Figure 1 The principle components of the immune system are listed, indicating which cells
26 February 8, 2002 OT
Table 2: Examples of cells of the mononuclear phagocytic system and their respective locations
Blood stream
Alveolar macrophages
Lungs
Sinus macrophages
Lymph nodes and spleen
Kupffer cells
Liver
Phagocytosis - the process
Phagocytosis is the process by which cells engulf microorganisms and particles ((FFiig gu urree 3 3)). Firstly, the phagocyte must move towards the microbe under the influence of chemotactic signals, e.g. complement (see later). For the process to continue, the phagocyte must attach to the microbe either by recognition of the microbial sugar residues (e.g. mannose) on its surface or complement/antibody, which is bound to the pathogen. Following attachment, the phagocyte’s cell surface invaginates and the microbe becomes internalised into a phagosome. The resultant p ph haag go osso om mee fuses with
multiple vesicles containing O 2 free radicals and
other toxic proteins known as lysosomes to form
a phagolysosome. The microbe is subsequently destroyed.
Figure 3
Phagocytes arrive at a site of inflammation
Dendritic cells
Opsonisation (“to make tasty” - Greek)
Dendritic cells consist of Langerhans’ and Op O psso on niin nss are molecules, which enhance the
by chemotaxis. They may then attach to
interdigitating cells and form an important efficiency of the phagocytic process by coating
microorganisms via their non-specific cell
bridge between innate and adaptive immunity, the microbe and effectively marking them for
surface receptors. Alternatively, if the
as the cells present the antigenic peptide to the their destruction. Important opsonins are the
organism is opsonised with a fragment of
T helper cell (adaptive immunity). Such cells are complement component C3b and antibodies.
the third complement component (C3b),
attachment will be through the phagocyte’s
therefore known as professional antigen
receptors for C3b. If the phagocyte
presenting cells ((A AP PCCss)). TTaab bllee 3 3 illustrates the
Natural killer (NK) cells
various types of dendritic cells together with an N NK K cells are also known as “large granular
membrane now becomes activated by the
example of their location. lymphocytes” (LGLs) and are mainly found in the
infectious agent, it is taken into a phagosome by pseudopodia extending
around it. Once inside, lysosomes fuse with
circulation. They comprise between 5-11% of the
the phagosome to form a phagolysosome
Eosinophils
total lymphocyte fraction. In addition to
Eosinophils (so called because their granules possessing receptors for immunoglobulin type G
and the infectious agent is killed. Undigested
stain with eosin – FFiig gu urree 4 4) are granulocytes (IgG), they contain two unique cell surface
microbial products may be released to the
that possess phagocytic properties. Despite the receptors known as killer activation receptor and
outside
fact that they represent only 2-5 % of the total killer inhibition receptor. Activation of the
leukocyte population, they are instrumental in former initiates cytokine (“communication”)
the fight against parasites that are too big to be molecules from the cell whilst activation of the
stain with a basic dye. Unlike mast cells, which
are present in close proximity to blood vessels in
phagocytosed.
latter inhibits the aforesaid action.
connective tissue, basophils reside in the
NK cells serve an important role in attacking
circulation.
virally-infected cells in addition to certain
Both cell types are instrumental in initiating
tumour cells. Destruction of infected cells is
the acute inflammatory response. Degranulation
achieved through the release of perforins and
is achieved either by binding to components of
granyzymes from its granules, which induce
the complement system or by cross-linking of
apoptosis (programmed cell death). NK cells are
the IgE antibody which results in the release of
also able to secrete interferon-γ (IFN-γ). This
pro-inflammatory mediators including histamine
interferon serves two purposes: first, to prevent
and various cytokines. The former induces
healthy host cells from becoming infected by a
vasodilation and augments vascular permeability
virus; and second, to augment the T cell
whilst the latter are important in attracting
response to other virally infected cells
both neutrophils and eosinophils.
(see later).
Table 3: Dendric cells and location
Mast cells and basophils
Cells
Location
Figure 4 Morphology of the eosinophil. The very similar in that both contain electron dense
Morphologically, mast cells and basophils are
Langerhans cell
Limbus, skin
multilobed nucleus is stained blue and the granules in the cytoplasm. Basophils are
Interdigitating cell
T cell areas in
cytoplasmic granules are stained red. so-called owing to the fact that their granules
lymph nodes
Leishman stain, x 1800
Molecules of the innate
Figure 5
immune system
When host cells become infected There are many molecules, which work in concert
by virus, they may produce with the cells of the innate immune system and
interferon. Different cell types which also foster close functional links with their
produce interferon-α (IFN-α ) or adaptive counterpart. The three major molecules
interferon-β (IFN-β); interferon-γ are:
(IFN-γ) is produced by some types • Complement
of lymphocyte (T H ) after activation • Acute phase proteins (APP)
by antigen. Interferons act on other • Interferons (IFNs)
host cells to induce a state of resistance to viral infection. IFN-γ
Complement
has many other effects as well The complement system represents a large group of independent proteins (denoted by the letter C
Table 4:
and followed by a number), secreted by both
Primary and secondary lymphoid organs
hepatocytes (liver cells) and monocytes. Although these proteins maybe activated by both
Secondary lymphoid organs the adaptive immune system (ccllaassssiiccaall p paatth hw waayy)
Primary lymphoid organs
or innate immune system (aalltteerrn naattiivvee p paatth hw waayy),
Bone marrow
Lymph nodes
the nomenclature is derived from the fact that MALT - mucosa associated lymphoid the proteins help (“complement”) the antibody
tissue (includes bronchus, gut, nasal and response.
