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    Basic immunology

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    مجاهد ادريس

    المساهمات : 164
    تاريخ التسجيل : 24/02/2010
    العمر : 26
    الموقع : we.ja2009@hotmail.com

    Basic immunology

    مُساهمة من طرف مجاهد ادريس في السبت مارس 06, 2010 6:47 am

    Basic immunology
    The immune system is the body’s natural defence in combating organisms.
    Immunology has developed rapidly over the past decade owing to the refinements made
    in the molecular tests employed in this area of research. Therefore, the keen reader is
    encouraged to peruse the ophthalmic and immunological literature in order to keep
    abreast of the latest developments in this field.
    The College of
    Optometrists has
    awarded this article 2
    CET credits. There are
    12 MCQs with a pass
    mark of 60%.
    Owing to the complex nature of this subject, it is
    far beyond the scope of this article to cover all
    aspects of immunology. Rather, the aims of the
    article are twofold: first to acquaint the busy
    practitioner with the basic concepts of the
    immune system; and second, to introduce the
    reader to the more specific topic of ocular
    immunology – the study of the ocular immune
    system.
    Finally, since it is envisaged that optometrists
    will one day prescribe therapeutic agents, the
    discussion is limited to the anterior segment and
    anterior uvea.
    Innate & adaptive immune systems
    The immune system can be thought of as having
    two “lines of defence”: the first, representing a
    non-specific (no memory) response to antigen
    (substance to which the body regards as foreign
    or potentially harmful) known as the innate
    immune system; and the second, the adaptive
    immune system, which displays a high degree of
    memory and specificity. The innate system
    represents the first line of defence to an
    intruding pathogen. The response evolved is
    therefore rapid, and is unable to “memorise” the
    same said pathogen should the body be exposed
    to it in the future. Although the cells and
    molecules of the adaptive system possess slower
    temporal dynamics, they possess a high degree
    of specificity and evoke a more potent response
    on secondary exposure to the pathogen.
    The adaptive immune system frequently
    incorporates cells and molecules of the innate
    system in its fight against harmful pathogens.
    For example, complement (molecules of the
    innate system - see later) may be activated by
    antibodies (molecules of the adaptive system)
    thus providing a useful addition to the adaptive
    system’s armamentaria.
    A comparison of the two systems can be seen
    in Table 1.
    ot
    www.optometry.co.uk
    Gregory Heath BSc (Hons), MCOptom, Dip. Clin. Optom
    ABDO has awarded this
    article
    2 CET credits (GD).
    26 February 8, 2002 OT
    Sponsored by
    a
    Cells of the innate
    immune system
    Phagocytes
    Although sub-divided into two main types,
    namely neutrophils and macrophages, they
    both share the same function - to engulf
    microbes (phago - I eat, Latin).
    Neutrophils
    Microscopically, these cells possess a
    characteristic, salient feature - a
    multilobular nucleus (Figure 2). As such,
    these cells have been referred to as
    polymorphonuclear leukocytes (PMNs) and
    have a pivotal role to play in the
    development of acute inflammation. In
    addition to being phagocytic, neutrophils
    contain granules and can also be classed as
    one of the granulocytes. The granules
    contain acidic and alkaline phosphatases,
    defensins and peroxidase - all of which
    represent the requisite molecules required for
    successful elimination of the unwanted
    microbe(s).
    Macrophages
    Macrophages (termed monocytes when in the
    blood stream) have a horseshoe-shaped nucleus
    and are large cells. Properties of macrophages
    include phagocytosis and antigen presentation
    to T cells (see later). Unlike neutrophils (which
    are short-lived cells), they are seen in chronic
    inflammation as they are long-lived cells.
    Mononuclear phagocytic system
    The cells comprising the monocyte phagocytic
    system are tissue bound and, as a result, are
    further sub-divided depending on their location.
    A list of the cells together with their
    corresponding location can be found in Table 2.
    Table 1: Cells and molecules of the innate and adaptive immune systems
    Immunity Cells Molecules
    Innate Natural killer (NK) cells Cytokines
    Mast cells Complement
    Dendritic cells Acute phase proteins
    Phagocytes
    Adaptive T and B cells Cytokines
    Antibodies
    Components of the immune system can be seen in Figure 1.
    Figure 1 The principle components of the immune system are listed, indicating which cells
    produce which soluble mediators. Complement is made primarily by the liver, with some
    synthesised by mononuclear phagocytes. Note that each cell only produces a particular set of
    cytokines, mediators etc
    Figure 2 Morphology of the neutrophil. This
    shows a neutrophil with its characteristic
    multilobed nucleus and neutrophilic granules
    in the cytoplasm. Giemsa stain, x 1500
    www.optometry.co.uk 27
    Table 2: Examples of cells of the
    mononuclear phagocytic system and their
    respective locations
    Cells Location
    Monocytes Blood stream
    Alveolar macrophages Lungs
    Sinus macrophages Lymph nodes
    and spleen
    Kupffer cells Liver
    Dendritic cells
    Dendritic cells consist of Langerhans’ and
    interdigitating cells and form an important
    bridge between innate and adaptive immunity,
    as the cells present the antigenic peptide to the
    T helper cell (adaptive immunity). Such cells are
    therefore known as professional antigen
    presenting cells (APCs). Table 3 illustrates the
    various types of dendritic cells together with an
    example of their location.
