7. Immunological Aspects of the Renal System Flashcards
Acute renal failure is defined as an abrupt decrease in kidney function which is mainly cause by what?
ischemic Acute kidney injury (AKI), which is common and causes impairment of kidney filtration via metabolic acidosis and ATP depletion
Some causes of hypoperfusion to the kidney cause AKI are sepsis (sterile inflammation), decreased effective intravascular volume, medications and?
intravascular volume depletion and hypotension
and renal vascular disease
sterile renal inflammation is induced by intrinsic damage-associated molecular patterns (DAMPs) which are released from dying kidney cells and generated during ECM degreadation. C reactive protein CRP can bind damps and do what?
activate complement via the classical pathway.
Immune cells also can recognize damps via TLRs which induce inflammation as well
Pamps and damps can be recognized by toll like receptors, nod like receptors and c type lectin which use what cytokines for inflammation? (3)
TNFA
IL6
IL1B
When there is trauma to renal tissue, necrosis/apoptosis occurs, dAMP signals bind receptors on resident cells and activate dendritic, macrophage and endothelial cells to start inflamation. Which leads to? (4)
leukocyte activation
cyotkine release
tissue migration
reduced flow
In earlier stages of renal damage, Th17 cells predominate but in later stages Th1 cells do. Which macrophages (M1/M2) play a role in AKI and tissue repair?
M1 = acute kidney injury (inflam/phagocytosis) M2= tissue repair (antiinflam)
M1 for AKI are classically activated via pamps and damps through TLRs/PRRs, IFNY promotoe m1 differentiation. How are M2 for tissue repair activated?
M2 is Alternatively activated, induced by IL4/IL13 by a subset of T cells, and M2 are controlled by IL10 and TGFB
Th17 cells secrete IL17 that stimulate resident renal cells to produce chemokines and inflammatory mediators- recruits primarily neutrophils. Th17 cells also faciliate infiltration of Th1, Th17 and monocytes by secreting?
CCL20 aka macrophage inflammatory protein 3 (MIP3)
Each of the three complement pathways have been linked to kidney disease. When there is damage to kidneys, DAMPs signal to all 3 pathways to make C3 and C5 which activate MAC and?
inflammation, which activate M1/M2 which leads to fibrosis and fibrotic repair
In kidney injury, complement activation occurs downstream of immune complex deposition (typeIII) or antibody mediated injury which is?
type II
Type II hypersensistivy reactions involve IgG or IgM and cell bound antigen. IgG/M binds to cellular antigen, leading to complement activation and cell lysis. An example of this reaction is?
patients with antiglomerular basement membrane (GBM) antibody mediate GN
Type III hypersensitivity involves IgG/M and soluble antigens. The antigen antibody complexes are deposited in tissues. Complement activation increases inflammation and recruits neutrophils, which release enzymes. An example of this reaction? (3)
post-streptococcal glomerulonephritis, rheumatoid arthritis, lupus
Kidney transplant is the only treatment for end-stage organ failure, with a barrier to this transplant being genetic compatibility. need to HLA match. What cuases transplant rejection?
host versus graft response, including histocompatitiblity Ags, hyperactue rejection, chronic rejection
(**need immunosuppressive drugs for successful trasnplant)
Autografts are grafts exchanged from one part to another part on the same person.
Isografts is exchange between same genetics (identical twin).
Allo grafts are exchange between nonidentical people of the same species
Xenografts is what?
grafts from different species which increases chance of rapid attack by body. inserting human genes into animals helps survival
what are the four key concepts in kidney transplantation? 4
- condition of allograft
- donor-host antigenic disparity
- strength of host anti-donor reponse
- Immunosuppressive regimen
When new tissue is transplanted, it sends mediators which leads to tissue damage via:
1. clotting cascade and fibrinopeptides
2. fibrinopeptides increase vascular permeability and attract neutrophils and Mø
3. kinin cascade produces bradykinin which causes vasodilation and increased vascular permaebility
4?
if these proinflammatory responses are uncontrolled, it can result in hyperacute allograft rejection
ABO is the major blood group system, and is a barrier to transplantation. Ags to A and B are in individuals without these antigens on their RBCs. What kind of transplants is ABO matching not important for? (3)
corneal transplant
heart valve transplant
bone/tendon grafts
NONVASCULARIZED TISSUES
Group AB is the universal acceptor while Group O is the universal donor (any blood takes donated O). What do A and B take?
A takes A or O
B takes B or O
When matchin donor and recipient, for which transplants is it not important to test for pre-existing non-ABO Abs such as anti-class I/II HLA abs?
non vascularized tissue transplants- such as corneal heart valves and bone
How do preexisting Abs appear?
pregnancy induced HLA sensitization leads to being able to detect anti-HLA class I/II Abs in humans
Microcytotoxicity test for preformed Abs has 3 steps.
- recipient serum with Abs is added to donor cells, binding to them
- complement is added (MAC), forming pores in the cells
- ?
