TRANSPLANTATION
Inflammation, immunity
and allergy
Darryl Stewart
Alistair Nichol
Abstract
Injury or foreign invasion will instigate a cascade of events directed at
eliminating the intruder and augmenting the healing process. This in-
volves the unification of two separate processes (inflammatory and im-
mune processes) to provide an effective host defence. Chemical
mediators converge on the site of tissue damage and exert local
and distant effects. The immune response is divided into innate and
acquired immunity. The immediate, non-specific innate response,
combined with the specifically targeted acquired response, provide
our major defence mechanisms. Lymphocytes and immunoglobulins
are the hallmark of acquired immunity. Regulation of these interlinked
systems provide cohesion and a group of soluble proteins called cyto-
kines have a major role. Protective immune mechanisms can some-
times cause detrimental effects to the host. We discuss and classify
allergic reactions, in particular, the most severe and potentially life
threatening form e anaphylaxis.
Keywords Allergy; cytokines; immunity; immunoglobulins; inflam-
mation; macrophages; neutrophils
Royal College of Anaesthetists CPD Matrix: 2C00, 3I00
The inflammatory response
Inflammation is a necessary defensive and reparative response
when tissue is injured by pathogens or trauma. The aim is ulti-
mately to eliminate causative micro-organisms and initiate a
healing process that is appropriate and controlled. The inflam-
matory process is designed to transport the necessary compo-
nents of the body’s response to the site of injury, where a
regulated cascade of events can occur.
The main features of the inflammatory response are:1
 vasodilation, thereby increasing blood flow to the affected
area
 increased vascular permeability to facilitate diffusion of
components to the injured site
Darryl Stewart MB BCh BAO FRCA FFICM is an Intensivist and
Anaesthetist at Craigavon Area Hospital, Portadown, Northern
Ireland. Conflicts of interest: none declared.
Alistair Nichol BA MB BCh BAO FCARCSI FCICM FJFICMI PhD is a
Consultant Anaesthetist/Intensivist at St Vincent’s University Hospital
and Intensivist at the Alfred Hospital, Melbourne, Australia; Chair of
Critical Care Medicine, University College Dublin and a Professor,
Australian and New Zealand Intensive Care-Research Centre in the
School of Public Health and Preventive Medicine, Monash University,
Australia. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:8
Learning objectives
After reading this article, you should be able to:
C describe the acute inflammatory response that occurs following
local tissue damage
C differentiate the innate from acquired, and cellular from hu-
moral immune responses
C highlight the multiple regulatory mediators involved, defining
their functions and looking at their roles in the critically ill
patient
C discuss immunomodulation and its potential role in critical care
C classify allergic reactions and describe the management of an
acute anaphylactic reaction
 cellular infiltration by inflammatory mediators
 activation of immune and enzyme systems.
In health, extracellular fluid is typically void of pro-
inflammatory mediators and the cells required to fight path-
ogen invasion. Inflammation therefore promotes the migration of
these components to where they are required. Vasodilation oc-
curs soon after the initial insult, with histamine from mast cell
release being the predominant influence. The increased capillary
capacity promotes the movement of leucocytes to the site of
injury and the increase in vascular permeability, also facilitated
by histamine, allows them to enter damaged tissue. Fluid
exudate consequently forms in the interstitium due to changes in
the colloid osmotic pressure.
Cellular infiltration by neutrophils and macrophages then
occurs via a process of margination where blood flow in the site
of injury actually slows and leucocytes leave the central axial
blood stream to come into contact with the endothelium. The
leucocytes then begin a process of rolling whereby they align
themselves with the endothelial wall forming bonds. This stage is
mediated by the selectin family of transmembrane adhesion re-
ceptors, with P-selectin the most prominent. The process of
cellular adhesion to the endothelium is dependent on leucocyte
integrins interacting with endothelial ICAMS (intercellular
adhesion molecules) and VCAMS (vascular cell adhesion mole-
cules). Once adhered to the endothelium they emigrate through
it, down a chemotactic gradient in a process called diapedesis.
This involves the leucocyte assuming a flattened form and using
pseudopodia to negotiate between the much smaller vascular
pores and into the extravascular space. The activation of leuco-
cytes is triggered by multiple immune and enzymatic processes
that ultimately result in suppuration, healing and repair of the
injured site.2 These regulatory processes also help ensure that an
excessive response is inhibited thus preventing further tissue and
organ destruction.
Immunity
Immunity is the balanced state of having an adequate system
to fight infection, while having adequate tolerance to
avoid inflammation, allergy and autoimmune dysfunction.2
There are two types of immunity; innate and acquired (or
adaptive).
488 Ó 2021 Published by Elsevier Ltd.
 TRANSPLANTATION
Innate immunity
Innate immunity consists of anatomical, physiological, cellular
and molecular barriers to pathogens. Importantly, it is immedi-
ate, non-specific and does not require previous exposure to an-
tigen. These barriers include body surfaces (skin, mucous
membranes), antibacterial secretions (unfavourable gastric pH,
salivary lysozymes and lactoperoxidase) and stasis prevention
(mucociliary activity, coughing, sneezing, vomiting and diar-
rhoea). In addition, the innate immune system comprises the
complement protein system along with active immune cells and
interferon.
The receptors associated with the innate immune system are
encoded on the genome and have the ability to detect threats via
