Immunological Aspects Of Renal System Flashcards
AKI has been traditionally described as a rapid decrease in kidney function as measured by increases in serum _____
Creatinine
Generally, how does AKI lead to CKD?
AKI involves hemodynamic alterations, inflammation, and endothelial and epithelial cell injury. Renal tissue repair can be adpative and restore epithelial integrity or maladaptive, leading to CKD (gradual loss of kidney function)
_______ is classically defined as an abrupt decrease in kidney function, and AKI is a major cause
Acute renal failure (ARF)
Impairment of kidney filtration is activated by ____ depletion in vascular and tubular cells
ATP
[caused by changes in perfusion]
What type of kidney injury results from generalized or local impairment of O2 and nutrient delivery to, and waste product removal from, cells of the kidney
Ischemia reperfusion injury
Effect of ischemia reperfusion injury on individual renal cells
Tubular epithelial cells undergo injury which may result in apoptosis or necrosis
May also be associated with renal tissue fibrosis if not healed correctly
Order of organs affected by ischemia reperfusion injury
Kidney
Liver
Brain
Intravascular volume depletion and hypotension
Decreased effective intravascular volume
Medications (cyclosporin A, tacrolimus, ACE inhibitors, etc.)
Hepatorenal syndrome
Sepsis
Renal vascular disease
The above conditions cause pathophysiological states that can contribute to generalized or localized ________
Ischemia (aka hypoxia, renal hypoperfusion, etc.)
Endothelial and smooth muscle cells of microcirculation play critical role in pathophys of AKI.
When th endothelium is injured d/t hypoxia, small arterioles in post-ischemic kidney ________ more than vessels from normal kidney; this effect is amplified partly by ______production of NO and other vasodilatory substances by damaged cell.
This is further augmented by release of inflammatory ________, generated as a result of enhanced leukocyte adhesion and activation
Small vessel ______ occurs d/t endothelial leukocyte interactions, and activation of the coagulation system
Vasoconstrict; reduced
Cytokines
Occlusion
General pathogenic mechanisms of ischemic AKI include endothelial injury, epithelial cell injury, and inflammation leading to what overall defects in kidney function?
Reduced GFR
High FeNa
Concentration defects
What type of patients are at signficantly increased risk of AKI?
Hospitalized patients and critically ill patients
How does inflammation occur in sterile renal tissue?
Sterile renal inflammation is induced by endogenous DAMPs (aka alarmins) which are released from dying parenchymal cells
Immune cells respond to DAMPs via TLR activation (i.e., TLR4) –> NFkB – > transcription of inflammatory mediators
DAMPs released from dying parenchymal cells
ATP
HMGB1 (nucleolus)
Uric acid
HSPs (exosomes)
Hyaluronans in ECM
S100 protein (cytoplasm)
What type of cell death results in release of DAMPs?
Necrosis only! - may result in fibrotic changes
Apoptosis does not release DAMPs, important in repair
Dendritic cell role in renal immunity
Antigen presentation
Migration
Type I IFNs, CXCL2, IL-1B, and IL-12
Involved in AKI and infections
Macrophage role in renal immunity
ROS, IL-1B, TNF, and chemokines
Involved in most kidney diseases
Role of endothelial cells in renal immunity
TNF, IL-6, chemokines, and IFN-a
Involved in IC-GN (glomerulonephritis), diabetes, and sepsis
T/F: Macrophages migrate in and out of renal tissue, acting as APCs
False; macrophages REMAIN IN THE TISSUE and interact with immune cells brought there by DC’s (tissue sampling = major function)
DC’s migrate to regional LNs and present to naive T cells, cytokines produced will determine helper cell type that develops
Macrophages have ________; they can acquire M1 or M2 type which changes outcome of damage in renal tissue
Plasticity
What type of macrophages are induced by PAMPs and DAMPs through binding to TLRs and other PRRs?
What are the cytokines that promote their differentiation?
What effect do they have on the kidney?
Classically activated M1 macrophages
Induced by IFN-gamma (pro-inflammatory cytokine)
Cytokines produced by M1 macrophages perpetuate the acute phase of inflammation in the kidney
What type of macrophages are induced by IL-4 and IL-13 produced by certain subsets of T cells?
What effect do they have on the kidney?
Alternatively activated M2 macrophages
Important in tissue repair and renal fibrosis which both are controlled by IL-10 and TGF-beta
Apoptotic cells may lead to differentiation of what type of macrophages?
M2
What cytokine produced by M2 leads to fibrosis?
TGF-beta (important for fibroblasts which deposit collagen)
AKI triggers recruitment of ______ and ____________ cells within several hours of tissue injury
Inflammatory _______ infiltrate to the site of tissue injury shortly after neutrophils, where they differentiate into macrophages and become M1 or M2
Neutrophils; NK cells
Monocytes
In acute kidney injury _____ macrophages dominate
In chronic kidney injury, ________ macrophages dominate
M2; M1
Outcomes of AKI are mediated by _______ immunity
Innate
What system associated with innate immunity plays a huge role in renal injury and inflammation?
