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Renal I Final > Lecture 4: Immunological Aspects of the Renal System > Flashcards

Lecture 4: Immunological Aspects of the Renal System Flashcards

1
Q

Impairment of kidney filtration is activated by the depletion of?

A

ATP in vascular and tubular cells

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2
Q

Ischemia reperfusion injury results from a generalized or local impairment in?

A

Oxygen and nutrient delivery to, and waste product removal from cell of the kidney

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3
Q

What occurs to tubular epithelial cells as a result of the imbalance caused by impaired oxygen and nutrient delivery?

A

Death by apoptosis (clean) and necrosis (dirty death = inflammation)

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4
Q

When endothelium is injured what occurs to the small arterioles in post-ischemic kidney; what amplifies this?

A

Vasoconstrict more than do vessels from normal kidney; amplified by reduced production of NO and other vasodilatory substances by the damaged endothelial cell

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5
Q

Which inflammatory cytokines amplify the vasoconstriction of the small arterioles; generated how??

A

TNF-alpha, IL-1B, IL-6, IL-12, IL-15, and IL-18; result of leukocyte-endothelial adhesion and leukocyte activation

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6
Q

The small vessel occlusion and activation of the coagulation system cause what defective functions of the kidney seen in AKI?

A
  • Reduced GFR
  • High FENa
  • Concentrating defect
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7
Q

What is one of the major causes of ARF?

A

Ischemic acute kidney injury

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8
Q

Sterile renal inflammation is induced by what, released from who?

A

Induced by DAMPs; released from dying parenchymal cells

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9
Q

What are the DAMPs released by dying parenchymal cells?

A
  • HMGB1 (nucleolus)
  • Uric acid
  • HSPs (exosomes)
  • Hyaluronans in ECM
  • S100 protein in cytoplasm
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10
Q

What happens upon the release of DAMPs?

A

Immune cells respond to DAMps and induce innate immune responses and subsequent renal inflammation

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11
Q

Which TLR is activated by DAMP’s and what occurs?

A

TLR-4 causing release of NF-kB in turn increasing production of proinflammatory cytokines and adhesion molecules, which elicits a strong inflammatory response

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12
Q

How does apoptosis and necrosis differ in the outcomes seen in AKI?

A
  • Necrosis is the only way DAMPs are released which increased the chance of fibrotic tissue during recovery
  • Apoptosis related damage is important for repair
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13
Q

Role of dendritic cells in AKI; cytokines released?

A
  • Regulation of adaptive immune response

- They are APC’s, migrate to lymph nodes, and present to T cells; can release Type I IFNs, CXCL2, IL-1B and IL-12.

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14
Q

Role of macrophages in most kidney diseases?

A
  • Regulation of inflammation and fibrosis

- Remain in the tissue of the kidney and secrete ROS, IL-1B, TNF-alpha, IL-6 and chemokines

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15
Q

Macrophages are able to be activated into which two types by what?

A

M1 - by PAMPs and DAMPs binding to TLR’s. IFN-y and other proinflammatory cytokines promote differentiation of M1. M1 then produces cytokine causing more inflammation

M2 - induced by IL-4 and IL-13 produced by TH2 cells. M2 are important in tissue repair and renal fibrosis, both controlled by IL-10 and TGF-B

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16
Q

What is the importance of TGF-B?

A

Released by M2 and is very important growth factor for fibroblasts (chemoattractant)

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17
Q

What is ratio of M1/M2 seen in AKI?

A
  • M1 will be acting first as neutrophils, NK cells, TH1 and TH17 cells are releasing INF-Y, inflammation will be further exacerbated
  • TH2 and Treg cells will promote the differentiation into M2 cells which will predominate and produce anti-inflammatory effects + tissue repair
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18
Q

What is ratio of M1/M2 in CKD?

A

Due to progressive injury and persistent inflammation, M1’s will persist, and this persistent inflammation and fibrotic factors will promote renal fibrosis.

*Products of M1 and M2 are mutually inhibitory, so if M1 is activated, this is inhibiting M2.

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19
Q

Explain how we know complement plays an important role in disease of the kidney; which receptor is the best target?

A
  • Animal models lacking C3, C5, and C6 are protected from renal IRI.
  • Deficiency of C3a receptor or C5aR protected mice from IRI, but C5aR were most protected
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20
Q

How do nephrologists determine activation of complement in a given patient?

A
  • Deposition of complement proteins within kidney
  • Disturbances of the level of C3 and C4 in the blood
  • Detection of C3a and C5a complement activation fragments in the plasma or urine
  • Association of mutations and polymorphisms in complement protein with the development of kidney disease
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21
Q

C3a and C5a stimulate chemotaxis of which kind of cell; participates in?

A

Mast cells increasing by as much as 60x and participate in kidney fibrosis

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22
Q

What starts the adaptive immune response?

