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IHO Week 5 > Immune Diseases Lecture 3 > Flashcards

Immune Diseases Lecture 3 Flashcards

1
Q

What is an autograft?

A

Self to self graft (e.g. skin graft from other area of the body)

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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

Between genetically different individuals of the same species.

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4
Q

What is a xenograft?

A

Between two species, e.g. pig (porcine) heart valve to human

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5
Q

What is the major barrier to successful transplantation?

A

Rejection
-Recipients immune system recognizes the graft as being foreign and attacks it. Both cell-mediated immunity and antibody mediated immunity can be involved.

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6
Q

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

A
  • ABO antigens
  • HLA antigens
  • ABO & HLA compatible grafts have a better chance of avoiding rejection.
  • Key HLA involved in rejection: HLA-A, HLA-B, HLA-C, HLA-DR
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7
Q

Where are ABO antigens expressed?

A

Endothelial cells & many epithelial cells

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8
Q

Where are MHC Class I molecules expressed?

A
  • All nucleated cells & platelets, including lymphocytes, hematopoietic cells, epithelial cells and endothelial cells (not on mature RBCs)
  • HLA-A, HLA-B, HLA-C
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9
Q

Where are MHC Class II molecules expressed?

A
  • Antigen presenting cells like macrophages and dendritic cells, B-cells
    ex: HLA-DR
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10
Q

What is the direct pathway of cellular rejection?

A
  1. Donor class I and class II MHC antigens on antigen-presenting cells in the graft are recognized by host CD8+ cytotoxic T cells and CD4+ helper T cells, respectively.
  2. CD4+ cells proliferate and produce cytokines (e.g. IFN-gamma) which induce tissue damage by a local delayed hypersensitivity reaction
  3. CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells.
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11
Q

What is the indirect pathway of cellular rejection?

A
  1. Graft antigens are picked up, processed, and displayed by host APCs.
  2. These APCs activate CD4+ T cells, which damage the graft by a local delayed hypersensitivity reaction and stimulate B lymphocytes to produce antibodies
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12
Q

What is humoral rejection of a graft?

A

Antibodies produced against alloantigens in the graft are important mediators of rejection (humoral rejection). These antibodies may be preformed (present before transplant) or develop following the transplant.

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13
Q

What are the preformed anti-donor (alloantibodies) antibodies?

A
  • Antibodies to ABO blood group antigens (naturally occurring)
  • Preformed anti-HLA antibodies (can be exposed to other individual’s HLA antibodies: pregnancy, previous transfusion, previous transplant)
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14
Q

What is the rationale for pre-transplant testing?

A
  • If preformed antibodies are present, a hyper acute rejection reaction is possible (like when you give an O blood person AB type blood)
  • Antibodies can cause injury via complement-dependent cytotoxicity, inflammation and antibody-dependent cell-mediated cytotoxicity.
  • The 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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15
Q

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

A

Chronic rejection of a kidney allograft

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16
Q

What is the immunologic mechanism of hyper acute rejection?

A
  • Result of ABO incompatibility or preformed anti-HLA antibodies in the recipient, which bind to endothelial antigens, activate complement, and result in vessel thrombi and ischemic necrosis (type II antibody-mediated hypersensitivity reaction).
  • Begins SUDDENLY, within minutes to hours following transplant
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17
Q

What is the immunologic mechanism of acute rejection?

A

Two ways it can occur:

  1. T cell-mediated hypersensitivity reaction: host CD4+ T cells release cytokines, activating host macrophages, and CD8+ T cells.
  2. Antibody-mediated hypersensitivity reaction: host CD4+ T cells release cytokines which promote B-cells to differentiate into plasma cells that produce anti-HLA antibodies that bind to endothelial antigens
    - Acute rejection occurs over DAYS to WEEKS
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18
Q

What is the immunologic mechanism of chronic rejection?

A
  • Occurs over MONTHS to YEARS

- Often secondary to vascular injury, as a result of both cell-mediated and antibody-mediated hypersensitivity reactions

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19
Q

What do you see in hyperacute rejection of a kidney allograft?

A
  • Endothelial damage, platelet and thrombin thrombi, early neutrophil infiltration, and severe ischemic injury in glomerulus.
  • ABO incompatibility or performed anti-HLA antibodies in recipient bind to endothelial antigens and result in recruitment of neutrophils with fibrinoid necrosis and vessel thrombosis. The vascular thrombi can result in acute necrosis of the kidney.
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20
Q

What do you see in acute cellular rejection of a kidney allograft?