conjunctival associated mucosal tissues) Activation of complement via the microbe
Spleen
itself is known as the alternative pathway. The classical pathway requires the interaction of antibody with specific antigen. The C3 component is the pivotal serum protein of the
proteins on the cell surface adjacent to special complement system. Binding of the antigen to
for the successful eradication of an invading
host proteins called major histocompatibility C3 results in two possible sequelae. In either
virus by the innate immune system.
complex (MHC) class II molecules. As discussed, case, C3 component becomes enzymatically
Type II IFN, IFN-γ, is produced by T Helper
antigen presenting cells which express MHC class converted to C3b. The bacterial cell wall can
cells and NK cells and is able to augment both
II molecules include dendritic cells and either remain bound to C3b and become
the antigen presenting properties together with
macrophages. This “afferent” phase must occur opsonised (since phagocytes have receptors for
the phagocytic properties of the APCs (e.g.
in order for the T cell to recognise the antigen. C3b) or act as a focus for other complement
macrophages and dentritic cells).
The “efferent” phase occurs when activated proteins (namely C5, 6, 7, 8 and 9). The latter
lymphocytes enter the tissue and meet antigen form the membrane attack complex (MAC), which
again. This results in multiplication and secretion induces cellular lysis.
Adaptive immunity
of cytokines or immunoglobins in order to The functions of the complement system may
As mentioned previously, there is a great deal of
synergy between the adaptive immune system
destroy the antigen.
be summarised as follows:
and its innate counterpart. The adaptive immune
• Opsonisation
system comprises two main types of leukocyte
T cells
• Lysis (destruction of cells through damage/
T cells can be broadly divided into both T helper rupture of plasma membrane)
known as B and T lymphocytes. Before describing
(T H ) and cytotoxic T cells (T c ). Furthermore, T H • Chemotaxis (directed migration of immune
these important cell types, it is necessary to
cells may be sub-divided into T H1 and T H2 . The cells)
acquaint the reader with both the primary and
former are pro-inflammatory T cells and • Initiation of active inflammation via direct
secondary lymphoid organs and tissues in the
body. These are summarised in TTaab bllee 4 4. stimulate macrophages whilst the latter activation of mast cells
The bone marrow represents the dominant site
orchestrate B cell differentiation and maturation
and hence are involved in the production of It is important that complement is regulated to
for haemopoiesis (production of blood cells and
humoral immunity (antibody mediated). T cells protect host cells from damage and/or their total
platelets). Although most of the haemopoietic
express cell surface proteins, described by cluster destruction. This is achieved by a series of
cells maturate in this region, T lymphocytes do
determination (CD) numbers. T H cells express CD4 regulatory proteins, which are expressed on the
so in the thymus. In the thymus, premature T
molecules on their cell surface, which enable the host cells themselves.
cells undergo a process of positive and negative
selection whereby the former are allowed to
lymphocyte to bind to a MHC class II molecule.
progress to maturity whilst the latter are marked
The T cell receptor is unique in that it is only
Acute phase proteins
able to identify antigen when it is associated These serum proteins are synthesised by
for termination via apoptosis (see central
with a MHC molecule on the surface of the cell. hepatocytes and are produced in high numbers
tolerance).
Cytotoxic T cells are primarily involved in the in response to cytokines released from
destruction of infected cells, notably viruses. macrophages.
Lymphocytes
Morphologically, there are three types of
Unlike T H cells, cytotoxic cells possess CD8 cell
lymphocytes: T, B and NK cells. However, only T
surface markers, which bind to antigenic
Interferons (IFNs)
peptides expressed on MHC class I molecules. IFNs are a group of molecules, which limit the
and B lymphocytes exhibit memory and
specificity and, as such, are responsible for the
spread of viral infections ((FFiig gu urree 5 5)). There are
unique quality of the adaptive immune system.
B cells and antibodies
two categories of IFNs, namely type I and type II.
Resting B lymphocytes are able to react with
(immunoglobulins - Ig)
Type I IFNs maybe sub-divided further into IFN-α
B cells are lymphocytes that produce antibodies and β. IFN-γ is the sole type II interferon. Type I
free antigen directly when it binds to their cell
(immunoglobulins) and can recognise free IFNs are induced by viruses, pro-inflammatory
surface immunoglobins which act as receptors. T
antigen directly. They are produced in the bone cytokines and endotoxins from gram negative
lymphocytes do not react with free antigen and
marrow and migrate to secondary lymphoid bacterial cell walls. Their presence remains vital
instead make use of APCs to phagocytose the
antigen and then to express its component
organs. B cells are responsible for the
28 February 8, 2002 OT
Sponsored by
Module 4 Part 2
Figure 6
When a microorganism lacks the
development of antibody mediated immunity
inherent ability to activate
known as h hu um mo orraall m meed diiaatteed mm d iim mu un niittyy.
complement or bind to
When activated by foreign antigen, B cells
phagocytes, the body provides
undergo proliferation and mature into antibody
antibodies as flexible adaptor
secreting p pllaassm maa cceellllss. The latter are rich in
molecules. The body can make
organelles such as rough endoplasmic reticulum
several million different antibodies
and mitochondria, which confer their ability to
able to recognise a wide variety
secrete soluble proteins (antibodies). Not all
of infectious agents. Thus the
proliferating B cells develop into plasma cells.
antibody illustrated binds microbe
Indeed, a significant proportion remain as
1, but not microbe 2, by its
memory B cells through a process known as
‘antigen-binding protein’ (Fab).