A

DC’s activate naive CD4+ T cells in the lymph nodes

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23
Q

Which cytokines and transcriptional factors cause differentiation into TH1, TH2, Treg, and TH17 cells?

A

TH1: IL-12 and T-bet

TH2: IL-4 and GATA3

Treg: TGF-B and FOXP3

TH17: TGF-B, IL-6 and RORyT

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24
Q

During the adaptive immune response which T cells predominate in the early stages vs later stages?

A

Early stages: Th17

Later stages: Th1

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25
Q

Resident macrophages are activated by?

A

IFN-y (Th1)

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26
Q

Treg cells produce which cytokine and protects against?

A

Produce IL-10 and are recruited to protect against overwhelming Th1 cell and Th17 cell-mediated immune responses

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27
Q

The clinical outcome of kidney disease mainly depends on?

A

The balance between pro-inflammatory and anti-inflammatory immune cell

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28
Q

Th17 cells infiltrating early in the immune response secrete what, which stimulates?

A

Secrete IL-17 which stimulates resident renal cells to produce chemokines and other inflammatory mediators

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29
Q

IL-17 causes the recruitment of ?

A

Neutrophils

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30
Q

What is produced by Th17 cells that recruits monocytes and Th1 cells?

A

CCL20

31
Q

What do Treg cells do to regulate the immunologic reactions occurring in renal tissues?

A

1) Inhibit pro- inflammatory cytokines from T-helper cells
2) Switching of MO to an anti-inflammatory M2 phenotype
3) Reduction of renal injury through IL-10 mediated suppression of the innate immune system, prevents accumulation of neutrophils

32
Q

Autografts vs. Isografts vs. Allografts vs. Xenografts?

A

Autograph: from one part to another part of same person

Isograft: individuals of identical genetic constituents

Allograft: between nonidentical members of same species

Xenograft: between members of different species

33
Q

Which 4 variables determine the transplant outcome?

A

1) Condition of the allograft
2) Donor-host antigenic dispairty
3) Strength of host anti-donor response
4) Immunosuppressive regimen

34
Q

5 immune events that occur in graft rejection?

A

1) APC’s trigger CD4+ and CD8+ T cells
2) Both a local and sytemic immune response develops
3) Cytokines recruit and activate immune cells
4) Development of specific T cells, NK cells, or MO mediated cytotoxicity
5) Allograft rejection

35
Q

What are non-immunological factors contributing to the condition of the allograft?

A
  • Mechanical trauma and ischemia-reperfusion injury to the graft tissues
  • Damaged graft tissues release mediators which trigger several biochemical cascades leading to tissue damage
36
Q

What are some of the biochemical cascades triggered by damaged graft tissue?

A
  • Generation of fibrin and fibrinopeptides, which increase vascular permeability + chemoattractant for neutrophils and MO’s
  • Kinin cascade produces bradykinin = smooth muscle vasodilation, contraction, and increased permeability
37
Q

What is the first, second, and third test for donor/recipient matching?

A

1) Blood group Ag’s (ABO)
2) Class I HLA compatibility
3) Pre-existing anti-class I/II HLA-Abs

38
Q

Matching is not important for which tissues?

A

Non-vascularized

  • Corneal transplantation
  • Heart valve transplantation
  • Bone and tendon grafts
39
Q

ABO is a barrier to transplantation of?

A

Solid organs

40
Q

Why is HLA compatibility between donor and recipient required?

A

Due to the extreme polymorphism of HLA

41
Q

How are HLA ag’s expressed?

A

Co-dominantly

42
Q

Which class of HLA are particularly strong barriers to transplantation?

A

Class- I (HLA-A and HLA-B)

43
Q

What is the other class/pairs most important for transplantation?

A

Class-II (HLA-DR, HLA-DP, and HLA-DQ)

44
Q

Identification of HLA Ags is dependent on?

A

Complement dependent

45
Q

Source of lymphocytes for HLA typing?

A
  • Spleen and lymph node (from cadaver)

- Peripheral blood (RBC’s and platelets removed)

46
Q

HLA antisera is obtained from; contains?

A

Multiparous women or from planned immunization volunteers; contains antibodies to HLA Ags

47
Q

What happens in class I HLA typing?

A

Abs bind to HLA Ag on surface of lymphocytes, Ag-Ab complex formed, classical complement cascade, lysis of lymphocytes detected by staining the cells.

48
Q

What is the microcytotoxicity test for class I MHC?

A

You use a panel and have several HLA antisera with the recipient and several donors. You will look at the columns for the least dismatched donor

49
Q

How can preexisting donor-specifc anti-HLA Abs may occur in recipients?

A

Pregnancy can induce HLA sensitization, as the mother is exposed to Ag’s during gestation and delivery

50
Q

How do you test for pre-formed Ab’s?

