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IHO Week 5 > Diseases of the Immune System 3 - Nelson > Flashcards

Diseases of the Immune System 3 - Nelson Flashcards

1
Q

Define Autograft

A

self-to-self, eg. skin graft

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2
Q

Define Allograft

A

between genetically different individuals of the same species

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3
Q

Define Isograft

A

syngeneic between identical twins

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4
Q

Define Xenograft

A

between two species (pig heart valve in 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

ABO

HLA (HLA-A, HLA-B, HLA-C, and HLA-Dr)

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7
Q

What are the two types of cellular rejection?

A

Direct and Indirect Pathway

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8
Q

Define cellular rejection

A

Donated graft cells are destroyed by recipient’s CD8+ T cells or delayed hypersensitivity rxn triggered by CD4+ T helper cells

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9
Q

Explain the process of the Direct Pathway of cellular rejection.

A

Donor class I and class II MHC antigens on APCs in the graft are recognized by host CD8+ cytotoxic T-Cells and CD4+ helper T-Cells, which produce cytokines (IFN-y) to induce tissue damage by a local delayed hypersensitivity reaction. CD8+ T-Cells respond to graft antigens to kill graft cells.

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10
Q

Explain the process of the Indirect Pathway of cellular rejection.

A

Graft antigens are picked up and processed and displayed on host APCs to activate CD4+ T-Cells with damage the graft by a local delayed hypersensitivity reaction and stimulate B-cells to produce antibodies

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11
Q

What type of antibodies are produced by humoral rejection mediators?

A

Antibodies against alloantigens in the graft

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12
Q

What are the two major types of pre-formed alloantibodies and what type of reaction do they cause?

A

Antibodies to ABO blood group antigens (naturally occurring) and Preformed anti-HLA antibodies (pregnancy, previous transfusion, transplant)
Cause a hyperacute rejection

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13
Q

What is the rationale for pretransplant testing?

A

The key immunologic factors affecting graft survival are ABO compatibility and close matching of HLA loci, along with an absence of preformed anti-HLA antibodies

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14
Q

In order to have the best possible chance for graft survival, what pre-transplant testing is performed?

A

ABO compatibility testing of donor and recipient
HLA typing of donor and recipient → assess degree of HLA compatibility
Detection of preformed anti-HLA Abs in recipient’s serum
React recipient serum to panel of HLA antigens
Perform lymphoctye cross-match (recipient serum against donor lymphocytes)

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15
Q

What is the immunologic mechanism of hyperacute rejection?

A

Result of ABO incompatibility or preformed anti-HLA antibodies in recipient, which binds endothelial antigens, activate complement, and results in vessel thrombi and ischemic necrosis
Causes Type II Ab-mediated hypersensitivity reaction
Begins suddenly, within minutes to hours following transplant

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16
Q

What is the immunologic mechanism of acute rejection?

A

Result from T-cell mediated hypersensitivity or from antibody-mediated hypersensitivity reactions
Over days to weeks
Cellular Rejection: Endotheliitis = swollen endothelial cells

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17
Q

What is the immunologic mechanism of chronic rejection?

A

Over months-years due to secondary vascular injury, from cell-mediated and antibody-mediated hypersensitivity reactions

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18
Q

What are the key pathologic features of hyperacute rejection?

A

Endothelial damage, platelet and thrombin thrombi, early neutrophil inflitration and severe ischemic injury

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19
Q

What are the key pathologic features of acute rejection?

A

Inflammatory cells and tubular damage, injury to vascular endothelial cells

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20
Q

What are the key pathologic features of chronic rejection?

A

Graft arteriosclerosis - vascular lumen replaced by accumulation of smooth muscle cells and connective tissue

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21
Q

What type of rejection is the most common cause of renal graft failure?

A

Chronic Rejection

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22
Q

What are the two major complications of immunosuppressive therapy in the transplant setting?

A

Increased susceptibility for opportunistic infections
(CMV, pneumocystis, common community acquired infectious disease) and Increased risk of malignancies
(EBV associated PTLD, squamous cell carcinoma, Kaposi sarcoma)

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23
Q

What is a hematopoietic cell transplant (HCT)?

A

Administration of Hematopoietic Progenitor cells from any source (bone marrow, peripheral blood, umbilical cord blood)

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24
Q

Define Autologous HCT (Auto-HCT).

A

Hematopoietic progenitor cells derived from the individual with the disorder; no GVHD

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25
Q

Define Allogeneic HCT (Allo-HCT).

A

Hematopoietic progenitor cells collected from someone other than the individual with the disorder

26
Q

Define Graft vs. Host Disease

A

In allogeneic HCT: transplanted T-cells from the donor (graft) recognize the recipient (host) cells HLA antigens as foreign and react to them

Recipient is immunocompromised and incapable of mounting a rxn
Graft lymphocytes are able to attack the host

27
Q

Define Acute Graft vs. Host Disease

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

28
Q

Define Chronic Graft vs. Host Disease

A

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

29
Q

If a malignancy relapses, why might having a graft vs. tumor reaction improve the patient survival?

