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Immunity

Immunity

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03/08/2013

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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 madein the molecular tests employed in this area of research. Therefore, the keen reader isencouraged to peruse the ophthalmic and immunological literature in order to keepabreast of the latest developments in this field.
The College of Optometrists hasawarded this article 2CET credits. There are12 MCQs with a passmark of 60%.
Owing to the complex nature of this subject, it isfar beyond the scope of this article to cover all aspects of immunology. Rather, the aims of thearticle are twofold: first to acquaint the busypractitioner with the basic concepts of theimmune system; and second, to introduce thereader to the more specific topic of ocularimmunology
the study of the ocular immunesystem.Finally, since it is envisaged that optometristswill one day prescribe therapeutic agents, thediscussion is limited to the anterior segment andanterior uvea.
Innate & adaptive immune systems
The immune system can be thought of as havingtwo “lines of defence”: the first, representing anon-specific (no memory) response toant
 
igen(substance to which the body regards as foreignor potentially harmful) known as theinnateimmune system; and the second,the ad
 
apt
 
iveimmune system, which displays a high degree of memory and specificity. The innate systemrepresents the first line of defence to anintruding pathogen. The response evolved istherefore rapid, and is unable to “memorise” thesame said pathogen should the body be exposedto it in the future. Although the cells andmolecules of the adaptive system possess slowertemporal dynamics, they possess a high degreeof specificity and evoke a more potent responseon secondary exposure to the pathogen.The adaptive immune system frequentlyincorporates cells and molecules of the innatesystem in its fight against harmful pathogens.For example,c
 
omplement(molecules of theinnate system - see later) may be activated byant
 
ibodies(molecules of the adaptive system)thus providing a useful addition to the adaptivesystem’s armamentaria.A comparison of the two systems can be seeninTable 1.
o
t
www.optometry.co.uk
 
Gregory Heath BSc (Hons), MCOptom, Dip. Clin. Optom
ABDO has awarded thisarticle2 CET credits (GD).
February 8, 2002 OT
26
Sponsored by
a
Cells of the innateimmune system
Phagocytes
Although sub-divided into two main types,namely neutrophils and macrophages, theyboth share the same function - to engulf microbes (phago - I eat, Latin).
Neutrophils
Microscopically, these cells possess acharacteristic, salient feature - amultilobular nucleus(F
 
igure 2). As such,these cells have been referred to aspolymorphonuclear leukocytes (PMNs) andhave a pivotal role to play in thedevelopment of acute inflammation. Inaddition to being phagocytic, neutrophilscontain granules and can also be classed asone of the granulocytes. The granulescontain acidic and alkaline phosphatases,defensins and peroxidase - all of whichrepresent the requisite molecules required forsuccessful elimination of the unwantedmicrobe(s).
Macrophages
Macrophages (termed monocytes when in theblood stream) have a horseshoe-shaped nucleusand are large cells. Properties of macrophagesinclude phagocytosis and antigen presentationto T cells (see later). Unlike neutrophils (whichare short-lived cells), they are seen in chronicinflammation as they are long-lived cells.
Mononuclear phagocytic system
The cells comprising the monocyte phagocyticsystem are tissue bound and, as a result, arefurther sub-divided depending on their location.A list of the cells together with theircorresponding location can be found inTable 2.
Table 1: Cells and molecules of the innate and adaptive immune systems
ImmunityCellsMolecules
InnateNatural killer (NK) cellsCytokinesMast cellsComplementDendritic cellsAcute phase proteinsPhagocytesAdaptiveTand B cellsCytokinesAntibodiesComponents of the immune system can be seen in
Figure 1.
 
Figure 1
The principle components of the immune system are listed, indicating which cellsproduce which soluble mediators. Complement is made primarily by the liver, with somesynthesised by mononuclear phagocytes. Note that each cell only produces a particular set ofcytokines, mediators etc
Figure 2
Morphology of the neutrophil. Thisshows a neutrophil with its characteristicmultilobed nucleus and neutrophilic granulesin the cytoplasm. Giemsa stain, x 1500
 