Complement (therapeutic agents = monoclonal Abs like anti-C5 antibody)
Activation of complement in AKI can be inferred from what types of clinical findings?
Deposition of complement proteins in the kidney
Perturbations of C3 and C4 levels in blood (C3 typically higher; if you have complement activation you will see reduction in circulating levels of C3 and 4 - must check urine for C3a and C5a to verify that it is being activated in renal system)
Detection of C3a and C5a fragments in plasma or urine (bc activation of complement requires formation of these)
Association of mutations and polymorphisms in complement proteins with the development of kidney disease
Why function do C3a and C5a serve once activated?
Chemoattractants for immune cells like neutrophils (which have receptors for these compounds), once those cells accumulate in the kidney there is ROS burst
What effect do C3a and C5a have on human mast cells?
Stimulate chemotaxis of mast cells
Note though that most healthy kidney tissue does not contain mast cells
In the adaptive response to renal disease, early stages are mediated by _____ cells, while _____ cells prevail in later stages
Resident macrophages are activated by ______ from Th1 cells
Treg cells, which produce _____ are also recruited to protect against overwhelming Th1 and Th17 immune response
Clinical outcome is a balance between proinflammatory and antiinflammatory immune cells
Th17; Th1
IFN-y
IL-10
Role of Th17 cells in kidney injury (note major chemokine)
Secretion of IL-17 that stimulates resident renal cells to produce chemokines and other inflammatory mediators which recruit neutrophils to renal tissue
Major chemokine = CCL20 which recruits monocyte and Th1 cells
Role of Treg cells in renal disease
Inhibitrion of proinflammatory cytokines from T helper cells
Switching of macrophages to M2 phenotype
Attenuation of renal injury through IL10 mediated suppression of innate immune system
[remember Tregs prevent autoimmunity by attenuating responses!]
Grafts exchanged from one part to another part of the same individual
Autografts
Grafts exchanged between different individuals of identical genetic constitutions (e.g. Twins)
Isografts
Grafts exchanged between nonidentical members of the same species
Allografts
Graft exchanged between members of different species
Xenografts
Which of the following is particularly susceptible to rapid attack by naturally occurring Abs and complement?
A. Autografts
B. Allografts
C. Xenografts
D. Isografts
What minimizes the chances of this type of reaction?
C. Xenografts
Insertion of human genes into genomes of donor animals minimizes risk
4 key concepts for organ transplantation success
- Condition of allograft
- Donor-host antigenic disparity
- Strength of host anti-donor response
- Immunosuppressive regimen
Overview of immune events leading to allograft rejection
- APCs trigger CD4 and 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
When transplanted, damaged graft tissues release mediators which trigger several biochemical cascades leading to immediate tissue damage:
Clotting cascade generates fibrin and _________, which increase local vascular permeability and serve as chemoattractant for _______ and ________.
The kinin cascade produces _______, which causes vasodilation, smooth muscle contraction, and _______vascular permeability.
These early proinflammatory responses, if uncontrolled, can result in hyperacute allograft rejection
Fibrinopeptides; neutrophils; macrophages
Bradykinin; increased
Major barriers to transplantation of a solid organ
Blood group antigens
HLA alleles
One example of ABO blood reactions (during blood typing) is group A blood being reacted with anti-A antibodies causing cell lysis.
How does this cell lysis occur?
Abs + Complement = MAC
There are hundreds of allelic forms of HLA molecules; each individual inherits only 10-12 alleles/person. These are __________ expressed.
Which HLA antigens are particularly strong barriers to transplantation?
Co-dominantly
The class I HLA Ags (HLA-A and HLA-B) are particularly strong barriers to transplantation
There are 3 most important class II HLA pairs for transplantation: HLA-DR, HLA-DP, and HLA-DQ
When would you NOT need to test for HLA compatibility prior to transplantation?
Non-vascularized tissues! Like cornea, heart valves, and bone
Order of tests to determine donor-host compatibility
- Blood group Ags
- HLA compatibility
* **
How is class I HLA typing done?
Complement-dependent serology
Take lymphocytes from spleen, lymph node, or peripheral blood (without RBCs or platelets)
Antisera contain antibodies to HLA Ags
Abs bind to HLA Ag on lymphocytes, the complex formed activates classical complement –> lymphocyte lysis - detected by staining the cells
Result of complement dependent microcytotoxicity test with non-identical class I HLA Ags
Abs do not bind, MACs do not form, and cells will not lyse or show up with dye
[not good to transplant!]
How do pre-existing donor-specific anti-HLA Abs occur in recipients?
Pregnancy can induce HLA sensitization
What type of result in a complement-dependent microcytotoxicity test for preformed Abs would prevent you from transplanting for fear of incompatibility?
Recipient serum Abs placed with donor cells –> dye accumulation (indicating that the two have reacted via formation of MAC)
The relevance of disparities in MHC Ags induced by MINOR Ags are not generally assessed by tissue typing but can be assessed in what way?
