Immunology Flashcards
(88 cards)
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
2
Q
Acute Kidney Injury (AKI)
A
Serum creatinine:
- increases by 50% within 7 days
- by 0.3 mg/dL within 2 days
Oliguria
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
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
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
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
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.
8
Q
Why Is an Ischemic Injury bad in kidney Injury?
A
Ischemic acute kidney injury (AKI) can cause:
- Metabolic acidosis
- Decrease of ATP–>
Leading to acute renal failure (ARF), an abrupt decrease in kidney function.
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
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.
11
Q
What are DAMPS?
A
Alarmins are endogenous intracellular structures such as
- HMGB1
- Uric acid
- HSPs
- S100 protein
- Hylauronans
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
13
Q
A
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
15
Q
What macrophages play a role in AKI and tissue repair?
A
- AKI–> M1 macrophages
- Tissue repair–> M2 macrophages
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.
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
-
T cells release IL4 and IL13–> induces M2 macrophages
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.
19
Q
________ has a anti-inflammatory role in AKI
A
Treg cells
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.
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
*
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).
23
Q
Components of the immune system cause four types of hypersensitivities. Which types causes problems with kidneys?
A
Type II and Type III
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.
25
How is **Type III hypersensitivity** activated and what is an example?
* 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.**
26
What is used in end-stage renal disease?
**Kidney transplantation.**
27
The barrier to transplantation is **genetic incompatibility**. ____________ is one of the best way to prevent graft rejections.
**HLA matching**
28
**Host vs. graft responses** cause the rejection of the transplant. _____________ are the targets for rejection. What are the three types?
**Histocompatibility antigens**
**Hyperacute rejection, acute rejection and chronic rejection.**
29
30
**-Hyperacute rejection**
**-Acute rejection**
**-Chronic rejection**
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.**
31
What are **graft versus host diseaes** (GVHD)? What are the types?
**Graft versus host reactions**- the donor WBCs in the transplating tissue recognize the graft receipient and attack.
GVHD can be ***acute*** or ***chronic***
32
Successful organ transplantation depends on the use of \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
**immunosuppressive drugs**
33
Grafts are classified based on the **_genetic relationship_** between the host and the donor. What are the 4 types of grafts?
**1. Autografts**
**2. Isografts**
**3. Allografts**
**4. Xenografts**
34
What are **autografts**?
Grafts exchanged from one part--\> another part of the same person.
35
What are **isografts**?
Grafts echanged between different individials with the **same genetics (identical twins).**
36
What are **allografts**?
Grafts exhcanged between ***non-identical members* of the same species.**
37
What are **xenografts**?
* 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
What are the characterstics of graft rejection?
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
What are the **4 key concepts** in transplantation that determine the outcome of the transplant?
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
The _condition of the allograft_ is a **non-immunological factor** that can determine the *outcome of the transplant.*
## Footnote
**What can happen with the graft is damaged?**
* 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
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?
**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
**Type A blood**
## Footnote
Abs present:
Antigens present:
Donor can be:
Abs present: **Anti-B**
Antigens present: **Ag A**
Donor can be: **A or O**
43
**Type B blood**
## Footnote
Abs present:
Antigens present:
Donor can be:
Abs present: **Anti-A**
Antigens present: **Ag B**
Donor can be: **B or O**
44
**Type AB blood**
## Footnote
Abs present:
Antigens present:
Donor can be:
Abs present: **None**
Antigens present: **A and B antigens**
Donor can be: **A, B, AB, O**
45
**Type O blood**
## Footnote
Abs present:
Antigens present:
Donor can be:
Abs present: **Anti-A/B**
Antigens present: **None**
Donor can be: **O**
46
Antibody + complement--\>
**MAC**
47
Matching donor and recipient involves testing for \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
**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
**How Do Pre-existing Abs Appear?**
* 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
**How does donor matching (testing for pre-existing anti-class I/II HLA abs) occur (generally)?**
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
**Describe the HLA system in reference to transplantation.**
* 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
* 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:
* 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
*Microtoxicity Test f*or Class I HLA Typing: **Match**
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
Microtoxicity Test for Class I MHC Typing: **No Match**
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
How to determining Class I MHC match
**Multiple dono**rs are tested against the recipient, and the one that contains the same HLA Ag profile will be used for transplantation
55
MATCHING DONOR AND RECIPIENT: Testing for class II HLA compatibility is called \_\_\_\_\_\_\_\_\_\_\_\_-
**Mixed Lymphocyte Reaction (MLR)**
56
**Mixed Lymphocyte Reaction** for Class II HLA typing
**Mix lymphocytes from 2 unrelated people**
**The donor cells is exposed to radiation, but does not proliferate. Instead, they present their antigens.**
57
**Mixed Lymphocyte Reaction** for Class II HLA typing: **No Match**
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
**Mixed Lymphocyte Reaction** for Class II HLA typing: Match
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 a*nd there is *NO recipient cell proliferation*
4. No reaction/No radiation --\> GOOD FOR TRANSPLANTATION :): Recipient cells share class II MHC of donor
59
What are the immune events involved in **allograft rejection?**
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
What are the two types of immune responses in transplantation?