A
  • Tubular damage (tubulitis)
  • CD8+ T lymphocytes may injure vascular endothelial cells, causing endotheliitis characterized by blood vessels exhibiting swollen endothelial cells with lymphocytic inflammation
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21
Q

What do you see in acute antibody-mediated (humoral) rejection of a kidney allograft?

A
  • Damage primarily within the blood vessels (endothelial regions)
  • Small vessel damage can cause thrombosis, leading to ischemic injury
  • Deposition of complement breakdown factor C4d can be seen in small vessels and glomeruli
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22
Q

What do you see in chronic rejection of a kidney allograft?

A
  • Changes primarily manifested in vessels
  • Graft arteriosclerosis
  • Vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the vessel intima.
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23
Q

What are the two potential complications of long term immunosuppressive therapy?

A
  1. Increased susceptibility for opportunistic infections (e.g. CMV, pneumocystis) as well as increased susceptibility for common community acquired infectious disease.
  2. Increased risk of malignancies, such as EBV associated post transplant lymphoproliferative disorders (PTLD), squamous cell carcinoma of skin and Kaposi sarcoma.
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24
Q

What is Hematopoietic cell transplantation (HCT)?

A
  • Administration of hematopoietic progenitor cells from any source (bone marrow, peripheral blood, umbilical cord blood) to reconstitute the bone marrow
  • Used to treat: hematologic malignancies, certain non-hematologic malignancies, aplastic anemais, thalassemias, and certain immunodeficiencies
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25
Q

What is autologous HCT (auto-HCT)?

A

-Uses hematopoietic progenitor cells derived from eh individuals with the disorder

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26
Q

What is allogeneic HCT (allo-HCT)?

A

-Uses hematopoietic progenitor cells collected from someone other than the individual with the disorder

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27
Q

What is Graft vs. Host Disease (GVHD)?

A
  • Transplanted immunocompetent T-cells from the donor (graft) may recognize the recipient (host) cells as foreign, thereby initiating a GVH reaction which may lead to GVHD
    1. Immunologically competent donor T cells recognize the recipient’s HLA antigens as foreign and react against them.
    2. The recipient is immunocompromised and the host is incapable of mounting a reaction against the grafted lymphocytes.
    3. This allows the graft lymphocytes to attack the host.
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28
Q

Why are transplants done between and donor and recipient HLA-matched in allogenic HCT?

A

It minimizes complications like GVHD due to HLA mismatch.

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29
Q

What patients do NOT get GVHD (EXAM!!)?

A

Patients undergoing autologous HCT!!

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30
Q

What is acute GVHD?

A
  • Occurs within the first 100 days following allogenic hematopoietic cell transplantation.
  • Mech: direct cytotoxicity by CD8+ T cells as well as cellular injury caused by cytokines released from activated CD4+ T cells.
31
Q

What systems are affected and symptoms are caused by acute GVHD?

A
  • Skin, liver and GI tract epithelium are most affected.

- Severe dermatitis, destruction of small bile ducts with jaundice, and GI tract mucosal ulceration with blood diarrhea

32
Q

What is Chronic GVHD?

A

-Occurs more than 100 days after allogenic HCT, may follow acute GVHD or occur insidiously

33
Q

What systems are affected and symptoms are caused by chronic GVHD?

A
  • Skin exhibits loss of skin appendages with dermal fibrosis
  • Chronic liver disease may result in cholestatic jaundice
  • GI tract by exhibit fibrous strucutres, along with malabsorption and chronic diarrhea
  • Lungs may show obliterative bronchiolitis
34
Q

Why are patients undergoing HCT immunodeficient?

A
  • They are given prior treatment, myeloablative therapy in preparation for the graft, and this can delay the repopulation (reconstitution) of the recipient’s immune system
  • At risk for a variety of opportunistic infections (e.g. Aspergillum, CMV, pneumocystitis, etc.)
35
Q

What is amyloidosis?

A

-A group of disorders characterized by the deposition of amyloid in the extracellular space of tissues and organs, resulting in tissue and organ dysfunction.

36
Q

What are the physical properties of amyloid?

A
  • Linear, non-branching fibrils in a characteristic cross-beta-pleated sheet configuration.
  • This configuration is seen regardless of the chemical composition and results in characteristic staining properties
37
Q

What special stain is typically used for amyloid?

