Immunological Aspects of the renal system Flashcards
what are some risk factors that can lead to AKI and CKD
- Age
- Race or ethnic group
- genetic factors
- Hypertension
- DM
- Metabolic syndrome
Why is an ischemic injury critical in kidney disease
since kidneys are the major filtering organ in the body they receive about 20% of the total cardiac output
the high renal oxygen demand is required due to large amount of ATP consumption of the necessary solute reabsorption
therefore an Ischemic acute kidney injury leading to metabolic acidosis and ATP depletion is one of the major causes of ARF
-abrupt decrease in kidney function
what are some causes of kidney hypoperfuusion and AKI
- Intravascular volume depletion and hypotension
- Decreased effective intravascular volume
- Hepatorenal syndrome
- Medications
- Sepsis
- Renal vascular disease
all lead to hypoxia leading to AKI
what is Sterile Inflammation and DAMPS
Sterile renal inflammation is induced by intrinsic Damage associated molecular patterns (DAMPs)
- released from dying parenchymal kidney cells
- generated during ECM degradation and remodeling
C reactive protein can bind DAMP to activate complemnt
Immune cells can recognize DAMPS via Toll like receptors to initiate an immune response
what are some DAMPS and what do they activate
Molecular patterns (alarmins) are endogenous intracellular molecular structures
-HMGB1 (nucleous protein) (recognized by RAGE) -Uric acid (recognized by NLRP3) -HSPs (exosomes) (recognized by scavenger receptor class A) -S100 protein (cytoplasm) -Hyaluronans in ECM
all these then activate NF-kB pathway leading to a release of inflammatory cytokines from dendritic cells
what are some Immune mediated mechanisms of AKI
activation of Dendritic cells, macrophages, and endothelial cells:
-Dendritic cells release IFN, CXCL2, IL-IB, and IL-12
- Macrophages release ROS, IL-1B, TNF, IL-6 and chemokines
- Endothelial cells release TNF, IL-6, chemokines and IFNa
leads to WBC recruitment: Neutrophils, Macrophages, lymphocytes, dendritic cell activation
-then leads to leukocyte activation, cytokine release, migration, tissue migration, released flow
what are Pro-inflammatory responses and the development of AKI via DC, Mo, and Tcells
DC: increase in Th1 and Th17 differentiation
-early stages of AKI immune responses mediated by Th17 cells dominate tissue injury
M0: will turn to M1 and increase TNF-a and IL-6
Tcell: increase CD4 Th1 response, increase IFN-y, IL-6 and decrease IL-4
-very prominate Th1 cells in late stage of AKI
what are some anti-inflammatory responses in response to AKI via DC, Mo, and Tcell
DC: nothing really
Mo: M2 play a key role in tissue repair and increase in arginase-1 and increase in IL-10 also increase clearance of early apototic cells
Tcells: decreases antigen specific T cell expansion
Effects of a M1 vs a M2 macrophage
M1: induced by PAMPs and DAMPs binding to TLR or PRR
- IFN-y are proinflammatory cytokines and promote differetiation of M1
- cytokines produced by M1 Mo perpetuate the acute phase of inflammation in kidney
- release IL-1, IL-12, IL-23 to increase inflammation
- ROS, NO, and lysosomal enzymes to cause killing
M2: induced by IL-4 and IL-13 produced by certain subsets of T cells
- important for tissue repair and renal fibrosis which are controlled by IL-10 and TGF-B
- release IL-10 and TGF-B to act as anti inflammatory effects
- proline, polyamines, and TGF-B to induce wound repair and fibrosis
- stimulation of pericyte accumulation and activation, myofibroblast differention, and production of ECM
Role of Th72 cells in AKI
accumulated Th17 cells secrete IL-17 that stimulates resident renal cells to produce inflammatory mediators like cytokines, chemokines and other mediators
IL-17 induces expression of chemokine CCL20 that leads to recruitment of neutrophils
Th17 facilitate infiltration of Monocytes, Th1 cells and Th17 cells directly by secretion of CCL20 and macrophage inflammatory protein -3 (MIP-3)
recruitment of other pro-inflammatory leukocyte subsets leads to progression of immune mediated kidney disease
How does Treg cells play a role in AKI
important for peripheral tolerance
will ihibit: Neutrophils, T and B lymphocytes via IL-10
activates tissue remodeling via TGF-B and increase tropic factors
How does Complement play a role in AKI
all three activation pathways are shown in KIdney diseases
The reason for the kidneys unique susceptabillity to complement induced damage is that filtration favors tissue deposition of immune complexes
- DAMPS lead to activation of complement that increases deposition of C3b and C5b and production of C3a and C5a (furthur activates complement and tissue resident cells, proinflammatory response)
- MAC C5b-9 leads to massive cell death and much collateral damage
- at the end of necrosis of kidney cells the Mo takes on M2 and control tissue repair and fibrosis
What is the Type II hypersensitivity in AKI terms
IgG or IgM
cell bound to antigen
- IgM or IgG antibody binds to cellular antigen leading to complement activation and cell lysis, this can happen because positvely charged Ags can be planted in the negatively charged glomerular basement membrane
- this leads to anti-glomerular basement membrane antibody mediated GN
what is the Type III hypersensitivity in AKI terms
IgG or IgM
soluble antigen
Antigen-antibody complexes deposited in tissues, complement activation leads to recruitment of inflammatory mediators
leads to post-streptocococcal glomerulonephritis, rheumatoid arthritis, and systematic lupus erythematosus
when do we use kidney transplantation and what is important for making it happen
is used for end stage renal disease
barrier to transplantation is the genetic incompatibility of donor to recipient
sucessful transplantation uses immunosuppressive drugs and also match the HLA to prevent rejection
what are the 4 different drafts and what one do we use the most
Autografts: exchanged from the same individual
Isografts: grafts exchanged between identical twins
Allografts: exchanged between the same species but are not identical
Xenografts: graft between different species
- normally susceptible to rapid attack
- insertion of human genes does increase the success rate
what are the 4 key concepts of Transplantation
1) the condition of the allograft
2) Donor host antigenic disparity
3) strength of host anti-donor response
4) immunosuppresive regime
why is damage of the allograft so bad for the success rate of a transplant
will release DAMPs that will lead to a biochemical cascade
- clotting cascade generates fibrin and fibrinopeptides
- fibrinopeptides increase local vascular permeabillity to then allow for accumulation of neutrophils and monocytes
- kinin cascade produces bradykinin which is a vasodilater also increasing vasodilation
leads all to hyperacute allograft rejection
when matching a donor and recipient what do we look for in the Blood group antigens
the donor and recipiet must not have counteracting Ags present and Abs present
if not can lead to rejection!
