. During growth and multiplication, micro-organisms can produce and
release exotoxins which are potent injuring
agents. Other micro-organisms, after destruction or lysis, release from phospholipid and
lipopolysaccharide envelopes, toxins known
as endotoxins (lipopolysaccharide or LPS).
Viruses do not produce exotoxins or endotoxins but use cells for their own replication and
damage cell structures leading to cell death.
The main purpose of inflammation is to
bring fluid, proteins and cells from the blood
into the damaged tissues. Tissues are normally bathed in extracellular fluid lacking most of
the proteins and cells present in blood, since
the majority of proteins are too large to cross
the endothelium. Therefore, mechanisms are
required to allow cells and proteins to gain
access to extravascular sites.
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British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 2 2003
© The Board of Management and Trustees of the British Journal of Anaesthesia 2003
Innate and acquired
immunity are both
important in the inflammatory response.
The inflammatory
response is both useful
and potentially harmful.
The inflammatory
response is carefully regulated by complex and
interlinked chemical messengers which act like
local hormones.
Many different cell types
are involved in the
inflammatory response.
There is considerable
overlap in the actions of
soluble mediators of
inflammation.
NR Webster PhD FRCA FRCP
Academic Unit of Anaesthesia and
Intensive Care, Institute of Medical
Sciences, University of Aberdeen,
Foresterhill, Aberdeen AB25 2ZD
Tel: 01224 273207
Fax: 01224 273066
E-mail: [email protected]
(for correspondence)
1.
Vasodilation to increase the blood flow to the
infected area.
2.
Increased vascular permeability to allow diffusible components to enter the site.
3.
Cellular infiltration by chemotaxis, or the
directed movement of inflammatory cells
through the walls of blood vessels to the site
of injury.
4.
Activation of cells of the immune system and
enzyme systems.
The movement of leucocytes to a site of
injury requires adhesive interactions between
leucocytes and endothelial cells. The nature and
magnitude of the leucocyte–endothelial cell
interaction taking place within post-capillary
venules is determined by a variety of factors,
including expression of adhesion molecules on
leucocytes and/or endothelial cells, the presence of products of leucocytes (e.g. superoxide)
and endothelial cells (e.g. nitric oxide), and the
physical forces generated by the movement of
blood along the vessel wall. Extravasation is a
complex event, dependent not only on adhesion
molecule expression and activation, but also on
cytoskeletal re-organisation and alteration in
membrane fluidity.
Innate and adaptive immunity
Innate immunity prevents entry of micro-organisms into tissues or, once they have gained entry,
eliminates them prior to the occurrence of disease. It is non-specific and does not require prior
exposure to antigen. Examples include mechanical barriers at body surfaces (skin, mucous
membranes), antibacterial substances in secretions (lysozyme, low pH in stomach) and prevention of stasis (ciliary activity, coughing,
vomiting).
DOI 10.1093/bjacepd/mkg014
Inflammation and immunity
Acquired immunity requires prior exposure to antigen and
involves antibodies and lymphocytes. An immune response
must: (i) recognise a micro-organism as foreign or non-self;
(ii) respond by production of specific antibodies and specific
lymphocytes; and (iii) mediate the elimination of microorganisms. The key cells are B- and T-cell lymphocytes.
B-cell lymphocytes
B-cells make antibodies of the same specificity, i.e. able to
react with the same antigenic determinants. Antibodies are
immunoglobulins (150,000–900,000 kDa), which act by one
end of the molecule binding to antigens (the Fab portion) and
the other end (Fc) being responsible for effector functions.
There are 5 classes of immunoglobulin – IgM, IgG, IgA, IgD
and IgE. Immunoglobulins occur in serum and in secretions
from mucosal surfaces and are produced by plasma cells
found mainly within lymph nodes. B lymphocytes evolve into
plasma cells under the influence of T-cell cytokines.
marginating and entering tissue pools, where they survive for
1–2 days. Cells of the circulating and marginated pools can
exchange with each other. Neutrophils contain cytoplasmic
granules full of antimicrobial or cytotoxic substances, proteinases, hydrolases and cytoplasmic membrane receptors. The
enzyme myeloperoxidase (MPO) catalyses the conversion of
hydrogen peroxide to hypochlorous acid. Proteases such as elastase and cathepsin G hydrolyse proteins in bacterial cell walls.
Lysosomal proteases are potentially very destructive to normal
tissue and regulation is mediated by protease inhibitors such as
macroglobulin and antiprotease which bind to the active sites of
proteases. The protease:antiprotease balance is important in the
pathogenesis of some diseases.