expression of families of pattern recognition receptors (PRRs).3
These include Toll-like receptors (TLRs), Nod-like receptors
(NLRs), Rig-I-like receptors (RLRs), C-type lectin receptors
(CLRs) and cytosolic DNA receptors. The localization of PRRs
reflects the specific ligands they sense. When activated, these
receptors lead to production of inflammatory mediators that
coordinate further recruitment of immune cells to the site of
injury.
The complement enzymatic system is synthesized by the liver
and is designed to enhance the activity of both the innate and the
acquired immune responses. It is comprised of two pathways:
the classical and the alternative. In the classical pathway, anti-
bodies bind antigen during a foreign invasion and the subsequent
complex is recognized by complement proteins that trigger a
cascade of inflammatory events (acquired). The alternative
pathway is initiated by exposure to carbohydrate chains found on
the surface of micro-organisms (innate). During the complement
cascade, each precursor is cleaved into two parts (C3 to C3a and
C3b, C4 to C4a and C4b, etc.) until C9a and C9b are generated.
All of these complement proteins help facilitate the three major
functions of this system, which include:
 chemotaxis and inflammation (C3a, C5a), thereby
recruiting phagocytes to the site of injury
 opsonization of pathogens (C3b), where they are tagged
for destruction by phagocytes
 development of membrane attack complexes (MAC) (C5-
9b). These specialized peptides adhere to the cell surface,
disrupting the phospholipid bilayer and cause cell lysis.
The cells of the innate immune system include granulocytes,
mast cells, natural killer cells and monocytes, none of which
require previous pathogen exposure to carry out their functions.
Mast cells are typically found on mucosal surfaces and have a
crucial role in allergic responses. Similarly, eosinophils and ba-
sophils also have a major role in allergy, releasing histamines,
leukotrienes and heparins. Neutrophils are another group of
granulocyte and comprise more than 50% of normal circulating
white cells. They are the first to attack pathogens and form the
body’s most aggressive cellular response to infection. They will
be discussed further below. Natural killer (NK) cells target virus-
infected cells and tumour cells, releasing chemicals to promote
cell lysis and death. It was initially thought that NK cells were
non-specific and lacked immune memory recall, but it is now
appreciated that the reverse may be true and that in some in-
stances NK cell memory responses to viral infections are well
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:8
established and so they play an active part in both innate and
adaptive immune responses.4
Interferon is another defence mechanism against viral insult.
It is composed of cytokines that are released by virally infected
host cells. Currently, there are three types of interferons classi-
fied by their nucleotide sequence, interaction with specific re-
ceptors, chromosomal location, structure and physicochemical
properties.5 A high level of antiviral protection is achieved by
IFN-a, IFN-b and IFN-l. Interferon essentially prevents viruses
from binding to cells and disrupts viral mRNA. It is important to
note that these molecules do not have actual anti-viral properties
but instead act as signals to other cells to produce anti-viral
agents.
Acquired/adaptive immunity
Acquired immunity requires a prior exposure to an antigen and
involves antibodies and lymphocytes. It is dependent on memory
and recognition of prior pathogens with antigen-specific memory
cells generating a more forceful response on re-exposure. This
system is therefore typically slower in its initial response to
attack with 72e96 hours required to generate specific T cells and
antibodies. Acquired immunity can be further divided into
cellular and humoral immunity.
Cellular immunity: is mediated by T lymphocytes that are pro-
duced in bone marrow but mature in the thymus. They provide
defence against most viruses and have a regulatory role in im-
mune mechanisms. T cells defend against organisms that infil-
trate into cells where antibodies and complement cannot access.2
They have a unique antigen T-cell receptor (TCR) on their cell
membranes that recognizes specific peptide sequences bound to
major histocompatibility complexes (MHCs) on antigen-
presenting cells and infected cells. The TCR and MHC interac-
tion allows T cells to activate and proliferate.
In humans, MHC is also known as human leucocyte antigen
(HLA). There are two classes, MHC class 1 and MHC class 2, with
numerous molecules per class. MHC class 1 molecules are pre-
sent on all nucleated cells of the body and cytotoxic (killer)
T cells are the main responders. In contrast, MHC class 2 mole-
cules are only found on lymphoid tissue cells with T helper cells
primarily activated.
Cytotoxic T cells destroy host cells harbouring any foreign
antigen such as viruses, tissue graft cells and tumour cells.
Helper T cells modulate responses of other immune cells. They
have the ability to activate other lymphocytes and macrophages
to upgrade the level of overall immune response by releasing
cytokines.6 Circulating helper cells are capable of unrestricted
cytokine expression and are guided into a focused pattern of
cytokine release based on signals received at the outset of
infection.1 Circulating helper cells account for 70% of circulating
T cells.
Neutrophils e are the most abundant leucocyte in humans and
their aggregation is the hallmark of acute inflammation. They are
released into the circulation from bone marrow in an inactive
form and remain in this state for 4e10 hours before marginating
and entering into tissue pools where they will survive in an
489 Ó 2021 Published by Elsevier Ltd.
 TRANSPLANTATION
activated form for 1e2 days. As alluded to earlier, chemotaxis
plays an essential role in the recruitment of neutrophils to the site
of inflammation. Once there, their function can be divided into
