Immunology

Crispian Scully Eleni A Georgakopoulou Yazan Hassona

The Immune System: Basis of

so much Health and Disease:
9. Control of Inflammation and
Immunity
Abstract: The immune system is the body’s primary defence mechanism against infections, and disturbances in the system can cause
disease if the system fails in defence functions (in immunocompromised people), or if the activity is detrimental to the host (as in auto-
immune and auto-inflammatory states). A healthy immune system is also essential to normal health of dental and oral tissues. This series
presents the basics for the understanding of the immune system, this article covering control of immunity and inflammation.
Clinical Relevance: Modern dental clinicians need a basic understanding of the immune system as it underlies health and disease.
Dent Update 2018; 45: 51–56

Control of inflammation Mediators of inflammation are inflammatory molecules such as

The cardinal features of
inflammation are:
 Redness (rubor);
 Swelling (tumour);
 Pain (dolor);
 Heat (calor);
 Altered function (functio
laesa).
Crispian Scully, CBE, DSc, DChD, DMed
(HC), Dhc(multi), MD, PhD, PhD (HC),
FMedSci, MDS, MRCS, BSc, FDS RCS, FDS
RCPS, FFD RCSI, FDS RCSEd, FRCPath,
FHEA, Eleni A Georgakopoulou, PhD,
MD, MSc, DDS, Research Fellow, University
of Athens and Dental Practitioner, 4
Fokaias Str, 14232 N Ionia, Greece and
Yazan Hassona, BDS, FFD RCSI, PhD,
Assistant Professor and Consultant in Oral
Medicine and Special Needs Dentistry, The
University of Jordan, Amman.
January 2018 DentalUpdate 51
shown in Tables 1 and 2 and involve the
following:
 Inflammation in most instances begins
to resolve within the first few hours
after it begins;
 Inflammation is perpetuated and
amplified in an ongoing imbalance
between pro- and anti-inflammatory
factors − the latter also are mainly
cytokines;
 Anti-inflammatory cytokines include the
interleukins and lymphokines, and cell
signal molecules such as TNF, and the
interferons, which regulate the immune
response intensity or duration by
modulating immunocyte proliferation,
or their secretion of other cytokines or
antibodies;
 Inflammation control is not a mere
passive regression of pro-inflammatory
products but is also an active process
which includes:
– Granulocytes, which inhibit pro-
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leukotrienes;
– Prostaglandins and leukotriene
production from arachidonic acid
switches to lipoxins, which initiate
a sequence leading to resolution
of inflammation;
– Lipo-oxygenases (LO) in mucosae,
leukocytes and platelets
convert arachidonic acid to anti-
inflammatory lipoxin LXA4 which
inhibits chemotaxis, superoxide
production and release of pro-
inflammatory cytokines, and
modulates macrophages to
develop anti-inflammatory actions;
– Apoptosis (programmed cell
death) is initiated by the synthesis
from omega-3 polyunsaturated
fatty acids (PUFA), of resolvins
and protectins, which critically
shortens the period of
neutrophil infiltration. Omega
3 polyunsaturated fatty acids
 Immunology

give rise to lipid mediators give rise to a number of untoward but is involved in the pathogenesis
which inhibit the conversion sequelae and may, if chronic, injure of many systemic diseases including
of arachidonic acid to pro- tissues; cancer, cardiovascular diseases, age-
inflammatory eicosanoids, and  The control of inflammation is thus related degenerative conditions like
include: important not only for resolution of Alzheimer’s disease, metabolic diseases
– Alpha linolenic acid (ALA) damage from trauma and infection such as diabetes (Figure 1) and possibly
– Eicosapentaenoic acid
(EPA) gives rise mainly to
resolvins (resolution phase
Mediators Source Action
interactive products), which
act mainly on phagocytes
Chemokines Endothelial cells Directs immune cells from
to inhibit production and
(eg CCL 1-28, CXC1-17) Monocytes blood into the affected
release of inflammatory
Lymphocytes tissue
mediators;
– Docosahexaenoic acid (DHA)
gives rise to protectins. Inflammatory cytokines Monocytes Directs immune cells from
– Apoptotic neutrophils are (eg interleukins and tumour Lymphocytes blood into the affected
removed by macrophage necrosis factor TNF) tissue
phagocytosis;
Pain mediators Damaged tissues Vasodilation increase the
– Macrophages release anti-
(eg bradykinin) Monocytes/macrophages permeability of capillaries
inflammatory and reparative
cytokines such as transforming
growth factor TGF-β1, IL-10, IL-13, Clotting mediators Damaged tissue Mediates clotting process
and IL-1ra and then leave the (eg fibrin peptides)
area via lymphatics;
– Neutrophil recruitment gradually Complement components Monocytes macrophages Attack and destroy and
subsides and ceases; (eg C5a, C3A, C4a) Cascade-activated opsonize bacteria
– The inflamed area returns to
normal. Table 1. Examples of inflammatory mediators.
 Inflammation, if not resolving, may

