Renal Immunology Flashcards
What is one of the major causes of Acute renal failure ARF
Ischemic acute kidney injury leading to metabolic acidosis and ATP depletion
What induces sterile renal inflammation
DAMPs released from dying parenchymal cells or during ECM degradation and remodeling
Activate PRRs causing release of TNFa, IL-6, IL-1
What activates complement pathways and what type of receptors are activated to induce innate immune response in sterile renal inflammation
CRP binds damps activating complement classic pathway Immune cells (dendritic, macrophage, endothelial cells) recognize DAMPs via TLRs inducing innate immune response
Macrophage activation
IFN-y is major cytokine activating macrophages
Macrophages are single largest contributor to inflammatory cytokines in body
M1 vs M2 macrophage
M1 play key role in acute kidney injury
-induced by PAMPs and DAMPs binding TLR/PRR
-IFN-y promotes their differentiation
-release IL-1/12/23, ROS/NO
M2 play key role in tissue repair
-activated by IL-4/13
-release IL-10 and TGF-b promoting repair
Early stage vs late stage of AKI what T cells dominate
Early stage is Th17 cells
Late stage is Th1 cells
Macrophage reprogramming
M1 macrophages can be reprogrammed to M2 macrophages by CSF-1 and IL-10
Macrophage stimulation of matrix deposition/tissue repair
Profibrotic factors TGF-b and PDGF attracting pericyte accumulation which differentiate into myofibroblasts and produce ECM
Th17 function
Secrete IL-17 stimulating resident renal cells to produce inflammatory mediators
IL-17 induces expression of CCL20 (MIP3-macrophage inflammatory protein 3) leading to neutrophil (mainly), monocyte, Th1 and Th17 cell recruitment
What causes the kidneys unique susceptibility to complement induced damage
Filtration favors tissue deposition of immune complexes
Compliment pathway role in damage
AKI and tissue damage leads to excessive generation of DAMPs which activate resident immune cells via PRRs
C3b and C5a activation causes further activation of tissue resident cells
Deposition of membrane attack complex leads to massive cell death
Which types of hypersensitivity reactions usually occur in AKIs
Type II and Type III
Type II hypersensitivity
IgG or IgM mediated
Formed by cell-bound antigen
IgG/IgM Ab binds to cellular antigen, leading to complement activation and cell lysis
Ex. Anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis (Positively charged Ags are planted on the negatively charged GBM, leading to type II hypersensitivity reaction)
Type III hypersensitivity
IgG or IgM mediated
Formed by soluble antibody
Antigen-antibody complexes are deposited in tissues
Complement activation provides inflammatory mediators and recruits neutrophils
Enzymes released from neutrophils damage tissues
Ex. Post streptococcal glomerulonephritis, rheumatoid arthritis, SLE
Xenografts
Exchanged b/w members of different species
Very susceptible to rapid attack by naturally occurring Abs activating complement
Insertion of human genes into genome of donor animal can help
What molecules are released by graft tissues leading to host immune responses and possible hyperacute allograft rejection
Mechanical trauma and ischemia-reperfusion injury (AKI) to graft tissues causes release of DAMPs, triggering the clotting cascade, which leads to increased vascular permeability and neutrophil/monocyte attraction
Also leads to kinin cascade w/bradykinin, causing vasodilation, smooth muscle contraction and further increasing vascular permeability
If these early responses aren’t controlled, you end up with hyperacute allograft rejection
ABO incompatible kidney transplant
Used to be absolute contraindication due to risk of hyperacute rejection
Now with better immunosuppression, ABOi-KT outcome is comparable to ABO compatible
ABO matching is not important for what types of transplantations
Corneal transplant, heart valve transplant, bone and tendon grafts (nonvascularized tissues)
ABO incompatibility is not a contraindication to stem cell transplantation
What Ig reacts with blood type antigens
Most likely IgM because they are carbohydrate antigens
Microcytotoxicity test for pre-existing non-ABO Abs against donor
Recipient serum with Abs is added to donor cells
Complement is added
