Transplant Pathology & Amyloidosis - Nelson Flashcards
1
Q
What is an autograph?
A
Self → self
(e.g. skin graft)
2
Q
What is an isograft?
A
Syngeneic
-between identical twins
3
Q
What is an allograft?
A
Graft between genetically different individuals of the same species.
4
Q
What is a xenograft?
A
Graft between two species.
(e.g. pig (porcine) heart valve → human)
5
Q
What is the major barrier to successful transplantation?
A
Rejection
6
Q
What are the two groups of antigens that are most important in determining the likelihood of transplant rejection?
A
- ABO
- HLA
7
Q
What is the process of cellular rejection?
A
- T cell-mediated
- destruction of donated graft cells by recipient CD8+ cytotoxic T lymphocytes
- delayed hypersensitivity reactions triggered by activated recipient CD4+ helper lymphocytes
- due to differences in the highly pleomorphic HLA alleles
8
Q
What is the difference between direct vs. indirect pathways of cellular rejection?
A
- Direct
- activation of CD8+
- kill graft cells
- activation of CD4+
- release cytokines (tissue damage)
- activate macrophages
- activation of CD8+
- Indirect
- activation of CD4+
- release cytokines
- activate macrophages
- activate B-lymphocytes
- production of antibodies
- endothelial injury
- activation of CD4+
9
Q
What is the process of humoral rejection?
A
- Antibodies are produced against alloantigens in the graft
- important mediators of rejection
10
Q
What are the major types of pre-formed alloantibodies?
A
- Pre-formed:
- Antibodies to ABO blood group
- Preformed anti-HLA antibodies
11
Q
What is the rationale of pretransplant testing?
A
- Will affect graft survival:
- ABO compatability
- Assess degree of HLA compatibility
- Detect preformed anti-HLA antibodies in the recipient’s serum
- lymphocyte cross-match
12
Q
What characterizes hyperacute rejection?
A
- Result of ABO incompatibility or preformed anti-HLA antibodies in recipient
- Causes Type II Ab-mediated hypersensitivity reaction
- Begins suddenly, within minutes to hours following transplant
13
Q
What characterizes Acute Rejection?
A
- Result from T-cell mediated hypersensitivity or from antibody-mediated hypersensitivity reactions
- Over days to weeks
14
Q
What characterizes Chronic Rejection?
A
- Over months-years
- Due to secondary vascular injury
- from cell-mediated reactions
- antibody-mediated hypersensitivity reactions
15
Q
What are the key pathologic features of hyperacute rejection in renal allografts?
A
- Endothelial damage
- Platelet and thrombin thrombi
- Neutrophil infiltration
- Severe ischemic injury in glomerulus
- Fibrinoid necrosis
- Vessel thrombosis
16
Q
What are the key pathologic features of acute rejection in renal allografts?
A
- Endotheliitis
- swollen endothelial cells with lymphocytic inflammation
- Tubular damage
17
Q
What are the key pathologic features of acute antibody-mediated (humoral) rejection in renal allografts?
A
- Blood vessel damage
- Thrombosis
- leads to ischemic injury
18
Q
What are the key pathologic features of chronic rejection in renal allografts?
A
- Vessel/vascular injury
- arteriosclerosis
19
Q
What is the most common cause of renal graft failure?
A
Chronic rejection
20
Q
What are two major complications of immunosuppressive therapy in the transplant setting?
A
- Increased susceptibility for opportunistic infections
- CMV, pneumocystis, common community acquired infectious disease
- Increased risk of malignancies
- EBV associated PTLD, squamous cell carcinoma of skin, Kaposi sarcoma
21
Q
What is autologous hematopoietic cell transplantation (HCT)?
A
- auto-HTC
- uses hematopoietic progenitor cells derived from the individual with the disorder
22
Q
What is allogeneic hematopoietic cell transplantation (HCT)?