Vasodilation Immediate action Delayed action Chemotaxis Opsonins Pain

Histamine * *** _ _ _ _

Serotonin * * _ _ _ _
(5 hydroxy
tryptamine)

Bradykinin * * _ _ _ ***

Complement C3a _ * _ _ _ _

C3b _ _ _ _ *** _

C5a _ * _ *** _ _

Prostaglandins *** * * *** _ _

Leukotrienes _ *** * *** _ _

Lysosomal proteases _ _ ** _ _ _

Oxygen free radicals _ _ ** _ _ _

Table 2. The action of mediators of inflammation. Key: *mild mediator; **moderate mediator; ***important mediator.

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 Immunology

periodontitis. Thus many of the

Autoimmune molecules involved in inflammation
disease (Table 3) are also mediators of
systemic diseases.

Cancer Alzheimer’s Control of the immune

system
Antigen recognition can be
n influenced by:
io
 Dose and route of antigen exposure;
Obesity and
at

 Absence of co-stimulation;
metabolic Cardiovascular
m

 Engagement of B7 on activated
syndrome disease
m

antigen-presenting cells (APC);

fla

 Presence of antibodies;
 Presence of immune complexes;
in

 Some MHC types.

Diabetes Musculoskeletal T-cell activation is influenced
disorders by cytokines:
 Th1 cells and Th2 cells respond to
Neurological different sets of chemokines;
disease  CD4 T-cells can deviate immune
responses to Th1 or Th2 type helper T
cell responses;
Figure 1. Inflammation is involved in the pathogenesis of many diseases.  Selective migration of lymphocyte
subsets to different sites can
modulate the local type of immune
response.
APCs produce CCL4
Dendritic cells
(chemokine [C-C motif ] ligand 4), a
chemokine which attracts regulatory T
cells (Tregs) to the area:
 Tregs are usually CD4 T cells (CD25+,
CD4+) which limit and suppress the
immune system (and may also control
aberrant immune responses to self-
antigens);
on
cti  Tregs can inhibit immune responses
C fun n by producing suppressive cytokines,
f D tio
Treg i o n o atura eg interleukin 10 (IL-10) and
t
ibi d m transforming growth factor-P (TGFP)
CD25, Foxp3 Inh an
 Tregs are under the control of a
specific transcription factor (FoxP3).
Effector T-cell Figure 2 shows the effects of Tregs on
T-cells and dendritic cells.
Cytokine release becomes
suppressed; for example, IL-1β and TNF-
Inhibition by cytokines
alpha fall under the control of the AUF1
(IL10,TGFβ)
Cytolysis (AU-rich element RNA-binding protein
Death because of cytokine gene) also known as heterogeneous
deprivation nuclear ribonucleoprotein D (HNRNPD).
Immunoglobulins can
influence the immune response
positively in several ways, as anti-
idiotypes or through immune complex
formation or negatively by reducing
Figure 2. The regulatory effects of T-regs.
antigenic challenge or by feedback
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 Immunology