Dye is added
If dye accumulates in the cells, that means a MAC complex was formed and there are indeed preformed Abs present
The success of transplantation is dependent on matching of
HLA Ags
What HLA class is strongest barrier to transplantation
HLA class I because all nucleated cells express them
Mixed lymphocyte response
Donor cells are radiated so they cannot proliferate but can serve as APCs
Mixed with recipient cells and lymphocytes + H-thymidine
If recipient cells proliferate and radioactive thymidine is seen- HLA class II of recipient does not match donor cells
If no radiation seen/no proliferation - good for transplant
Sequence of events in allograft rejection
APCs trigger CD4/CD8 T cells
Both a local and systemic immune response develop
Cytokines recruit and activate immune cells
Development of specific T cells, NK cells, or macrophage mediated cytotoxicity
Allograft rejection
Host vs graft disease
When a kidney is transplanted and the recipients T cells attack the transplant
Adaptive immune response
If a second graft is performed from the same donor, it is rejected more rapidly
Direct allorecognition
T cells recognize intact allogenic MHC molecules on the surface of donor antigen-present cells in the graft
Indirect allorecognition
Alloantigens are recognized in the context of recipients MHC class II molecules after they have been processed and presented by recipient APCs
Host vs graft response trigger
Non-immune injury of the graft (DAMPs released) activates endothelial cells, and T cells enter the allograft
Ag specific T cells interact with APC and become stimulated, release cytokines which further the process
Effector mechanisms of host vs graft response
Humeral rejection - Th2 - IL-4, 5, 10
Cellular rejection - Th1 - IL-2, IFN-y
Hyperacute rejection
Occurs immediately
Type II hypersensitivity - Humeral response caused by accidental ABO blood type incompatibility or previous sensitization to Ags- Preformed Ab mediated complement activation, endothelial damage, inflammation and thrombosis
Acute rejection
Occurs in weeks to months
Type IV hypersensitivity - Cell mediated response against foreign MHC- can be both CD4/CD8 mediated
Donor DCs (passenger leukocytes) play important role in triggering rejection
Donor DCs migrate to lymph nodes and stimulate a primary immune response in recipient lymphocytes
There can also be some indirect response involved
Most common type
Chronic rejection
Occurs in months to years
Type IV hypersensitivity - Cell mediated response (mainly an indirect response) resulting from foreign MHC “looking like” a self MHC carrying an antigen - M2 macrophages and T cells
Deposition of complement/Ab complexes can also be involved
Chronic DTH reaction in vessel wall, intimal smooth muscle proliferation (repair process), vessel occlusion and ischemia
Important non-immunologic factors in chronic rejection
Ischemia-reperfusion damage
Recurrence of the disease that caused failure of kidney
Nephrotoxicity of drugs
-Chronic rejection does not respond to immunosuppressive therapy
Graft vs host disease
Reaction of grafted mature T cells in bone marrow is directed against Minor H Ags of the recipient when HLA Ags are usually matched
Occurs in the immunocompromised recipients because their immune system is unable to reject the allogeneic cells in the graft
Acute GVHD
Epithelial death in the skin, liver and GI
-Rash, jaundice, diarrhea
Chronic GVHD
Fibrosis and atrophy of the affected organ
- may lead to complete dysfunction of the affected organ
- may produce obliteration of small airways
What tissues are commonly involved in GVHD
Small bowel, lung, liver- they naturally contain a number of T cells
GVHD mechanisms
Donor APC recognize recipient Ag and activate donor CD4/CD8 cells by cross presentation
Cell killing mediated by Fas-FasL or Perforin/Granzyme methods
Examples of DAMPs and what receptor recognizes them and what downstream pathway they activate
HMGB1- RAGE
Uric Acid- NLRP3
HSPs- Scavenger receptor class A
All activate NF-kB pathway
Activated T cells release what cytokines to activate Th1, Th2 and Th17 cells, respectively
Th1- IL-12 –> antigen presentation/cellular immunity
Th2- IL-4 –> humoral immunity and allergy
Th17- IL-6/TGF-B –> tissue inflammation
