Immunological Aspects of the Renal System Flashcards
1
Q
major cause of Acute Renal Failure
A
ischemic Acute Kidney Injury (AKI)
2
Q
What activates kidney filtration impairment
A
ATP depletion
3
Q
what % of total cardiac output do kidneys receive
A
20% (~1L/ml more than other organs in the body)
4
Q
Normal GFR and SCr (serum creatinine) for NKD
A
GFR >= 60ml/min per 1.73 m2
Stable SCr
5
Q
What criteria must be met for AKI
A
- Increase in SCr by 50% in 7 days
- SCR increase by 0.3 mg/dL in 2 days
- Oliguria (little urine output)
6
Q
What criteria must be met for Chronic Kidney Disease (CKD)
A
Decreased GFR <60ml/min for >3 months
structural kidney damage for >3 months
7
Q
another name for kidney failure
A
ESRD (end state renal disease)
8
Q
6 causes of kidney hypoperfusion & AKI
A
- Intravascular volume depletion & hypotension
- Decreased effective intravascular volume
- medications
- hepatorenal syndrom
- sepsis
- renal vascular disease
9
Q
what perfusion condition leads to AKI
A
hypoxia
10
Q
body locations that contribute to intravascular volume depletion/hypotension
A
- GI tract
- dermal losses
- renal
- hemorrhage
11
Q
conditions that contribute to decreased effective intravascular volume
A
- congestive heart failure
- cirrhosis
- nephrosis
- peritonitis
12
Q
what contributes to large vessel renal vascular disease
A
- renal artery thrombosis
- arterial occlusion during surgery
- renal artery stenosis
13
Q
what contributes to small vessel renal vascular disease
A
- vasculitis
- atheroembolism
- hemolytic uremic syndrome
- malignant HTN
- scleroderma
- pre-eclampsia
- sickle cell anemia
- hypercalcemia
- transplant rejection
14
Q
Most times AKI is not caused by infection but rather…
A
sterile inflammation
15
Q
How are DAMPs introduced to the blood stream
A
- released by dying parenchymal kidney cells
2. ECM degradation
16
Q
compare C-Reactive protein (CRP) to IgM
A
both have 5 subunits
17
Q
how do DAMPs activate complement
A
DAMPs bind CRP –>activate complement via classical pathway
18
Q
what are DAMPs
A
Alarmins
endogenous molecular strucutures
19
Q
How do DAMPs cause renal inflammation
A
TLRs recognize DAMPs–> TRLs activated –> innate immune response induced –> RENAL INFLAMMATION
20
Q
HMGB1
A
nucleolus protein that’s a DAMP
21
Q
uric acid
A
DAMP/alarmin
22
Q
HSP
A
exosome that’s a DAMP
23
Q
S100 protein
A
found in the cytoplasm
DAMP
24
Q
Hyaluronans
A
fond in ECM
DAMP
25
What are Exogenous ligands and where are they found
PAMPs
found on pathogens: bacteria and viruses
Result: Innate Immunity
26
CPG and ds RNA
PAMP nucleic acids
27
lipid A
PAMP lipids
28
PGN
PAMP proteins
29
What are endogenous ligands and where are they found
stuff from ECM degradation
| Result: homeostatic inflammation
30
ATP
DAMP nucleic acid
31
oxLDL and saturated fatty acids
DAMP lipids
32
SP and HMGB1
DAMP proteins
33
Inflammation sensors for DAMPS
TLRs
34
Inflammation sensors for PAMPs
NOD-like receptors
| C-type Lectin
35
Mediators for DAMP and PAMP inflammation
TNF-alpha
IL-6
IL-1 beta
36
```
What renal cell is involved with:
Type 1 IFNs
CXCL2
IL-1 beta
IL-12
antigen presentation
migration
```
What is the result?
Dendritic Cells
Result: AKI + infections
37
```
What renal cell is involved with:
IL-1 beta
TNF
IL-6
chemokines
ROS
```
What is the result?
macrophages
Result: most kidney disease
38
What renal cell is involved with:
TNF
IL-6
IFN-alpha
What is the result?