clonal selection. This process is vital in
The ‘Fc portion’ may activate
eliminating the antigen should the body become
complement or bind to Fc
re-exposed to it in the future. T cells are also
receptors on host cells,
clonally selected and this confers to the
particularly phagocytes.
production of T memory cells. Although T and B cells behave differently, both are able to recirculate around the body
Table 5:
migrating from blood to tissue and vice versa. Antibody isotypes and corresponding functions
The ability to recirculate obviously increases the efficiency with which cells of the immune system
Antibody Characteristics
can home onto the invading antigen. IgG
Crosses placenta thus providing newborn with useful humoral immunity High affinity
Antibodies
Predominant antibody in blood and tissue fluid Antibodies have two roles to play - the first is to bind antigen and the second is to interact with
IgM Large pentameric structure in circulation host tissues and effector systems in order to Present in monometric form on B cell surface
ensure removal of the antigen Secreted form is predominant antibody in early immune
((FFiig gu urree 6 6)).
response against antigen There are five different types (known as Reaches 75% of adult levels at 12 months of age
iisso ottyyp peess) of antibody in the human immune IgA
system - namely IgM, IgG, IgA, IgE and IgD. In Exists in both a monometric and dimeric form
addition, there are four sub classes of IgG Secretory IgA (dimeric form) represents 1st line of defence against
(IgG1-4). The basic antibody unit consists of a microbes invading the mucosal surface, e.g. tears
glycosylated protein consisting of two heavy and IgE
Low levels in circulation two light, polypeptide chains. The region which Increased levels in worm infections
binds to the antigen is known as the FFaab b region, Fc region has high affinity for mast cell thus involved in allergy
while the constant region, FFcc, not only determines the isotype but is the region
IgD Antigen receptor on B cells responsible for evoking effector systems, e.g. Absent from memory cells
mast cell activation. The term immune complex refers to the combination of antigen and
Table 6:
antibody and will be discussed later in the article Various cytokines, their sources and functions
(see type III hypersensitivity). The antibody isotypes together with their
Cytokine
corresponding function are illustrated in TTaab bllee 5 5.. IL-1
1. T, B cell activation
2. Mobilisation of PMNs
MHC
3. Induction of acute phase proteins
Major histocompatability complex (MHC) are cell surface proteins classified as class I (also termed
IL-2
human leucocytic antigen [HLA] A, B and C), Il-4
T cells
Proliferation of T and NK cells
Th2 cells
B cell activation
found on all nucleated cells and class II (termed
Mast cells
IgE response
HLA, DP, DQ and DR), found on all antigen presenting cells (APCs). MHC molecules are the
IL-8
Macrophages
Chemotaxis of PMNs
sine qua non of T cell induced immunity.
T cells
Clinically, there is a strong association
Fibroblasts
between HLA and certain systemic and ocular
diseases (see later). IL-10
Keratinocytes
TH2 cells
B cell activation
Macrophages
Suppress macrophages
Cytokines
Cytokines (also termed interleukins [IL] meaning IL-12
B cells
Stimulate T H1 “between white blood cells”) are small molecules Inhibit T H2 that act as a signal between cells and have a
variety of roles including chemotaxis, cellular TGF β
growth and cytotoxicity. Owing to their ability to TNF α (tumour necrosis factor)
(transforming growth factor)
T cells
Inhibits other cytokines
Macrophages
Inflammation
control immune activity, they have been described as the “hormones” of the immune system.
TTaab bllee 6 6 summarises some of the cytokines
endothelial cells and the presence of junctional
4 and their progenitors. Since interferons have amongst ophthalmologists and immunologists cells . alike. It appears such suppression is achieved by been discussed earlier in the article, they have
complexes linking retinal pigment epithelial
various factors present in the aqueous humour been omitted from the table.
Lymphatic role
(e.g. transforming growth factor - β).
The fact that skin allografts were not rejected
Central and peripheral
following lymph node removal 5 led investigators
Anterior chamber associated immune
tolerance: nature’s way of
to hypothesise that immune privilege was solely
deviation (ACAID)
containing the immune
due to the absence of the same said system at a
As a result of experiments with rats,
investigators discovered that antigens placed in Since various cells of the immune system are
response
particular anatomical site. However, although
6 capable of reacting with self-antigens, it is the anterior chamber resulted in systemic lymphatic drainage, others such as the testes therefore essential that the human body has
certain immune privileged sites do indeed lack
inhibition of delayed type hypersensitivity (DTH
or type IV hypersensitivity) reactions to the mechanisms to suppress/eliminate autoreactive
and eye 7
do possess such a system. It appears
same said antigens 17 . This phenomenon has been cells. Failure to do so, can, in some cases, lead
that a proportion of the aqueous humour drains
coined anterior chamber associated immune to the development of autoimmune diseases
via the uveoscleral pathway into the lymphatic
deviation (ACAID). The anterior chamber is thus (see later).
vessels in the head and neck.
able to suppress delayed type hypersensitivity
The eye, APCs & MHCs
reactions and inhibit the production of
Central tolerance
complement fixing antibodies 18,19 . However, it Central tolerance refers to the process whereby
As mentioned previously, APCs, through their
has no inhibitory effect on cytotoxic T cell both immature B and T cell lymphocytes, which
ability to express MHC class II molecules, are
activity and has a minimal influence on the react against normal, healthy cells
potent progenitors of the immune response.
production of non-complement fixing (self-antigens), are eliminated via apoptosis.
