Transcript Systemic Immune Complex Disease The

These may result from:
1. Excessive immune responses
(hypersensitivity reactions)
2. Unwanted or inappropriate immunes
response ( Autoimmune diseases )
3. Inadequate immune responses
(immunodeficiency disease
Hypersensitivity Reactions
The purpose of the immune response is to protect against invasion by foreign organisms,
but they often lead to host tissue damage. An exaggerated immune response that results in
tissue injury is broadly referred to as a hypersensitivity reaction.
Classification:
a. According to Gell and Comb’s classification, hypersensitivity reactions can be divided
into four types (type I, II, III, and IV) depending on the mechanism of immune recognition
involved and on the inflammatory mediator system recruited.
b. Types – I, II, and III reactions are dependent on the interaction of specific antibodies with
the given antigen, whereas, in type IV reactions recognition is achieved by antigen
receptors on T-cells.
a. Type 1 hypersensitivity (IgE)
anaphylactic type
• may be defined as a rapidly developing
immunologic reaction occurring within minutes
after the combination of Ag with Ab (IgE) bond
to mast cells or basophiles in individuals
previously sensitized to the Ag .
• Example of diseases
• Local reaction
– Atopic dermatitis ( acute eczema )
– Allergic rhinitis (Hay fever) often associated with
• Atopic conjunctivitis
• Extrinsic allergic asthma
• Food allergy
• Systemic reaction
– Systemic anaphylaxis e,g, Penicillin, bee
venom
Sequence of events in
immediate (type 1)
hypersensitivity
Immediate hypersensitivity
reactions are
- initiated by the introduction of an
allergen,
- which stimulates TH2 responses &
IgE production.
- IgE binds to Fc receptors on mast
cells,
-& exposure to the allergen
--activates the mast cells to secrete
the mediators that are responsible
for the pathologic manifestations of
immediate hypersensitivity
Ag.
Epithelium
Rexposure
APC
Cross linking
IgE
B-cell
TCR
IL-4
TH2
IgE-A.b.
Mast cell
IL-4,5
1°&2°
Mediators
Activation Release
Granules
eosinophil
Initial
Phase
Late
Phase
1- Vasoactive amine
released from granule
stores :e,g, Histamine,
2-Newly synthesized lipid
mediators e.g,
Prostaglandins & Leukotrienes
3- Cytokines these are
important for the late
phase e.g. TNF &
Chemokines for leukocytes
,IL-4 & IL-5
Thus, type I reactions have two well-defined phases.
a. Initial phase (response):
Characterized by vasodilatation, vascular leakage, and depending on the
location, smooth muscle spasm or glandular secretions.
b. Late phase
As it is manifested for example in allergic rhinitis and bronchial asthma, more
intense infiltration of eosinophiles, neutrophiles, basophilic, monocytes and CD4 + T
cells are encountered and so does tissue destruction (epithelial mucosal
cells).
Mast cells and basophiles are central to the development of Type I reaction.
Mast cells are bone marrow driven cells widely distributed in tissues around
blood vessels, and sub epithelial sites where type I reaction occurs.
Antibody-Mediated Diseases
(Type II Hypersensitivity)
• Antibody-mediated (type II) hypersensitivity disorders are
caused by antibodies directed against target antigens on the
surface of cells or other tissue components.
• The antigens may be normal molecules intrinsic to cell
membranes or extracellular matrix, or they may be adsorbed
exogenous antigens (e.g., a drug metabolite).
• Antibody-mediated abnormalities are the underlying cause of
many human diseases
• Antibodies cause disease by targeting cells for phagocytosis,
by activating the complement system, and by interfering with
normal cellular functions
• The antibodies that are responsible are typically high-affinity
antibodies capable of activating complement and binding to
the Fc receptors of phagocytes
.
Three different antibody-dependent mechanisms are involved in this type of reaction
(i) Complement-dependent reaction
i. Direct lysis:
a) It is effected by complements activation, formation of membrane attack complex (C5 –9)
. This membrane attack complex then disrupts cell membrane integrity by drilling a
Hole.
b) Opsoinization: By C3b, fragment of the complement to the cell surface enhances
Phagcytosis
Examples include red blood cells, leukocytes and platelets disorders: Transfusion reaction;
haemolytic anemia; A; Thrombocytopenia; Certain drug reaction
Antibody-Mediated Diseases
(Type II Hypersensitivity
• Opsonization and phagocytosis .( ADCC) When circulating cells, such
as erythrocytes or platelets, are coated (opsonized) with autoantibodies, with or
without complement proteins, the cells become targets for phagocytosis by
neutrophils and macrophages .
• These phagocytes express receptors for the Fc tails of IgG antibodies and for
breakdown products of the C3 complement protein, and use these receptors to
bind and ingest opsonized particles. Opsonized cells are usually eliminated in the
spleen, and this is why splenectomy is of some benefit in autoimmune
thrombocytopenia and hemolytic anemia .