Phagocytosis
Phagocytosis is a complex process composed of several morphological and biochemical steps:
1.
Recognition and binding to the phagocyte surface.
T-cell lymphocytes
2.
Ingestion (engulfment).
There are two types of T-cells, T-helper (Th) cells and T-cytotoxic (Tc) cells. Th-cells secrete cytokines (chemical regulators of the immune response, see below), which activate various phagocytic cells, B-cells, Tc-cells, macrophages and various other cells. Tc-cells do not secrete cytokines but have
cytotoxic activities, including the elimination of cells displaying antigen, i.e. altered self cells, such as virus-infected cells,
foreign tissue grafts and tumour cells. Circulating Th-cells are
capable of unrestricted cytokine expression and are prompted
into a more focused pattern of cytokine production depending
on signals received at the outset of infection. The cells can be
classified according to the pattern of cytokines they produce
and Th1-cells secrete cytokines which push the system
towards cellular immunity (cellular cytotoxicity) while Th2cells are associated with humoral or antibody-mediated
immunity. The local balance of cytokines, particularly early in
the inflammatory response, is therefore an important determinant of subsequent Th immune responses and may dictate the
final outcome of the septic insult.
3.
Phagosome and then phagolysosome formation (fusion of
phagosome with lysosomes).
4.
Killing and degradation of ingested cells or other material.
5.
Respiratory burst – simultaneously with the recognition and
particle binding there is a dramatic increase in oxygen consumption associated with production of superoxide and other
oxygen radicals.
Neutrophils – central cells in acute inflammation
Neutrophils (polymorphonuclear leucocytes or PMNs) constitute the ‘first line of defence’ against infectious agents. Upon
release into the circulation from bone marrow, the cells are in a
non-activated state and have a half-life of only 4–10 h before
An essential part of the killing process of neutrophils is the
production of free radicals – reactive oxygen intermediates
and reactive nitrogen intermediates. Upon activation, neutrophils and mononuclear phagocytes have increased oxygen
consumption (the respiratory burst) when oxygen is reduced
by NADPH-oxidase to superoxide anion which can interact
with hydrogen peroxide or a variety of transition metals to
form hydroxyl radical. Superoxide anion can pass through
cell membranes via anion channels and may exert its toxicity
by penetration to important sites where it is converted to
hydrogen peroxide and the more toxic hydroxyl radical.
Reactive oxygen species also promote the margination of neutrophils by triggering the expression of adhesion molecules on
endothelial cells. Reactive oxygen species are implicated in a
variety of pathological conditions (e.g. ARDS, hyperoxia,
asbestosis, silicosis, paraquat toxicity, bleomycin toxicity,
cigarette smoking, ionising radiation and others).
Reactive nitrogen intermediates such as nitric oxide are also
produced. Three isoforms of the enzyme nitric oxide synthase
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Inflammation and immunity
(NOS) have been identified but, in inflammation, the
inducible form (iNOS or type II NOS) is probably the most
important. Stimuli causing the induction of iNOS formation
include the cytokines IFN-γ, IL-1β, IL-6, GM-CSF (granulocyte-macrophage colony stimulatory factor) and platelet activating factor as well as LPS. Although nitric oxide itself
exerts many effects, it also reacts with superoxide to form the
highly toxic peroxynitrite anion.
Biological functions of macrophages
Macrophages are involved at all stages of the immune
response. They act as a rapid protective mechanism which can
respond before T-cell-mediated amplification has taken place.
In addition, through antibody-dependent cell-mediated cytotoxicity, they are able to kill or damage extracellular targets.
They also take part in the initiation of T-cell activation by processing and presenting antigen. Finally, and perhaps most
importantly, they are central effector and regulatory cells of
the inflammatory response.
Macrophages are important producers of arachidonic acid
metabolites and, on phagocytosis, release up to 50% of their
arachidonic acid from membrane phospholipid which is
immediately metabolised into prostaglandins, thromboxanes
and leucotrienes. Macrophages secrete not only cytotoxic- and
inflammation-controlling mediators but also substances participating in tissue reorganisation such as enzymes (e.g.
hyaluronidase, elastase, collagenase), enzyme inhibitors (e.g.
antiproteases) and regulatory growth factors.
and endothelial cells. A wide range of cytokines has been identified and many have overlapping and complementary activities.
