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CPRI - Final > Immunnology of the renal system > Flashcards

Immunnology of the renal system Flashcards

1
Q

What constitutes an AKI?

A

Increase in serum Creatinine by 50% within 7 days or by 0.3 mg/dL within 2 days or oliguria

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2
Q

What constitutes CKD?

A

GFR <60 mL/min per 1.73 m2 for >3 months or kidney damage for >3 months

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3
Q

Why Is Ischemic Injury Critical in Acute Renal Failure?

A
  • kidneys receive 20% of total cardiac output (~ 1 L/min) - more than any other organ in the body; high perfusion is dictated by tubular O2 consumption necessary for solute reabsorption
  • ischemic AKI leads to metabolic acidosis and ATP depletion and acute renal failure
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4
Q

What is the major immunological cause of AKI?

A

Sterile inflammation

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5
Q

What causes the release of DAMPs by cells?

A

Necrosis, or death by injury. Nuclear, mitochondrial, and cytosolic residues released as DAMPs causing cell activation via PRRs

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6
Q

What induces sterile renal inflammation?

A

intrinsic DAMPs released by necrotic parenchymal kidney cells due to ECM degradation; DAMPs are also called alarmins

CRP can bind DAMPs and activate classical complement pathway

TLRs on immune cells recognize DAMPs and produce inflammation

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7
Q

What is the role of complement in AKI?

A

complement activation generates chemoattractants, C3a and C5a, which induce leukocyte infiltration and the formation of the membrane attack complex.

MAC causes cell lysis and release of DAMPs causing immune cell activation, release of proinflammatory mediators and further tissue injury

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8
Q

What is the consequence of the high filtration rate in the kidney?

A

unique susceptibility to deposition of immune complexes in renal tissue; AKI and damage leads to DAMPs activating complement and C3b, C5b, C3a, and C5a production and MAC complex -> cell death

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9
Q

What role do immune cells play in AKI?

A

inflammation -> neutrophils (release proteases and free radicals) and monocytes (differentiate into inflammatory M1 macs) infiltrate due to complement and C3a and C5a

phagocytes regulated by complement and Fc receptors

M1 macs release: ROS, cytokines chemokines, gorwth factors, eicosanoids, NO

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10
Q

What are the pro-inflammatory immune cells in AKI?

A

Th1 and Th17, M1 macrophages

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11
Q

What are the anti-inflammatory immune cells in AKI?

A

M2 macrophages and IL-10 release, clearance of early apoptotic cells

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12
Q

How are Th17 cells generated and what do they do?

A

IL-1, IL-6, TGF-b produced by DCs turn naive CD4+ into Th17 cell that releases IL-17 or IL-22. If IL-17 predominates then inflammatory response ensues, if IL-22 then homeostatic mechanisms prevail.

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13
Q

What role do Th17 cells play in AKI?

A

Accumulation of Th17 and thus IL-17, induces kidneys to produce pro-inflammatory cytokines and other mediators.

Induces CCL20 leading to recruitment of neutrophils, monocytes, Th1 and Th17 ->kidney damage

Th1 cells release IFN-g inducing M1 macs

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14
Q

How are Th1 cells generated and what is their function?

A

DCs release IL-12 and convert Naive T cells into IFN-g releasing Th1 cells

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15
Q

What is the role of Macrophages in renal injury?

A

M1 macs are drawn by inflammation and release IL-12 and 23 can be reprogrammed by CSF-1 and IL-10 to M2 for tissue repair; TGF-b and PDGF cause fibrosis by pericyte to myofibroblast transition

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16
Q

How do Treg cells prevent AKI progression?

A

By promoting repair and regeneration via inhibition of B and T cells and release of IL-10 and TGF-b

17
Q

What two hypersensitivites dominate in kidney injury?

A

Type II (cell bound antigen) and Type III (soluble antigen) - IgG or IgM

18
Q

What is the major barrier to successful kidney transplantation?

A

genetic incompatibility

19
Q

What is the target for transplant rejection?

A

HLA Ags; HLA matching and immunosuppression prevent graft rejection

20
Q

What are the two types of transplant complications?