. Antibody dependent cell - mediated cytotoxicity /ADCC/
􀂾 This type of antibody mediated Cell injury does not involve fixation of complements.
The target cells coated with IgG antibodies are killed by a variety of nonsensitized
cells that have Fc receptors.
􀂾 The non-sensitized cells included in ADCC are monocytes/large granular/ lympholytes
/ Natural killer cells, neutrophils and eosinophils.
􀂾 The cell lysis proceeds without phagocytosis. Example include graft rejection
iii. Antibody-mediated cellular dysfunction
􀂾 In some cases, antibodies directed against cell surface receptors impair or
dysregulated function without causing cell injury or inflammation. For example: In
Myasthenia Gravis, antibodies reactive with acetylcholine receptors in the motor end
plates of skeletal muscles impair neuromuscular transmission and cause muscle
weakness.
􀂾 The converse is noted in Graves disease where antibodies against the thyroid stimulating
hormone receptor on thyroid epithelial cells stimulate the cells to produce
more thyroid hormones.
ii
2` ab dependent cell mediated cytotoxicity (ADCC)
NK receptor
A.g.
Target
cell
FC-receptor
NK
FC-receptor
Target
cell
Macrophage
Cell Lysis Proceed without
Phagocytosis
Antibody-Mediated Diseases (Type II
Hypersensitivity
• Inflammation .Antibodies bound to cellular or tissue antigens
activate the complement system by the "classical" pathway
• Products of complement activation recruit neutrophils and
monocytes, triggering inflammation in tissues, opsonize cells
for phagocytosis, and lyse cells, especially erythrocytes.
• Leukocytes may also be activated by engagement of Fc
receptors, which recognize the bound antibodies
X
Antibody-Mediated Diseases (Type II HSR)
• Antibody-mediated cellular dysfunction
• .Antibodies can stimulate cell function inappropriately. In Graves' disease,
antibodies against the thyroid-stimulating hormone receptor stimulate thyroid
epithelial cells to secrete thyroid hormones, resulting in hyperthyroidism
• In some cases, antibodies directed against cell surface receptors impair or
dysregulate cellular function without causing cell injury or inflammation .In
myasthenia gravis, antibodies against acetylcholine receptors in the motor end
plates of skeletal muscles inhibit neuromuscular transmission, with resultant
muscle weakness.
• Antibodies against hormones and other essential proteins can neutralize and block
the actions of these molecules, causing functional derangements .
3` ab mediated cellular dysfunctions
Myasthenia graves
Graves disease (ab against TSH receptor of thyroid epithelial cells
lead to hyperthyroidism ) . X
3) Type III hypersensetivity / immune complex-mediated
Type III hypersensitivity reaction is induced by antigen-antibody complex that produces
tissue damage as a result of their capacity to activate the complement system. The
antibodies involved in this reaction are IgG, IgM or IgA.
Sources of antigens include:
a. Exogenous origin Bacteria –streptococcus (infective endocarditis) Viruses –Hepatitis B
virus (Polyarteritis nodosa) Fungi – Actinomycetes (farmer’s lung) Parasites –
plasmodium species (glomerulonephritis) Drugs – quinidin (hemolytic anemia) Foreign
serum (serum sickness)
b. Endogeneous origin
Nuclear components (systemic lupus erythematosis) Immunoglobulins (rheumatoid
arthritis) Tumour antigen (glomerulonephritis) Therefore, autoimmune diseases are
hypersensitivity diseases in which the exaggerated immune response is directed against
the self antigens as exemplified by the above three diseases.
c. Type III hypersensitivity (immune complex
mediated )
systemic (serum sickness)
local (arthus reaction)
the pathogenesis of systemic immune complex :
formation of ag-ab complexes in the circulation.
deposition of immune complexes in various tissues
through out the body.
Thus initiating an inflammatory reactions in
various tissues through the body.
Systemic Immune
Complex Disease
The pathogenesis of
systemic immune
complex disease can be
divided into three phases:
(1) formation of antigenantibody complexes in the
circulation and
(2) deposition of the
immune complexes in
various tissues, thus
initiating
(3) an inflammatory
reaction in various sites
throughout the body
Inflammatory reaction
After immune complexes are deposited in tissues acute inflammatory reactions
ensues and the damage is similar despite the nature and location of tissues. Due to
this inflammatory phase two mechanisms operate
i) Activation of complement cascades:
- C-3b, the opsonizing, and -C-5 fragments, the chemotaxins are characterized by
neutrophlic aggregation, phagocytosis of complexes and release of lysosomal
enzymes that result in necrosis.-C3a, C5a – anaphylatoxins contribute to vascular
permeability and contraction of smooth muscles that result in vasodilation and
edema-C5-9 – membrane attack complexes formation leads to cell lysis (necrosis)
ii) Activation of neutrophiles and macrophages through their Fc receptors.Neutorphiles
and macrophages can be activates by immune complexes even in absence of
complements. With either scenario, phagocytosis of immune complexes is effected
with subsequent release of chemical mediators at site of immune deposition and
subsequent tissue necrosis.