Mixed lymphocyte response (MLR) testing - aka class II HLA typing
MLR is used for class II HLA typing, which can also stimulate a reaction just more minor than class I. How is MLR done?
Peripheral blood lymphocytes from radioactivated donor and recipient are mixed in tissue culture
If rapid proliferation occurs, lymphocytes are INCOMPATIBLE (measured by thymidine which will be incorporated into DNA) - indicates donor and recipient do not have the same class II
After performing a MLR class II HLA typing, you note no reaction/no radioactivity in the cells after several days. Would you proceed with the transplantation?
Yes; donor and recipient share class II HLAs
When a kidney is transplanted the recipient’s T cells attack the transplant = an example of what type of immune response to transplantation?
Host vs graft disease
[adaptive immune response]
When bone marrow is transplanted the T cells in the transplant attack the recipient’s tissue = example of what type of immune response to transplantation?
Graft vs. host disease
[Can also happen in intestine, lung, liver transplantations because immune cells are transplanted along with organ - no way to get rid of them without damaging the tissue]
Difference between direct and indirect allorecognition during allograft rejection
Direct alloantigen recognition:
T cells recognize donor MHC and bound peptides on DC from graft –> direct CTL killing of graft cells
Indirect alloantigen presentation:
Recipient DC takes up and processes donor MHC molecules –> Ab-mediated injury to graft cells and inflammation mediated injury to graft
Host vs. graft response involves non-immune injury to the graft via DAMP activation and T cells enter the allograft. Ag specific T cells are activated and inflammatory cytokine field is created.
What are the 2 major effector mechanisms of graft rejection including associated cytokines?
Humoral rejection via Th2 (IL-4, IL-5, IL-10)
Cellular rejection via Th1 (IL-2, IFN-y)
Which of the following types of rejections is associated with reactivation of sensitized T cells and takes days to develop?
A. Hyperacute
B. Accelerated
C. Acute
D. Chronic
What is the predominant mechanism of rejection: humoral or cellular?
B. Accelerated
[humoral]
Which of the following types of rejections is associated with primary activation of T cells and takes days to weeks to develop?
A. Hyperacute
B. Accelerated
C. Acute
D. Chronic
What is the predominant mechanism of rejection: humoral or cellular?
C. Acute
[if cellular-acute it is cellular rejection via Th1, if it is vascular-acute it is humoral via Th2]
Which of the following types of rejections is associated with preformed antidonor Abs and complement and takes minutes to hours to develop?
A. Hyperacute
B. Accelerated
C. Acute
D. Chronic
What is the predominant mechanism of rejection: humoral or cellular?
A. Hyperacute
[humoral]
Which of the following types of rejections is associated with both immunologic and nonimmunologic factors and takes months to years to develop?
A. Hyperacute
B. Accelerated
C. Acute
D. Chronic
What is the predominant mechanism of rejection: humoral or cellular?
D. Chronic
[humoral usually; thought to be delayed type hypersensitivity which would likely make it a cellular response]
Which of the following types of rejection is associated with complement activation, endothelial damage, inflammation, and thrombosis due to the existance of preexisting Abs?
A. Hyperacute
B. Accelerated
C. Acute
D. Chronic
A. Hyperacute
Which of the following types of rejection is associated with parenchymal cell damage, interstitial inflammation, and endothelialitis via primary activation of T cells?
A. Hyperacute
B. Accelerated
C. Acute
D. Chronic
C. Acute rejection
Which of the following types of rejection is associated with chronic DTH reaction in vessel wall, intimal smooth muscle cell proliferation, and vessel occlusions?
A. Hyperacute
B. Accelerated
C. Acute
D. Chronic
C. Chronic
2 phases of host vs. graft disease
- Recognition - adhesion, initiation of apoptosis
2. Effector phase - mobilization of perforin and granzyme –> apoptosis and DNA fragmentation
Which of the following types of rejection does NOT respond to immunosuppresive therapy?
A. Hyperacute
B. Accelerated
C. Acute
D. Chronic
D. Chronic
T/F: one reason that graft vs. host disease might occur is because the host is immunocompromised and unable to reject the allogeneic cells in the graft
True
For solid grafts, graft vs. host disease might be classified as what 2 types?
Acute = epithelial cell death in skin, liver, and GI; clinical presentation with rash, jaundice, diarrhea, and GI hemorrhage
Chronic = fibrosis and atrophy of affected organ; clinical presentation with organ dysfunction and obliteration of small airways
Graft vs. host disease mechanism
Donor APCs activate donor CD8 T cells by cross presenting recipient Ags on MHC class I
Direct vs. indirect allorecognition
Direct: T cell recognizes MHC itself as foreign (not Ag) - acute rejection
Indirect: T cell recognizes process Ag - chronic rejection
Which of the following does not respond to immunosuppressive therapy?
A. Hyperacute rejection
B. Acute rejection
C. Accelerated rejection
D. Chronic rejection
D. Chronic rejection