endothelial cells
Result: IC-GN (immune complex glomerulonephritis)
39
What processes are triggered by inflammation
1. leukocyte activation
2. cytokine release
3. margination
4. tissue migration (DCs)
5. reduced flow
40
what is margination
free flowing leukocytes exit central blood stream and initiate leukocyte and endothelial cell reactions
41
what cells mediate early immune response causing renal tissue injury
Th17 cells
42
what cells mediate late immune response
Th1 cells
43
AKI macrophages
M1 macrophages
44
tissue repair macrophages
M2 macrophages
45
which cells differentiate into Th1 and Th17
dendritic cells
| PRO-inflammatory
46
pro or anti-inflammatory:
| increase TNF-alpha
pro inflammatory
| M1
47
pro or anti-inflammatory:
| increase IL-6
pro inflammatory
| M1
48
pro or anti-inflammatory:
| increase arginase-1
anti-inflammatory
| M2
49
pro or anti-inflammatory:
| increase IL-10
anti-inflammatory
| M2
50
pro or anti-inflammatory:
| increase CD4 Th1 response
pro inflammatory
51
pro or anti-inflammatory:
| increase IFN-gamma
pro-inflammatory
**promotes differentiation of M1 macrophages
52
pro or anti-inflammatory:
| decrease IL-4
pro-inflammatory
53
pro or anti-inflammatory:
| decrease antigen specific T-cell expansion
anti-inflammatory
54
Of DCs, macrophages, and T-cells, which is NOT involved in anti-inflammation
DCs
DCs, Macrophages, and T-cells are all involved in pro-inflammation BUT
ONLY macrophages and T-cells are involved in anti-inflammation (tissue repair)
55
characteristics of M1 machrophages
- classical activation (Th1)
- make NO
- induced by PAMPs and DAMPs (TLR binding + PRRs)
- cytokines made by M1 macs cause the acute phase of kidney inflammation
56
what induces the monocyte to differentiate to an M2 macrophage
IL-13 and IL-4
57
functions of M2 macs
- anti-inflammation
- would repair
- RENAL FIBROSIS
58
what induces the monocyte to differentiate to an M1 macrophage
- microbial TLR-ligands
| - IFN-gamma
59
functions of M1 macs
- phagocytosis
- bacteria/fungi killing
- INFLAMMATION
60
what releases IL-1, IL-12, IL-23, chemokines
M1 macs
| -result: inflammation (IL-12 & IL-23) via antigen presentation
61
what releases ROS, NO, lysosomal enzymes
M1 macs
| -result: phagocytosis + killing
62
what releases IL-10, TGF-beta
M2 macs
| -anti inflammatory
63
what releases proline, polyamines, TGF-beta
M2 macs
- wound repair
- renal fibrosis
64
characteristics of M2 macs
- alternative activation (Th2)
- induced by IL-4 and IL-13
- controlled by IL-10 and TGF-beta
- key for tissue repair (build ECM)
- none of these: Ag presentation, NO
65
what increases adhesion and proinflammatory activators for M1 differentation
ICAM-1
| osteopontin
66
what reprograms M1 macs to turn into M2 macs
CSF-1 (M-CSF)
| IL-10
67
what cell is produced by macs that stimulate ECM production
pericytes (--> myofibroblasts-->matrix deposition)
68
Steps leading to activation of naive CD4+ T-cell and ultimately tissue inflammation
naive CD4+--> activated Tcell--> +IL-6 & TFG beta--> Th17 cell --> +IL-17--> TISSUE INFLAMMATION
69
what 2 substances are secreted by Th17 cells
IL-17
| CCL20/Macrophage Inflammatory Protein-3 (MIP-3)
70
result of CCL20 secretion
1. recruit monocytes
2. recruit Th1 cells (later stages of inflammation)
3. recruit Th17 cells (early stages of inflammation)
71
What cells have receptors for IL-17 that's secreted by Th17 cells
- tubular epithelial cells
- mesangial cells
**both of these renal cells release chemokines and other inflammatory mediators
72
role of Treg cells in AKI
Treg cells inhibit inflammatory signals such as:
TGF-beta, IL-10, B & T lymphocytes
Goal: prevent inflammation (ANTI-INFLAMMATION)
73
Immunoglobulins for Type II hypersensitivity
IgG or IGM
74
Immunoglobulins for Type III hypersensitivity
IgG AND IGM
75
components of Type II hypersensitivity mechanisms
- IgG or IgM binds to cellular Ag
- complement activation + cell lysis
- ADCC (Ab dependent cellular cytotoxicity)
- ACCC w/T cells, NK cells, Macs, & neutrophils
76
Type II hypersensitivity Reactions
RBC destruction post-transfusion (bc of mismatched blood types)
hemolytic disease of the newborn
77
components of Type III hypersensitivity mechanisms
- Ag-Ab complexes
- complement activation --> inflammatory mediators
- recruit neutrophils and release enzymes from damaged tissues
78
Type III hypersensitivity Reactions
-post-strep glomerulonephritis
RA
SLE (systemic lups erythematosus)
79
What methods are used to prevent graft (transplant) rejection
HLA matching
immunosuppression
80
types of host vs graft responses
4 types that cause transplant rejection:
1. histocompatibility Ags
2. hyper-acute rejection
3. acute rejection
4. chronic rejection
81
histocompatibility Ags
Host vs graft rejection
| -targets for rejection
82
hyper-acute rejection
```
host vs graft rejection
Time: immediately post-Transplant
Cause: pre-formed antibody & complement (classical)
hypersensitivity: type II
