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IMMUNOPATHOLOGY
DR.MAYSEM
LEC.4
Rejection of Tissue
Transplants:
-Allografts transplantation of organs from
one individual to another of the same
species.
Rejection is a complex phenomenon
involving both cell- and antibody-mediated
reactions that destroy the graft.
Immune Recognition of Allografts
 Rejection of allografts is a response
mainly to MHC molecules.
 There are two main mechanisms by
which the host immune system
recognizes and responds to the MHC
molecules on the graft:
1.Direct pathway: Host T cells recognize
donor HLA on antigen presenting cell s
(APC) derived from the donor.
2.Indirect pathway: Host T cells
recognize donor HLA after
processing and presention on host APC
(analogous to any other
exogenous processed antigen).
Effector Mechanisms of Graft
Rejection

• Direct cytotoxic T cell (CTL-) mediated parenchymal and
endothelial cytolysis
• Macrophage-mediated damage
• Cytokine-mediated vascular and parenchymal dysfunction
• Microvascular injury also causes downstream tissue
ischemia
• Antibody-mediated responses can also be important; these
tend to induce injury to endothelial cells rather than
parenchymal cells
Hyperacute rejection:
 Pre-formed antidonor antibodies
bind to graft endothelium
immediately after
transplantation, leading to
thrombosis, ischemic damage,
and rapid graft failure
 Hyperacute rejection occurs when the
recipient has been previously sensitized to
graft antigens (e.g., by blood transfusion or
pregnancy). Preformed, circulating
antibody binds to graft endothelial HLA
with an immediate (minutes to days)
complement- and antibody -mediated injury.
Acute Rejection
Acute rejection typically occurs
within days or months of
transplantation or after cessation
of immunosuppressive therapy.
Both cellular and humoral
mechanisms can contribute.
• Acute cellular rejection T cells destroy graft parenchyma
(and vessels) by cytotoxicity and inflammatory
reactions.
• Acute humoral rejection (rejection vasculitis) is
mediated by newly synthesized (not preformed) anti-donor
antibodies that cause a necrotizing vasculitis with
consequent thrombosis.
Chronic Rejection
Chronic rejection occurs over 
months to years and is characterized
by progressive organ dysfunction.
Dominated by arteriosclerosis, this
type is probably caused by T cell
reaction and secretion of cytokines
that induce proliferation of vascular
smooth muscle cells, associated
with parenchymal fibrosis
Transplantation of Hematopoietic Stem
Cells(HSC)
Hematopoietic stem cell (HSC)
transplantation is used as therapy for:
1. hematopoietic malignancies.e.g.
leukemia and some non hematopoietic
malignancies
2.aplastic anemias,
3. certain inherited disorders e.g. immune
deficiency states and severe forms of
thalassemia.
Sources of Hematopoietic Stem
Cells for Transplantation:
1.from donor bone marrow,
2. from the peripheral blood.
3. from the umbilical cord blood of
newborns, a readily available rich source
of HSCs
Stem cells
 The recipient receives chemotherapy
and/or irradiation to destroy
malignant cells (e.g., in leukemia)
and to create a graft bed; then, HSCs
are infused into the peripheral blood,
from which they home to bone
marrow .
 Rejection of allogeneic HSC
transplants seems to be mediated by
some combination of host T cells
and NK cells that are resistant to
radiation therapy and chemotherapy.
Major problems complicate this form
of transplantation:
1.graft-versus-host disease(GVHD) :
This occurs when immunologically
competent T cells (or their precursors)
are transplanted into recipients who are
immunologically compromised.
-Acute
GVHD (occurring days to weeks after
transplantation) causes epithelial cell
necrosis in three principal target organs:
liver, skin, and gut.
-Chronic GVHD may follow the acute
syndrome or may occur insidiously. The
patients develop skin lesions
resembling those of systemic seclerosis.
2. Immune Deficiencies. These are often of
prolonged duration in recipients of HSC
transplants. Recipients are susceptible to a
variety of infections, mostly viral, such as
cytomegalovirus (CMV) and EBV infections.
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Amyloidosis
Amyloidosis is a disorder characterized by
the extracellular deposits of misfolded
proteins that aggregate to form
insoluble fibrils.