three primary capacities: generation of oxidative bursts; release
of cytotoxic granules; and formation of neutrophil extracellular
traps (NETs).7 The most abundant neutrophil-granule protein is
myeloperoxidase, which has an important role in the formation
of hypochlorous acid. This has considerable microbicidal prop-
erties. Neutrophils also contain cytoplasmic granules full of
antimicrobial substances, proteases, lipases and cytoplasmic
membrane receptors. Many of these substances act to hydrolyse
bacterial cell walls but it should be noted that they can be
destructive to normal tissue also. For this reason, the release of
these cytoplasmic enzymes are mediated by protease inhibitors
such as macroglobulin and antiprotease.1 More recently, it has
become clear that neutrophils not only have a fundamental role
in the acute phase of inflammation when they actively eliminate
pathogens, but they are also capable of modifying the overall
immune response. They achieve this by exchanging information
with macrophages, dendritic cells, and other cells of the adaptive
immune system through either soluble mediators or direct cell
ecell contact.8
Phagocytosis is an important part of the neutrophil armoury.
Other professional phagocytes include monocytes, macrophages,
dendritic cells, osteoclasts and eosinophils.9 All phagocytes
participate in elimination of apoptotic bodies but only some also
eliminate microorganisms. Phagocytes must be able to identify
potential targets, and this is achieved using specialized receptors
on their plasma membranes. These receptors can be divided into
nonopsonic and opsonic receptors. Nonopsonic receptors
recognize molecular groups on the cell surface of phagocyte
targets, while nonopsonic receptors recognize host-derived op-
sonins that bind to foreign bodies, targeting them for ingestion.
These opsonins include antibodies, complement and fibro-
nectin.9 The process of phagocytosis is rather complex but can be
broken down into several discrete steps:
1. Recognition and binding
2. Pseudopodium development leading to engulfment of the
target and the formation of a phagosome
3. Fusion of the phagosome with lysosomes. These contain
hydrogen peroxide, peroxidase, lysozyme and other hydro-
lytic enzymes.
4. Release of lysosomal enzymes producing an ‘oxidative burst’
with production of superoxide and other oxygen radicals.
Phagolysosomal contents are digested.
5. Exocytosis with extrusion of destroyed material.
Macrophages e are key components of the inflammatory
response, in which they have a regulatory capacity. They are
early responders to infection and have a role in presenting anti-
gen to T-cell lymphocytes. Macrophages destroy extracellular
targets through antibody-dependent cell-mediated cytotoxicity.
They are involved in producing arachidonic acid from phos-
pholipids on their cell membranes during phagocytosis. This is
then immediately converted to prostaglandins, thromboxanes
and leukotrienes. Macrophages also produce enzymes (elastase,
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:8
collagenase), enzyme inhibitors (antiproteases) and regulatory
hormones.
Humoral immunity: is provided by B lymphocytes. These bind
antigens and produce active plasma cells or dormant memory
cells. The main function of this system is to produce antibodies
(immunoglobulins) from active plasma cells. Immunoglobulins
can be divided into five main subgroups depending on their
activity:
1. IgM e acts as the B-cell receptor for antigen attachment.
2. IgG e the most abundant immunoglobulin in blood.
3. IgE e associated with hypersensitivity and allergic reactions.
Also provides protection against parasitic infections.
4. IgA e found in the secretions of the respiratory, digestive
and urogenital systems.
5. IgD e found on the surface of many B cells but its function is
still uncertain.
The immunoglobulin molecule has two functional ends: the
Fab end that binds antigens and the Fc end that is responsible for
effector functions. IgM and IgG antibodies are the most important
in the provision of the immune response. Serum levels of these
immunoglobulins can be difficult to interpret due to their
involvement in a large number of pathological and inflammatory
states. Nevertheless they may provide valuable insight in diag-
nosing conditions such as monoclonal gammopathies (MGUS),
macroglobulinaemia, myeloma and arthropathies. The adminis-
tration of intravenous immunoglobulin (IVIG) is gaining
increased following in the treatment of multiple autoimmune and
infective states. It provides the cornerstone of treatment for
Guillain-Barre, myasthenia gravis and acute disseminated
encephalomyelitis.
IVIG continues to be used in patients with severe septic shock,
particularly when endotoxaemia is proven or strongly suspected.
In this setting immunoglobulin may have a dual role both as a
pro-inflammatory and anti-inflammatory agent. The suspected
mechanism of this is highlighted in Figure 1.10
It should be noted, however, that to date the evidence for
polyclonal IVIG as an immunomodulatory agent in sepsis is
insufficient to support widespread use.11,12
Mediators of inflammation
Leucocytes release inflammatory mediators upon their arrival at
sites of inflammation. These endogenous soluble diffusible
molecules control the accumulation and activation of other cells.
They include cytokines (discussed in detail below), prostaglan-
dins, leukotrienes, platelet activating factors and activated oxy-
gen species. Endogenous mediators are also produced from
molecules normally found in an inactive form in plasma such as
peptide fragments from the complement, coagulation and kinin
systems. Exogenous mediators play an important role too, most
notably endotoxin that is produced by some strains of Gram
positive cocci. If left untreated, these molecules can result in life-
threatening endotoxaemic shock, by acting as ‘super-antigens’,
stimulating massive immune cell expansion and cytokine pro-
duction with devastating end-organ consequences.13
490 Ó 2021 Published by Elsevier Ltd.
 TRANSPLANTATION