A

1) Take donor cells and mix with recipient serum (recipient Ab’s in serum bind to donor cells)
2) Add complement (MAC forms and pores in cell form)
3) Add dye (if you see staining, you know the recipient has Ab’s against the Ag’s from the donor)

51
Q

What is used for class II HLA typing?

A

Mixed lymphocyte response

52
Q

Explain the mixed lymphocyte response test for class II HLA typing?

A

1) Treat donor cells with radioactivity, stopping proliferation
2) Mix in peripheral blood lymphocytes from recipient, add thymidine (radioactive), and allow to sit for several days
3) Lymphocytes from incompatible individuals will stimulate each other to proliferate significantly (taking up the thymidine)
4) If the pallet shows signifiant radioactivity you know the recipient cells do not share class II with the donor and this is not good for transplant

53
Q

In a mixed lymphocyte response the best transplant will be the one that shows what kind of proliferation/radioactivity?

A

Either zero or the smallest range.

54
Q

When a kidney is transplanted and the recipient’s T cells attack the transplant, what kind of disease is this?

A

Host-versus-graft disease

55
Q

When bone marrow is transplanted the T cells in the transplant attack the recipients tissue, what kind of disease is this?

A

Graft-versus-host disease

56
Q

What is the reason for graft-versus-host disease; common in which tissues?

A

Common in tissues that are very hard to perfuse, cleanse completely of their immune cells i.e., intestinal, lung, and liver

57
Q

Host-versus-graft is what kind of response

A

Adaptive immune response

58
Q

Why is the response in host-versus-graft so vigorous and strong?

A

Higher frequency of T cells that recognize the graft as foreign, class I HLA is expressed on nearly every tissue in the body, and cells are constantly surveying these Ag’s

59
Q

What occurs to the second graft from the same donor; caused by?

A

Rejected more rapidly, caused by immune memory

60
Q

What is direct alloantigen recognition?

A

Circulation is restored and donor dendritic cells in its own tissue is activated by DAMPs. Picks up Ag’s and migrates to the peripheral lymph node. They are expressing class II HLA and this is enough to activate recipient T cells. These effector CD8+ T cells recognize donor MHC on graft tissue cells and cause direct CTL killing of the graft

61
Q

What is indirect alloantigen recognition?

A

This time recipient DC takes up and processes donor MHC molecules and travels to lymph nodes to present to naive T cells, activate them, and effector CD4+ T cells go back to the tissue.

62
Q

What 2 things occur from indirect alloantigen recognition?

A

1) Effector CD4+ T cells recognize donor MHC bound to recipient MHC on recipient B cell = Ab-mediated injury
2) Effector CD4+ T cells recognize donor MHC bound to recipient MHC on recipient MO in graft = Inflammation-mediated injury to graft

63
Q

Which T-cell and cytokines are involved in humoral rejection of a graft?

A

Th2 (IL-4, IL-5 and IL-10)

64
Q

Which T-cell and cytokines are involved in cellular rejection of a graft?

A

Th1 (IL-2, IFN-y)

65
Q

How fast is a hyperacute rejection and what would be the cause; what tests for this cause?

A
  • Minutes to hours
  • Pre-existing anti-donor Ab’s (humoral)
  • This is what class I HLA testing is for and ABO blood group
66
Q

How fast is accelerated rejection and what is the cause?

A
  • Days

- Reactivation of sensitized T cells (humoral)

67
Q

How fast is an acute rejection and what is the cause if cellular vs vascular?

A
  • Days to weeks
  • Primary activation of T cell (Ag’s are taken from donor tissue and presented to naive T cells) - DONOR DC’s
  • Cellular = Th1
  • Vascular = Th2
68
Q

How fast is a chronic rejection and what is the cause; what is the current view on this?

A
  • Months to years
  • Both immunologic and non-immunologic factors
  • Current view = DTH reactions
69
Q

What is the main pathogenic mechanism in chronic graft rejection; response to immunosuppressive therapy?

A
  • Indirect pathway

- Does NOT respond to immunosuppressive therapy

70
Q

GVHD is caused by the rxn of what; what class HLA usually involved?

A

Grafted mature T cells in the marrow inoculum with allo-Ags of the host - rxn is directed against minor H Ags of the recipient (Class II)

71
Q

Acute GVHD vs Chronic GVHD; how is each seen clinically?

A

Acute - epithelial cell death in the skin, liver, and GI

  • Clinically - rash, jaundice, diarrhea, and GI hemorrhage

Chronic - fibrosis and atrophy of affected organ

  • Clinically - may lead to complete dysfunction of the affected organ
  • May produce obliteration of small airways
72
Q

GVHD is most likely to occur in which individuals because of?

A

Immunocompromised individuals because their immune system is unable to reject the allogenic cells in the graft

73
Q

What do donor APC’s do with recipient Ag’s in GVHD?

A

Donor APC’s can activate donor CD8+ T cells by cross-presenting recipient Ag’s on MHC class I molecules

Renal I Final (6 decks)

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