1. **Host-versus-graft disease** (kidney is transplanted and the r*ecipients T-cells attack the transplant*).
2. **Graft-versus-host diseas**e (bone marrow is transplanted and the **T-cells in the transplant attack the recipients tissues)**.
61
Host-Versus-Graft (HVG) Disease
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
**Immune and non-immune factors that influence HVG disease**
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 allograf**t--\> interact with **APC and become activated**--\> inflammatory cytokine/chemokine field is created, causing increase activation of APC, endothelium and leukocytes.
63
Effector mechanisms of HVG disease
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
List **types** of graft rejection
* *1) Hyperacute
2) Accelerated
3) Acute
4) Chronic**
65
Hyperacute Graft Rejection: Onset
**Minutes to hours**
66
Hyperacute Graft Rejection: Cause
**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) **Ab**s bind to the endothelial cells which **activates** the **classical** **pathway** of complement activation, which can leads to death of the endothelium
67
Hyperacute Graft Rejection: Mechanisms
**Humoral +++, Cellular -**
68
Hyperacute Graft Rejection: Results
1. **Complement activation**
2. **Endothelial damage**
3. **Inflammation**
4. **Thrombosis**
69
**Accelerated Graft Rejection: Onset**
**Days**
70
**Accelerated Graft Rejection:** Cause
**Reactivation of sensitized T cells**
71
Accelerated Graft Rejection: Mechanisms
**Humoral ++, Cellular +**
72
**Acute Graft Rejection:** Onset
**Days to weeks**
73
Acute Graft Rejection: Cause
* **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
What type of T-cells can cause graft rejection?
CD4 and CD8
75
**Chronic Graft Rejection:** Onset
**Months to years**
76
**Chronic Graft Rejection:** Cause
**Both immunology and non-immunologic factors:**
* Chronic will occur to due vascular trauma (type 4 hypersensitivity) or d/t proinflammatory mediators
77
The main pathogenic mechanism of chronic graft rejection is what?
**indirect pathway**
78
Does chronic rejection respond to immunosuppressive therapy?
**No**
79
Chronic Graft Rejection: Mechanisms
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
The most important thing to look for when determining the the type is rejection is what?
the timeframe for the onset of symptoms
81
What type of hypersensitivity is
- Hyperacute
- acute
- chronic
Hyperacute- II
- acute- IV
- chronic- Iv
82
**Graft-versus-Host Disease (GVHD)**
- 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
For solid grafts, GVHD may be classified as:
* *1) Acute GVHD
2) Chronic GVHD**
84
Acute GVHD
- Epithelial cell death in the skin, liver, and GI
- Rash, jaundice, diarrhea, and GI hemorrhage
85
## Footnote
**Chronic GVHD** is when there is *fibrosis* and *atrophy* of the affected organ, presents as?
complete dysfunction of the affect organ, obliterating small airways
86
Onset of **Graft vs Host** \_\_\_\_\_\_\_\_
Type of hypersensitivity: \_\_\_
**varies**
**IV**
87
**Evolution of GVHD**
```
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
What are the **2 effector mechanisms** of GVHD?
**1. Fas-FasL**
**2. Perforin/Granzyme**