.
Pathogenesis of Amyloidosis :
 Normally, misfolded proteins are
degraded intracellularly in
proteasomes, or extracellularly by
macrophages. It appears that in
amyloidosis, these quality control
mechanisms fail,
 allowing the misfolded protein to
accumulate outside cells. Misfolded
proteins often are unstable leading to the
formation of oligomers and fibrils that are
deposited in tissues
Proteins that form amyloid are
either:
• Normal proteins that have a propensity to
fold improperly and associate to form fibrils;
over-production (or defective catabolism)
thus leads to deposition.
• Mutant proteins that are prone to misfolding
and aggregation; even “normal” levels of
synthesis can cause deposition
 Of the many biochemically distinct
forms of amyloid proteins that have
been identified, three are most
common:
1• The AL (amyloid light chain)
protein
 is produced by plasma cells and is
made up of complete immunoglobulin
light chainsor the amino-terminal
fragments of light chains, or both.
The deposition of amyloid fibril protein 
of the AL type is associated with some
form of monoclonal B cell proliferation
2.The AA (amyloid-associated)
fibril
 derived from a larger serum precursor
called SAA (serum amyloid-associated)
protein that is synthesized in the liver
under the influence of cytokines that
are produced during inflammation;
thus, long-standing inflammation leads
to elevated SAA levels, and ultimately
the AA form of amyloid deposits
3.β-Amyloid (Aβ):
A peptide that forms the core of
cerebral plaques and deposits within
cerebral vessel walls in Alzheimer
disease; it derives from a
transmembrane amyloid precursor
protein
Other less-common forms of
amyloid:
• Transthyretin (TTR): A normal serum
protein that binds and transports
thyroxine and retinol.
Excess amounts of normal TTR can
deposit in hearts in senile systemic
amyloidosis.
while mutant forms of the protein are
deposited in a group of hereditary
diseases called familial amyloid
polyneuropathy
β2-microglobulin:
component of class I HLA molecules
and a normal serum protein; it is
deposited in a form of amyloidosis
that complicates long-term
hemodialysis.
Classification of Amyloidosis
Amyloid may be:
1.systemic (generalized), involving
several organ systems, or
2.localized, when deposits are limited to
a single organ, such as the heart.
 On clinical grounds, the systemic, or
generalized, pattern is subclassified
into primary amyloidosis and
secondary amyloidosis .
Also there is Hereditary or familial
amyloidosis
Primary amyloidosis: Immunocyte
dyscrasias with amyloidosis
is due to AL-type amyloid; it occurs in
5% to 15% of patients with multiple
myeloma
Reactive secondary amyloidosis
This is due to AA-type amyloid.
Secondary amyloidosis is associated
with chronic inflammatory
states (e.g., rheumatoid arthritis,
scleroderma, bronchiectasis, chronic
osteomyelitis), and non-immunocyte
tumors (e.g., Hodgkin lymphoma
and renal cell carcinoma).
Hemodialysis-associated
amyloidosis:
 In patients on chronic hemodialysis.
 -due to deposition (in joints,
synovium, and tendon sheaths) of
 β2-microglobulin not filtered by
normal dialysis membranes.

- Familial (Hereditary) Amyloidosis
A variety of Rare familial forms of
amyloidosis have been Described.
The best-characterized is an autosomal
recessive condition called familial
Mediterranean fever
characterized by attacks of fever 
accompanied by inflammation of serosal
surfaces, including peritoneum, pleura,
and synovial membrane. This disorder is
encountered largely in persons of
Armenian, Sephardic Jewish, and Arabic
origins .
- Localized Amyloidosis
 Sometimes deposition of amyloid is
limited to a single organ or tissue
without involvement of any other site in
the body.
. 
The deposits may produce grossly 
detectable nodular masses or be evident
only on microscopic examination.
Nodular (tumor-forming) deposits of
amyloid are most often encountered in
the lung, larynx, skin, urinary bladder,
tongue, and the region about the eye
Endocrine amyloid
-occurs in tumors associated with
hormone
synthesis; for example, thyroid medullary
carcinoma making
procalcitonin that deposit as amyloid
fibrils
Amyloid of aging
 • occurs typically in the eighth and
ninth decades and is most
commonly due to deposition of nonmutant transthyretin. Although
amyloid distribution is systemic, the
dominant involvement is of the
heart.
 Amyloid deposits cause tissue
injury and impair normal
function by causing pressure on
cells and tissues. They do not
evoke an inflammatory
response.
The diagnosis of amyloidosis
1 -Biopsy and subsequent Congo red
staining is the most important tool in
the diagnosis of amyloidosis.
In general, biopsy is taken from the
organ suspected to be involved Rectal
and gingival biopsy specimens
contain amyloid in as many as 75% of
cases with generalized amyloidosis
 Haematoxylin and eosin-stained tissue
: amorphous, acellular, hyaline,
eosinophilic extracellular material
 -Congo red staining: amyloid is
salmon-pink, which produces green
birefringence under cross-polarized
light and is the diagnostic gold
standard.
2. Electrone microscope
3.In suspected cases of AL amyloidosis
and immunoelectrophoresis should be performed.
Bone marrow examination in such cases usually
shows plasmacytosis,
4. Proteomic analysis of affected tissue is now
being
widely used for detection of small amounts of
amyloid
(from fat aspirates) and for definitive identification
of the
type of amyloid.