Increasing numbers of cytokines are being discovered. Broad
groupings of cytokine families are now known including interleukins (ILs), tumour necrosis factors (TNFs), interferons (IFNs)
and colony stimulating factors (CSFs). Another way of grouping
cytokines is by their action – either pro-inflammatory or antiinflammatory. The importance of the balance between these two
opposing actions – in many ways similar to the coagulation system with procoagulants and profibrinolytics and anti-coagulants
– is now becoming better appreciated.
Cytokines make up a major class of soluble intercellular
signalling molecules and possess typical hormonal activities
in that: (i) they are secreted by a single cell type, react specifically with other cell types (target cells) and regulate specific
vital functions controlled by feedback mechanisms; (ii) they
act at short range in a paracrine or autocrine manner; and (iii)
they interact first with high-affinity cell surface receptors (distinct for each type or even subtype) and regulate gene transcription. This altered transcription (which can be enhanced or
inhibited) results in changes in cell behaviour.
Target cells may be in any body compartment (sometimes a long
distance from the site of secretion). Other types of cytokine act
mostly on neighbouring cells in the micro-environment where
released. During paracrine secretion, some cytokines may escape
cell binding and spill over into the general circulation. Cytokines
are synthesised, stored and transported by various cell types, not
only those of the immune system.
Table 1 Components of inflammation
Regulation of the inflammatory response
The inflammatory response must be well ordered and controlled and a variety of interconnected cellular and soluble
mechanisms are activated when tissue damage and infection
occur. Examples include cytokines, by-products of the plasma
enzyme systems (complement, the coagulation, kinin and fibrinolytic pathways), lipids (prostaglandins, leukotrienes,
platelet activating factor), and vasoactive mediators. Once
leucocytes have arrived at a site of inflammation, they release
mediators which control the later accumulation and activation
of other cells. The main humoral and cellular components
involved in the amplification and propagation of both acute
and chronic inflammation are shown in Table 1.
Cytokines are soluble proteins which regulate host-cell
function through interaction with specific receptors. They are
produced by neutrophils, lymphocytes, monocytes/macrophages
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Process
Antigen recognition
Specific
Non-specific
Effector cells and molecules
B and T lymphocytes
Antibodies
Professional phagocytes
Non-professional phagocytes
Complement pathway
Coagulation cascade
Amplification
Complement system
Arachidonic acid products
Platelet activating factor (PAF)
Bradykinin
Serotonin
Cytokines
Growth factors
Antigen destruction
Neutrophils
Macrophages
Complement system
Perforins
Reactive oxygen and nitrogen species
British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 2 2003
Inflammation and immunity
Table 2 Main types of cytokines
Table 3 Cytokines involved in inflammatory reactions
Cytokine type
Individual cytokine examples
Group
Lymphokines
Macrophage activating factor
Macrophage chemotactic factor
Histamine releasing factors
Pro-inflammatory cytokines
TNF-α
IL-1
IL-6
IL-8
Anti-inflammatory cytokines
IL-4
IL-10
IL-13
Interleukins
IL-1, IL-2, etc.
Tumour necrosis factors
TNF-α,TNF-β
Interferons
IFN-α, IFN-β, IFN-γ
Colony stimulating factors
G-CSF, GM-CSF
Polypeptide growth factors
Epidermal growth factor
Nerve growth factor
Vascular endothelial growth factor
Transforming growth factors
TGF-α,TGF-β
α-Chemokines
IL-8
Platelet factor 4
β-Chemokines
Monocyte chemo-attractant protein 1
(MCP-1)
Macrophage inflammatory protein 1
(MIP-1α)
RANTES
Stress proteins
Individual cytokines
Table 4 Mediators of inflammation
Heat shock proteins
Superoxide dismutase
Function
Mediators
Increased vascular permeability
Histamine
Serotonin
Bradykinin
C3a and C5a
PgE2, prostacyclins, LTC4 and LTD4
Vasoconstriction
TXA2, LTB4, LTC4 and LTD4
C5a
Smooth muscle contraction
C3a and C5a
Histamine
LTB4, LTC4, LTD4 and TXA2
Serotonin
Platelet activating factor (PAF)
Bradykinin
Increased endothelial cell stickiness
Endotoxin, IL-1 and TNF-α
LTB4
Mast cell degranulation
C3a and C5a
Chemotaxis
C5a
LTB4
IL-8 and other chemokines
PAF
Histamine
Pyrogens
IL-1, IL-6 and TNF-α
PgE2
Pain
PgE2
Bradykinin
RANTES, regulated upon activation normal T expressed and presumably
secreted chemokine.