A
- hematopoietic progenitor cells collected from someone other than the individual with the disorder
23
Q
What are the underlying immunologic mechanisms of graft vs. host disease (GVHD)?
A
- transplanted immunocompetent T-cells from the donor (graft) may recognize the recipient (host) cells as foreign
24
Q
What is the rationale behind HLA matching in allogeneic HCT?
A
to prevent the immunologically competent donor T cells from recognizing the recipient’s (host’s) HLA antigens as foreign
(try to prevent reaction against them - GVHD)
25
What kind of hematopoietic cell transplantation does not/cannot result in GVHD?
Patients undergoing **autologous HCT** do not get GVHD.
26
What is acute GVHD? What are the principle organ systems involved?
* Occurs in the **1st 100 days** following allogeneic HCT
* Direct cytotoxicity by CD8+ T cells and cell injury from cytokines released from CD4+ T cells
* Organ systems: skin, liver, GI tract epithelium
27
What is chronic GVHD? What are the principle organ systems involved?
* Occurring **more than 100 days** after allogeneic HCT
* May follow acute GVHD or occur insidiously
* Skin, liver (jaundice), GI tract, lungs
28
Why are patients undergoing HCT immunodeficient?
* Prior treatment
* Myeloablative therapy in preparation for the graft
* Delay in repopulation (reconstitution) of recipient’s immune system
29
What is amyloidosis?
* Refers to a group of disorders characterized by the deposition of amyloid in the extracellular space of tissues and organs
* resulting in tissue and organ dysfunction
30
What is the characteristic appearance of amyloid in tissue sections?
* Linear, non-branching fibrils
* characteristic **cross-beta-pleated sheet** configuration
31
What special stain is typically used to stain amyloid?
* Congo Red
* pink-red deposits of amyloid in the walls of blood vessels and along sinusoids
* Under polarizing microscope
* amyloid = yellow-apple-green birefringence under polarized light
32
Is amyloidosis a single disease entity, or a group of diseases?
Group of diseases/disorders
33
How does amyloid injure adjacent cells?
* abnormal folding of proteins → become insoluble → aggregate
* **deposit as fibrils in the extracellular space**
* "quality control" mechanisms fail (degradation by proteasomes / macrophages)
* **results in pressure atrophy of adjacent cells**
34
What are the five types of amyloid protein discussed in class?
* AL (amyloid light chain)
* AA (amyloid-associated)
* Beta-amyloid protein (Aß)
* Transthyretin (TTR)
* ß2-microglobulin
35
What are the pathogenic mechanisms involved in the production of AL (amyloid light chain) amyloid protein, including precursor proteins?
* Complete Ig light chains or fragments of light chains
* Monoclonal lambda or kappa free light chain protein
* Secreted by a monoclonal population of plasma cells
36
What are the pathogenic mechanisms involved in the production of AA (amyloid-associated) amyloid protein, including precursor proteins?
* Proteolysis of a larger precursor protein in the serum called SAA (Serum Amyloid-Associated)
* Synthesized in the liver and circulates in serum
* SAA production increased in inflammation - associated with chronic inflammation
37
What are the pathogenic mechanisms involved in the production of Beta-amyloid (Aß) protein, including precursor proteins?
* Proteolysis of a large precursor protein calls Amyloid Precursor Protein
* In cerebral plaques and vessels of Alzheimer disease
38
What are the pathogenic mechanisms involved in the production of Transthyretin (TTR) amyloid protein, including precursor proteins?
* Normal serum protein that binds and transports thyroxine and retinol
* Mutations to Transthyretin result in amyloid deposition
* Due to genetic disorders (heritable neuropathic and/or cardiomyopathic amyloidosis)
* TTR can also be deposited in heart of aged individuals w/o mutation → Aggregation
39
What are the pathogenic mechanisms involved in the production of ß2-microglobulin amyloid protein, including precursor proteins?
* Hemodialysis-Associated Amyloidosis
* Normal serum protein that cannot be filtered through dialysis
40
What is systemic amyloidosis?