    Eosinophils
    Eosinophils (so called because their granules
    stain with eosin – Figure 4) are granulocytes
    that possess phagocytic properties. Despite the
    fact that they represent only 2-5 % of the total
    leukocyte population, they are instrumental in
    the fight against parasites that are too big to be
    phagocytosed.
    Phagocytosis - the process
    Phagocytosis is the process by which cells engulf
    microorganisms and particles (Figure 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 phagosome fuses with
    multiple vesicles containing O2 free radicals and
    other toxic proteins known as lysosomes to form
    a phagolysosome. The microbe is subsequently
    destroyed.
    Opsonisation (“to make tasty” - Greek)
    Opsonins are molecules, which enhance the
    efficiency of the phagocytic process by coating
    the microbe and effectively marking them for
    their destruction. Important opsonins are the
    complement component C3b and antibodies.
    Natural killer (NK) cells
    NK cells are also known as “large granular
    lymphocytes” (LGLs) and are mainly found in the
    circulation. They comprise between 5-11% of the
    total lymphocyte fraction. In addition to
    possessing receptors for immunoglobulin type G
    (IgG), they contain two unique cell surface
    receptors known as killer activation receptor and
    killer inhibition receptor. Activation of the
    former initiates cytokine (“communication”)
    molecules from the cell whilst activation of the
    latter inhibits the aforesaid action.
    NK cells serve an important role in attacking
    virally-infected cells in addition to certain
    tumour cells. Destruction of infected cells is
    achieved through the release of perforins and
    granyzymes from its granules, which induce
    apoptosis (programmed cell death). NK cells are
    also able to secrete interferon-γ (IFN-γ). This
    interferon serves two purposes: first, to prevent
    healthy host cells from becoming infected by a
    virus; and second, to augment the T cell
    response to other virally infected cells
    (see later).
    Mast cells and basophils
    Morphologically, mast cells and basophils are
    very similar in that both contain electron dense
    granules in the cytoplasm. Basophils are
    so-called owing to the fact that their granules
    stain with a basic dye. Unlike mast cells, which
    are present in close proximity to blood vessels in
    connective tissue, basophils reside in the
    circulation.
    Both cell types are instrumental in initiating
    the acute inflammatory response. Degranulation
    is achieved either by binding to components of
    the complement system or by cross-linking of
    the IgE antibody which results in the release of
    pro-inflammatory mediators including histamine
    and various cytokines. The former induces
    vasodilation and augments vascular permeability
    whilst the latter are important in attracting
    both neutrophils and eosinophils.
    Table 3: Dendric cells and location
    Cells Location
    Langerhans cell Limbus, skin
    Interdigitating cell T cell areas in
    lymph nodes
    Figure 4 Morphology of the eosinophil. The
    multilobed nucleus is stained blue and the
    cytoplasmic granules are stained red.
    Leishman stain, x 1800
    Figure 3
    Phagocytes arrive at a site of inflammation
    by chemotaxis. They may then attach to
    microorganisms via their non-specific cell
    surface receptors. Alternatively, if the
    organism is opsonised with a fragment of
    the third complement component (C3b),
    attachment will be through the phagocyte’s
    receptors for C3b. If the phagocyte
    membrane now becomes activated by the
    infectious agent, it is taken into a
    phagosome by pseudopodia extending
    around it. Once inside, lysosomes fuse with
    the phagosome to form a phagolysosome
    and the infectious agent is killed. Undigested
    microbial products may be released to the
    outside
    ot
    February 8, 2002 OT www.optometry.co.uk
    for the successful eradication of an invading
    virus by the innate immune system.
    Type II IFN, IFN-γ, is produced by T Helper
    cells and NK cells and is able to augment both
    the antigen presenting properties together with
    the phagocytic properties of the APCs (e.g.
    macrophages and dentritic cells).
    Adaptive immunity
    As mentioned previously, there is a great deal of
    synergy between the adaptive immune system
    and its innate counterpart. The adaptive immune
    system comprises two main types of leukocyte
    known as B and T lymphocytes. Before describing
    these important cell types, it is necessary to
    acquaint the reader with both the primary and
    secondary lymphoid organs and tissues in the
    body. These are summarised in Table 4.
    The bone marrow represents the dominant site
    for haemopoiesis (production of blood cells and
    platelets). Although most of the haemopoietic
    cells maturate in this region, T lymphocytes do
    so in the thymus. In the thymus, premature T
    cells undergo a process of positive and negative
    selection whereby the former are allowed to
    progress to maturity whilst the latter are marked
    for termination via apoptosis (see central
    tolerance).
    Lymphocytes
    Morphologically, there are three types of
    lymphocytes: T, B and NK cells. However, only T
    and B lymphocytes exhibit memory and
    specificity and, as such, are responsible for the
    unique quality of the adaptive immune system.
    Resting B lymphocytes are able to react with
    free antigen directly when it binds to their cell
    surface immunoglobins which act as receptors. T
    lymphocytes do not react with free antigen and
    instead make use of APCs to phagocytose the
    antigen and then to express its component
    28
    Molecules of the innate
    immune system
    There are many molecules, which work in concert
    with the cells of the innate immune system and
    which also foster close functional links with their
    adaptive counterpart. The three major molecules
    are:
    • Complement
    • Acute phase proteins (APP)
    • Interferons (IFNs)
    Complement
    The complement system represents a large group
    of independent proteins (denoted by the letter C
    and followed by a number), secreted by both
    hepatocytes (liver cells) and monocytes.
