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David's- Renal Exam 2 > Immunology > Flashcards

Immunology Flashcards

1
Q

Define no kidney disease (NKD)

A

=No damage to kidneys.

GFR is more than 60mL/minute per 1.73 m2.

Serum creatinine is stable

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2
Q

Acute Kidney Injury (AKI)

A

Serum creatinine:

  • increases by 50% within 7 days
  • by 0.3 mg/dL within 2 days

Oliguria

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3
Q

Chronic Kidney Disease (CKD)

A

CKD–> Damage to the kidney for more than 3 months.

  • GFR is less than 60 ml/min per 1.73 m2 for more than 3 months
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4
Q

What are risk factors for kidney disease? (6)

A

1. age

2. race

3. genetics

4. HTN

5. DB melitus

6. metabolic syndrome

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5
Q

Disease modifiers for AKI and CKD (what determines if kidney injury is chronic or acute)?

A

1. Severity of the acute kidney injury

2. Stage of the CKD

3. Number of episodes

4. Duration of the acute kidney injury

5. Proteinuria

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6
Q

Outcomes of kidney disease

A

1. Cardiovascular events

2. Kidney events

3. ESRD (end stage renal dz)

4. Disability

5. Diminished quality of life

6. Death

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7
Q

Why is damage to the kidneys so bad?

A

Because kidneys are the majoring filtering organ and even though they only take up 0.5% of our body mass, they receive 20% (1L/mL) of our CO.

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8
Q

Why Is an Ischemic Injury bad in kidney Injury?

A

Ischemic acute kidney injury (AKI) can cause:

  1. Metabolic acidosis
  2. Decrease of ATP–>

Leading to acute renal failure (ARF), an abrupt decrease in kidney function.

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9
Q

Causes of [kidney hypoperfusion, which causes hypoxia] & [AKI]

A

AKI is a result of ischemia (hypoxia), which is most commonly caused by sterile inflammation, not an infection.

Hypoxia can be caused by:

  • Intravascular volume depetion and hypotension
  • Hepatorenal syndrome
  • Renal vascular disease
  • Decreased effective intravascular volume
  • Certain medication
  • Sepsis
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10
Q

The cause of AKI is most often sterile renal inflammation.

What induces sterile renal inflammation?

A

Sterile renal inflammation is induced by intrinics DAMPS.

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11
Q

What are DAMPS?

A

Alarmins are endogenous intracellular structures such as

    1. HMGB1
    1. Uric acid
    1. HSPs
    1. S100 protein
    1. Hylauronans
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12
Q

What causes DAMPS to be released and

how do they initiate immune responses and renal inflammation?

A

[Dying parenchymal kidney cells] or [ECM degradation and remodeling]–> releases DAMPS

  • C-reactive protein (CRP) binds DAMPs –> + complement system via classical path.
  • DAMPS active PRRs, such as toll-like receptors, on immune cells
  • Release inflammatory mediators (such as TNF alpha, IL6, ILB, etc)–>
  • Cause [innate immune responses and renal inflammation].
  • –> Activates leukocytes, cytokines, margination, tissue migration and reduces flow
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13
Q
A
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14
Q

What T-cell is responsible for tissue inflammation during acute kidney injury?

A
  • At earlier stages of AKI, Th17 cells predominate, releasing IL-17–> tissue inflammation
  • At later stages, Th1 cells prevail
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15
Q

What macrophages play a role in AKI and tissue repair?

A
  • AKI–> M1 macrophages
  • Tissue repair–> M2 macrophages
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16
Q

How are M1 macrophages activated during AKI?

A
  • M1 macrophages are induced by PAMPs and DAMPS
  • IFN-y and proinflammatory cytokines cause M1 macrophages to differentiate.
  • During AKI, these cytokines will remain.
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17
Q

How are M2 macrophages activated during tissue repair?