Moreover, such cells are capable of activating T
cells within the tissue itself. It is therefore not
antibodies.
unreasonable to assume that a paucity of APCs
With respect to the endothelium, two
adaptations prevent it from immunological This involves the removal of mature lymphocytes,
Peripheral tolerance
may play an important role in immune
injury: first, avoidance of cytotoxic T lymphocyte which are not tolerant to healthy cells.
privilege. In addition, failure to express MHC
class I molecule would make a tissue immune
(CTL)-mediated lysis; and second, inhibition of
against the lytic action of the cytotoxic T cells.
DTH responses in the anterior chamber 22 . It
Ocular immune privilege
achieves the former through the cells inability There are numerous sites in the body whereby
Although the aforementioned mechanisms
to express MHC class I molecules 21 . The corollary tissue may be grafted with minimal risk of
are theoretically plausible, cells expressing both
of this, however, is that virally infected cells rejection. Such regions include, inter alia, the
MHC class I and II molecules have been
may persist in this region. The râison d’etre of testis, thyroid lens, anterior chamber, cornea,
detected in the eye. TTaab bllee 7 7 illustrates the
ACAID is to protect the eye from the DTH iris and ciliary body 1,2.
relationship between histocompatability class
response to pernicious antigens. As a result of It is important that immune privilege is not
and ocular cell type.
its location in relation to the anterior chamber, simple interpreted as the host’s inability to
It is noteworthy that the epithelial cells of
14 initiate an immune response to a transplanted the corneal endothelium seems well placed to expression and that the Langerhans’ cells reap the benefits of ACAID. tissue. Rather, it is an area of the body in which
the crystalline lens are devoid of class I
ACAID is beneficial in reducing the incidence there exists a paucity of various elements of the
(class II expression) are absent from the central
of stromal keratitis in herpes simplex virus human immune system in response to an
cornea 15 .
infection. It therefore seems reasonable to antigen.
It is interesting that not all cells, which
express MHC class II act as professional APCs in
assume that such an unwanted corneal side-
the eye. Indeed, it has been shown that such
effect occurs as a result of a DTH response
Factors
rather than the toxic effect of the virus per se 22 . The factors purported by investigators that
cells reside in the iris and ciliary body and not
Corneal graft rejection may be due, in part, contribute to the phenomenon of ocular immune
only fail to present alloantigens to T cells, but
to failure to invoke ACAID. Streilein at al 23 privilege include:
have the ability to suppress mixed lymphocyte
not
only discovered that the immunosuppressive • Isolation from a vascular supply
reactions 16
effects of the cornea were abolished in corneas • Isolation from a lymphatic supply • Presence of a vascular barrier
The failure to incite the inflammatory
Table 7:
• Ability to suppress the immune response
MHC and ocular cell type 8-13
• Anterior chamber associated immune deviation (ACAID)
Ocular cell type
MHC class I
MHC class II
Corneal epithelium
Vascular supply
Corneal stroma
The healthy cornea is a good example of an ocular site devoid of a vascular network. The
Corneal endothelium
evidence to support the role a vascular network
Trabecular meshwork
has to play in the mechanism of graft rejection
Pigmented and non pigmented
is unequivocal since the risk of failure correlates
cells of ciliary body
positively with the degree of host vascularisation 3 .
Anterior iris
RPE cells
Vascular barrier
• There is a plethora of evidence in the
Corneal limbus
• ophthalmic literature to support the existence of
Iris and ciliary body
• said barrier encompasses different elements
a blood-ocular barrier. Furthermore, the same
Uveoscleral pathway
• including tight junctions between retinal
Ora serrata
February 8, 2002 OT
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that had ACAID removed via cauterisation or
limbal region. The latter antibody is restricted keratoplasty but also abolished in corneas that
the microorganism enables the tears to wash
from the central cornea owing to its large size. had been denervated.
them away. IgA possesses other functions
including opsonisation and inactivation of
Antibodies in the cornea are found in the
various bacterial enzymes and toxins. In
stroma since they are cationically charged. Due
Ocular immunology
to their positive ionic charge, they bind to Anterior segment immunology may be
addition, it may be involved in antibody
proteoglycans and the anionic sub-divided into the following aspects:
dependent cell-mediated cytotoxicity. It must be
glycosaminoglycans 38 . • Tear film
emphasised, however, that IgA is unable to bind
Antigen/antibody complexes may sometimes • Corneal immunology
to complement and, as such, is not involved in
be observed in the corneal stroma in a variety • Conjunctival immunology
the classical pathway 27 .
of pathological conditions (e.g. herpes simplex • Scleral immunology
keratitis), and because of their ringed shaped • Uveal immunology
4. Miscellaneous proteins
β-Lysin, a bacteriocidal cationic protein, is
appearance are known as “Wessley rings”.
present both in the tears and aqueous humour 28 .
Tear film
Its bacteriocidal properties are conferred
Complement
The elements of complement found in the This layer is produced both by the conjunctival
a) Mucous layer
through their ability to disrupt the micro-
cornea include C1-7 39 in addition to the goblet and epithelial cells. The glycocalyx
organisms’ walls. Various components of
regulatory proteins H and I and C1 inhibitor 40 . synthesised by the corneal epithelial cells serves
complement are present in varying degrees
Interestingly, C1 is present in high to attach the mucous layer and in doing so binds
depending on whether the eye is closed or not.
concentrations in the limbus and is restricted
from the central cornea. This finding is suggested that the latter immunological sign may
to immunoglobulin in the aqueous 24 . It has been
Closed eye vs open eye
significant since the limbal region is susceptible have antiviral effects. The evidence to support
to ulceration following complement activation this is that certain intestinal mucosa, which have
Open eye
and immune complex deposition. It has been similar binding properties to those seen in the
In addition to the components of complement
suggested that C1 is produced by corneal eye, are able to exert an inhibitory action against
mentioned above, the tears are rich in lysozyme,
fibroblasts whereas the remaining components viral replication 25 .