    Although these proteins maybe activated by both
    the adaptive immune system (classical pathway)
    or innate immune system (alternative pathway),
    the nomenclature is derived from the fact that
    the proteins help (“complement”) the antibody
    response.
    Activation of complement via the microbe
    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
    complement system. Binding of the antigen to
    C3 results in two possible sequelae. In either
    case, C3 component becomes enzymatically
    converted to C3b. The bacterial cell wall can
    either remain bound to C3b and become
    opsonised (since phagocytes have receptors for
    C3b) or act as a focus for other complement
    proteins (namely C5, 6, 7, 8 and 9). The latter
    form the membrane attack complex (MAC), which
    induces cellular lysis.
    The functions of the complement system may
    be summarised as follows:
    • Opsonisation
    • Lysis (destruction of cells through damage/
    rupture of plasma membrane)
    • Chemotaxis (directed migration of immune
    cells)
    • Initiation of active inflammation via direct
    activation of mast cells
    It is important that complement is regulated to
    protect host cells from damage and/or their total
    destruction. This is achieved by a series of
    regulatory proteins, which are expressed on the
    host cells themselves.
    Acute phase proteins
    These serum proteins are synthesised by
    hepatocytes and are produced in high numbers
    in response to cytokines released from
    macrophages.
    Interferons (IFNs)
    IFNs are a group of molecules, which limit the
    spread of viral infections (Figure 5). There are
    two categories of IFNs, namely type I and type II.
    Type I IFNs maybe sub-divided further into IFN-α
    and β. IFN-γ is the sole type II interferon. Type I
    IFNs are induced by viruses, pro-inflammatory
    cytokines and endotoxins from gram negative
    bacterial cell walls. Their presence remains vital
    proteins on the cell surface adjacent to special
    host proteins called major histocompatibility
    complex (MHC) class II molecules. As discussed,
    antigen presenting cells which express MHC class
    II molecules include dendritic cells and
    macrophages. This “afferent” phase must occur
    in order for the T cell to recognise the antigen.
    The “efferent” phase occurs when activated
    lymphocytes enter the tissue and meet antigen
    again. This results in multiplication and secretion
    of cytokines or immunoglobins in order to
    destroy the antigen.
    T cells
    T cells can be broadly divided into both T helper
    (TH) and cytotoxic T cells (Tc). Furthermore, TH
    cells may be sub-divided into TH1 and TH2. The
    former are pro-inflammatory T cells and
    stimulate macrophages whilst the latter
    orchestrate B cell differentiation and maturation
    and hence are involved in the production of
    humoral immunity (antibody mediated). T cells
    express cell surface proteins, described by cluster
    determination (CD) numbers. TH cells express CD4
    molecules on their cell surface, which enable the
    lymphocyte to bind to a MHC class II molecule.
    The T cell receptor is unique in that it is only
    able to identify antigen when it is associated
    with a MHC molecule on the surface of the cell.
    Cytotoxic T cells are primarily involved in the
    destruction of infected cells, notably viruses.
    Unlike TH cells, cytotoxic cells possess CD8 cell
    surface markers, which bind to antigenic
    peptides expressed on MHC class I molecules.
    B cells and antibodies
    (immunoglobulins - Ig)
    B cells are lymphocytes that produce antibodies
    (immunoglobulins) and can recognise free
    antigen directly. They are produced in the bone
    marrow and migrate to secondary lymphoid
    organs. B cells are responsible for the
    Figure 5
    When host cells become infected
    by virus, they may produce
    interferon. Different cell types
    produce interferon-α (IFN-α ) or
    interferon-β (IFN-β); interferon-γ
    (IFN-γ) is produced by some types
    of lymphocyte (TH) after activation
    by antigen. Interferons act on other
    host cells to induce a state of
    resistance to viral infection. IFN-γ
    has many other effects as well
    Table 4:
    Primary and secondary lymphoid organs
    Primary lymphoid organs Secondary lymphoid organs
    Bone marrow Lymph nodes
    MALT - mucosa associated lymphoid
    tissue (includes bronchus, gut, nasal and
    conjunctival associated mucosal tissues)
    Spleen
    www.optometry.co.uk
    Module 4 Part 2
    29
    Sponsored by
    a
    development of antibody mediated immunity
    known as humoral mediated immunity.
    When activated by foreign antigen, B cells
    undergo proliferation and mature into antibody
    secreting plasma cells. The latter are rich in
    organelles such as rough endoplasmic reticulum
    and mitochondria, which confer their ability to
    secrete soluble proteins (antibodies). Not all
    proliferating B cells develop into plasma cells.
    Indeed, a significant proportion remain as
    memory B cells through a process known as
    clonal selection. This process is vital in
    eliminating the antigen should the body become
    re-exposed to it in the future. T cells are also
    clonally selected and this confers to the
    production of T memory cells.
    Although T and B cells behave differently,
    both are able to recirculate around the body
    migrating from blood to tissue and vice versa.
    The ability to recirculate obviously increases the
    efficiency with which cells of the immune system
    can home onto the invading antigen.
    Antibodies
    Antibodies have two roles to play - the first is to
    bind antigen and the second is to interact with
    host tissues and effector systems in order to
    ensure removal of the antigen
    (Figure 6).