A
    • T cells release IL4 and IL13–> induces M2 macrophages
      • ​M2 macrophages are then controlled by IL10 and TGF-B
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18
Q

Role of Th17 cells in AKI

A

Th17 cells release IL-17, causing renal cells to make [chemokines and other inflammatory mediators]–> recruit neutrophils, monocytes, Th1 cells and Th17 cells.

  • Th17 also secretes CCL20 (macrophage inflammatory protein (MIP-3)–> which will also recruit mononcytes, TH1 and Th17 cells
  • Leads to the progression of immune-mediated kidney damage.
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19
Q

________ has a anti-inflammatory role in AKI

A

Treg cells

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20
Q

What is seen in biopsies from patients with various kidney diseases (such as glomerulonephritis)?

A

Complement proteins and each of the three activation pathways.

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21
Q

What is the role of complement in renal-ischemis-reperfusion injury, inflammation and progression to kidney fibrosis.

A
  • Ischemia-reperfusion injury releases DAMPs and activates the three pathways of the compliment system.
  • –> Forms of the (MAC complex)–> injures kidney by causing apoptosis of epithelial tubular cells
  • –>Cleaves C3 and C5 and release of C3a/C5a–> recruits inflammatory cells and the release of pro-inflammatory cytokines/chemokines and ROS–> intensifies the immune response–> + necrosis and apoptosis
  • –> which activate M1/M2 which leads to fibrosis and fibrotic repair via TGF-B

*

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22
Q

AKI in terms of hypersensitivity reactions

A

When the kidneys are injured, compliment activation occurs

  • downstream of immune complex deposition (type III)
  • antibody-mediated injury (type II).
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23
Q

Components of the immune system cause four types of hypersensitivities. Which types causes problems with kidneys?

A

Type II and Type III

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24
Q

How is Type II hypersensitivity activated and what is an example?

A

IgG and IgM antibodies–> binds to cell-bound antigens–> compliment activation and cell lysis.

An example are patients with glomerular basement membrane (GBM) antibody-mediated GN.

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25
Q

How is Type III hypersensitivity activated and what is an example?

A
  • IgG and IgG bind to soluble antigens–> complexes are deposited in tissues.
  • Complement activation activates [inflammatory mediators & recruits neutrophils]–> releases enzymes that damage tissue.
  • -Can cause post-strep glomerulonephritis.
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26
Q

What is used in end-stage renal disease?

A

Kidney transplantation.

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27
Q

The barrier to transplantation is genetic incompatibility. ____________ is one of the best way to prevent graft rejections.

A

HLA matching

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28
Q

Host vs. graft responses cause the rejection of the transplant. _____________ are the targets for rejection. What are the three types?

A

Histocompatibility antigens

Hyperacute rejection, acute rejection and chronic rejection.

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29
Q
A
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30
Q

-Hyperacute rejection

-Acute rejection

-Chronic rejection

A
  1. Hyperacute rejection- immediate and is due to the antibody
  2. Acute rejection- occurs days to weeks after transplant and is due to T-cells
  3. Chronic rejection- occurs months-years after transplant and is due to vascular trauma, inflammatory products of T-cells and antibodies.
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31
Q

What are graft versus host diseaes (GVHD)? What are the types?

A

Graft versus host reactions- the donor WBCs in the transplating tissue recognize the graft receipient and attack.

GVHD can be acute or chronic

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32
Q

Successful organ transplantation depends on the use of _______________.

A

immunosuppressive drugs

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33
Q

Grafts are classified based on the genetic relationship between the host and the donor. What are the 4 types of grafts?

A

1. Autografts

2. Isografts

3. Allografts

4. Xenografts

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34
Q

What are autografts?

A

Grafts exchanged from one part–> another part of the same person.

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35
Q

What are isografts?

A

Grafts echanged between different individials with the same genetics (identical twins).

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36
Q

What are allografts?

A

Grafts exhcanged between non-identical members of the same species.

37
Q

What are xenografts?

A
  • Grafts exchanged between members of different species.
  • These are, however, susceptibile to rapid attack from naturally occuring antibodies and complement.
  • Inserting human genes into the donor–> increases change of survival.
38
Q

What are the characterstics of graft rejection?