* Amyloidosis involving several organ systems
* Primary amyloidosis
* Secondary amyloidosis
41
What is localized amyloidosis?
Involves a single organ
42
What is primary amyloidosis?
Associated with a clonal proliferative disorder of plasma cells producing Lt Ig
43
What is secondary amyloidosis?
Occurs as complication of underlying chronic inflammatory process
44
What is hereditary (familial) amyloidosis?
* Group of heterogenous, heritable forms of amyloidosis with distinct patterns
* Familial Mediterranean Fever - autoinflammatory syndrome with autosomal recessive inheritance, associated with a gene mutation that produces proteins that regulate inflammatory reactions (AA protein)
* Familial Amyloidotic Neuropathies - mutated forms of TTR
45
What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for primary amyloidosis?
* Most common (AL type)
* Monoclonal proliferation of plasma cells → production of monoclonal Ig with monoclonal kappa or lambda free light chain protein (Bence-Jones protein)
* Affected Sites: heart, kidney, peripheral nerve, GI, respiratory tract, other organs
* Can be associated with multiple myeloma
46
What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for reactive systemic amyloidosis (AA amyloidosis, secondary amyloidosis)?
* Amyloid protein is AA type with systemic distribution
* Secondary to chronic inflammatory condition, such as RA
* Can be seen with CT disorders, inflammatory bowel disease, infectious disease, renal cell carcinoma, Hodgkin lymphoma
* Sites affected = kidney, liver, spleen
47
What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for hemodialysis-associated amyloidosis?
* Due to deposition of amyloid derived from beta-2 microglobulin, which accumulates in patients with end-stage renal disease
* Sites Affected: osteoarticular structures
48
What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for age-related (senile) systemic amyloidosis (senile cardiac amyloidosis)?
* Amyloid deposition associated with normal TTR protein
* Heart is typically involved → restrictive cardiomyopathy and arrhythmias
* Inherited mutation in TTR seen in blacks
49
What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for localized (organ specific) amyloidosis?
* Amyloid deposits limited to single organ or tissue
* Examples: nodular deposits in lung, larynx, skin, urinary bladder, tongue, orbit
* Frequently infiltrates of lymphocytes and plasma cells at periphery
50
What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for the amyloidosis associated with Alzheimer disease?
51
What is the pathogenesis of cardiac amyloidosis that can be seen in older adults?
52
What organ systems are most commonly affected by systemic amyloidosis?
* Kidneys
* Heart
* Liver
53
What are some of the key clinical symptoms of systemic amyloidosis?
* Waxy skin and easy bruising
* Enlarged muscles (tongue, deltoids)
* Sx and signs of heart failure
* Cardiac conduction abnormalities
* Hepatomegaly
* Renal dysfunction
* heavy proteinuria
* nephrotic syndrome
* Peripheral and/or autonomic neuropathy
* Impaired coagulation
* acquired factor X deficiency due to this coagulation factor binding to amyloid
54
How is a diagnosis of amyloidosis established? What techniques can be used to determine the type of amyloid that is deposited?
* Tissue Biopsy with staining for amyloid
* Can be directed at the clinically involved organ (kidney, heart)
* Immunohistochemistry or liquid chromatography-mass spectrometry
* Used to determine the type of amyloid present
55
How can amyloidosis be treated?
* Treatment varies with cause of amyloid production:
* Treat underlying infectious or inflammatory disorder in AA amyloidosis
* Treat monoclonal plasma cell proliferation in AL amyloidosis
* Treat with different mode of dialysis or renal transplant in dialysis-related amyloidosis
* Treat with liver transplant in mutant TTR or mutant precursor protein produced in the liver
56
According to Mayo's website, what are the treatment options for Amyloidosis?
* Melphalan and dexamethasone
* High-dose steroids
* Hematopoietic stem cell transplantation
* Clinical trials
* Organ transplantation