    There are five different types (known as
    isotypes) of antibody in the human immune
    system - namely IgM, IgG, IgA, IgE and IgD. In
    addition, there are four sub classes of IgG
    (IgG1-4). The basic antibody unit consists of a
    glycosylated protein consisting of two heavy and
    two light, polypeptide chains. The region which
    binds to the antigen is known as the Fab region,
    while the constant region, Fc, not only
    determines the isotype but is the region
    responsible for evoking effector systems, e.g.
    mast cell activation. The term immune complex
    refers to the combination of antigen and
    antibody and will be discussed later in the article
    (see type III hypersensitivity).
    The antibody isotypes together with their
    corresponding function are illustrated in Table 5.
    MHC
    Major histocompatability complex (MHC) are cell
    surface proteins classified as class I (also termed
    human leucocytic antigen [HLA] A, B and C),
    found on all nucleated cells and class II (termed
    HLA, DP, DQ and DR), found on all antigen
    presenting cells (APCs). MHC molecules are the
    sine qua non of T cell induced immunity.
    Clinically, there is a strong association
    between HLA and certain systemic and ocular
    diseases (see later).
    Cytokines
    Cytokines (also termed interleukins [IL] meaning
    “between white blood cells”) are small molecules
    that act as a signal between cells and have a
    variety of roles including chemotaxis, cellular
    growth and cytotoxicity. Owing to their ability to
    control immune activity, they have been
    described as the “hormones” of the immune
    system.
    Characteristics
    Crosses placenta thus providing newborn with useful humoral immunity
    High affinity
    Predominant antibody in blood and tissue fluid
    Large pentameric structure in circulation
    Present in monometric form on B cell surface
    Secreted form is predominant antibody in early immune
    response against antigen
    Reaches 75% of adult levels at 12 months of age
    Exists in both a monometric and dimeric form
    Secretory IgA (dimeric form) represents 1st line of defence against
    microbes invading the mucosal surface, e.g. tears
    Low levels in circulation
    Increased levels in worm infections
    Fc region has high affinity for mast cell thus involved in allergy
    Antigen receptor on B cells
    Absent from memory cells
    Table 5:
    Antibody isotypes and corresponding functions
    Antibody
    IgG
    IgM
    IgA
    IgE
    IgD
    Table 6:
    Various cytokines, their sources and functions
    Cytokine Source Function
    IL-1 Macrophages 1. T, B cell activation
    2. Mobilisation of PMNs
    3. Induction of acute phase proteins
    IL-2 T cells Proliferation of T and NK cells
    Il-4 Th2 cells B cell activation
    Mast cells IgE response
    IL-8 Macrophages Chemotaxis of PMNs
    T cells
    Fibroblasts
    Keratinocytes
    IL-10 TH2 cells B cell activation
    Macrophages Suppress macrophages
    IL-12 B cells Stimulate TH1
    Inhibit TH2
    TGF β (transforming growth factor) T cells Inhibits other cytokines
    TNF α (tumour necrosis factor) Macrophages Inflammation
    Figure 6
    When a microorganism lacks the
    inherent ability to activate
    complement or bind to
    phagocytes, the body provides
    antibodies as flexible adaptor
    molecules. The body can make
    several million different antibodies
    able to recognise a wide variety
    of infectious agents. Thus the
    antibody illustrated binds microbe
    1, but not microbe 2, by its
    ‘antigen-binding protein’ (Fab).
    The ‘Fc portion’ may activate
    complement or bind to Fc
    receptors on host cells,
    particularly phagocytes.
    Table 6 summarises some of the cytokines
    pertinent to ocular immunology, their functions
    and their progenitors. Since interferons have
    been discussed earlier in the article, they have
    been omitted from the table.
    Central and peripheral
    tolerance: nature’s way of
    containing the immune
    response
    Since various cells of the immune system are
    capable of reacting with self-antigens, it is
    therefore essential that the human body has
    mechanisms to suppress/eliminate autoreactive
    cells. Failure to do so, can, in some cases, lead
    to the development of autoimmune diseases
    (see later).
    Central tolerance
    Central tolerance refers to the process whereby
    both immature B and T cell lymphocytes, which
    react against normal, healthy cells
    (self-antigens), are eliminated via apoptosis.
    Peripheral tolerance
    This involves the removal of mature lymphocytes,
    which are not tolerant to healthy cells.
    Ocular immune privilege
    There are numerous sites in the body whereby
    tissue may be grafted with minimal risk of
    rejection. Such regions include, inter alia, the
    testis, thyroid lens, anterior chamber, cornea,
    iris and ciliary body1,2.
    It is important that immune privilege is not
    simple interpreted as the host’s inability to
    initiate an immune response to a transplanted
    tissue. Rather, it is an area of the body in which
    there exists a paucity of various elements of the
    human immune system in response to an
    antigen.
    Factors
    The factors purported by investigators that
    contribute to the phenomenon of ocular immune
    privilege include:
    • Isolation from a vascular supply
    • Isolation from a lymphatic supply
    • Presence of a vascular barrier
    • Ability to suppress the immune response
    • Anterior chamber associated immune
    deviation (ACAID)
    Vascular supply
    The healthy cornea is a good example of an
    ocular site devoid of a vascular network. The
    evidence to support the role a vascular network
    has to play in the mechanism of graft rejection
    is unequivocal since the risk of failure correlates
    positively with the degree of host
    vascularisation3.
    Vascular barrier
    There is a plethora of evidence in the
    ophthalmic literature to support the existence of
    a blood-ocular barrier. Furthermore, the same
    said barrier encompasses different elements
    including tight junctions between retinal
    ot
    30 February 8, 2002 OT
    endothelial cells and the presence of junctional
    complexes linking retinal pigment epithelial
    cells4.