A
  1. -Prior exposure to donor MHC molecules leads to accelerated graft rejection (indicating memory and specificity)
  2. -Depletion or inactivation of T lymphocytes by drugs or Abs leads to reduced graft rejection (indicating mediation by T cells)
  3. Lymphocytes can transfer the ability to reject a graph rapidly from a naive person–> sensitized ( d/t lymphocytes)
39
Q

What are the 4 key concepts in transplantation that determine the outcome of the transplant?

A
  1. Condition of the allograft.
  2. Antigenic disparity between the donor and host.
  3. Strength of the host anti-donor response
  4. Immunosuppressive regimen
40
Q

The condition of the allograft is a non-immunological factor that can determine the outcome of the transplant.

What can happen with the graft is damaged?

A
  • Damaged graft tissue (either due to mechanical trauma or ischemia-reperfusion) transplanted –> releases mediators that damage tissue.
    • Such as:
      1. [Clotting cascade] makes fibronopeptide–> + vascular permeability and attracts neutrophils and macrophages
      2. [Kinin cascade] makes bradykinin–> vasodilation, SM contraction & + vascular permeability
  • These proinflammatory responses–> hyperacute allograft rejection.
41
Q

ABO incompatible kidney transplantation (ABOi‐KT ) was previously considered to be a [absolute contraindication] for patients with ESKD due to hyperacute rejection. Is this still true?

A

No.

  • ABO is only a barrier to transplantation of solid organs without immunosuppression.
  • ABO matching is not important for
    • corneal transplants
    • heart valve transplants
    • bone and tendon grafts
  • ABO imcompatibility is not a contraindication for stem-cell transplants.
42
Q

Type A blood

Abs present:

Antigens present:

Donor can be:

A

Abs present: Anti-B

Antigens present: Ag A

Donor can be: A or O

43
Q

Type B blood

Abs present:

Antigens present:

Donor can be:

A

Abs present: Anti-A

Antigens present: Ag B

Donor can be: B or O

44
Q

Type AB blood

Abs present:

Antigens present:

Donor can be:

A

Abs present: None

Antigens present: A and B antigens

Donor can be: A, B, AB, O

45
Q

Type O blood

Abs present:

Antigens present:

Donor can be:

A

Abs present: Anti-A/B

Antigens present: None

Donor can be: O

46
Q

Antibody + complement–>

A

MAC

47
Q

Matching donor and recipient involves testing for ________________.

A

Pre-existing non-ABO antibodies (anti-class I/II HLA antibodies).

(aka HLA matching)

This is not important for transplants that are non-vascularized (cornea, heart valve and bone).

48
Q

How Do Pre-existing Abs Appear?

A
  • pregnancy induced HLA sensitization leads to being able to detect anti-HLA class I/II Abs in humans
  • Screning test was done to detect anti-HLA class I and class II antibodies.
  • 49.3% were + in the screening (52.9% for class I and 61.7 for class II antibodies.
49
Q

How does donor matching (testing for pre-existing anti-class I/II HLA abs) occur (generally)?

A
  1. Recipients serum is added to the donor cells.
  2. Antibodies in the recipient’s serum bind to donor cell.
  3. Complement is added, forming the MAC.
  4. MAC forms pores in the cells
  5. Dye is then added
  6. If preformed antibodies are present, dye accumulates in the cells.
50
Q

Describe the HLA system in reference to transplantation.

A
  • Because of the differences of HLAs, successful transplantation depends on matching HLA antigens, which are encoded with MHC HLA class-1 and class-2.
51
Q
  • HLA antigens are co-dominantely expressed.
  • Which HLA antigens are strong barriers to transplantation?
  • Which are the three most important for transplantation pairs of the HLA class II antigens:
A
  • Which HLA antigens are strong barriers to transplantation? class I HLA antigens (A and B)
  • Which are the three most important for transplantation pairs of the HLA class II antigens: HLA-DR, HLA-DP, HLA-DQ (class 2)
52
Q

