The immune system consists of several cell types that work together to protect the body. Macrophages play major roles in the immune system by destroying pathogens and clearing dead/diseased tissue. Dendritic cells activate T cells and produce IL-12 to initiate immune responses. The eye was once thought to be an immune-privileged site, but it is now known that resident ocular cells like RPE and Müller cells can participate in immune responses by presenting antigens and secreting cytokines. Uveitogenic antigens like S-antigen, IRBP, and rhodopsin have been identified and are capable of inducing uveitis when presented to T cells. Cell adhesion molecules are also involved in uveitis by

2.  The immune system is the result of several cell
types,
 lymphocytes (T and B cells),
 macrophages,
 polymorphonuclear cells.
 dendritic cells
 ocular resident cells in the eye

3. Macrophages/monocytes
 The presence of esterase is a useful marker
to distinguish macrophages from
granulocytes and lymphocytes.
 Macrophages play major roles within the
immune system.
 destroy foreign pathogens as well as clearing
dying or diseased tissue.
 Killing of invading microbes is in part
mediated by a burst of hydrogen peroxide
(H2O2) activity by the activated macrophage.

4.  activate the immune system.
 antigen-specific activation ofT lymphocytes.
 macrophage is often described as an antigen-
presenting cell (APC). Other cells, such as B cells,
can also serve this function.

5.  the macrophage is a potent secretory cell.
Proteases can be released in abundance,
which can degrade vessel surfaces and
perivascular areas.

6.  Macrophages produce IL-12 and IL-18 IL-10,
and transforming growth factor (TGF)-β.

 the production of IL-12 by the macrophage
plays an important role inT-cell activation

7. Dendritic cells
 They are a subset of cells, perhaps of different
lineage from macrophages, from which they can be
distinguished by a lack of persistent adherence and
by the bearing of an antigen on their surface,
features that macrophages do not possess.
 The major role of dendritic cells is to serve as
initiators ofT-cell responses, for both CD4+ and
CD8+ cells. Like macrophages, dendritic cells
produce IL-12,

9. T cells
 thymocytes mature toT cells they migrate to the
medulla and are ultimately released into the
systemic circulation.
 Some important qualities possessed by these cells
are their immunologic recall
 They also have the capacity to produce cellular
products called cytokines.

11.  Cytokines are produced by lymphocytes and
macrophages, as well as by other cells.
 They are hormone-like proteins capable of
amplifying an immune response as well as
suppressing it.
 With the activation of aT lymphocyte, the
production and release of various
lymphokines will occur. One of the most
important is IL-2.

12. Chemokines
This family of chemoattractant cytokines is
characterized by its ability to induce
directional migration of white blood cells.
They will direct cell adhesion, homing, and
angiogenesis

13. B cells
 .The B cell, under proper conditions, will
develop into a plasma cell that is capable of
secreting immunoglobulin.
 role is to function as the effector cell in humoral
immunity.
 The unique characteristic of these cells is the
presence of surface immunoglobulin on their cell
membranes.

15.  Five major classes of immunoglobulin are
identified on the basis of the structure of their
heavy chains: α, γ, µ, δ, and ε, corresponding
to IgA, IgG, IgM, IgD, and IgE

16. Mast Cells
 This large (15–20 µm) cell is intimately
involved with type I hypersensitivity reactions
. Its most characteristic feature is the
presence of large granules in the cytoplasm

17.  . Mast cells contain a large number of
biologically active agents, including
histamine, serotonin, prostaglandins,
leukotrienes, and chemotactic factors of
anaphylaxis
cytokines and chemokines.

18. Eosinophils
 Defense against parasitic infections
 Defense against intracellular bacteria
 Modulation of immediate hypersensitivity reactions

19. Neutrophils
 Neutrophils are the most abundant type of white
blood cell
 important role in acute inflammation
 main functions is phagocytosis, in particular killing
microbes using reactive oxygen species and
hydrolytic enzymes.

20. Resident Ocular Cells
 several cells of the eye, including RPE and
Müller cells, either have functions similar to
cells within the immune system
 can be induced to bear markers that
potentially permit them to participate in
immune-mediated events.
 RPE, when activated, can act as efficient
APCs.