Local Immune Complex Disease
( Arthus reaction)
• The pathogenesis of Local
immune complex disease
can be divided into 4 phases:
(1) Deposition of the immune
complexes in vascular wall
(2) Complement activation
(3) Chemotactic attration &
activation of PMNs
)4) an inflammatory reaction
in various sites throughout
the body
Chronic forms of systemic immune complex diseases result from repeated or
prolonged exposure of an antigen. Continuous antigen is necessary for the
development of chronic immune complex disease. Excess ones are most likely to be
deposited in vascular beds.
Clinical examples of systemic immune complex diseases:
Various types of glomerulonephritis
Rhematic fever
Various vasculitides
Systemic lupus erytomatosis
Rheumatoid arthritis
4) Type IV hypersensitivity (Cell-mediated) reaction
Definition: The cell-mediated type of hypersensitivity is initiated by specifically sensitized Tlymphocytes.
It includes the classic delayed type hypersensitivity reactions initiated by
CD4+Tcell and direct cell cytotoxicity mediated by CD8+Tcell. Typical variety of intracellular
microbial agents including M. tuberculosis and so many viruses, fungi, as well as contact
dermatitis and graft rejection are examples of type IV reactions
The two forms of type IV hypersensitivity are:
1. Delayed type hypersensitivity: this is typically seen in tuberculin reaction, which is
produced by the intra-cutaneous injection of tuberculin, a protein lipopolysaccharide
component of the tubercle bacilli.
Steps involved in type lV reaction include
a. First the individual is exposed to an antigen for example to the tubercle bacilli where
surface monocytes or epidermal dendritic (Langhane’s) cells engulf the bacilli and
present it to naïve CD4+ T-cells through MHC type ll antigens found on surfaces of
antigen presenting cells (APC),
b. The initial macrophage (APC) and lymphocytes interactions result in differentiation of
CD4+TH type 1cells
c. Some of these activated cells so formed enter into the circulation and remain in the
memory pool of T cells for long period of time.
d. An intracutanous injection of the tuberculin for example to a person previously
exposed individual to the tubercle bacilli , the memory TH1 cells interact with the
antigen on the surface of APC and are activated with formation of granulomatous
Reactions
2. T-cell mediated cytotoxicity
In this variant of type IV reaction, sensitized CD8+T cells kill antigen-bearing cells. Such
effector cells are called cytotoxic T lymphocytes (CTLs). CTLs are directed against cell
surface of MHC type l antigens and it plays an important role in graft rejection and in
resistance to viral infections. It is believed that many tumour-associated antigens are
effected by CTLs. Two mechanisms by which CTLs cause T cell damage are:
Preforin-Granzyme dependant killing where perforin drill a hole into the cell membrane
with resultant osmotic lysis and granzyme activates apoptosis of the target cells
.FAS-FAS ligand dependant killing which induce apoptosis of the target cells.
A. delayed –type hypersensitivity (DTH)
e.g. tuberculin reaction

B. T-cell-mediated
cytotoxcity
\
here sensitized CD8-T cell
kill antigen bearing target
cells :
1. graft rejection
2.virus infection
3.tumor immunity
T-cell-mediated
cytotoxcity by NK
cell
. Immunologic Tolerance
Immunologic tolerance is a state in which an individual is incapable of developing an
immune response to specific antigens. Self-tolerance refers to lack of responsiveness to an
individual’s antigens. Tolerance can be broadly classified into two groups: central and
peripheral tolerance.
i) Central tolerance
􀂾 This refers to clonal deletion where immature clones of T and B-lymphocytes that bear
receptors for self-antigens are eliminated from the immune system during development
in central lymphoid organs. T cells that bear receptors from self-antigens undergo
apoptosis within/ during the process of T-cell maturation.
ii) Peripheral tolerance
1. Clonal deletion by activation–induced cell death. The engagement of Fas by Fas
ligand co-expressed on activated T-cells dampens the immune response by inducing
apotosis of activated T-cells ( Fas mediated apoptosis)
2. Clonal anergy: Activaton of Ag specific T-cell requires two signals
a). Recognition of peptide Ag wtih self-MHC molecules
b). Co-stimulatory signals such as CD 28 must bind to their ligand called B7-1 and B72 on antigen presenting cells (APC) and if the Ag is presented by cell that do not
bear CD 28 ligand /i.e B7-1 or B7-2/ a negative signal is delivered and the cell
becomes anergic.
iii). Peripheral suppression by T- cell suppressor.
• There are some evidence that peripheral suppression of autoreactivity may be
mediated in part by the regulated secretion of cytokines.
• The CD+ T cells of the TH2 type have been implicated in mediating self-tolerance by
regulating the functions of pathogenic TH1 type cells. Cytokines produced by TH2 T
cell can down regulate autoreactive CD+Th1 by elaborating IL-4, IL-10 and TGF-B.
When normal tolerance of the self antigens by the immune system fails, autoimmune
diseases result.