    Lymphatic role
    The fact that skin allografts were not rejected
    following lymph node removal5 led investigators
    to hypothesise that immune privilege was solely
    due to the absence of the same said system at a
    particular anatomical site. However, although
    certain immune privileged sites do indeed lack
    lymphatic drainage, others such as the testes6
    and eye7 do possess such a system. It appears
    that a proportion of the aqueous humour drains
    via the uveoscleral pathway into the lymphatic
    vessels in the head and neck.
    The eye, APCs & MHCs
    As mentioned previously, APCs, through their
    ability to express MHC class II molecules, are
    potent progenitors of the immune response.
    Moreover, such cells are capable of activating T
    cells within the tissue itself. It is therefore not
    unreasonable to assume that a paucity of APCs
    may play an important role in immune
    privilege. In addition, failure to express MHC
    class I molecule would make a tissue immune
    against the lytic action of the cytotoxic T cells.
    Although the aforementioned mechanisms
    are theoretically plausible, cells expressing both
    MHC class I and II molecules have been
    detected in the eye. Table 7 illustrates the
    relationship between histocompatability class
    and ocular cell type.
    It is noteworthy that the epithelial cells of
    the crystalline lens are devoid of class I
    expression14 and that the Langerhans’ cells
    (class II expression) are absent from the central
    cornea15.
    It is interesting that not all cells, which
    express MHC class II act as professional APCs in
    the eye. Indeed, it has been shown that such
    cells reside in the iris and ciliary body and not
    only fail to present alloantigens to T cells, but
    have the ability to suppress mixed lymphocyte
    reactions16.
    The failure to incite the inflammatory
    response has attracted a great deal of interest
    amongst ophthalmologists and immunologists
    alike. It appears such suppression is achieved by
    various factors present in the aqueous humour
    (e.g. transforming growth factor - β).
    Anterior chamber associated immune
    deviation (ACAID)
    As a result of experiments with rats,
    investigators discovered that antigens placed in
    the anterior chamber resulted in systemic
    inhibition of delayed type hypersensitivity (DTH
    or type IV hypersensitivity) reactions to the
    same said antigens17. This phenomenon has been
    coined anterior chamber associated immune
    deviation (ACAID). The anterior chamber is thus
    able to suppress delayed type hypersensitivity
    reactions and inhibit the production of
    complement fixing antibodies18,19. However, it
    has no inhibitory effect on cytotoxic T cell
    activity and has a minimal influence on the
    production of non-complement fixing
    antibodies.
    With respect to the endothelium, two
    adaptations prevent it from immunological
    injury: first, avoidance of cytotoxic T lymphocyte
    (CTL)-mediated lysis; and second, inhibition of
    DTH responses in the anterior chamber22. It
    achieves the former through the cells inability
    to express MHC class I molecules21. The corollary
    of this, however, is that virally infected cells
    may persist in this region. The râison d’etre of
    ACAID is to protect the eye from the DTH
    response to pernicious antigens. As a result of
    its location in relation to the anterior chamber,
    the corneal endothelium seems well placed to
    reap the benefits of ACAID.
    ACAID is beneficial in reducing the incidence
    of stromal keratitis in herpes simplex virus
    infection. It therefore seems reasonable to
    assume that such an unwanted corneal sideeffect
    occurs as a result of a DTH response
    rather than the toxic effect of the virus per se22.
    Corneal graft rejection may be due, in part,
    to failure to invoke ACAID. Streilein at al23 not
    only discovered that the immunosuppressive
    effects of the cornea were abolished in corneas
    www.optometry.co.uk
    Table 7:
    MHC and ocular cell type8-13
    Ocular cell type MHC class I MHC class II
    Corneal epithelium •
    Corneal stroma •
    Corneal endothelium •
    Trabecular meshwork •
    Pigmented and non pigmented •
    cells of ciliary body
    Anterior iris •
    RPE cells •
    Corneal limbus •
    Iris and ciliary body •
    Uveoscleral pathway •
    Ora serrata •
    www.optometry.co.uk
    Module 4 Part 2
    Sponsored by
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    31
    that had ACAID removed via cauterisation or
    keratoplasty but also abolished in corneas that
    had been denervated.
    Ocular immunology
    Anterior segment immunology may be
    sub-divided into the following aspects:
    • Tear film
    • Corneal immunology
    • Conjunctival immunology
    • Scleral immunology
    • Uveal immunology
    Tear film
    a) Mucous layer
    This layer is produced both by the conjunctival
    goblet and epithelial cells. The glycocalyx
    synthesised by the corneal epithelial cells serves
    to attach the mucous layer and in doing so binds
    to immunoglobulin in the aqueous24. It has been
    suggested that the latter immunological sign may
    have antiviral effects. The evidence to support
    this is that certain intestinal mucosa, which have
    similar binding properties to those seen in the
    eye, are able to exert an inhibitory action against
    viral replication25.
    b) Aqueous layer
    The aqueous layer contains the following
    antimicrobial factors:
    1. Lactoferrin
    2. Lysozyme
    3. IgA
    4. Miscellaneous proteins
    1. Lactoferrin
    Lactoferrin is produced via the acinar cells of the
    lacrimal gland. Its main function is to bind iron,
    which is required for bacterial growth. It
    therefore possesses both bacteriostatic and
    bacteriocidal properties. Furthermore, it is able
    to enhance the effects of certain
    immunoglobulins.