lactoferrin and lipocalin (tear pre albumin)
together with low levels of IgA 29,30 .
detected in the cornea appear to be derived from the plasma via linked vessels.
b) Aqueous layer
Closed eye
The aqueous layer contains the following
In the closed eye environment, levels of IgA and
Conjunctival immunology
antimicrobial factors:
complement components are increased. In
The conjunctival associated lymphoid tissue
1. Lactoferrin
addition, neutrophils are also recruited. The eye
(CALT) is part of the more general mucosa
2. Lysozyme
can be interpreted as being in a state of
associated lymphoid tissue (MALT). Langerhans’
3. IgA
subclinical inflammation. However, the eye is
cells and lymphocytes exist within the
4. Miscellaneous proteins
protected from damage induced by either
conjunctival epithelial layer. In the substantia
complement or neutrophils by DAF (Decayed
propria, neutrophils, lymphocytes, IgA and IgG,
dendritic cells and mast cells all reside. It is Lactoferrin is produced via the acinar cells of the
1. Lactoferrin
Accelerating Factor [an inhibitory component of
noteworthy that eosinophils and basophils are lacrimal gland. Its main function is to bind iron,
the complement system]) 31 and α 1 –antitrypsin 33 .
not present in the healthy conjunctiva. which is required for bacterial growth. It
Langerhans’ cells and dendritic cells present therefore possesses both bacteriostatic and
Corneal immunology
the antigenic peptide to the conjunctival T bacteriocidal properties. Furthermore, it is able
Paradoxically, the cornea, an immune privileged
helper cells. Following antigenic presentation, to enhance the effects of certain
site, is capable of evoking an immunological
the T cells secrete the cytokine IFN-γ which immunoglobulins.
response evidenced by the presence of
subepithelial infiltrates, keratic precipitates,
serves to promote antigen elimination by
epithelial and stromal keratitis under certain
macrophages. This is the delayed-type
hypersensitivity (DTH) response (see later) and Produced by type A cells in the lacrimal gland,
2. Lyszome
clinical conditions.
is characteristic of conjunctival pathology such lysozome constitutes up to 25% of the total tear
Cytokine release
as phlyctenulosis.
protein. It is surprising somewhat that despite
Numerous cytokines are synthesised in the
being effective at lysing gram positive bacterial
cornea including IL-1, IL-6, IL-8, TNF-α, IFN-γ,
Scleral immunology
cell walls, staphylococcus aureus appears
There exists only a small number of immune recalcitrant to its action 26 . However, it is
C5a and prostaglandins 33 . Phagocytosis of certain
cells in the sclera compared to the conjunctiva instrumental in enhancing IgA against gram
antigens via corneal epithelial cells initiate the
since it is relatively avascular. In its resting negative bacteria.
release of IL-1 which, in turn, gives rise to the
recruitment of Langerhans’ cells from the limbus
state, IgG appears to be present in large
to the central cornea. It is worthy of note that
amounts 41 . However, a sclera under stress, may
become immunologically active as a result of This is the predominant isotype found in the
3. IgA
the same said APC may be recruited centrally in
migrating cells from the overlying episcleral and human tears in the non-inflamed eye. Very little
response to chemical or localised damage 34,35 .
underlying choroidal vasculature 42,43 . is present in serum with the majority secreted
Investigators have discovered that stromal
fibroblasts synthesise
through epithelial cells of structures such as the
IL-8 in response to infection by the herpes
Uveal immunology
The uveal tract is an important site from an present in the tears is produced by plasma cells
lacrimal gland and the lactating breast. The IgA
simplex virus 36 . Furthermore, it seems plausible
immunological perspective for two reasons: situated underneath the secretory cells lining the
that the latter cytokine release may be
first, it is highly vascular in nature; and second, acini in the lacrimal gland.
responsible for the neutrophilic infiltration
the majority of vessels are highly fenestrated IgA is very effective at binding microbes and,
observed in cases of herpetic keratitis.
which facilitates the recruitment of leukocytes as such, prevents the microbe from adhering to
during the inflammatory cascade. The uvea the mucosal surface. The antibody achieves this
Immunoglobulins
contains numerous cellular components of the either by interfering with the binding site
The three isotypes detected in the cornea are
immune system including macrophages, mast directly or by agglutination. Successful binding of
IgM, G and A. IgG predominates in the central
cornea 37 . By contrast, IgM predominates in the
cells, lymphocytes and plasma cells in addition
Table 8:
Hypersensitivity reactions
Hypersensitivity Appearance
Mediators
Mechanism
type time
I. Immediate 2-30 mins
IgE
Mast cell response (enhance acute inflammation)
II. Cytotoxic 5-8 hours
IgM and IgG
Antibody and complement
III. Immune 2-8 hours
IgM and IgG
Antibody/antigen
complex
immune complexes
complexes
IV. Delayed type 24-72 hours
CD4 and CD8 T cells, T cell mediated
APCs
Macrophages activated Include granulomatous reactions
Figure 7:
V. Stimulatory
Autoantibodies
Autoantibodies against hormone
Corneal thinning and vascularisation in AKC, excess mucous is present
to an appreciable number of immune factors.
diffuses throughout the body until it comes into
Although IgG and IgM have been detected in
contact with mast cells and basophils. Both
both the choroid and iris, they exist in greater
these cell types have receptors for IgE antibody.
numbers in the former structure. The reason for
Although the patient experiences no symptoms
such disparate levels is the dearth of anionic
after the initial binding, reintroduction of the
antibody binding sites on the iris surface 44 . By
antigen/allergen induces the production of
contrast, the ciliary body harbours tremendous
more IgE and, furthermore, increase the
amounts of IgG by virtue of its anionic tissue
likelihood of cross-linking with existing
sites.
antibodies on the mast cell surface. Such cross- linking induces the mast cell to degranulate and
Immunopathology and the eye
release a host of inflammatory mediators such
Immunopathology encompasses both pathology
as histamine, prostaglandins and bradykinin.