27
www.optometry.co.uk
Table 2:
Examples of cells of themononuclear phagocytic system and theirrespective locations
CellsLocation
MonocytesBlood streamAlveolar macrophagesLungsSinus macrophagesLymph nodesand spleenKupffer cellsLiver
Dendritic cells
Dendritic cells consist of Langerhans’ andinterdigitating cells and form an importantbridge between innate and adaptive immunity,as the cells present the antigenic peptide to theT helper cell (adaptive immunity). Such cells aretherefore known as professional antigenpresenting cells(APCs).Table 3illustrates thevarious types of dendritic cells together with anexample of their location.
Eosinophils
Eosinophils (so called because their granulesstain with eosin –Figure 4) are granulocytesthat possess phagocytic properties. Despite thefact that they represent only 2-5 % of the total leukocyte population, they are instrumental inthe fight against parasites that are too big to bephagocytosed.
Phagocytosis - the process
Phagocytosis is the process by which cells engulf microorganisms and particles(Figure 3). Firstly,the phagocyte must move towards the microbeunder the influence of chemotactic signals, e.g.complement (see later). For the process tocontinue, the phagocyte must attach to themicrobe either by recognition of the microbial sugar residues (e.g. mannose) on its surface orcomplement/antibody, which is bound to thepathogen. Following attachment, thephagocyte’s cell surface invaginates and themicrobe becomes internalised into aphagosome. The resultantphagosomefuses withmultiple vesicles containing O
2
free radicals andother toxic proteins known as lysosomes to forma phagolysosome. The microbe is subsequentlydestroyed.
Opsonisation
(
“to make tasty” 
- Greek)
Opsoninsare molecules, which enhance theefficiency of the phagocytic process by coatingthe microbe and effectively marking them fortheir destruction. Important opsonins are thecomplement component C3b and antibodies.
Natural killer (NK) cells
NKcells are also known as “large granularlymphocytes” (LGLs) and are mainly found in thecirculation. They comprise between 5-11% of thetotal lymphocyte fraction. In addition topossessing receptors for immunoglobulin type G(IgG), they contain two unique cell surfacereceptors known as killer activation receptor andkiller inhibition receptor. Activation of theformer initiates cytokine (“communication”)molecules from the cell whilst activation of thelatter inhibits the aforesaid action.NK cells serve an important role in attackingvirally-infected cells in addition to certaintumour cells. Destruction of infected cells isachieved through the release of perforins andgranyzymes from its granules, which induceapoptosis (programmed cell death). NK cells arealso able to secrete interferon-
γ
(IFN-
γ
). Thisinterferon serves two purposes: first, to preventhealthy host cells from becoming infected by avirus; and second, to augment the T cell response to other virally infected cells(see later).
Mast cells and basophils
Morphologically, mast cells and basophils arevery similar in that both contain electron densegranules in the cytoplasm. Basophils areso-called owing to the fact that their granulesstain with a basic dye. Unlike mast cells, whichare present in close proximity to blood vessels inconnective tissue, basophils reside in thecirculation.Both cell types are instrumental in initiatingthe acute inflammatory response. Degranulationis 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 histamineand various cytokines. The former inducesvasodilation and augments vascular permeabilitywhilst the latter are important in attractingboth neutrophils and eosinophils.
 
Table 3:
Dendric cells and location
CellsLocation
Langerhans cellLimbus, skinInterdigitating cellTcell areas inlymph nodes
Figure 4
Morphology of the eosinophil. Themultilobed nucleus is stained blue and thecytoplasmic granules are stained red.Leishman stain, x 1800
Figure 3
Phagocytes arrive at a site of inflammationby chemotaxis. They may then attach tomicroorganisms via their non-specific cellsurface receptors. Alternatively, if theorganism is opsonised with a fragment ofthe third complement component (C3b),attachment will be through the phagocyte’sreceptors for C3b. If the phagocytemembrane now becomes activated by theinfectious agent, it is taken into aphagosome by pseudopodia extendingaround it. Once inside, lysosomes fuse withthe phagosome to form a phagolysosomeand the infectious agent is killed. Undigestedmicrobial products may be released to theoutside
 
o
t
February 8, 2002 OTwww.optometry.co.uk
for the successful eradication of an invadingvirus by the innate immune system.Type II IFN, IFN-
γ
, is produced by T Helpercells and NK cells and is able to augment boththe antigen presenting properties together withthe 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 systemand its innate counterpart. The adaptive immunesystem comprises two main types of leukocyteknown as B and T lymphocytes. Before describingthese important cell types, it is necessary toacquaint the reader with both the primary andsecondary lymphoid organs and tissues in thebody. These are summarised inTable 4.The bone marrow represents the dominant sitefor haemopoiesis (production of blood cells andplatelets). Although most of the haemopoieticcells maturate in this region, T lymphocytes doso in the thymus. In the thymus, premature T cells undergo a process of positive and negativeselection whereby the former are allowed toprogress to maturity whilst the latter are markedfor 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 andspecificity and, as such, are responsible for theunique quality of the adaptive immune system.Resting B lymphocytes are able to react withfree antigen directly when it binds to their cell surface immunoglobins which act as receptors. T lymphocytes do not react with free antigen andinstead make use of APCs to phagocytose theantigen and then to express its component
28
Molecules of the innateimmune system
There are many molecules, which work in concertwith the cells of the innate immune system andwhich also foster close functional links with theiradaptive counterpart. The three major moleculesare:ComplementAcute phase proteins (APP)Interferons (IFNs)
Complement
The complement system represents a large groupof independent proteins (denoted by the letter Cand followed by a number), secreted by bothhepatocytes (liver cells) and monocytes.Although these proteins maybe activated by boththe adaptive immune system (cl 
 