    2. Lyszome
    Produced by type A cells in the lacrimal gland,
    lysozome constitutes up to 25% of the total tear
    protein. It is surprising somewhat that despite
    being effective at lysing gram positive bacterial
    cell walls, staphylococcus aureus appears
    recalcitrant to its action26. However, it is
    instrumental in enhancing IgA against gram
    negative bacteria.
    3. IgA
    This is the predominant isotype found in the
    human tears in the non-inflamed eye. Very little
    is present in serum with the majority secreted
    through epithelial cells of structures such as the
    lacrimal gland and the lactating breast. The IgA
    present in the tears is produced by plasma cells
    situated underneath the secretory cells lining the
    acini in the lacrimal gland.
    IgA is very effective at binding microbes and,
    as such, prevents the microbe from adhering to
    the mucosal surface. The antibody achieves this
    either by interfering with the binding site
    directly or by agglutination. Successful binding of
    the microorganism enables the tears to wash
    them away. IgA possesses other functions
    including opsonisation and inactivation of
    various bacterial enzymes and toxins. In
    addition, it may be involved in antibody
    dependent cell-mediated cytotoxicity. It must be
    emphasised, however, that IgA is unable to bind
    to complement and, as such, is not involved in
    the classical pathway27.
    4. Miscellaneous proteins
    β-Lysin, a bacteriocidal cationic protein, is
    present both in the tears and aqueous humour28.
    Its bacteriocidal properties are conferred
    through their ability to disrupt the microorganisms’
    walls. Various components of
    complement are present in varying degrees
    depending on whether the eye is closed or not.
    Closed eye vs open eye
    Open eye
    In addition to the components of complement
    mentioned above, the tears are rich in lysozyme,
    lactoferrin and lipocalin (tear pre albumin)
    together with low levels of IgA29,30.
    Closed eye
    In the closed eye environment, levels of IgA and
    complement components are increased. In
    addition, neutrophils are also recruited. The eye
    can be interpreted as being in a state of
    subclinical inflammation. However, the eye is
    protected from damage induced by either
    complement or neutrophils by DAF (Decayed
    Accelerating Factor [an inhibitory component of
    the complement system])31 and α1 –antitrypsin33.
    Corneal immunology
    Paradoxically, the cornea, an immune privileged
    site, is capable of evoking an immunological
    response evidenced by the presence of
    subepithelial infiltrates, keratic precipitates,
    epithelial and stromal keratitis under certain
    clinical conditions.
    Cytokine release
    Numerous cytokines are synthesised in the
    cornea including IL-1, IL-6, IL-8, TNF-α, IFN-γ,
    C5a and prostaglandins33. Phagocytosis of certain
    antigens via corneal epithelial cells initiate the
    release of IL-1 which, in turn, gives rise to the
    recruitment of Langerhans’ cells from the limbus
    to the central cornea. It is worthy of note that
    the same said APC may be recruited centrally in
    response to chemical or localised damage34,35.
    Investigators have discovered that stromal
    fibroblasts synthesise
    IL-8 in response to infection by the herpes
    simplex virus36. Furthermore, it seems plausible
    that the latter cytokine release may be
    responsible for the neutrophilic infiltration
    observed in cases of herpetic keratitis.
    Immunoglobulins
    The three isotypes detected in the cornea are
    IgM, G and A. IgG predominates in the central
    cornea37. By contrast, IgM predominates in the
    limbal region. The latter antibody is restricted
    from the central cornea owing to its large size.
    Antibodies in the cornea are found in the
    stroma since they are cationically charged. Due
    to their positive ionic charge, they bind to
    proteoglycans and the anionic
    glycosaminoglycans38.
    Antigen/antibody complexes may sometimes
    be observed in the corneal stroma in a variety
    of pathological conditions (e.g. herpes simplex
    keratitis), and because of their ringed shaped
    appearance are known as “Wessley rings”.
    Complement
    The elements of complement found in the
    cornea include C1-739 in addition to the
    regulatory proteins H and I and C1 inhibitor40.
    Interestingly, C1 is present in high
    concentrations in the limbus and is restricted
    from the central cornea. This finding is
    significant since the limbal region is susceptible
    to ulceration following complement activation
    and immune complex deposition. It has been
    suggested that C1 is produced by corneal
    fibroblasts whereas the remaining components
    detected in the cornea appear to be derived
    from the plasma via linked vessels.
    Conjunctival immunology
    The conjunctival associated lymphoid tissue
    (CALT) is part of the more general mucosa
    associated lymphoid tissue (MALT). Langerhans’
    cells and lymphocytes exist within the
    conjunctival epithelial layer. In the substantia
    propria, neutrophils, lymphocytes, IgA and IgG,
    dendritic cells and mast cells all reside. It is
    noteworthy that eosinophils and basophils are
    not present in the healthy conjunctiva.
    Langerhans’ cells and dendritic cells present
    the antigenic peptide to the conjunctival T
    helper cells. Following antigenic presentation,
    the T cells secrete the cytokine IFN-γ which
    serves to promote antigen elimination by
    macrophages. This is the delayed-type
    hypersensitivity (DTH) response (see later) and
    is characteristic of conjunctival pathology such
    as phlyctenulosis.