Intravenous immunoglobulin in septic shock

Pathogen Toxin Scavenging

clearance scavenging of mediators
IgM +++ IgM + IgM +
IgG ++ IgG ++ IgG +++
Pro-inflammatory effects (Fcy receptors)
IgM +?
IgG ++

Anti-apoptotic effect
on immune cells
IgM ++
Early death
IgG ?
(organ injury)
Homeostasis
Sepsis
Anti-inflammatory

Late death Clearance of the

onset (secondary infection) apoptotic cells
IgM +++
IgG ?

From Busani S, Damiani E, Cavazzuti I, Donati A, Girardis M. Intravenous immunoglobulin

in septic shock: review of the mechanisms of action and meta-analysis of the clinical
effectiveness. Minerva Anestesiologica 2016; 82 (5): 559–572. With kind permission

Figure 1

Most endogenous mediators act locally; however, if they are
in high enough concentrations they can produce widespread
systemic effects. These include vasodilation, pain, fever and
tissue damage seen in inflammatory and septic states.
The early phase mediators produced by mast cells and
platelets are particularly important in acute inflammation. These
include histamine, serotonin and other vasoactive substances.1
Platelets have a considerable contribution to the inflammatory
response through several pathways:2
 release of vasoactive amines
 release of lysosomal enzymes
 release of coagulation factors
 formation of thrombi
chemotactic activities) and interleukins (cytokines made by one
leucocyte and acting on others). Cytokines may act on cells that
secrete them (autocrine action), on nearby cells (paracrine ac-
tion) or on distant cells (endocrine action).14 Essentially, these
proteins can be classed as pro-inflammatory or anti-
inflammatory, with their interaction determining the extent of
the inflammatory response. The actions of individual cytokines
are not always predictable as they may have multiple and oc-
casionally contradictory functions depending on the cell type
they are acting on, their concentration in plasma and the pres-
ence of other mediators.1 Examples of cytokine function are
provided in Table 1.6

