Download Lec.2 Dr.Maysem M.Alwash Hypersensitivity Reaction s (cont.)

Hypersensitivity Reaction s
(cont.):
Lec.2
Dr.Maysem M.Alwash
2.Antibody-Mediated Diseases (Type
II Hypersensitivity)
is mediated by antibodies against
endogenous antigens present on
cell surfaces or in the extracellular
matrix or adsorbed exogenous
antigens (e.g., a drug metabolite).
Subsequent pathology is a
consequence of three mechanisms:
i.Opsonization and
phagocytosis
ii.Inflammation `
iii. Antibody-mediated
cellular dysfunction.
i.Opsonization and phagocytosis
Antibodies can coat (opsonize)
cells, with or without complement
proteins, and target these cells for
phagocytosis by macrophages,
. The result is depletion of the
opsonized cells.e.g. Autoimmune
hemolytic Anemia, Autoimmune
thrombocytopenic purpura.
i.Opsonization and
phagocytosis
ii. Inflammation Antibodies and
immune complexes may deposit in
tissues or blood vessels, and elicit an
acute inflammatory reaction by
activating complement, or by
engaging Fc receptors of leukocytes.
The inflammatory reaction causes
tissue injury.e.g. Goodpasture
syndrome and pemphigus vulgaris
•
Inflammation
iii. Antibody-mediated cellular
dysfunction.
Antibodies can bind to cell surface
receptors or essential molecules,
and cause functional derangements
either inhibition( e.g myasthenia
Gravis), or unregulated activation(
e.g. Graves disease ) without cell
injury.
Antibody-mediated cellular
dysfunction.
3.Immune Complex Diseases
(Type III Hypersensitivity):
are caused by antibodies binding to
antigens to form complexes that
circulate and deposit in vascular
beds and stimulate inflammation,
typically as a consequence of
complement activation.
-
The antigens in these complexes 
may be exogenous antigens, such
as microbial proteins, or
endogenous antigens, such as
nucleoproteins
Immune complex–mediated 
disease can be either
systemic or local:
A.Systemic Immune
Complex Disease
complexes are formed in the
circulation and are deposited in
several organs.
E.g.
-Acute serum sickness : inoculation of a
large volume of exogenous antigen
-Systemic lupus erythematosus.
-polyarteritis nodosa (response to
infectious agents)
The pathogenesis of systemic immune
complex disease can be divided into three
phases:
(1) formation of antigen– antibody
complexes in the circulation .
(2) deposition of the immune
complexes in various tissues.
(3) an inflammatory reaction in
various sites throughout the body.
-
The antibody classes that induce
such lesions are complement-fixing
antibodies (i.e., IgG and IgM)
.-
Single large antigen exposures tend
to induce acute, self-limited disease
that resolves as the antigen is
eliminated (e.g.,poststreptococcal
glomerulonephritis) ;
repeated or prolonged exposure
leads to chronic, recurrent tissue
injury (e.g.SLE ).
-Histopathologic Lesions :
Inflammation, necrotizing vasculitis
(fibrinoid necrosis)
B. Local Immune Complex
Disease:
-The complexes are formed
and deposited in a specific
site.
Local immune complex
disease is characterized by a
localized tissue vasculitis
and necrosis.
A model of local immune
complex diseases is the Arthus
Reaction(Intracutaneous antigen
injection in previously sensitized
hosts carrying the appropriate
circulating antibody).
4 . Cell–Mediated (Type IV)
Hypersensitivity :
T cell–mediated (type IV)
hypersensitivity is mediated by
antigen specific T lymphocytes and
includes delayed-type hypersensitivity
(CD4+ T) cells and T cell–mediated
cytotoxicity (CD8+ T) cells.
A-Reactions of CD4+ T cells : delayed-type
hypersensitivity and immune inflammation :
This response is largely mediated
by helper CD4+ T cells and can
be of two major types;
responses associated with TH1
CD4+ T cells are predominated by
macrophages, while those driven
by TH 17 cells are characterized by
a greater neutrophil infiltration.
