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IHO Week 5 - WLB > Transplant Pathology & Amyloidosis - Nelson > Flashcards

Transplant Pathology & Amyloidosis - Nelson Flashcards

1
Q

What is an autograph?

A

Self → self

(e.g. skin graft)

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2
Q

What is an isograft?

A

Syngeneic

-between identical twins

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3
Q

What is an allograft?

A

Graft between genetically different individuals of the same species.

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4
Q

What is a xenograft?

A

Graft between two species.

(e.g. pig (porcine) heart valve → human)

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5
Q

What is the major barrier to successful transplantation?

A

Rejection

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6
Q

What are the two groups of antigens that are most important in determining the likelihood of transplant rejection?

A
  1. ABO
  2. HLA
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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
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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
  • Indirect
    • activation of CD4+
      • release cytokines
      • activate macrophages
      • activate B-lymphocytes
        • production of antibodies
        • endothelial injury
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9
Q

What is the process of humoral rejection?

A
  • Antibodies are produced against alloantigens in the graft
    • important mediators of rejection
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10
Q

What are the major types of pre-formed alloantibodies?

A
  • Pre-formed:
    • Antibodies to ABO blood group
    • Preformed anti-HLA antibodies
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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
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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
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13
Q

What characterizes Acute Rejection?

A
  • Result from T-cell mediated hypersensitivity or from antibody-mediated hypersensitivity reactions
  • Over days to weeks
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14
Q

What characterizes Chronic Rejection?

A
  • Over months-years
  • Due to secondary vascular injury
    • from cell-mediated reactions
    • antibody-mediated hypersensitivity reactions
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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
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16
Q

What are the key pathologic features of acute rejection in renal allografts?

A
  • Endotheliitis
    • swollen endothelial cells with lymphocytic inflammation
  • Tubular damage
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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
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18
Q

What are the key pathologic features of chronic rejection in renal allografts?

A
  • Vessel/vascular injury
    • arteriosclerosis
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19
Q

What is the most common cause of renal graft failure?

A

Chronic rejection

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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
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21
Q

What is autologous hematopoietic cell transplantation (HCT)?

A
  • auto-HTC
  • uses hematopoietic progenitor cells derived from the individual with the disorder
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22
Q

What is allogeneic hematopoietic cell transplantation (HCT)?

A
  • hematopoietic progenitor cells collected from someone other than the individual with the disorder
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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
Q

What kind of hematopoietic cell transplantation does not/cannot result in GVHD?

A

Patients undergoing autologous HCT do not get GVHD.

26
Q

What is acute GVHD? What are the principle organ systems involved?

A
  • 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
Q

What is chronic GVHD? What are the principle organ systems involved?

A
  • Occurring more than 100 days after allogeneic HCT
  • May follow acute GVHD or occur insidiously
  • Skin, liver (jaundice), GI tract, lungs
28
Q

Why are patients undergoing HCT immunodeficient?

A
  • Prior treatment
  • Myeloablative therapy in preparation for the graft
  • Delay in repopulation (reconstitution) of recipient’s immune system
29
Q

What is amyloidosis?

A
  • 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
Q

What is the characteristic appearance of amyloid in tissue sections?

A
  • Linear, non-branching fibrils
    • characteristic cross-beta-pleated sheet configuration
31
Q

What special stain is typically used to stain amyloid?

A
  • 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
Q

Is amyloidosis a single disease entity, or a group of diseases?

A

Group of diseases/disorders

33
Q

How does amyloid injure adjacent cells?

A
  • 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
Q

What are the five types of amyloid protein discussed in class?

A
  • AL (amyloid light chain)
  • AA (amyloid-associated)
  • Beta-amyloid protein (Aß)
  • Transthyretin (TTR)
  • ß2-microglobulin
35
Q

What are the pathogenic mechanisms involved in the production of AL (amyloid light chain) amyloid protein, including precursor proteins?

A
  • 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
Q

What are the pathogenic mechanisms involved in the production of AA (amyloid-associated) amyloid protein, including precursor proteins?

A
  • 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
Q

What are the pathogenic mechanisms involved in the production of Beta-amyloid (Aß) protein, including precursor proteins?

A
  • Proteolysis of a large precursor protein calls Amyloid Precursor Protein
  • In cerebral plaques and vessels of Alzheimer disease
38
Q

What are the pathogenic mechanisms involved in the production of Transthyretin (TTR) amyloid protein, including precursor proteins?

A
  • 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
Q

What are the pathogenic mechanisms involved in the production of ß2-microglobulin amyloid protein, including precursor proteins?

A
  • Hemodialysis-Associated Amyloidosis
  • Normal serum protein that cannot be filtered through dialysis
40
Q

What is systemic amyloidosis?

A
  • Amyloidosis involving several organ systems
    • Primary amyloidosis
    • Secondary amyloidosis
41
Q

What is localized amyloidosis?

A

Involves a single organ

42
Q

What is primary amyloidosis?

A

Associated with a clonal proliferative disorder of plasma cells producing Lt Ig

43
Q

What is secondary amyloidosis?

A

Occurs as complication of underlying chronic inflammatory process

44
Q

What is hereditary (familial) amyloidosis?

A
  • 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
Q

What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for primary amyloidosis?

A
  • 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
Q

What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for reactive systemic amyloidosis (AA amyloidosis, secondary amyloidosis)?

A
  • 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
Q

What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for hemodialysis-associated amyloidosis?

A
  • Due to deposition of amyloid derived from beta-2 microglobulin, which accumulates in patients with end-stage renal disease
  • Sites Affected: osteoarticular structures
48
Q

What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for age-related (senile) systemic amyloidosis (senile cardiac amyloidosis)?

A
  • Amyloid deposition associated with normal TTR protein
  • Heart is typically involved → restrictive cardiomyopathy and arrhythmias
  • Inherited mutation in TTR seen in blacks
49
Q

What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for localized (organ specific) amyloidosis?

A
  • 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
Q

What is the underlying pathogenic mechanism and typical distribution of amyloid deposition for the amyloidosis associated with Alzheimer disease?

A
51
Q

What is the pathogenesis of cardiac amyloidosis that can be seen in older adults?

A
52
Q

What organ systems are most commonly affected by systemic amyloidosis?

A
  • Kidneys
  • Heart
  • Liver
53
Q

What are some of the key clinical symptoms of systemic amyloidosis?

A
  • 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
Q

How is a diagnosis of amyloidosis established? What techniques can be used to determine the type of amyloid that is deposited?

A
  • 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
Q

How can amyloidosis be treated?

A
  • 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
Q

According to Mayo’s website, what are the treatment options for Amyloidosis?

A
  • Melphalan and dexamethasone
  • High-dose steroids
  • Hematopoietic stem cell transplantation
  • Clinical trials
  • Organ transplantation

IHO Week 5 - WLB (6 decks)

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