inhibition of B-cells.  Enhanced by sleep and rest; innate and acquired immune
Genetic factors which  Enhanced by a diet rich responses;
influence the immune system include in fresh fruits and vegetables, and by – Male sex hormones suppress the
both MHC-linked and non-MHC-linked polyunsaturated fatty acids; immune system;
genes.  Impaired by stress; – Vitamin D (a hormone) may
Tolerance mechanisms are  Modulated by: suppress the immune system;
needed because the immune system – Female sex hormones stimulate – The neuroendocrines prolactin and
randomly generates a vast diversity of
antigen-specific receptors and some of
these will be self-reactive. Self-reactive Acronym Full meaning
T-cells share the following features:
AP-1 Activator Protein 1
 May ignore self antigens, for
example when antigens are in tissues AA Arachidonic Acid
sequestered from the circulation; CARD15 Caspase Recruitment Domain Family, Member 15 (also known as NOD2)
 Response to a self antigen may be
suppressed if the antigen is present in CRP C Reactive Protein
a privileged site; ESR Erythrocyte Sedimentation Rate
 May, under certain conditions, be
deleted or rendered anergic and Fas Fast antigen (also termed APO-1, APT1 and CD95, and now known as
unable to respond; tumour necrosis factor receptor superfamily 6 [TNFRSF6])
 May be maintained by immune
FADD Fas Associated Death Domain
regulation in a state of tolerance to
self antigens; Fas L Fas Ligand
 Central thymic tolerance to self IFN Interferon-γ
antigens (auto-antigens) results
from the deletion of differentiating IL Interleukin
T-cells that express antigen-specific JNK Jun-n-terminal Kinase
receptors and thereby have high LPS Lipopolysaccharide
binding affinity for intra-thymic self
antigens; MAPK Mitogen-Activated Protein Kinase
 Low-affinity self-reactive T-cells, and NFκB Nuclear Factor-κB
T-cells with receptors specific for
antigens that are not represented NOD2 Nucleotide-Binding Oligomerization Domain Containing 2 (also known
intra-thymically, mature and join the as the caspase recruitment domain family, member 15; CARD15)
peripheral T-cell pool. NSAID Non-Steroidal Anti-inflammatory Drugs
The fates of T-cells, as derived
from thymocytes, are depicted in Figure PAMP Pathogen Associated Molecular Pattern
3. PG Prostaglandin
B-cell deletion takes place
in both bone marrow and peripheral ROS Reactive Oxygen Species (chemically reactive molecules containing
lymphoid organs. Differentiating B-cells oxygen, such as peroxides, superoxide, hydroxyl radical and singlet
that express surface immunoglobulin oxygen)
receptors with high binding affinity for SAA Serum Amyloid A protein
self-membrane-bound antigens will be TNF Tumour Necrosis Factor-α
deleted soon after their generation in
the bone marrow. A high proportion of TNFR TNF Receptor
short-lived, low-avidity, auto-reactive TNFRI TNF Receptor Type I (also termed p55 or CD120a)
B-cells appear in peripheral lymphoid TNFRII TNF Receptor Type II
organs, and may be recruited to fight
infection. TNFRSF TNF Receptor Super Families
TNFSF1A The gene encoding TNF Receptor Type I
Immune system
TRADD TNF Receptor Type 1-Associated DEATH Domain protein
responsiveness
Immune system TRAF TNF Receptor-Associated Factor
responsiveness is affected by the
Table 3. Terms related to inflammation.
following:
January 2018 DentalUpdate 55
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 Immunology

growth hormone can modulate

Low avidity for immune responses;
CD4
– Corticosteroids in particular
self-peptide-MHC
downregulate immune responses
and macrophage activation;
– Prostaglandins (PG) and
apoptosis thromboxanes (TX) belong to the
group of biologically active lipid-
CD8
termed eicosanoids synthesized
by most nucleated cells. PGs and
TXs are mediators of pain, and
intermediate avidity inflammation − by vasodilatation
for self-peptide and increased vascular
high affinity for permeability. They are inhibited by
self-peptide-MHC corticosteroids and non-steroidal
complexes Treg anti-inflammatory drugs (NSAIDs).
Foxp3 The main actions of
corticosteroids and NSAIDs are depicted in
Control Figure 4.
autoimmunity
Figure 3. Thymic regulation of auto-reactive T-cell control.
Conclusion
Inflammation is beneficial to
the organism as it consists of a primary
Phospholipase A2 barrier against external and internal
(Liberates arachidonic acid detrimental processes. Failure of the
from cell membrane
mechanism that controls the process
phospholipids following
cellular injury or of inflammation may result in chronic
PHOSPHOLIPIDS pro-inflammatory signalling) inflammatory conditions. Uncontrollable
inflammation is also involved in the
Arachidonic acid Cytokines and pathogenesis of degenerative diseases
mucous secretion such as cancer, diabetes, autoimmune and
cardiovascular diseases.

Cyclo-oxygenase 1,2

NSAIDs
CPD ANSWERS
Thromboxane Prostaglandins Corticosteroids November 2017
Proliferation and
cytokine secretion
of lymphocytes 1. B 6. D

Eosinophils
2. B 7. D

Cytokines
produced by 3. A 8. C
macrophages
eg TNF
4. A 9. B

5. C 10. C
Figure 4. The main actions of corticosteroids and NSAIDs.

56 DentalUpdate January 2018

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