The main types of cytokines are listed in Table 2. They control the direction, amplitude, and duration of immune
responses and the remodelling of tissues. Individual cytokines
have multiple, overlapping and sometimes contradictory,
functions depending on local concentration, cell type they are
acting on, and the presence of other mediators. Thus, the
information which an individual cytokine conveys depends on
the pattern of regulators to which a cell is exposed, and not on
just one cytokine. Because of the potent and profound biological effects of cytokines, it is not surprising that their activities
are tightly regulated, mainly at the levels of secretion and
receptor expression.
From the point of view of inflammation, there are two main
groups of cytokines: pro-inflammatory and anti-inflammatory
(Table 3). Pro-inflammatory cytokines up-regulate inflammatory reactions. Anti-inflammatory cytokines are generally T-cellderived cytokines and down-regulate inflammatory reactions.
TNF-α and IL-1 have a central role in inflammatory
response since administration of their antagonists, such as IL1 receptor antagonist (IL-1ra), soluble fragment of IL-1 receptor, or monoclonal antibodies to TNF-α and soluble TNF
receptor, block various responses in models of inflammation.
Some have also been used in the treatment of human chronic
inflammatory states such as rheumatoid arthritis. On the other
hand, anti-inflammatory cytokines (IL-4, IL-10, IL-13) are
responsible for the down-regulation of inflammation. They
suppress the production of pro-inflammatory cytokines and
their strong anti-inflammatory activity may suggest a role in
the management of many inflammatory conditions. IL-10 has
been extensively investigated in both healthy volunteers and
in patients with both chronic and acute inflammatory diseases.
Patients with rheumatoid arthritis, inflammatory bowel disease, and hepatitis C infections have received IL-10 for
extended periods (up to several months). The safety profile in
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Inflammation and immunity
patients receiving IL-10 has been very good to date, with no
evidence of an increased susceptibility to either bacterial or
viral infections. Future clinical studies in acute inflammatory
diseases will need to address the unresolved issues of the
quantitative importance of IL-10’s anti-inflammatory and
immunosuppressive properties in critically ill patients. It is
possible that treatment targeted to increasing tissue levels
rather than plasma concentrations will be more useful.
Mediators of inflammation
Once leucocytes have arrived at a site of infection or inflammation, they release mediators which control the later accumulation and activation of other cells. Inflammatory mediators are soluble, diffusible molecules that act locally at the site
of tissue damage and infection and, when present at high
enough concentrations, at more distant sites. Bacterial products and toxins can act as exogenous mediators of inflammation; for example, endotoxin can trigger complement activation, resulting in the formation of anaphylatoxins C3a and C5a
resulting in vasodilation and increased vascular permeability.
Endogenous mediators of inflammation are produced from
within the immune system itself, as well as by other systems.
For example, they can be derived from molecules normally
present in the plasma in an inactive form such as peptide fragments of some components of complement, coagulation and
kinin systems. Mediators of inflammatory responses are also
released at sites of injury by a number of cell types that either
contain them as preformed molecules within storage granules
(e.g. histamine) or which can rapidly switch on the machinery
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required to synthesise the mediators when they are required
(e.g. to produce metabolites of arachidonic acid).
The early phase mediators, produced by mast cells and
platelets, are especially important in acute inflammation and
include histamine, serotonin and other vasoactive substances
(Table 4). Platelets may contribute to inflammatory responses
as a consequence of tissue injury through several mechanisms
including: (i) release of vasoactive amines and other permeability factors; (ii) release of lysosomal enzymes; (iii) release
of coagulation factors which lead to localised and generalised
fibrin deposition; and (iv) formation of thrombi which result
in blocking of vessels and capillaries. There is considerable
functional redundancy of the mediators of inflammation and
this explains why certain new treatment options although
appearing promising in the laboratory and in animal models
have not been so successful in human sepsis.
Key references
Blackwell TS, Christman JW. Sepsis and cytokines: current status. Br J
Anaesth 1996; 77: 110–7
Galley HF,Webster NR.The immuno-inflammatory cascade. Br J Anaesth
1996; 77: 11–6
Oberholzer A, Oberholzer C, Moldawer LL. Interleukin-10: a complex
role in the pathogenesis of sepsis syndromes and its potential as an
anti-inflammatory drug. Crit Care Med 2002; 30: S58–63
Westendorp RG, Langermans JA, Huizinga TW et al. Genetic influence on
cytokine production and fatal meningococcal disease. Lancet 1997;
349: 170–3
Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM.The plateletactivating factor signalling system and its regulators in syndromes of
inflammation and thrombosis. Crit Care Med 2002; 30: S294–301
See multiple choice questions 40–44.
British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 2 2003