    Scleral immunology
    There exists only a small number of immune
    cells in the sclera compared to the conjunctiva
    since it is relatively avascular. In its resting
    state, IgG appears to be present in large
    amounts41. However, a sclera under stress, may
    become immunologically active as a result of
    migrating cells from the overlying episcleral and
    underlying choroidal vasculature42,43.
    Uveal immunology
    The uveal tract is an important site from an
    immunological perspective for two reasons:
    first, it is highly vascular in nature; and second,
    the majority of vessels are highly fenestrated
    which facilitates the recruitment of leukocytes
    during the inflammatory cascade. The uvea
    contains numerous cellular components of the
    immune system including macrophages, mast
    cells, lymphocytes and plasma cells in addition
    ot
    32 www.optometry.co.uk
    to an appreciable number of immune factors.
    Although IgG and IgM have been detected in
    both the choroid and iris, they exist in greater
    numbers in the former structure. The reason for
    such disparate levels is the dearth of anionic
    antibody binding sites on the iris surface44. By
    contrast, the ciliary body harbours tremendous
    amounts of IgG by virtue of its anionic tissue
    sites.
    Immunopathology and the eye
    Immunopathology encompasses both pathology
    as a result of an over-active immune system
    (hypersensitivity and autoimmunity) together
    with that acquired through an individuals
    inability to fight off infection – namely
    immunodeficiency. Unfortunately, it is far
    beyond the scope of this article to describe the
    latter and its ophthalmic correlates.
    In this section, the classification system
    pertaining to hypersensitivity reactions will be
    described and each subtype with an anterior
    segment manifestation will be discussed. The
    association between HLA and systemic and
    ophthalmic disease will be illustrated together
    with a brief overview of the concepts pertaining
    to autoimmunity.
    Hypersensitivity
    The term hypersensitivity refers to the process
    whereby the adaptive immune response overreacts
    to a variety of infectious and inert
    antigens resulting in damage to the host tissue.
    Five types of hypersensitivity reactions exist –
    all of which vary in their timing following
    contact with the antigen (Table Cool.
    • Type I hypersensitivity: allergy
    Allergies may affect approximately 17% of the
    population45. The term atopic is used to describe
    those individuals who possess a genetic
    predisposition to allergy. Allergies may occur to
    otherwise innocuous antigens (known as
    allergens) and infectious agents, e.g. worms.
    Type I hypersensitivity exists in two phases, the
    sensitisation and effector phases.
    Firstly, a harmless allergen causes production
    of IgE antibody on first exposure. This IgE
    February 8, 2002 OT
    diffuses throughout the body until it comes into
    contact with mast cells and basophils. Both
    these cell types have receptors for IgE antibody.
    Although the patient experiences no symptoms
    after the initial binding, reintroduction of the
    antigen/allergen induces the production of
    more IgE and, furthermore, increase the
    likelihood of cross-linking with existing
    antibodies on the mast cell surface. Such crosslinking
    induces the mast cell to degranulate and
    release a host of inflammatory mediators such
    as histamine, prostaglandins and bradykinin.
    Histamine characteristically causes the itchy
    symptoms experienced by patients and as a
    result of binding to H1 receptors in the eye,
    induces vasodilation and enhances mucous
    secretion by the goblet cells. Bradykinin
    augments vascular permeability, decreases
    blood pressure and contracts smooth muscle.
    Prostaglandins are also powerful inflammatory
    mediators.
    Ocular correlates:
    The following anterior segment conditions are
    due, if not only in part, to type I
    hypersensitivity:
    • Seasonal allergic conjunctivitis (type I)
    • Giant papillary conjunctivitis (types I and IV)
    • Vernal keratoconjunctivitis (VKC)
    (type I and IV)
    • Atopic keratoconjunctivitis (AKC)
    (types I and IV) (Figure 7)
    Seasonal allergic conjunctivitis can be easily
    recognised by chemosis and hyperaemia of the
    conjunctiva, lid swelling and excessive
    lacrimation. The cornea is not affected.
    GPC is well known to optometrists as an
    allergic response to contact lenses, prosthetic
    lenses, protruding corneal sutures and scleral
    buckles. Histological examination of eyes
    suffering from GPC have revealed degranulated
    mast cells (type I hypersensitivity)46 and CD4+ T
    cells (type IV)47, thus corroborating the theory
    that such a condition is mediated by both types
    of hypersensitivity.
    Vernal conjunctivitis can present either in a
    palpebral form characteristically exhibiting
    giant cobblestone papillae, or in a limbal form
    with gelatinous deposits known as Trantas’-dots,
    which represent degenerating epithelial cells and
    eosinophils. The first corneal change is a
    punctate epithelial keratitis, which if left
    unchecked develops into a macroerosion
    (Figure Cool and finally a corneal plaque develops
    (Figure 9). The conjunctiva itself is
    characteristically oedematous and contains an
    array of immunological cells including
    lymphocytes and mast cells. Evidence of type I
    involvement includes the histological detection
    of, inter alia, degranulated mast cells,
    eosinophils and increased levels of IgE in
    affected eyes49. The detection of CD4+ T cells and
    macrophages is indicative of a delayed
    inflammatory component49.
    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
    V. Stimulatory Autoantibodies Autoantibodies against hormone
    Figure 8:
    Epithelial macroerosion in VKC
    Figure 9:
    Corneal plaque in VKC
    Figure 7:
    Corneal thinning and vascularisation in AKC,
    excess mucous is present
    www.optometry.co.uk 33
    Sponsored by
    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 cells50 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 eye51. 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 autoantibodies
    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-B2752.