A

Congo red stain. The amyloid exhibits green birefringence in the stain.

38
Q

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

A

Group of diseases having in common the deposition of similar appearing proteins

39
Q

How does amyloid injure adjacent cells?

A

It’s presence (size) can result in pressure atrophy of adjacent cells.

40
Q

What are the five types of amyloid protein?

A
  1. AL (amyloid light chain) amyloid
  2. AA (amyloid-associated) amyloid
  3. Beta-amyloid protein (Abeta)
  4. Transthyretin (TTR)
  5. Beta2-microglobulin
41
Q

What is the pathogenic mechanism and precursor protein for AL (amyloid light chain) amyloid?

A
  • Made up of complete Ig light chains, the amino-terminal fragments of light chains, or both
  • Usually the light chains are made of LAMBDA LIGHT CHAIN and less likely kappa
  • The amyloid is produced from free Ig light chain protein secreted by a monoclonal population of plasma cells (kappa or lambda)
42
Q

What is the pathogenic mechanism and precursor protein for AA (amyloid-associated) amyloid?

A
  • Derived by proteolysis of a larger percursor protein in serum called SAA (serum amyloid-associated) protein
  • SAA is synthesized in the liver and circulated in serum associated with HDL
  • SAA is increased in inflammatory conditions as part of acute phase response
  • Associated with CHRONIC INFLAMMATION
43
Q

What is the pathogenic mechanism and precursor protein for Beta-amyloid protein (Abeta)?

A
  • Derived by proteolysis from amyloid precursor protein

- Found in cerebral plaques as well as in the walls of the cerebral vessels of Alzheimer disease.

44
Q

What is the pathogenic mechanism and precursor protein for Transthyretin (TTR)?

A
  • Normal serum protein that binds and transports thyroxine and retinol
  • Mutations in TTR cans cause amyloid deposition
  • Disorders associated with this are called heritable neuropathic and/or cardiomyopathic amyloidosis
  • TRR can be deposited in heart of aged individuals (as part of senile systemic amyloidosis) without mutation of TTR
45
Q

What is the pathogenic mechanism and precursor protein for Beta2-microglobulin?

A
  • This normal serum protein cannot be filtered through dialysis membranes and can accumulate in patients on long term dialysis (>20 years)
  • Condition called: Hemodialysis-associated Amyloidosis
46
Q

What is systemic amyloidosis?

A

(generalized) Involving several organ systems

47
Q

What is localized amyloidosis?

A

Involving a single organ (e.g. heart)

48
Q

What are the two subclasses of systemic amyloidosis?

A
  • Primary amyloidosis

- Secondary amyloidosis

49
Q

What is primary amyloidosis?

A

Systemic amyloidosis associated with a clonal proliferative disorder of plasma cells producing light chain Ig.

50
Q

What is secondary amyloidosis?

A

Systemic amyloidosis that occurs as a complication of an underlying chronic inflammatory process.

51
Q

What is hereditary or familial amyloidosis?

A

It refers to a group of heterogenous, heritable forms of amyloidosis with several distinctive patterns of organ involvement.

52
Q

What amyloid type is associated with Primary Amyloidosis?

A

-Amyloid protein is of the AL type, usually systemic deposition

53
Q

What is the most common form of amyloidosis in the USA?

A

Primary Amyloidosis

54
Q

What are the causes of primary amyloidosis?

A
  • Typically associated with monoclonal proliferation of plasma cells
  • Some cases associated with multiple myeloma (5-15% of MM patients get amyloidosis/tumor masses)
  • Ig secreting B-cell lymphomas (e.g. lymphoplasmacytic lymphoma) may also cause primary amyloidosis
55
Q

What sites are usually affected in primary amyloidosis?

A

-Heart, kidney, peripheral nerve, GI tract, respiratory tract, but any another other organ could be involved

56
Q

What do you use to detect monoclonal immunoglobulin in multiple myeloma?

A
  • Protein electrophoresis (serum and urine)
  • Monoclonal Ig as well as monoclonal kappa or lambda free light chain protein (light chain without the heavy chain, known as Bence-Jones protein). In some cases only monoclonal kappa or lambda free light chain protein is secreted – this is what protein electrophoresis detects.
57
Q

What is Reactive Systemic Amyloidosis?

A

-a.k.a. AA amyloidosis, Secondary Amyloidosis, Second most common type of amyloidosis in the USA

58
Q

What protein is associated with Reactive Systemic Amyloidosis?