21. Complement system
 The complement system is a cascade of
soluble proteins that ‘complement’ the
function of antibodies in the immune system.
 complement protein is a proteolytic enzyme
that acts as a substrate for the enzymes that
precede it in the cascade, and which then acts
as a part of a proteolytic

23.  Complement has become an area of special
focus because of its possible role in the
pathogenesis of age-related macular
degeneration (AMD).
 Complement factors have been found in the
drusen of AMD eyes, suggesting that an
immune response may have occurred after
the activation of the complement cascade.
 Several reports have appeared showing an
association between a complement factor H
variant and AMD.

24. Classic immune
hypersensitivity reactions

25. Type II
 This type of reaction is mediated by cytotoxic
antibodies and is thought to mediate hemolytic
disorders, such as blood mismatch reactions and
the scarring seen in ocular pemphigoid

26. PATHOGENESIS
 understanding of the mechanisms of ocular
inflammatory disease will be valuable in choosing the
appropriate therapy for the patient.
 For years the eye was considered to be a ‘privileged’
immune site
 meaning they are able to tolerate the introduction of
antigens without eliciting an inflammatory immune
response

27.  Immune characteristics
of the eye

28. Absence of lymphatic drainage
 Like the brain, placenta, and testes, the eye has
no direct lymphatic drainage
 The environment in which antigen presentation
occurs plays an important role in the type of
immune response the organism may mount.

29. Intraocular microenvironment
Eye has at least four ways to protect itself against
unwanted or nuisance inflammatory processes.
The first is having a barrier such as the blood– ocular
barrier.
The second is the presence of soluble or membrane-
bound inhibitors that block the function of an
organism.
The third strategy is to kill an invading organism or
cell that may be inducing an unwanted
inflammation (by perhaps speeding up apoptosis
or programmed cell death),

30.  the fourth is to devise a method by which a
state of tolerance is induced.
 All of these barriers appear to exist in the eye.

37. Fas-Fas Ligand Interactions
and Apoptosis.
 apoptosis is one method of immune privilege in the
eye.
 Fas ligand (FasL) is a type II membrane protein that
belongs to theTNF superfamily.
 It is found in the eye and can induce apoptotic cell
death in cells that express Fas.
 Fas is part of theTNF receptor family and is found
on lymphocytes.

38.  Organs that appear to be able to limit immune
responses, such as the eye, testes, and brain,
express FasL.

40. Resident Ocular Cells and
Immune System

45.  Müller cells have been shown to have a
profound affect onT cells.
 Müller cells will downregulate the
proliferative capabilities of S-Ag-specificT
cells capable of inducing uveitis.

46.  the RPE has many characteristics of macrophages.
These cells have the capacity to migrate and engulf
particles and have features that strongly suggest a
capacity to participate in the local immune response.

 The RPE has been shown to produce cytokines, the
one of most note to date being perhaps IL-6
 RPE cells, which express MHC class I antigens
constitutively on their surface, can express class II
antigens when activated

47.  Glucocorticoid-inducedTNF-related receptor ligand
(GITRL) is expressed constitutively at low levels on
the RPE (and other ocular cells).
 When GITRL expression is upregulated on RPE cells,
the suppressive effects of the RPE onT-cell
proliferation is stopped.

49. 0 cytokines can be termed ‘proinflammatory’ or
‘immunosuppressive’ in the intraocular milieu
 IL-6 (produced locally), IL-2, and IFN-γ are
perhaps the most important cytokines to be
considered when an intraocular inflammatory
response occurs.
 In autoimmune uveitis, IL-1α, IL-1β, IL-1
receptor antagonist, IL-6, andTNF-α were
highly expressed .

50. Features of choroid

51.  systemic influences can be assumed to rapidly affect
this portion of the eye. Indeed, the relatively large
blood flow and its anatomy would act as a sort of
trap for many bloodborne problems,
 choroid has the capacity to function as a repository
for immunoreactive cells
 center for profound immune responses
 The high concentration of mast cells in the choroid
may be one mechanism by which immunoreactive
cells in the choroid could spread to other parts of
the eye.

52. Uveitogenic antigens
 There are several uveitogenic antigens in the
eye that are capable of inducing disease
 several antigens have been isolated that are
capable of inducing ocular disease
 This number of identifiable antigens capable
of stimulating the immune system makes the
eye unique, and suggests that the concept of
autoimmunity may be an important factor in
ocular disease.