- dye is added and accumulated in cells = preformed Abs are present
Successful transplant is dependent on HLA Ags, MHC/HLA class 1 and 2. Compatibility between donor and recipient is required due to the?
extreme polymorphism of HLA
class 1 HLA(A and B) are strong barriers to transplantation, the 3 most important for class 2 are?
HLA-DR/DP/DQ
The source of lymphocytes for HLA class 1 typing is in the spleed and LN (dead cadaver). HLA antisera are obtained (vaccine) which contains abs to HLA ags. The abs bind to HLA Ag on lymphocytes. the ab-ag complex formed, activates complement and lysis. what does it mean if both the donor and recipient end up with dye inside the cell?
the HLA ag are identical
when the same process is done for both donor and recipient and the donor has dye inside but the recipient does not, then that menas the HLA Ag are NOT identical
MICROCYTOTOXICITY TEST FOR CLASS I HLA
When testing for class II HLA compatibility, donors which dont proliferate d/t radiation but can serve as APCS are mixed with recipient cells, add H-thymidine, proliferation occurs and radioactivity is incorporated in DNA that allows cell proliferation. What does this mean in regards to if the donor/recip match?
this result means the recipient cells do not share the same class II MHC as the donor
MIXED LYMPHOCYTE RESPONSE MLR
When radiation to donor cells when testing class II HLA is done and added to recipient cells along with H-thymidine radioactivity is NOT incorporated into the DNA if there is NO cell proliferation. The result is no proliferation/radiation in recipient cells so this means?
Recipient cells share the same class II MHC as donor = good for tranplantation
What are the 5 event in allograft rejection?
- APCs trigger CD4 and CD8 T cells
- Local and systemic Immune response
- Cytokines recruit/activate immune cells
- specific T cells, NK cells, Mø for mediated cytotoxicity
- Allograft rejection
Host versus graft disease is when a kidney is transplanted and the recipients T cells attack the transplant while graft versus host diesase is when?
When bone marrow is transplanted, the T cells in the transplant attack the recipients tissues
Host v graft is an adaptive immune response, much more strong and vigorous than response against pathogen. Why is this?
there is a higher frequency of T cells (1/100) which respond to allogeneic APCs (graft) as compared to 1/100000 T cells that respond to a virus
What is important to remember about immune memory of previous encounters with the donors Ags?
the SECOND graft from the same donor is rejected MORE rapidly
During direct allorecognition, T cells recognize intact allogeneic MHC molecules on the surface of donor APCs in the graft. In indirect allorecognition?
alloantigens are recognized in the context of recipient MHC class II molecules after they have been processed and presented by recipient APCs
Host V Graft: injury via DAMPs activate endothelial cells and T cells enter the allograft which interact with APC and become stimulated which causes inflammation and further activation. what are the humoral and cellular mechanisms for graft rejection?
humoral rejection via Th2 (IL4 IL5 IL10)
cellular rejection via Th1 (IL2, IFNY)
H vs G hyperacute rejection occurs immediately due to TYPE II hypersensitivity. the mechanism is that there are preformed antibodies directed against the donor tissue caused by?
accidental ABO blood type incompatability, presents in surgery with thrombosis and occlusion of graft vessels
***RARE
H vs G acute rejection occurs weeks to months via type IV hypersensitivity. T cell mediated immune response is directed against the foreign MHC, resulting in?
inflammation and leukocyte infilitration of graft vessels
**MOST COMMON
via CD4/CD8
H vs. G chronic rejection occurs months to years via type IV hypersensitivity. T cell mediated process resulting from the foreign MHC ‘looking like’ a self MHC carrying an Ag. resulting in?
intimal thickening and fibrosis of graft vessels as well as graft atrophy
**ischemia causes occlusion of blood = macrophages attack
What are the times and types of hypersensitivity reactions for the following?
Hyperacute
Acute
Chronic
H: immediately, Type II
A: weeks to months, type IV
C: months to years, Type IV
Graft vs Host disease (GVHD) is caused by reaction of grafted mature T cells in the marrow with allo-ags of the host, occuring more in what type of recipients?
immunocompromised
***occurs most in small bowel, lung, or liver
Acute GVHD is when epithelia cell death occurs in the skin, liver and GI. clincally presents as?
rash, jaundice, diarrhea, and GI hemmorhage
Chronic GVHD is when there is fibrosis and atrophy of the affected organ, presents as?
complete dysfunction of the affect organ, obliterating small airways
GVHD onset varies and it is a type IV hypersensitivity. Donor t cells in the graft proliferate and attack the recipients tissue. most commonly seen in____ and presents with? (3)
bone marrow transplants
presents with diarrhea, rash and jaundice
what are the two different ways the graft attacks and kills recipient tissue?
either via Fas-Fas-L or Perforin/Granzyme, both resulting in apoptosis of recipient cell