Microtoxicity Test for Class I HLA Typing: Match

A
  1. Donor Cell + Recipient Cell + add the anti-antibodies –>
  2. Abs bind HLA-A3 Ag on both donor and recipient cells –>
  3. Add complement –> MAC complex–> forms pores
  4. Add dye –>
  5. Dye accumulated in both donor and recipient cells –>
  6. Result: HLA Ag identical
  7. GOOD MATCH :)
53
Q

Microtoxicity Test for Class I MHC Typing: No Match

A
  1. Donor Cell + Recipient Cell + Anti-HLA-A7 Abs (example) –>
  2. Abs bind HLA-A7 Ag on donor cell but not recipient cell –>
  3. Add complement –> MAC complex–> forms pores
  4. Add dye
  5. Dye accumulates in donor cells but not recipients
  6. Result: HLA Ag is NOT identical= no match :(
54
Q

How to determining Class I MHC match

A

Multiple donors are tested against the recipient, and the one that contains the same HLA Ag profile will be used for transplantation

55
Q

MATCHING DONOR AND RECIPIENT: Testing for class II HLA compatibility is called ____________-

A

Mixed Lymphocyte Reaction (MLR)

56
Q

Mixed Lymphocyte Reaction for Class II HLA typing

A

Mix lymphocytes from 2 unrelated people

The donor cells is exposed to radiation, but does not proliferate. Instead, they present their antigens.

57
Q

Mixed Lymphocyte Reaction for Class II HLA typing: No Match

A
  1. Donor cells are exposed to radioactivity and then mixed with recipients cells.
  2. H+ thymidine is then added.
  3. Radioactivity is incorperated into the recipients DNA and there is recipient cell proliferation
  4. Result: Recipient cells do NOT share class II MHC of donor= no match
58
Q

Mixed Lymphocyte Reaction for Class II HLA typing: Match

A
  1. Donor cells are exposed to radioactivity and then mixed with recipients cells.
  2. H+ thymidine is then added.
  3. Radioactivity is NOT incorperated into the recipients DNA and there is NO recipient cell proliferation
  4. No reaction/No radiation –> GOOD FOR TRANSPLANTATION :): Recipient cells share class II MHC of donor
59
Q

What are the immune events involved in allograft rejection?

A
  1. APCs –> CD4+ and CD8+ T-cells
  2. Develop local and system immune responses
  3. Cytokines recruit and activate immune cells
  4. Specific T-cell, NK cell or macrophage-mediated cytotoxicity occur
  5. Allograft is rejected
60
Q

What are the two types of immune responses in transplantation?

A
  1. Host-versus-graft disease (kidney is transplanted and the recipients T-cells attack the transplant).
  2. Graft-versus-host disease (bone marrow is transplanted and the T-cells in the transplant attack the recipients tissues).
61
Q

Host-Versus-Graft (HVG) Disease

A

Host’s immune systems (t-cells) will attack the graft via an adaptive immune response. The immune response to a graft is worse than to a pathogen because T-cells think its forein

62
Q

Immune and non-immune factors that influence HVG disease

A
  1. Immune memory of previous encounters with donor Ags–> causes a second graft will be rejected more rapidly)
  2. Non-immune injury to the graft: Danger signals (DAMPS) activate endothelial cells –> cause T cells to enter the allograft–> interact with APC and become activated–> inflammatory cytokine/chemokine field is created, causing increase activation of APC, endothelium and leukocytes.
63
Q

Effector mechanisms of HVG disease

A

Inflammatory cytokine/chemokine field is created and causes further activation of APCs, endothelium, and leukocyte traffic

  • 1) Humoral rejection via Th2 production of IL-4, IL-5, and IL-10
  • 2) Cellular rejection via Th1 production of IL-2 and IFN-gamma
64
Q

List types of graft rejection

A
  • *1) Hyperacute
    2) Accelerated
    3) Acute
    4) Chronic**
65
Q

Hyperacute Graft Rejection: Onset

A

Minutes to hours

66
Q

Hyperacute Graft Rejection: Cause

A

Caused by: Type 2 hypersensitivity. Preformed antibodies are present against the donor due to

