Immunnology of the renal system

Question 1

What constitutes an AKI?

Answer 1

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

Question 2

What constitutes CKD?

Answer 2

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

Question 3

Why Is Ischemic Injury Critical in Acute Renal Failure?

Answer 3

• 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

Question 4

What is the major immunological cause of AKI?

Answer 4

Sterile inflammation

Question 5

What causes the release of DAMPs by cells?

Answer 5

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

Question 6

What induces sterile renal inflammation?

Answer 6

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

Question 7

What is the role of complement in AKI?

Answer 7

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

Question 8

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

Answer 8

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

Question 9

What role do immune cells play in AKI?

Answer 9

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

Question 10

What are the pro-inflammatory immune cells in AKI?

Answer 10

Th1 and Th17, M1 macrophages

Question 11

What are the anti-inflammatory immune cells in AKI?

Answer 11

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

Question 12

How are Th17 cells generated and what do they do?

Answer 12

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.

Question 13

What role do Th17 cells play in AKI?

Answer 13

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

Question 14

How are Th1 cells generated and what is their function?

Answer 14

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

Question 15

What is the role of Macrophages in renal injury?

Answer 15

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

Question 16

How do Treg cells prevent AKI progression?

Answer 16

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

Question 17

What two hypersensitivites dominate in kidney injury?

Answer 17

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

Question 18

What is the major barrier to successful kidney transplantation?

Answer 18

genetic incompatibility

Question 19

What is the target for transplant rejection?

Answer 19

HLA Ags; HLA matching and immunosuppression prevent graft rejection

Question 20

What are the two types of transplant complications?

Answer 20

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

Question 21

What are the major graft classifications?

Answer 21

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

Question 22

What is the outcome of a transplantation determined by?

Answer 22

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

Question 23

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

Answer 23

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

Question 24

What is the microcytotoxicity test for preformed Abs?

Answer 24

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

Question 25

What is the microcytoxicity test for class I HLA compatibility?

Answer 25

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

Question 26

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

Answer 26

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.

Question 27

Describe the immune responses associated with HVGD.

Answer 27

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

Question 28

Define direct and indirect allorecognition.

Answer 28

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

Question 29

The effector mechanisms of graft rejection are:

Answer 29

Th2 (IL-4 and IL-5) by Abs | Th1 (IL-2 and IFN-g) by CD8+ T cells

Question 30

hyperacute graft rejection is caused by:

Answer 30

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

Question 31

acute graft rejection is caused by:

Answer 31

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

Question 32

chronic graft rejection is caused by:

Answer 32

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

Question 33

What causes GVHD?

Answer 33

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

Question 34

Acute GVHD is mediated by what?

Answer 34

epithelial cell death in skin, liver, GI *clinical note: rash jaundice, diarrhea, GI hemorrhage

Question 35

chronic GVHD is mediated by what?

Answer 35

fibrosis and atrophy of affected organ *clinical note: may lead to complete dysfunction of organ