Regulation of the inflammatory response

Much like the clotting cascade, the inflammatory process must be Examples of cytokine function
controlled and regulated to prevent both inadequate and over- Pro-inflammatory cytokines TNF, IL-1, IL-2, IL-6,
reactive responses. It requires a complex structure with feed- chemokines
back processes occurring between multiple cellular and soluble Anti-inflammatory cytokines IL-4, IL-10, IL-13, TGF-beta
mechanisms. Leucocytes form the cornerstone of this process, Antiviral cytokines IFN-alpha, IFN-beta
secreting antibodies and other chemical mediators, namely Macrophage activating cytokines IFN-gamma
cytokines. B-cell activating cytokines IL-4, IL-5, IL-6, IL-21
Cytokines are soluble proteins that have a specific effect on T-cell activating cytokines IL-2, IL-4, IL-12, IFN-gamma
the interactions between cells, regulating the amplitude and Eosinophil and/or mast cell activating IL-3, IL-4, IL-5, IL-13
duration of the immune response. Cytokine is a collective term cytokines
that includes lymphokines (cytokines made by lymphocytes),
monokines (made by monocytes), chemokines (cytokines with Table 1

ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:8 491 Ó 2021 Published by Elsevier Ltd.
 TRANSPLANTATION
TNF-a and IL-1 antagonists are well-established anti-inflam-
matory agents and are used in the treatment of chronic inflam-
matory diseases such as rheumatoid arthritis, psoriasis and
Crohn’s disease. The administration of anti-inflammatory cyto-
kines such as IL-4, IL-10 and IL-13 have also been studied with
encouraging results in a broad spectrum of inflammatory
conditions.
The concept of immunomodulation has been attractive for
many years in critical care as we become more aware of the marked
destruction that an unregulated immune response can have. This is
seen in a wide variety of conditions ranging from ARDS, septic
shock, cardiomyopathies, traumatic brain and spinal cord injuries.
Unfortunately a ‘magic bullet’ has never been found, yet when the
complexity of the immune response is considered, this may be an
unrealistic goal. The most commonly administered of these agents
has probably been corticosteroids, which have been trialed
extensively for over 20 years, the most recent of which has resulted
in another negative study.15 Ongoing optimism persists though
that through better understanding of the regulation of inflamma-
tion, the pathology and disease states associated with it may be
dampened. The dose, timing and stage of the patient’s immune
response will all have to be considered if the administration of
these drugs is to be effective.
Allergy
An allergy is the production of an inappropriate specific immune
reaction to a normally harmless substance (allergen). Re-
exposure of the sensitized individual to the allergen results in
an immune response that can range from mild to life-threatening.
Allergic responses can be classed as immediate or delayed hy-
persensitivity reactions.
Immediate hypersensitivity
In immediate hypersensitivity the immune response differs
from the normal antibody-mediated events after exposure to a
foreign substance. The allergic response is evident within
20e30 minutes.16
Common allergens include:
 pollen
 foods
 penicillin
 insect stings
 dust.
The allergens bind to IgE antibodies rather than IgG anti-
bodies that are associated with bacterial antigens. When the host
is first exposed to the allergen helper T cells secrete IL-4 that in
turn causes B cells to release IgE. This initial exposure is the
sensitization period during which no symptomatic reaction oc-
curs. Memory cells are formed and on re-exposure to the allergen
a more significant reaction is produced. IgE antibodies have their
tail portions attached to both mast cells and basophils, which
produce and store inflammatory mediators (e.g. histamine).2
Mast cells congregate where they can come in contact with the
environment such as skin and the lining of respiratory and
digestive systems. Upon binding with the allergen, the IgE
molecule is perfectly placed to stimulate rupture of the mast cell
or basophil releasing their inflammatory mediators.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:8
There are several important mediators released during an im-
mediate hypersensitivity reaction. Histamine leads to vasodilation
and an increase in vascular permeability. Slow-reactive substance
of anaphylaxis (SRS) causes prolonged and severe smooth muscle
contraction, particularly in small bronchioles. Eosinophil chemo-
tactic factor attracts eosinophils to the affected region.2