major probs: occlusion & thrombosis
```
83
acute rejection
host vs graft rejection
Time: days to weeks post-Transplant
Cause: T-cell mediated (Th1 cells & CTLs), CD4+, CD8+ T-cells
hypersensitivity: type IV
major probs: inflammation & leukocytes infiltrate graft vessels
other: donor DCs (passenger leukocytes) are key
84
chronic rejection
host vs graft rejection
time: months to years post-Transplant
cause: vascular trauma, inflammatory T cell products, Antibodies, (DTH)
cells: M2 macs, T-cells
hypersensitivity: type IV
probs: intimal thickening & fibrosis of graft vessels
NOTE: does NOT respond to immunosuppressive therapy
85
graft vs host reactions (GVHD)
when the donor lymphocytes attack the graft recipient
- acute or chronic
cause: Donor T-cells proliferate & attack recipient tissues
hypersensitivity: type IV
probs: diarrhea, rash, jaundice
* *common in bone marrow transplants
* *common in immunocompromised patients
86
what's required post-transplant to minimize rejection
immunosuppressive drugs
***Note: cannot be used for chronic rejection
87
autograft
graft exchanged from one part of the body to another (same person)
88
isograft
exchanged btwn different ppl (twins)
89
allograft
exchanged btwn different ppl (non-twins)
| -same species
90
xenograft
exchanged btwn diff members of DIFF species
- rapid attack
- increase chance of survival by inserting human genes into genome
91
4 variables that determine successful transplant
1. allograft condition
2. donor-host antigenic disparity
3. strength donor-host response
4. immunosuppressive regimen
92
immune events that cause rejection
1. APCs trigger CD4+ and CD8+ T cells
2. local AND systemic immune response
3. cytokines recruit and activate immune cells
4. develop specific T-cells, NK cells, macs = CYTOTOXICITY
5. Rejection!!
93
what non-immuno factors cause rejection
mechanical trauma + ischemia-reperfusion injury
94
how does the clotting cascade impact rejection
makes: fibrinopeptides
result 1: increased local vascular permeability (same as bradykinin)
result 2: chemoattractant for neutrophils & macs
if not controlled: HYPER-ACUTE REJECTION!
95
how does the kinin cascade impact rejection
makes: bradykinin
result 1: vasodilation
result 2: smooth muscle contraction
result 3: increased vascular permeability (same as clotting cascade)
if not controlled: HYPER-ACUTE REJECTION!
96
why is ABO matching NOT important for corneal, heart valve and bone/tendon grafts
non-vascularized tissues
anti-class I/II HLA abs not important here
97
chromosomal arm with HLA region
short arm
98
how are HLA Ags expressed
co-dominantly expressed
99
most important HLA Ags for successful transplantation
class II HLA
* HLA-DR
* HLA-DP
* HLA-DQ
100
HLA Ags that are the strongest barriers to transplantation
class I HLA
HLA-A
HLA-B (most number of alleles -->polymorphism)
101
Steps for: microcytotoxicity test for preformed Abs
step1: recipient serum + donor cells
step2: add complement
step 3: add dye
step 4: PREFORMED ANTIBODIES PRESENT
102
steps for: serological Class I HLA typing for HLA-A3
step1: Abs are added to donor and recipient cell
step2: complement added to both
step 3: pores formed
step 4: dye added
result: HLA ag are identical
Note: classical complement cascade
103
Microtoxicity test (Class I MHC) for HLA-A7
step1: Abs are added to donor and recipient cell
step2: complement added to both
step 3: pores formed (donor only)
step 4: dye added
result: HLA ag are identical
104
How do you know if recipient cells DON'T share class II MHC donor
There is proliferation of the recipient cells!
step1: add radiation to donor cells
step2: donor + recipient cells mixed
step3: add 3H-thymidine
step 4: if radioactivity see in cells = recipient cells proliferation
*recipient cells DO NOT share class II MHC donor
105
How do you know if recipient cells share class II MHC donor
NO proliferation- means that recipient cells SHARE class II MHC of donor
step1: add radiation to donor cells
step2: donor + recipient cells mixed
step3: add 3H-thymidine
step 4: radioactivity NOT incorporated = no proliferation
106
direct recognition
T-cell recognizes unprocessed MHC
| -on graft APcs
107
indirect allorecognition
T cell recognizes processed MHC bound to self MHC
| -on host APC
108
Host vs Graft Response
- non-immune injury of the graft (Danger signals, DAMPs)
- humoral rejection Th2 (IL-4, IL-5, IL-10)
- cellular rejection Th1 (IL-2, INF-gamma)
109
non-immunologic factors for chronic graft rejection
1. ischemia-reperfusion damage
2. recurrence of disease
3. nephrotoxic drugs (cyclosporine A)
110
Acute GVHD causes and Sx
epithelial cell death in skin, liver, GI
| Sx: rash, jaundice, diarrhea, GI hemorrhage
111
Chronic GVHD causes and Sx
fibrosis and atrophy of affected organ
| Sx: complete dysfunction of the organ, obliteration of small airways
112
2 effector mechanisms of GVHD
1. Fas-FasLigand (result: apoptosis)
| 2. perforin/granzyme (result: apoptosis)