    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.
    Table 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 Figures 7 to 9.
    ot
    34 February 8, 2002 OT www.optometry.co.uk
    Figures 1 to 6 reprinted from
    Immunology, Third Edition, Roitt,
    Brostoff and Male, 1993 by
    permission of the publisher
    Mosby.
    About the author
    Gregory Heath is an optometrist
    working part-time in private
    practice. He was recently awarded
    the diploma in clinical optometry
    at City University and is currently
    reading medicine at the Royal
    Free and University College,
    London, Medical School.
    References
    References are available upon
    request. Please fax 01252-816176
    or email info@optometry.co.uk.
    Table 9:
    HLA and ophthalmic disease
    Disease HLA Relative risk 54 Ocular
    association manifestation
    Ankylosing spondylitis B27 90 Anterior uveitis
    Reiter’s disease B27 33 Mucopurulent conjunctivitis
    Anterior uveitis
    Keratitis
    Rheumatoid DR4 7 Keratoconjunctivitis sicca
    Keratitis
    Scleritis
    Primary Sjögrens’ syndrome DR3, DR5 10 Keratoconjunctivitis sicca
    Sarcoidosis DR3 Not known Anterior uveitis (acute and chronic)
    Dacryoadentis
    Retinal vasculitis,
    neovascularisation,
    Optic nerve granulomata
    Cicatrical pemphigoid DQw7 Not known Shrinkage of conjunctiva
    Behcet’s disease B5 3 Anterior uveitis
    Retinitis, periphlebitis,
    retinal oedema
    Sympathetic DR4, A11, Not known Panuveitis
    ophthalmia B40
    Systemic lupus DR2, DR3 3 Punctate epithelial keratopathy
    erythematosus Keratopathy
    Necrotising scleritis
    Retinal lesions (cotton wool spots)
    Autoimmune optic neuropathy
    1. Which one of the following is not part of the
    innate immune system?
    a. Mast cells
    b. Complement
    c. Phagocytes
    d. T cells
    2. Which one of the following statements is
    correct regarding the innate immune system?
    a. It is specific
    b. It evokes a more potent response on
    secondary exposure
    c. It represents the first line of defence
    d. It is able to memorise pathogens on
    subsequent exposures
    3. Which one of the following statements is
    correct regarding the cells of the innate
    system?
    a. Basophils are important phagocytes
    b. During phagocytosis the pathogen becomes
    initially internalised as a phago-lysosome
    c. Eosinophils play an important role in
    combating virally-infected cells
    d. Langerhans’ cells form a bridge between
    innate and adaptive immunity
    4. Which one of the following statements is
    correct regarding the adaptive immune
    system?
    a. It consists of all types of lymphocytes
    b. T cells produce antibodies
    c. T cells maturate in the thymus
    d. B cells are produced in the spleen
    5. Which one of the following statements is
    correct regarding T cells?
    a. T cells can be subdivided into TH1 and TH2
    subtypes only
    b. T cells alone can identify any type of antigen
    c. T cells express cell surface proteins denoted by
    cluster determinant (CD) numbers
    d. All T cells are involved in initiating the
    inflammatory response
    6. Which one of the following statements is
    incorrect?
    a. B cells have antibodies as their cell surface
    receptor
    b. There are five types of antibody
    c. IgE is an important antibody in allergies
    d. All B cells differentiate into plasma cells
    7. Which one of the following statements is
    correct regarding ocular immune privilege?
    a. There is an absence of Langerhans’ cells in the
    central cornea
    b. Aqueous humour has no role
    c. Abundant vascular supply is vital
    d. All ocular cells express MHC class II
    8. Which one of the following statements
    concerning ocular immunology is incorrect?
    a. Levels of IgA and complement
    increase when the eyes are closed
    b. IgA is the predominant antibody
    in blood and tissue fluid
    c. IgM, IgG and IgA antibody isotypes have been
    identified in the cornea
    d. The sclera contains a smaller number of
    immune cells than the conjunctiva
    9. In a patient suffering from vernal conjunctivitis,
    which one of the following statements is
    correct?
    a. Trantas’-dots represent infiltrating T cells
    b. Affected eyes have increased levels of IgD
    c. Histologically, mast cells, lymphocytes and
    macrophages have been identified
    d. Is due to type III Hypersensitivity
    10. Which one of the following statements is
    incorrect?
    a. HLA-B27 is a risk factor for both anterior uveitis
    and ankylosing spondylitis
    b. Granulomas are present in type IV
    hypersensitivity reactions
    c. Histamine is an important vasoconstrictor
    d. IgE mediated hypersensitivity is of rapid onset
    11. What proportion of patients with acute iritis will
    harbour HLA-B27?
    a. 15%
    b. 25%
    c. 45%
    d. 65%
    12. Which one of the following statements is correct
    regarding a type I hypersensitivity reaction?
    a. It always occurs in isolation
    b. It is characterised by the presence of
    macrophages
    c. It is associated with myasthenia gravis
    d. It involves the degranulation of mast cells
    following the cross-linking of IgE bound to its
    cell surface
    Multiple choice questions - Basic immunology Please note there is only one correct answer
    An answer return form is included in this issue. It should be completed and returned to: CPD Initiatives (c4082c),
    OT, Victoria House, 178–180 Fleet Road, Fleet, Hampshire,
    Mugahid
    GU51 4DA by
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