53. Retinal S-Antigen
(Arrestin) The retinal S-Ag is one of the most potent of the
uveitogenic antigens defined to date.
 This intracellular protein is localized to the
photoreceptor region of the retina
 It demonstrate high levels of cross-reactivity
 Arrestin has the ability to mediate rhodopsin-
catalyzed adenosine triphosphate binding and to
quench cyclic guanosine monophosphate
phosphodiesterase (PDE) activation. It will bind to
photoactivated phosphorylated rhodopsin,
preventing the transducin-mediated activation of
PDE.

54. Interphotoreceptor
Retinoid-Binding Protein
(IRBP) second uveitogenic retinal antigen is IRBP
 It is believed to carry vitamin A derivatives
between the photoreceptors and the RPE. It
has four homologous domains.
 It has potent uveitogenic properties, with
disease induction occurring at dosages as low
as 0.3 µg
 The course of the disease in the IRBP-
induced Uveitis is shorter than that seen with
Arrestin

56. Recoverin
 It is a calcium-binding protein that localizes to the
retina and the pineal gland.
 This antigen has been shown to be the target of
antibodies in the cancerassociated retinopathy
syndrome.

58. Bovine Melanin Protein
 Bovine melanin protein is derived from choroid-
containing remnants of adherent RPE.
 anterior uveitis was the prominent aspect of the
disease to be a more constant finding with
choroidal involvement

59. Rhodopsin
 High concentrations of rhodopsin will induce
Arrestin like disease
 Opsin (rhodopsin’s form in the light) seems to be
less uveitogenic than rhodopsin.

61. Phosducin
 It is thought to play a role in the phototransduction
of rods.
 It does not appear to be as potent as some of the
other antigens
 Patchy focal chorioretinal lesions with vitreitis and
retinal vascular involvement have been reported.

62. RPE 65
 RPE 65 is a 61-kDa protein that is found specifically
and abundantly in the RPE. It is associated with the
microsomal fraction of the RPE
 It appears to play an important role in vitamin A
metabolism.
 Mutations of RPE65 have been associated with
Leber congenital amaurosis and retinitis
pigmentosa

63. RPE 65

64. Tyrosinase
 Tyrosine proteins are found in melanocytes.
 Two of these, tyrosinase-related proteins 1 (TRP1)
and 2 (TRP2), have been isolated.
 these antigens induced a severe anterior and
posterior uveitis

65.  The main role in disease progression is by
T cells (T helper ) and IL 2 receptors
 The mast cells in the choroid degranulate just
before the influx ofT cells into the eye, thus
suggesting that these cells ‘open the door’
into the eye for theT cells.
 mastcell degranulation can be induced not
only by IgE antibodies but also byT cells.

66.  During the initial phase of S-Ag-induced EAU,
helperT cells invade the eye, but later on it is
the cytotoxicT subset that predominates .
 The widespread expression of class II antigens
on several resident ocular cells is seen uveitis.

67.  In Anterior uveitis associated with myelin
basic protein , uveitis can be moderate and
the immune response appears to target
myelinated neurons in the iris.
 As with other models, CD4+Th1 cells appear
to mediate this disorder as well.

68. INDUCTION
OF
UVEITIS

70. Cell adhesion molecules and
their role in uveitis
 adhesion molecules are especially important for
directing leukocytes to areas of inflammation.
 The upregulation of CAM expression on the
vascular endothelium and surrounding area allows
inflammatory cells to home to inflamed tissues.
 CAMs are divided into three structural groups:
selectins, integrins, and the immunoglobulin gene
superfamily

71.  selectins are a group of CAMs that appear to
mediate the initial adhesion of inflammatory
cells to the vascular endothelium, leading to a
rolling of the cells along the vascular wall.
 The integrins and members of the
immunoglobulin supergene family then
interact to form a more firm adherence
between the leukocytes and the vascular
endothelium, leading to transendothelial
migration of the cells into the inflamed tissue.

73.  expression of E-selectin was found in eyes
with uveitis .
 CAM expression is important for the
recruitment of leukocytes into eyes with
uveitis
 expression of ICAM-1 (CD54) found on the
corneal endothelium, and the expression of
this cell adhesion molecule also appears to be
important to the development of keratic
precipitates.

74.  major effects of cytokines in the pathogenesis
of uveitis involves the upregulation of
adhesion molecule expression.
 Adhesion molecules are also involved in the
pathogenesis of lens-induced uveitis.
 CAM is expressed in the retina and choroid of
human eyes with posterior uveitis.
 CAMs are involved in the pathogenesis of
inflammation but also that drugs to block
these adhesion molecules should provide
effective therapy for disease.