Figure 8:
as a result of an over-active immune system
Epithelial macroerosion in VKC with that acquired through an individuals
Histamine characteristically causes the itchy
(h hyyp peerrsseen nssiittiivviittyy and aau utto oiim mm mu un niittyy) together
symptoms experienced by patients and as a
result of binding to H1 receptors in the eye,
inability to fight off infection – namely
induces vasodilation and enhances mucous
immunodeficiency. Unfortunately, it is far
secretion by the goblet cells. Bradykinin
beyond the scope of this article to describe the
augments vascular permeability, decreases
latter and its ophthalmic correlates.
blood pressure and contracts smooth muscle.
In this section, the classification system
Prostaglandins are also powerful inflammatory
pertaining to hypersensitivity reactions will be
mediators.
described and each subtype with an anterior segment manifestation will be discussed. The
Ocular correlates:
association between HLA and systemic and
The following anterior segment conditions are
ophthalmic disease will be illustrated together
due, if not only in part, to type I
with a brief overview of the concepts pertaining
hypersensitivity:
to autoimmunity.
• Seasonal allergic conjunctivitis (type I) • Giant papillary conjunctivitis (types I and IV)
Hypersensitivity
• Vernal keratoconjunctivitis (VKC)
Figure 9:
The term hypersensitivity refers to the process
Corneal plaque in VKC whereby the adaptive immune response over-
(type I and IV)
• Atopic keratoconjunctivitis (AKC)
reacts to a variety of infectious and inert
giant cobblestone papillae, or in a limbal form antigens resulting in damage to the host tissue.
(types I and IV) ((FFiig gu urree 7 7))
with gelatinous deposits known as Trantas’-dots, Five types of hypersensitivity reactions exist –
which represent degenerating epithelial cells and all of which vary in their timing following
Seasonal allergic conjunctivitis can be easily
eosinophils. The first corneal change is a contact with the antigen ((TTaab bllee 8 8)).
recognised by chemosis and hyperaemia of the
conjunctiva, lid swelling and excessive
punctate epithelial keratitis, which if left
lacrimation. The cornea is not affected.
unchecked develops into a macroerosion
• Type I hypersensitivity: allergy
((FFiig gu urree 8 8)) and finally a corneal plaque develops Allergies may affect approximately 17% of the
GPC is well known to optometrists as an
((FFiig gu urree 9 9)). The conjunctiva itself is population 45 . The term atopic is used to describe
allergic response to contact lenses, prosthetic
characteristically oedematous and contains an those individuals who possess a genetic
lenses, protruding corneal sutures and scleral
array of immunological cells including predisposition to allergy. Allergies may occur to
buckles. Histological examination of eyes
lymphocytes and mast cells. Evidence of type I otherwise innocuous antigens (known as
suffering from GPC have revealed degranulated
involvement includes the histological detection aalllleerrg geen nss) and infectious agents, e.g. worms.
mast cells (type I hypersensitivity) 46 and CD4+ T
of, inter alia, degranulated mast cells, Type I hypersensitivity exists in two phases, the
cells (type IV) 47 , thus corroborating the theory
eosinophils and increased levels of IgE in sensitisation and effector phases.
that such a condition is mediated by both types
affected eyes 49 . The detection of CD4+ T cells and Firstly, a harmless allergen causes production
of hypersensitivity.
macrophages is indicative of a delayed of IgE antibody on first exposure. This IgE
Vernal conjunctivitis can present either in a
palpebral form characteristically exhibiting
inflammatory component 49 .
32
February 8, 2002 OT
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Module 4 Part 2 a
Type II hypersensitivity: cytotoxic
This classification of hypersensitivity involves either IgG or IgM antibodies, which may induce cellular lysis due to the involvement of the classical complement pathway (as seen in blood transfusion reactions) or recruit and activate inflammatory cells via complement. The components of complement include the C5a, which serves to attract inflammatory cells to the site of interest. The hypersensitivity reaction is a result of the excessive amount of extracellular mediators released by the inflammatory cells to antigens that are too big to be completely phagocytosed.
Antibodies to self-antigens, such as the acetylcholine receptor in myasthenia gravis, is not only another example of type II hypersensitivity but also an example of autoimmune disease.
Ocular manifestations
• Mooren’s ulcer • Cicatrical pemphigoid
Mooren’s ulcer is a rare peripheral ulcerative keratitis that exists either as a unilateral, non-progressive form which has a predilection for elderly patients or as a more severe, progressive form affecting both eyes of relatively young individuals. The signs range from a small patch of grey infiltrate near the margin to frank ulceration involving the entire corneal circumference and, in some cases, the central region as well. The healing process results in a thin, vascularised, opaque cornea. Investigators have identified a significant number of
lymphocytes, neutrophils and plasma cells 50 in
the cornea, thus providing unequivocal evidence to support the theory that this condition has an immunopathological aetiology.