A

AA type, systemic distribution

59
Q

What sites in the body are commonly affected in Reactive Systemic Amyloidosis?

A

-Kidney, liver and spleen

60
Q

What diseases are associated with Reactive Systemic Amyloidosis?

A
  • Chronic inflammatory conditions like RA (rheumatoid arthritis - most common cause of 2ndary amyloidosis in USA, 3% of RA patient have it)
  • Can be seen with other connective tissue disorders (ankylosing spondylitis)
  • Inflammatory bowl disease
  • Developing world: most common cause of amyloidosis - chronic inflammation associated with infectious disease (e.g. TB, leprosy, osteomyelitis)
  • Can be seen with renal cell carcinoma and Hodgkin lymphoma
61
Q

What type of amyloid deposition is associated with Hemodialysis-Associated Amyloidosis?

A

-This is due to deposition of amyloid derived from beta-2 microglobulin

62
Q

In what types of patients does beta-2 microglobulin accumulate in?

A
  • Patient with end-stage renal disease who are being maintained for prolonged periods of time by dialysis.
  • This disorder tends to target osteoarticular structures
63
Q

What type of amyloid deposition is associated with age-related (senile) systemic amyloidosis?

A

Amyloid deposition associated with normal (wild-type) TTR protein.

64
Q

What types of patients is age-related (senile) systemic amyloidosis associated with?

A
  • Individuals with advanced age (70s and 80s)
  • Heart is typically involved, resulting in restrictive cardiomyopathy and arrhythmias
  • Significant renal involvement
  • Was once known as senile cardiac amyloidosis
65
Q

What is localized amyloidosis?

A
  • Amyloid deposits limited to a single organ or tissue without involvement of other tissues or sites
  • Frequently there are infiltrates of lymphocytes and plasma cells at the periphery of the amyloid
  • Some of these cases are associated with AL amyloid, and may be localized forms of plasma cell or lymphocyte derived amyloid
66
Q

Where can localized amyloidosis occur?

A

-Some examples include nodular deposits of amyloid in the lung, larynx, skin, urinary bladder, tongue and orbit

67
Q

What amyloidosis is associated with Alzheimer’s Disease?

A

Beta-amyloidosis - production and deposition of beta-amyloid peptide

68
Q

What organ systems are most commonly affected by systemic amyloidosis?

A
  • Major sites of clinically important deposition are in the kidneys, heart and liver
  • In some disorders, amyloid deposition is limited to one organ
69
Q

What are the key clinical symptoms with systematic amyloidosis?

A

-Waxy skin, easy bruising, enlarged muscles (e.g. tongue, deltoids), symptoms and signs of heart failure, cardiac conduction abnormalities, hepatomegaly, renal dysfunction (heavy proteinuria or the nephrotic syndrome), peripheral and/or autonomic neuropathy, impaired coagulation (acquired factor X deficiency due to this coagulation factor binding to amyloid)

70
Q

How is amyloidosis diagnosed?

A
  • Tissue biopsy with staining for amyloid
  • Biopsy can be directed at a suspected clinically involved organ (e.g. kidney, nerve) or a clinically uninvolved site if systemic disease is suspected
  • In patients who might have systemic disease, fat pad aspiration (e.g. abdomen) or rectal biopsy may be performed
  • Fat pad aspiration is less likely to result in blooding complications (fat pad sensitivity is 57-85%)
71
Q

What techniques are used to determine the type of amyloid that is deposited in amyloidosis?

A

Immunohistochemistry or liquid chromatography - mass spectrometry

  • Can be performed on tissue to determine what type of amyloid is present (AL, AA, TTR)
  • Not all patients with monoclonal light chain protein detected on protein electrophoresis (serum or urine) have amyloidosis
72
Q

How can amyloidosis be treated?

A

Treatment varies with cause of amyloid production.

  1. In AA amyloidosis - therapy aimed at underlying infectious or inflammatory disorder
  2. In AL amyloidosis - therapy aimed at underlying monoclonal plasma cell proliferation
  3. Dialysis-related amyloidosis - therapy aimed at either altering the mode of dialysis or considering renal transplantation in patients with dialysis-related amyloidosis
    - -For some hereditary forms in which mutant precursor protein is produced in the liver (e.g. mutant TTR), liver transplantation can be considered
73
Q

What is the best type of bone marrow donor?

A

Sibling!

IHO Week 5 (7 decks)

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