Symptoms of immediate hypersensitivity can be localized to
the area affected such as skin (hives) or the respiratory tract (hay
fever). More serious reactions can be widespread and multi-
systemic. Anaphylaxis or anaphylactic shock represents the most
serious manifestation, characterized predominantly by severe
hypotension and bronchospasm but with individual variability.
Not all anaphylaxis is IgE-mediated and these may be referred to
as anaphylactoid.17
Anaphylaxis: is life threatening and requires immediate recog-
nition and management. The reaction can affect numerous organ
systems resulting in a combination of an urticarial rash,
angioedema, bronchospasm, hypotension, nausea and vomiting.
Other more unusual presentations can involve seizure activity,
headache and substernal pain.17 Anaphylactic reactions can
follow three patterns as they develop: uniphasic, biphasic and
protracted reactions. A uniphasic reaction occurs within 30 mi-
nutes of exposure to the offending allergen and lasts 1e2 hours
before resolving spontaneously or with treatment. A biphasic
reaction has the initial uniphasic response but with a second
wave of symptoms typically occurring within 8 hours of the first.
It is estimated that approximately 20% of patients experience
biphasic reactions and therefore hospital admission for at least 8
hours following resolution of symptoms from the immediate re-
action is strongly recommended. A protracted anaphylactic re-
action can last for up to several days with a severe shocked state
and bronchospasm despite appropriate therapy.
The treatment of anaphylaxis should begin with an airway,
breathing, circulation (ABC) approach and removal of all po-
tential allergens.18 Upper airway oedema occurs in over 50% of
patients with severe anaphylaxis so appropriate recognition and
caution is imperative.17 The only therapy shown to improve
mortality in anaphylaxis is epinephrine. This should be admin-
istered immediately if anaphylaxis is suspected. A bolus of 50
micrograms intravenously should be administered or 500 mi-
crograms via the intramuscular route. This should be repeated as
necessary in conjunction with a fluid bolus, recognizing the
relative hypovolaemia present in this distributive shocked state.
It is not unusual for patients to require several litres of intrave-
nous crystalloid and an epinephrine infusion before haemody-
namic instability has been resolved. Secondary treatment
involves bronchodilator therapy along with steroids and anti-
histamines. These patients are best cared for in a high de-
pendency or intensive care unit if their symptoms are ongoing
and to guard against a biphasic response.
Mast cell tryptase is released during anaphylaxis and can aid
in differentiating it from other causes of distributive shock. The
first serum sample should be collected just after resuscitation has
started with the second sample collected after 1 hour and the
third sample after 24 hours. The serum tryptase levels peak after
30e90 minutes after the onset of anaphylaxis. All patients who
492 Ó 2021 Published by Elsevier Ltd.
 TRANSPLANTATION
suffer an anaphylactic reaction should be followed up by an
immunologist.
Delayed hypersensitivity
A delayed hypersensitivity reaction is a T-cell-mediated immune
response, unlike immediate, which is B-cell driven. Examples of
allergens include cosmetics, household cleaning agents and
poison ivy. The most common manifestation is a delayed skin
eruption, 1 to 3 days after exposure to the allergen (to which the
T-cell system has had previous exposure).2
Conclusion
The inflammatory response is a tightly controlled cascade of events
designed to eliminate pathogens and initiate healing. It is multi-
faceted requiring cellular and non-cellular interactions that can
have profound effects beyond the local site of injury. The imme-
diate, non-specific innate response, combined with the specifically
targeted acquired response, provide our major defence mecha-
nisms. Meanwhile lymphocytes and immunoglobulins are the
hallmark of our acquired immunity. The role of cytokines and their
ability to be pro- and anti-inflammatory is being increasingly
revealed thus allowing us as clinicians to consider their roles in
immunomodulatory therapies. Immune responses can be exag-
gerated and detrimental such as in anaphylaxis. A therapy in patients with septic shock. N Engl J Med 2018; 378:
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Acknowledgements
The authors acknowledge the contribution of Dr Cormac O’Connor to
an earlier version of this article.
493 Ó 2021 Published by Elsevier Ltd.