if have A antigens then have Anti B Abs
O has no antigens but both anti A/B
AB has no Abs to antigens
when do we not have to worry about matching blood group antigens during transplantation
during non vascularized tissue transplants
Corneal transplantation
Heart valve transplantation
Bone and tendon grafts
ABO is also not a contradiction to stem cell transplantation
How do we test for pre-existing non ABO abs
called Microcytotoxicity Test for preformed ABs
- take donor cells and add to recipient serum with Abs
- complement is then added to make MAC if there is preformed Abs Dye will go into cells
- if not then no preformed Abs
what is the significance of the HLA system and why its important to match them between donor and recipient
Since all cells have antigens presenting on them that the Immune system identifies if they are foreign or not, it is important that they match between donor and recipient
2 class system: Class I (present on all cells) and Class II (present on APC cells)
- critical that the Class I matches
- has 6 HLA class I alleles (3 maternal and 3 paternal) (same for class 2)
How do we test for class I HLA compatibility
Complement-dependant Serology
gather lympocytes and then HLA antisera from planned immunization of volunteers or from multiparous women
antisera contain Abs to HLA ags
they will bind on surface of lymphocytes
-create the classical complement cascade and then will caused lymphocyte lysis
Microcytototoxity test for Class I HLA
- add Antibodies to whatever HLA antigen
- then add complement to both and see if dye enters the cells
- if both do then there is a match
- if not they dont match
Testing for class II HLA compatibillity
not as important as class I
Mixed lymphocyte response:
give radiation to donor cells so wont proliferate but serve as APCs
-add recipent cells with radioactive thymidine
-if cells proliferate then they dont match
-if cells radioactivity dont add DNA and no proliferation then good for transplant
what are the 5 immune events during Allograft rejection
1) APCs trigger CD4 and CD8 T cells
2) both a local and systemic immune response
3) cytokines recruit and activate immune cells
4) Development of specific T cells, NK cells, or Mo mediated cytotoxicity
5) Allograft rejection
what are the two types of immune responses in transplantation
Host vs graft disease (kidney)
Graft vs host disease (bone marrow)
Host vs Graft responses and what are the two types of Allorecognition
host immune system attacks donor tissue via an adaptive immune response
- much more vigorous and strong then normal response
- second graft from same donor gets rejected faster
- can be humoral rejection Th2 (IL-4,5,10)
- can be cellular rejection Th1 (IL-2 IFN-y)
Direct Allorecognition: T cells recognize intact Allogeneic MHC molecules on the surface of donor APCs in the graft
Indirect allorecognition: alloantigens are recognized in the context of recipents MHC class II molecules after they have been processed and presented by recipient APCs
What are the 3 types of rejections
Hyperacute: Onset is immediate, performed antibodies directed against the donor tissue, caused by accidental ABO blood type incompatibility which is rare or sensitized to the donor via transplants, multiple blood transfusions or pregnancy, type II hypersensitivity
Acute: weeks to months, T cell mediated immune response directed against the foreign MHC. inflammation and leukocyte infiltration of graft vessels results. most common type. Type of hypersensitivity IV
Chronic: months to years, T cell mediated process resulting from the foreign MHC looking like a self MHC carrying an antigen. An indirect response. results in intimal thickening and fibrosis of graft vessels as well as graft atrophy. Type IV hypersensitivity.
-does not respond to immunosuppressive therapy
Graft vs host disease and 2 types
Reaction of grafted mature T cells in the marrow that allo-ags of the host
directed against minor H ags because the HLA are usually matched
recipient is usually immunocomprimised because immune system is unable to reject the allogenic cells in the graft
-occurs in transplants that are of the small bowel, lung or liver which contain a number of T cells
Acute GVHD: epithelial cell death in the skin, liver and GI
-clinically rash, jaundice, diarrhea, and GI hemorrhage
Chronic GVHD, Fibrosis and atrophy of affected organ
- dysfunction of organ
- produce small airways
Donor T cells attack the recipients tissue
- Type IV hypersensitivity
- Fas-FasL binding of CD8 T cells to target cell to kill
- Perforin/granzyme release on target cell to kill