The classic delayed-type 
hypersensitivity (DTH) response is
the tuberculin reaction to
intracutaneous injection of
purified protein derivative (PPD)
derived from the tubercle
bacillus.
Prior tuberculosis infection 
results in circulating PPDresponsive memory CD4+T cells;
subsequent PPD injection into
such an individual leads to the
recruitment and activation of
these cells beginning at 6 to 8
hours and peaking at 24 to 72
hours (the delayed in DTH).
Granulomatous
inflammation
occurs when persistent or
nondegradable antigens (e.g.,
foreign bodies) lead to chronic
macrophage activation manifesting
as large epithelioid cells; nodules
of these activated cells are called
granulomas.
Granulomatous inflammation
Contact dermatitis; multiple
sclerosis; type 1 diabetes;
tuberculosis
are examples of a DTH
response
B-Reactions of CD8+ T cells:
cell-mediated cytotoxicity:
Class I MHC molecules bind to
intracellular peptide antigens
and present the peptides to CD8+ T
lymphocytes, stimulating
the differentiation of these T cells into
effector cells called cytotoxic T- cell(
CTLs) .
CTLs play a critical role in
resistance to virus infections and
some tumors and allograft rejection
AUTOIMMUNE DISEASES
Autoimmunity: Immune reactions to
self antigens
Autoimmune diseases
range from those in
which specific immune
responses are directed
against one particular
organ or cell type and
result in localized tissue
damage,
to multisystem diseases
characterized by lesions in
many organs and associated
with multiple autoantibodies
or T cell–mediated reactions
against numerous self
antigens.
In many of the systemic diseases that
are caused by immune complexes and
autoantibodies, the lesions affect
principally the connective tissue and
blood vessels of the various organs
involved.
Therefore, these diseases are often
referred to as “collagen vascular” or
“connective tissue” disorders, even
though the immunologic reactions are
not specifically directed against
constituents of connective tissue or
blood vessels.
Normal persons are unresponsive
(tolerant) to their own (self)
antigens, and autoimmunity results
from a failure of self-tolerance.
- Self tolerance:
refers to a lack of immune
responsiveness one’s own tissue
antigens.
Central Tolerance :
This refers to the process by which T
and B cells that recognize self
antigens are either killed (negative
selection) or rendered harmless
during their maturation in central
(generative) lymphoid organs (i.e., in
the thymus for T cells and in the bone
marrow for B cells).
Peripheral Tolerance
Self reactive cells that escape
central regulatory mechanisms can
be removed or inactivated in the
periphery through one of the
following pathways:
1.Anergy: This term refers to
functional inactivation (rather
than death) of lymphocytes induced
by encounter with
antigens under certain conditions.
2. suppression by regulatory T
lymphocytes,
3. Activation-induced cell death (
apoptosis).
Mechanisms of Autoimmunity:
It is believed that the breakdown of
self-tolerance and development of
autoimmunity result from a
combination of inherited
susceptibility genes, which
influence lymphocyte tolerance,
and environmental factors, such as
infections or tissue injury, that alter
the display of self antigens
-Autoimmune diseases have a
tendency to run in families.
-Several autoimmune diseases are
linked with the HLA locus, especially
class II alleles (HLA-DR, -DQ) e.g.
- Rheumatoid arthritis and HLA DRB1
-Ankylosing spondylitis and
HLA- B*27
-many genetic polymorphisms in (
non - HLA Genes) are associated
with different autoimmune diseases.
e.g. PTPN-22 gene and type I
diabetes and rheumatoid
arthritis.
Microbes may induce autoimmune
reactions by several mechanisms:
-Viruses and other microbes may share
cross-reacting epitopes with self
antigens,This phenomenon is called
molecular mimicry.
.
• Microbial infections with resultant
tissue necrosis and inflammation can
expose self-antigens and activate APCs and
lymphocytes in the tissues.

Autoimmune diseases are , more
common in women than in men.
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