A very quick look at the innate immune response, and the role of T cells in the adaptive immune response.

1. Innate and Adaptive Immunity
HDT 2:1 – Semester 2

2. Innate Immunity
• When barriers to infection are compromised, such as a graze or a reduction in mucociliary
escalation, the innate immune response is initiated. It has no memory, is non-specific and is
readily available.
• It is called into action via recognition of non-specific elements such as PAMPs and DAMPs, which
are recognised by professional antigen-presenting cells, like macrophages, eosinophils,
neutrophils, mast cells, dendritic cells, monocytes and basophils. The threat is then contained and
destroyed by granulocytes and phagocytes. Both contain vesicles which merge with engulfed
material, destroying it.
• The innate system contains; acute phase proteins (i.e. CRP, opsonizing proteins); cytokines which
cause chemoattraction, modulate cell activity and complement activation, and; a cascade of
proteins involved with opsonisation, killing and chemoattraction.

3. Acute Phase Response
• Acute phase response (inflammation) is described by four characteristics; dolor (pain, caused by
local mediators), tumor (swelling, caused by increased vascular permeability), rubor (redness,
caused by vasodilation) and calor (heat, caused by cytokines). The purpose of this response is to
allow the easy passage of innate immunity cells to the site of infection, so that it can be contained
and resolved.
• Histamine causes junctional widening of venous vessels, endothelial cell contraction and
vasodilation. This is to allow exit of cells and fluid into the surrounding tissue. Antihistamines work
by opposing this method of inflammation and thus reducing redness and swelling.
• Arachidonic acid derivatives prolong vasodilation and oedema via the cyclooxygenase pathway;
examples include prostaglandins and thromboxane. COX inhibitors like NSAIDs and paracetamol
can reduce fever and pain through blocking this mechanism of inflammation.
• Leukotrienes are also mediators of inflammation, which can cause chemotaxis, bronchospasm,
vasoconstriction and increased vascular permeability. This is why leukotriene antagonists like
montelukast are used in asthma to treat bronchospasm.

4. Acute Phase Response
• The threat is recognised by pattern recognition receptors on innate immunity cells (pAPCs) which
leads to cellular activation, complement activation and cytokine release. The problem is then dealt
with via phagocytosis or the recruitment of the adaptive response cells, if needed. Prolonged
inflammation can result in long-term damage such as asthma or COPD.
• Leucocytes (generic term for white blood cells) can be found in elevated levels during the acute
phase of infection/inflammation and the type of infection determines the type of leucocyte found in
elevated levels.
• Increased eosinophils (eosinophilia) indicates that the infection is due to allergy or parasites.
Increased neutrophils (neutrophilia) indicates that the infection is bacterial. Lymphocytosis
indicates that the infection is viral in origin.
• In the acute phase response, IL-6, IL-1 and TNFα will be found in increased levels, which have
the following effects throughout the body.
Cytokine(s) Target Effect
IL-1, IL-6,
TNFα
Endothelium
Vasodilation, activation of cells, increased
permeability
Hypothalamus Fever
Fat, muscle Increased respiratory substrate mobilisation
Liver Increased metabolism, increased ACPs
Bone marrow Neutrophil mobilisation, phagocytosis of pathogens
Dendritic cells Migration to lymph nodes and subsequent maturation

5. Acute Phase - Intervention
• Various drugs exist which block certain cytokines involved in the acute phase
response/inflammation. Anti TNFα drugs like infliximab, etancercept, adalilumab, anti-IL-1 drugs
like humira, canakinumab and anti-IL-6 drugs like tocilizumab all reduce the effects of
inflammation, thus reducing fever, neutrophilia, CRP levels and pose an increased risk of
infection.

6. Organising the Response
• Pattern recognition receptors (PRRs) are found on innate immune cells, which recognise pattern-
associated molecular patterns (PAMPs) on pathogens.
• The purpose of opsonisation is to increase the presentation of these PAMPS to the immune
system so that the pathogen can be dealt with. Interaction via PAMP/PRR promotes inflammation
and the acute phase response.
• Toll-like receptors (TLRs) are a family of PRRs that detect bacterial lipopolysaccharides (LPS)
fragments, which cause intracellular signalling pathways to become active such as Myd88, IRAK<
TRAF and MAPK, which results in inflammatory gene transcription.
• The acute phase response results in the assembly of the inflammasome, promoting the
maturation of inflammatory cytokines IL-1β and IL-18 and the development of the inflammatory
process. Assembly can be initiated through PAMPs or damage (DAMPs).
• The maturation of monocytes in the blood into macrophages in the spleen, tissues, liver and bone
marrow allows phagocytosis of pathogens to be stimulated throughout the body. All cells of the
innate immune system originate in the bone marrow and mature from pre-cursors, differentiating
under the influence of growth factors.
• EPO is a growth factor that can be given to treat anaemia (erythrocyte target), TPO can be given
to treat thrombocytopenia (platelet target) and G-CSF can be given to treat neutropenia
(granulocyte target).