assic
 
al p
 
athway)or innate immune system (al 
 
ternat
 
ive pathway),the nomenclature is derived from the fact thatthe proteins help (“complement”) the antibodyresponse.Activation of complement via the microbeitself is known as the alternative pathway. Theclassical pathway requires the interaction of antibody with specific
antigen 
. The C3component is the pivotal serum protein of thecomplement system. Binding of the antigen toC3 results in two possible sequelae. In eithercase, C3 component becomes enzymaticallyconverted to C3b. The bacterial cell wall caneither remain bound to C3b and becomeopsonised (since phagocytes have receptors forC3b) or act as a focus for other complementproteins (namely C5, 6, 7, 8 and 9). The latterform the membrane attack complex (MAC), whichinduces cellular lysis.The functions of the complement system maybe summarised as follows:OpsonisationLysis (destruction of cells through damage/rupture of plasma membrane)Chemotaxis (directed migration of immunecells)Initiation of active inflammation via directactivation of mast cellsIt is important that complement is regulated toprotect host cells from damage and/or their total destruction. This is achieved by a series of regulatory proteins, which are expressed on thehost cells themselves.
Acute phase proteins
These serum proteins are synthesised byhepatocytes and are produced in high numbersin response to cytokines released frommacrophages.
Interferons (IFNs)
IFNs are a group of molecules, which limit thespread of viral infections(Figure 5). There aretwo 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 IIFNs are induced by viruses, pro-inflammatorycytokines and endotoxins from gram negativebacterial cell walls. Their presence remains vital 
 
proteins on the cell surface adjacent to special host proteins called major histocompatibilitycomplex (MHC) class II molecules. As discussed,antigen presenting cells which express MHC classII molecules include dendritic cells andmacrophages. This “afferent” phase must occurin order for the T cell to recognise the antigen.The “efferent” phase occurs when activatedlymphocytes enter the tissue and meet antigenagain. This results in multiplication and secretionof cytokines or immunoglobins in order todestroy the antigen.
T cells
T cells can be broadly divided into both T helper(T 
H
) and cytotoxic T cells (T 
c
). Furthermore, T 
H
cells may be sub-divided into T 
H1
and T 
H2
. Theformer are pro-inflammatory T cells andstimulate macrophages whilst the latterorchestrate B cell differentiation and maturationand hence are involved in the production of humoral immunity (antibody mediated). T cellsexpress cell surface proteins, described by clusterdetermination (CD) numbers. T 
H
cells express CD4molecules on their cell surface, which enable thelymphocyte to bind to a MHC class II molecule.The T cell receptor is unique in that it is onlyable to identify antigen when it is associatedwith a MHC molecule on the surface of the cell.Cytotoxic T cells are primarily involved in thedestruction of infected cells, notably viruses.Unlike T 
H
cells, cytotoxic cells possess CD8 cell surface markers, which bind to antigenicpeptides expressed on MHC class I molecules.
B cells and antibodies(immunoglobulins - Ig)
B cells are lymphocytes that produce antibodies(immunoglobulins) and can recognise freeantigen directly. They are produced in the bonemarrow and migrate to secondary lymphoidorgans. B cells are responsible for the
Figure 5
When host cells become infectedby virus, they may produceinterferon.Different cell typesproduce interferon-
α
(IFN-
α
) orinterferon-
β (
IFN-
β);
interferon-
γ
(IFN-
γ)
is produced by some typesof lymphocyte (T
H
) after activationby antigen. Interferons act on otherhost cells to induce a state ofresistance to viral infection. IFN-
γ
has many other effects as well
Table 4:
Primary and secondary lymphoid organsPrimary lymphoid organsSecondary lymphoid organsBone marrowLymph nodesMALT- mucosa associated lymphoidtissue (includes bronchus, gut, nasal andconjunctival associated mucosal tissues)Spleen

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