A

The tumor will have the HLA antigens of the recipient and be recognized as foreign by the donor T-cells of the patient’s new immune system

30
Q

What are the causes of immunodeficiency?

A

1) Prior treatment
2) Myeloablative therapy in preparation for the graft
3) Delay in repopulation (reconstitution) of recipient’s IS

31
Q

What is amyloidosis?

A

A group of disorders characterized by deposition of amyloid in the extracellular space of tissues and organs

32
Q

What is amyloid?

A

A group of pathologic proteins that share similar physical properties

33
Q

What is the characteristic appearance of amyloid in tissue sections?

A

Linear, non-branching fibrils in characteristic cross-beta-pleated sheet configuration
–H&E Stain: amorphous, eosinophilic, hyaline, extracellular substance that can result in pressure atrophy of adjacent cells

34
Q

What special stain is typically used to stain amyloid?

A

Congo-Red stain with green birefringence under polarizing microscope

35
Q

What is the pathogenic mechanism of the production of AL (Amyloid Light Chain) Amyloid?

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 is the pathogenic mechanism of the production of AA (Amyloid-Associated Amyloid?

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 is the pathogenic mechanism of the production of AB (Beta) Amyloid Protein?

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

What is the pathogenic mechanism of the production of Transthyretin (TTR)?

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 is the pathogenic mechanism of the production of B2-Microglobulin (Hemodialysis-Associated Amyloidosis)?

A
  • Normal serum protein that cannot be filtered through dialysis
40
Q

Define Systemic Amyloidosis

A

Involves several organ systems

41
Q

Define Localized Amyloidosis

A

Involves a single organ

42
Q

Define Primary Amyloidosis

A

Associated with a clonal proliferative disorder of plasma cells producing light chain immunoglobulin

43
Q

Define Secondary Amyloidosis

A

Occurs as complication of underlying chronic inflammatory process

44
Q

Define Hereditary (Familial) Amyloidosis

A

Group of heterogenous, heritable forms of amyloidosis with distinct patterns

45
Q

Define Familial Mediterranean Fever

A

Autoinflammatory syndrome with autosomal recessive inheritance, associated with a gene mutation that produces proteins that regulate inflammatory reactions (AA protein)

46
Q

Define Familial Amyloidotic Neuropathies

A

Mutated forms of TTR

47
Q

What is the underlying pathogenic mechanism for primary amyloidosis?

A
  • Monoclonal proliferation of plasma cells → production of monoclonal Ig with monoclonal kappa or lambda free light chain protein (Bence-Jones protein)
  • Can be associated with multiple myeloma
  • Monoclonal plasma cell proliferation which produces an abnormal light chain protein
  • Ig secreting B-cell lymphomas (lymphoplasmacytic lymphoma)
48
Q

What is the typical distribution of amyloid deposition for primary amyloidosis?

A

Heart, kidney, peripheral nerve, GI, respiratory tract, other organs

49
Q

What is the underlying pathogenic mechanism for reactive systemic 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
50
Q

What is the typical distribution of amyloid deposition for reactive systemic amyloidosis?

A

Kidney, liver, spleen

51
Q

What is the underlying pathogenic mechanism for hemodialysis-associated amyloidosis?

A

Due to deposition of amyloid derived from beta-2 microglobulin, which accumulates in patients with end-stage renal disease

52
Q

What is the typical distribution of amyloid deposition for hemodialysis-associated amyloidosis?

A

Osteoarticular structures

53
Q

What is the underlying pathogenic mechanism for age-related (senile) systemic amyloidosis?

A

Amyloid deposition associated with normal TTR protein

54
Q

What is the typical distribution of amyloid deposition for age-related (senile) systemic amyloidosis?

A

Heart is typically involved → restrictive cardiomyopathy and arrhythmias

55
Q

What is the underlying pathogenic mechanism for localized (organ specific) amyloidosis?

A

Amyloid deposits limited to single organ or tissue; Frequently infiltrates of lymphocytes and plasma cells at periphery

56
Q

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

A

Nodular deposits in lung, larynx, skin, urinary bladder, tongue, orbit

57
Q

What is the underlying pathogenic mechanism for cardiac amyloidosis?

A

Restrictive cardiomyopathy

58
Q

What organ systems are most commonly affected by systemic amyloidosis?

A

Kidney
Heart
Liver

59
Q

What are some 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
  • Peripheral and/or autonomic neuropathy
  • Impaired coagulation due to binding to factor A
60
Q

How is amyloidosis diagnosed?

A

Tissue Biopsy with staining for amyloid that can be directed at the clinically involved organ (kidney, heart)

61
Q

What techniques can be used to determine the type of amyloid deposited?

A

Immunohistochemistry or liquid chromatography-mass spectrometry

62
Q

How can amyloidosis be treated?

A
  • 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

IHO Week 5 (5 decks)

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