7. Complement Activation
• Part of the acute phase response is the activation of the complement pathway, which is involved in
antigen recognition and opsonisation. The complement proteins are found inactive in the blood,
and are activated sequentially in a complement cascade.
• Some people are deficient in complement proteins or other substances involved in the pathway
and are at risk of infections as a result of this.
• Various elements of the complement pathway are necessary for development of the acute phase
response. C3a initiates inflammation through the release of histamine, which increases vascular
permeability, widens vascular junctions, causes vasodilation and endothelial cell contraction.
• The membrane attack complex (MAC) is assembled later on in the pathway, involving C7, C8 and
C9, which forms pores that insert themselves into the membranes of pathogens, causing death.
• C3b is an important opsonisation protein that facilitates the targeting of cells as foreign and the
recruitment of further complement proteins.
• C5a is a chemoattractant, causing the migration of neutrophils to the site of infection so that
phagocytosis may occur.
• Regulation of the pathways of complement activation (classical [antigen/antibody binding],
alternative [microbial polysaccharides], mannose-lectin binding [carbohydrate sugars] pathways),
allows the prevention of autoimmunity that could be caused by rogue component proteins.
• Deficiency in regulators like C1-Inh can lead to problems; increased bradykinin, increased
intravascular permeability; non-inflammatory oedema, which can be life-threatening.

8. Inflammation – Results, Issues
• Natural termination of the acute phase response is necessary so that long-term damage does not
ensue, which would be detrimental to life.
• Depletion of the stimulus allows complement activation to return to normal, and anti-inflammatory
cytokines like TNFβ and IL-10 can inhibit the production of inflammatory cytokines.
• Additionally, most cytokines/mediators have a short half-life of a few hours to a day, and
neutrophils likewise only have a short lifespan of a day or so. The metabolism of arachidonic acid
also produces lipoxin and resolvins, which have anti-inflammatory activity.
• The outcome of inflammation can be any of the following; resolution of the issue, the formation of
an abscess (pathogen encapsulated in pus), chronic inflammation (long-term damage) or healing
with the formation of a scar.
• When neutrophil production is not controlled, they can accumulate (causing pus) and lead to the
further accumulation of destructive enzymes in extracellular space – leading to chronic diseases
like emphysema, bronchiectasis, COPD and α1-antitrypsin deficiency.
• Inflammation can become chronic where there is persistent injury (continued stimulation via
DAMPs), autoimmune diseases (i.e. rheumatoid arthritis) or prolonged exposure to a toxic agent
(i.e. silica).
• Damage is done chronically by cellular infiltration, destruction of tissue via degradative enzymes
and repair attempts causing fibrosis. Fibrosis leads to tough, non-compliant tissue with a high
collagen content.

9. Inflammation – Results, Issues
• The acute phase duration can be monitored through bloods, where levels of the pro-inflammatory
CRP, serum amyloid, ESR, C3/C4, fibrinogen and ferritin molecules can be checked.
• CRP (C-reactive protein) is a pathogen recognition molecule that binds to phosphocholine on
some bacterial and fungal cell walls. The pathogen becomes opsonised and the complement
cascade is activated through binding of C1q.
• Levels of CRP in the blood rise in response to injury, inflammation and infection and so levels can
be monitored to observe changes in acute phase response duration or efficacy.
• Serum amyloid A is an acute phase protein that increases the production of enzymes that degrade
the extracellular matrix, promotes the transport of cholesterol to the liver to be secreted into bile,
and the recruitment of immune cells to inflammatory sites.
• Levels of serum amyloid A can be monitored for over-production, which can lead to chronic
inflammatory diseases like atherosclerosis, rheumatoid arthritis and amyloidosis.
• The erythrocyte sedimentation rate (ESR) can be measured to observe the presence of excess
acute phase proteins, which cause an increased sedimentation rate due to loss of erythrocyte
surface negative charge, which otherwise repels cells from each other. This therefore results in
aggregation of cells and a quicker sedimentation.