Cicatrical pemphigoid is a chronic, blistering disease, which has a predilection for both the ocular and oral mucous membranes. Unlike its self-limiting counterpart, pemphigus vulgaris, cicatrical pemphigoid rarely affects the skin. Ocular cicatrical pemphigoid is a serious, bilateral condition that represents effective shrinkage of the conjunctiva. Although the initial presentation may be subacute and non-specific, it frequently progresses to symblepharon, entropion with secondary trichiasis, dry eye, ankyloblepharon and conjunctival fornix shortening. There is evidence to support the presence of IgG antibodies directed against self-antigen in the basement
membrane of both the skin and eye 51 . Binding of
the aforementioned antibodies may activate complement with subsequent recruitment of inflammatory cells into the area. The process of cicatrisation is achieved through the secretion of collagen via fibroblasts as a result of stimulation via cytokines released from the invading inflammatory cells.
Type III hypersensitivity: immune complex
Large pathogens with multiple antigenic sites have several antibodies bound to them forming
immune complexes. Normally, these complexes are removed by the mononuclear phagocytes in the liver and spleen with no adverse sequelae. However, persistence of immune complexes does occur in certain individuals leading to their deposition in tissue. As a consequence of the latter action, complement may be activated thus paving the way for inflammatory cells to enter the deposition site. Since blood vessels (which filter plasma at high pressure and exhibit a great deal of tortuosity) are more susceptible for immune complex deposition, the ciliary body is particularly vulnerable to this type of hypersensitivity reaction.
Ocular manifestations
• Uveitis (Crohn’s disease) • Peripheral corneal lesions associated with
rheumatoid arthritis • Stevens Johnson syndrome • Sjögren’s syndrome
The signs and symptoms of the above will be described in future articles in the series.
Type IV hypersensitivity: delayed-type hypersensitivity (DTH)
The term DTH has been used to describe such a reaction owing to its prolonged time-scale relative to the other hypersensitivity types. Although DTH can be transferred by T cells that have been previously sensitised by an antigen, it cannot be transferred in serum.
The sequence of events leading to DTH begins with initial presentation of the antigen peptide to T cells by APCs (e.g. Langerhans’ cells). The primed T cell migrates to the site of antigenic entry whereby it releases pro-inflammatory mediators such as TNF. The release of these cytokines facilitates blood flow and extravasation of plasma contents to the area. The activation of CD4 T helper and CD8 cells results in the release of IFN-γ and, as a consequence, enhances macrophage activity in that area. Resolution of DTH is dependent on the efficacy with which such phagocytes can remove the offending antigen.
Recalcitrant infectious agents result in a chronic DTH that causes the chronically activated macrophages to fuse together and form multinucleated giant cells. In an attempt to contain the infectious agent, macrophages may undergo further inter connections to resemble an epithelial layer. Owing to the similarity to this layer they are referred to as epitheloid cells. Both epitheloid and multinucleated giant cells secrete factors that induce fibrosis resulting in granuloma formation. Thus granulomata are the hallmark of chronic inflammation. Damage and loss of function of the neighbouring tissues frequently ensues until the agent is removed either chemically or surgically.
Ocular manifestations
• Ocular allergies (VKC, AKC GPC) • Idiopathic uveitis • Sympathetic ophthalmia • Phlyctenulosis
Type V hypersensitivity
This relatively new category encompasses the concept of autoantibodies binding to hormone receptors that mimic the hormone itself. This results in stimulation of the target cells. Examples include thyrotoxicosis.
Autoimmunity
The ability to react against self-antigens is known as autoimmunity. However, a significant number of people exist who harbour auto- antibodies and yet remain asymptomatic. The corollary of this is that the presence of autoreactive cells per se is not sufficient to trigger autoimmune disease. In fact, autoimmune disease is a result of breakdown of one of the immunoregulatory mechanisms. Furthermore, autoimmune disease may be classified as either being organ specific (e.g. insulin dependent diabetes mellitus, Grave’s disease) or non-organ specific (e.g. Sjögren’s syndrome, ankylosing spondylitis).
It is important to realise that the causes of autoimmune diseases are multifactorial. The main predisposing factors are age, gender, infection and genetics. However, one of the most important factors of interest to immunologists and clinicians alike is the association between HLA and autoimmune disease. When determining the likelihood of contracting a disease both epidemiologists and clinicians refer to the relative risk. In the case of HLA antigen, the relative risk compares the chance of a person who has a particular HLA antigen acquiring a disease to those individuals who do not have such an antigen. The association is exemplified by the relative risk of suffering from ankylosing spondylitis (AS) in individuals who possess HLA-B27. In patients suffering from AS, the prevalence of HLA-B27 is 90% and this figure rises to 95% in patients who suffer both with the disease and acute iritis. Indeed, in the UK approximately 45% of patients who present with acute iritis will
harbour HLA-B27 52 . It is therefore important that patients who present with anterior uveitis are screened for HLA-B27 because although a positive result may not necessarily be diagnostic, its presence will certainly improve the sensitivity of further radiological tests.
TTaab bllee 9 9 compares the HLA associations with both ophthalmic disorders together with those systemic disorders relevant to the ophthalmic practitioner.
Conclusion
This article has only broached the fascinating subject of ocular immunology. A basic understanding of immunology is required if practitioners are to therapeutically manage their patients. Further articles in the series will help to reinforce the concepts of this challenging subject.
Acknowledgement
The author would like to thank Professor Roger Buckley for his permission to use FFiig gu urreess 7 7 tto o 9 9.
