IMMUNOPATHOLOGY - PowerPoint Presentation

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IMMUNOPATHOLOGY

DR.MAYSEM

LEC.4

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Rejection of Tissue Transplants:

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-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.

 

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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:

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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).

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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

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Hyperacute rejection:

Pre-formed

antidonor

antibodies bind to graft endothelium immediately after transplantation, leading to thrombosis, ischemic damage, and rapid graft failure

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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.

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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.

 

 

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•

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.

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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

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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.

 

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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

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Stem cells

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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 .

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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.

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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.

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-

Acute GVHD

(occurring days to weeks after

transplantation)

causes

epithelial cell necrosis in three principal target organs: liver, skin, and gut.

 

-

Chronic GVH

D

may

follow the acute syndrome or

may

occur

insidiously. The patients develop skin lesions

resembling those of systemic

seclerosis

.

 

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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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THANK YOU

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Amyloidosis

 

 

Amyloidosis

is a disorder characterized by the

extracellular

deposits

of

misfolded

proteins that aggregate to form

insoluble fibrils.

.

 

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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,

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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

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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

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Of the many biochemically distinct forms of amyloid proteins that have been identified,

three

are most common:

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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

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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

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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

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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.

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while

mutant

forms of the protein are deposited in a group

of

hereditary

diseases called

familial amyloid polyneuropathy

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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

.

 

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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.

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On clinical grounds, the systemic, or generalized, pattern is

subclassified

into

primary amyloidosis

and

secondary amyloidosis

.

Also there is Hereditary or familial amyloidosis

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Primary amyloidosis:

Immunocyte

dyscrasias

with amyloidosis

is due to AL-type amyloid; it occurs in 5% to 15% of patients with multiple

myeloma

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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).

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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

.

 

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-

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

feve

r

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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

.

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- Localized Amyloidosis

Sometimes

deposition of amyloid is limited to a single organ or tissue without involvement of any other site in the body.

.

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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

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Endocrine amyloid

-

occurs

in tumors associated with hormone

synthesis; for example, thyroid medullary carcinoma making

procalcitonin

that deposit as amyloid fibrils

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Amyloid of aging

•

occurs

typically in the eighth and ninth

decades

and

is most commonly due to deposition of non-mutant

transthyretin

. Although amyloid distribution is systemic, the dominant involvement is of the heart.

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Amyloid deposits cause tissue injury and impair

normal

function

by causing pressure on cells and tissues. They

do

not

evoke an inflammatory response.

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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

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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.

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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.

 

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