A

HVGD: host versus graft disease
- caused by rejection of transplant by hosts immune
system
- can be hyperacute (Ab), acute (T cells or Ab), or
chronic rejection (T cells and Abs)

GVHD: graft versus host disease

  • caused by donor immune cells attacking host tissues
  • can be acute or chronic
21
Q

What are the major graft classifications?

A

autografts: grafts of the same individuals
isografts: grafts exchanged between identical twins
allografts: grafts bewteen family members
xenografts: grafts from a different species

22
Q

What is the outcome of a transplantation determined by?

A
  1. the condition of the allograft
  2. donor-host antigenic disparity
  3. strength of host anti-donor response
  4. applied immunosuppression
23
Q

Why are ABO Ags a barrier to transplantation if not matched?

A

ABO Ags are also expressed on other tissues so anti A or B Abs may be present in individuals if their RBS don’t express them; not imp. for cornea, heart, bone, tendon, or stem cell transplantation

24
Q

What is the microcytotoxicity test for preformed Abs?

A

Step 1: recipient serum with Abs is added to donor cells
Step 2: complement is added
Step 3: Dye is added
Step 4: Results are interpreted, if it has entered cell then there is a mismatch due to Ab presence

25
Q

What is the microcytoxicity test for class I HLA compatibility?

A

Similar to test for preformed Abs, only difference is that you are looking for same HLA Ags on both donor and recipient cells using commercial anti-HLA specific Abs

26
Q

What is the mixed lymphocyte response for testing class II HLA compatibility?

A
  1. After radiation, donor T cells can’t proliferate because DNA is damaged but DCs in the specimen can serve as professional APCs.
  2. Recipient cells (T cells) and labelled thymidine are added to the donor cells. If recipient T cells find Ags on donor DCs cells they will be activated and proliferate.
  3. During cell division, DNA is replicated and labelled thymidine is incorporated in replicated DNA. The more radioactivity incorporated, the greater class II HLA disparity between the donor and recipient.

RESULT INTERPRETATION: Cell proliferation and accumulation of radioactivity show that the donor and recipient don’t have class II HLA compatibility and vice versa.

27
Q

Describe the immune responses associated with HVGD.

A
  1. APCs trigger CD4 and CD8 T cell responses against
    graft Ags
  2. local and systemic immune responses develop
  3. cytokines recruit and activate immune cells
  4. cytotoxic reactions mediated by CD8, NK and
    Macrophages occur.
  5. allograft rejection is in progress
28
Q

Define direct and indirect allorecognition.

A

Direct: recipient T cells arrive into the graft and recognize intact allogeneic MHC molecules on donor APCs in graft

Indirect: donor MHC molecules are taken up, processed, and presented by the recipient APCs for activation of recipient T cells

29
Q

The effector mechanisms of graft rejection are:

A

Th2 (IL-4 and IL-5) by Abs

Th1 (IL-2 and IFN-g) by CD8+ T cells

30
Q

hyperacute graft rejection is caused by:

A

Pre-existing Abs that bind to endothelial cells lining the blood within minutes to hours, activate complement and C3a/C5a, leukocyte influx and cell death

31
Q

acute graft rejection is caused by:

A

donor DCs migrate to the lymph nodes and stimulate immune responses in recipient lymphocytes via direct allorecognition; activated T cells migrate to graft and cause damage (type IV hypersensitivity)

CD4 and CD8 can cause rejection; indirect can also play a role

32
Q

chronic graft rejection is caused by:

A

occlusion of blood vessels and subsequent ischemia of organ; macrophages infiltrate and induce smooth muscle prolif. main pathogenic mechanism is indirect allorecognition, Abs can also be involved

non-immunologic factors: ischemia reperfusion damage, nephrotoxicity

does not respond to immunosuppression

33
Q

What causes GVHD?

A

reaction of grafted T cells in the marrow; often occurs in immunocompromised individuals due to lack of ability to reject allogeneic T cells in graft

type IV hypersensitivity

34
Q

Acute GVHD is mediated by what?

A

epithelial cell death in skin, liver, GI

*clinical note: rash jaundice, diarrhea, GI hemorrhage

35
Q

chronic GVHD is mediated by what?

A

fibrosis and atrophy of affected organ

*clinical note: may lead to complete dysfunction of organ

CPRI - Final (17 decks)

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