  • 1) ABO blood group incompatibility
  • 2) Recipient sensitized to the donor MHC by previous transplants, multiple blood transfusions, or pregnancy
  • 3) Abs bind to the endothelial cells which activates the classical pathway of complement activation, which can leads to death of the endothelium
67
Q

Hyperacute Graft Rejection: Mechanisms

A

Humoral +++, Cellular -

68
Q

Hyperacute Graft Rejection: Results

A
  1. Complement activation
  2. Endothelial damage
  3. Inflammation
  4. Thrombosis
69
Q

Accelerated Graft Rejection: Onset

A

Days

70
Q

Accelerated Graft Rejection: Cause

A

Reactivation of sensitized T cells

71
Q

Accelerated Graft Rejection: Mechanisms

A

Humoral ++, Cellular +

72
Q

Acute Graft Rejection: Onset

A

Days to weeks

73
Q

Acute Graft Rejection: Cause

A
  • Donor DCs (passenger leukocytes) migrate to the LN that drain the organ and cause a primary recipient response.
  • Once activated, T-cells migrate to the organ and cause tissue damage by
    • Making cytotoxic T cells
    • Causing delayed-type hypersensitivity reactions
    • —Most common: CD4 and CD8—
    • Type 4 hypersensitivity
74
Q

What type of T-cells can cause graft rejection?

A

CD4 and CD8

75
Q

Chronic Graft Rejection: Onset

A

Months to years

76
Q

Chronic Graft Rejection: Cause

A

Both immunology and non-immunologic factors:

  • Chronic will occur to due vascular trauma (type 4 hypersensitivity) or d/t proinflammatory mediators
77
Q

The main pathogenic mechanism of chronic graft rejection is what?

A

indirect pathway

78
Q

Does chronic rejection respond to immunosuppressive therapy?

A

No

79
Q

Chronic Graft Rejection: Mechanisms

A

Humoral ++, Cellular +(?)

  • Main pathogenic mechanism is indirect pathway
  • Abs can also be involved (i.e. deposition of complement graft tissues)
  • Macrophages infiltrate
  • Smooth muscle cell proliferation
80
Q

The most important thing to look for when determining the the type is rejection is what?

A

the timeframe for the onset of symptoms

81
Q

What type of hypersensitivity is

  • Hyperacute
  • acute
  • chronic
A

Hyperacute- II

  • acute- IV
  • chronic- Iv
82
Q

Graft-versus-Host Disease (GVHD)

A
  • GVHD is caused by the reaction of T cells in the bone marrow of the graft with allow-ags of the host, often occuring in immunocomprimised patients because their immune system cannot reject allogenic cells in the graft.
  • occur most in small bowl, lung and liver.
83
Q

For solid grafts, GVHD may be classified as:

A
  • *1) Acute GVHD
    2) Chronic GVHD**
84
Q

Acute GVHD

A
  • Epithelial cell death in the skin, liver, and GI
  • Rash, jaundice, diarrhea, and GI hemorrhage
85
Q

Chronic GVHD is when there is fibrosis and atrophy of the affected organ, presents as?

A

complete dysfunction of the affect organ, obliterating small airways

86
Q

Onset of Graft vs Host ________

Type of hypersensitivity: ___

A

varies

IV

87
Q

Evolution of GVHD

A 
After initiation phase, donor APCs can activate donor CD8+ T cells by cross-presenting exogenously acquired Ags through the uptake of apoptotic recipient or shed protein on MHC class I molecules---donor APCs could re-prime donor CD8+ T cells previously activated by recipient APCs against the same Ags expressed by recipient APCs 
-Alternatively or in addition, donor APCs could activate naive donor CD8+ T cells against new, non-hematopoietic Ags (i.e. epitope spreading)
88
Q

What are the 2 effector mechanisms of GVHD?

A

1. Fas-FasL

2. Perforin/Granzyme

David's- Renal Exam 2 (12 decks)

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