Relative risk 54 Figures 1 to 6 reprinted from Ocular
Immunology, Third Edition, Roitt, Brostoff and Male, 1993 by
90 Anterior uveitis permission of the publisher
Ankylosing spondylitis
B27
33 Mucopurulent conjunctivitis Mosby.
Reiter’s disease
B27
Anterior uveitis Keratitis
About the author
7 Keratoconjunctivitis sicca Gregory Heath is an optometrist
working part-time in private
Scleritis
practice. He was recently awarded
10 Keratoconjunctivitis sicca the diploma in clinical optometry
Primary Sjögrens’ syndrome
DR3, DR5
Anterior uveitis (acute and chronic) at City University and is currently
Sarcoidosis
DR3
Not known
Dacryoadentis reading medicine at the Royal
Retinal vasculitis, Free and University College,
neovascularisation, London, Medical School.
Optic nerve granulomata
Cicatrical pemphigoid
DQw7
Not known
Shrinkage of conjunctiva
References
References are available upon
B5 3 Anterior uveitis request. Please fax 01252-816176
Behcet’s disease
Retinitis, periphlebitis, retinal oedema
or email info@optometry.co.uk.
Sympathetic
DR4, A11,
Not known
Systemic lupus
DR2, DR3
3 Punctate epithelial keratopathy
erythematosus
Keratopathy Necrotising scleritis
Retinal lesions (cotton wool spots) HLA and ophthalmic disease Autoimmune optic neuropathy
Table 9:
Multiple choice questions - Basic immunology
Please note there is only one correct answer
1 1.. W Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng no g is n ott p paarrtt o off tth hee
9 9.. IIn n aa p paattiieen ntt ssu uffffeerriin ng om g ffrro m vveerrn naall cco on njju un nccttiivviittiiss,, iin nn naattee iim mm mu un nee ssyysstteem m??
5.. W 5 Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss is
cco orrrreecctt rreeg gaarrd diin ng g TT cceellllss??
wh w hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss is
a. Mast cells
a. T cells can be subdivided into TH 1 and TH 2 cco orrrreecctt??
b. Complement
subtypes only
a. Trantas’-dots represent infiltrating T cells
c. Phagocytes
b. T cells alone can identify any type of antigen
b. Affected eyes have increased levels of IgD
d. T cells
c. T cells express cell surface proteins denoted by
c. Histologically, mast cells, lymphocytes and
cluster determinant (CD) numbers
macrophages have been identified
2 2.. W Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss is
d. Is due to type III Hypersensitivity cco orrrreecctt rreeg gaarrd diin ng hee iin g tth nn naattee iim mm mu un nee ssyysstteem m??
d. All T cells are involved in initiating the
inflammatory response
a. It is specific
6 6.. W Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss is
1 10 0.. W Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss is
b. It evokes a more potent response on
iin ncco orrrreecctt??
iin ncco orrrreecctt??
secondary exposure
a. B cells have antibodies as their cell surface
a. HLA-B27 is a risk factor for both anterior uveitis
c. It represents the first line of defence
receptor
and ankylosing spondylitis
b. Granulomas are present in type IV subsequent exposures
d. It is able to memorise pathogens on
b. There are five types of antibody
c. IgE is an important antibody in allergies
hypersensitivity reactions
d. All B cells differentiate into plasma cells
c. Histamine is an important vasoconstrictor
3 3.. W Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss is
d. IgE mediated hypersensitivity is of rapid onset cco orrrreecctt rreeg gaarrd diin ng hee cceellllss o g tth off tth hee iin nn naattee
7 7.. W Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss is
ssyysstteem m??
cco orrrreecctt rreeg gaarrd diin ng occu ullaarr iim g o mm mu un nee p prriivviilleeg gee??
a. There is an absence of Langerhans’ cells in the
1 11 1.. W Wh haatt p prro op po orrttiio on n o off p paattiieen nttss w wiitth uttee iritis w h aaccu wiillll
a. Basophils are important phagocytes haarrb h bo ou urr H HLLA A--B B2 27 7??
b. During phagocytosis the pathogen becomes
central cornea
initially internalised as a phago-lysosome
b. Aqueous humour has no role
a. 15%
b. 25%
c. Eosinophils play an important role in
c. Abundant vascular supply is vital
c. 45%
combating virally-infected cells
d. All ocular cells express MHC class II
d. 65%
d. Langerhans’ cells form a bridge between
8.. W 8 Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss
innate and adaptive immunity
cco on ncceerrn niin ng occu ullaarr iim g o mm mu un no ollo og gyy is iin ncco orrrreecctt??
12 1 2.. W Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss is cco orrrreecctt
rreeg gaarrd diin ng g aa ttyyp pee II h hyyp peerrsseen nssiittiivviittyy rreeaaccttiio on n?? 4.. W 4 Wh hiicch on nee o h o off tth hee ffo ollllo ow wiin ng g ssttaatteem meen nttss is
a. Levels of IgA and complement
a. It always occurs in isolation cco orrrreecctt rreeg gaarrd diin ng hee aad g tth daap pttiivvee iim mm mu un nee
increase when the eyes are closed
b. It is characterised by the presence of ssyysstteem m??
b. IgA is the predominant antibody
in blood and tissue fluid
macrophages
a. It consists of all types of lymphocytes
c. IgM, IgG and IgA antibody isotypes have been
c. It is associated with myasthenia gravis
b. T cells produce antibodies
identified in the cornea
d. It involves the degranulation of mast cells
c. T cells maturate in the thymus
d. The sclera contains a smaller number of
following the cross-linking of IgE bound to its
d. B cells are produced in the spleen
immune cells than the conjunctiva
cell surface