The Role of Immunity In Renal Disease & Transplantation Flashcards
What is the immune complexes deposition?
Deposition of circulating immune complexes in the glomeruli, causing inflammation and glomerular damage
What are examples of immune complex deposition diseases?
SLE
IgA nephropathy
What is molecular mimicry?
Antibodies generated against a foreign pathogen cross-react with kidney antigens, causing an autoimmune response
What are examples of diseases that portray molecular mimicry?
Post-streptococcal glomerulonephritis
What is the direct autoimmune response?
Antibodies directly targeting kideny-specific antigens or autoantigens
What are examples of diseases where there is direct autoimmune response?
Primary membranous nephropathy (phospholipase A2 receptor, PLA2R-specific antibodies)
What is antibody-mediated glomerular damage?
Formation of antibodies against podocyte antigens, leading to direct podocyte injury and proteinuria
What are examples of diseases with antibody-mediated glomerular damage?
Minimal change disease (suspected immune-mediated injury to podocytes)
What is immune-mediated vasculitis?
Uncontrolled activation of the complement system, particularly the alternative complement pathway, leading to inflammation and tissue injury
What are example-disease of immune-mediated vasculitis?
Anti-neutrophil cytoplasmic-associated vasculitis (ANCA) (granulomatosis with polyangiitis)
What is complement dysregulation?
Uncontrolled activation of the complement system, particularly the alternative complement pathway, leads to inflammation and tissue injury
What are examples of diseases with complement dysregulation?
Atypical Hemolytic Uremic Syndrome (aHUS)
What is cell-mediated immune response mechanism?
T-cells mediate immune responses that lead to localized inflammation and tissue injury
What are example diseases of cell-mediated immune response?
Acute interstitial nephritis
What is the mechanism of delayed-type hypersensitivity?
Direct action of sensitized T cells when stimulated by contact with antigen
What are example-diseases of delayed-type hypersensitivity?
Allergic interstitial nephritis (commonly drug-induced)
What is the mechanism of innate immune activation via DAMPs?
Damage-associated molecular patterns released from injured kidney cells activate an immune response
What are example diseases of innate-immune activation via DAMPs?
Ischemic acute kidney injury
What is the immune response to infections?
Immune response against kidney infections caused by pathogen can lead to immune-mediated damage
What are example diseases of immune response to infections?
Bacterial pyelonephritis
Which bacterium causes bacterial pyelonephritis?
E. coli
What is thrombotic microangiopathies mechanism?
Immune-mediated injury to the microvasculature, leading to thrombosis and tissue ischemia
What are examples diseases of thrombotic microangiopathy mechanisms?
Shiga-toxin-producing E. coli-induced hemolytic uremic syndrome
What is the proteinuria-induced inflammation mechanism?
Increased levels of protein in the urine induce a stress response in the tubular cells, triggering inflammation and tubulointerstitial damage
What are example diseases of proteinuria-induced inflammation?
Focal segmental glomerulosclerosis (FSGS)
What can be transplated? (5)
- Blood/products
- Whole organs
- Partial organs
- Cells & Tissues
- HCT (hematopoietic cell transplantation)
What are pre-transplant procedure that the recipient receives?
Dialysis
LVAD
What are intra-operative procedures the recipient receives?
Surgery Cardiopulmonary Bypass
What are post-operative consequences to the recipient?
Reperfusion
What are the complications that the recipient might face?
Acute Rejection (acute)
Infection
Injury Repair (chronic)
In the example HLA-A* 24020102L what does A signify?
Locus
In the example HLA-A* 24020102L what does * signify?
Signifies DNA
In the example HLA-A* 24020102L what does “24” signify?
Type, corresponds to the serologic antigen or family
In the example HLA-A* 24020102L what does the first “02” signify?
Subtype
In the example HLA-A* 24020102L what does “01” signify?
Silent substitution
In the example HLA-A* 24020102L what does the second “02” signify?
Differences outside the coding region (introns)
In the example HLA-A* 24020102L what does “L” signify?
Expression
When may an SNP appear twice?
If it has been associated with more than one disease
What are the different types of allograft rejection?
- Hyperacute rejection
- Accelerated rejection
- Acute rejection (acute humoral and acute cellular)
- Chronic rejection
What is hyperacute graft rejection like?
- Normal kidney grafted into a patient with defective kidney and pre-existing antibodies against donor blood group antigens
- Antibodies against donor blood group antigens bind the vascular epithelium of the graft initiating an inflammatory response, which occludes blood vessels
- Graft becomes engorged and purple-coloured because of the hemorrhage
Which immune response is initiated during the hyperacute graft rejection, and how fast?
Complement mediated reaction within MINUTES of transplantation
What causes the hyper-acute graft rejection?
Pre-existing alloantibodies against blood group antigens or MHC antigens
What is the mechanism of Hyperacute rejection?
Preformed antibodies react with:
1. alloantigens on the vascular epithelium on the graft
2. activate complement
3. trigger rapid intravascular thrombosis and necrosis of the vessel wall
What is the mechanism of acute rejection?
In acute cellular rejection:
1. CD8+ T lymphocytes reactive with alloantigens on graft endothelial cells and parenchymal cells cause damage to these cell types.
What is endothelium inflammation called?
Endothelialitis
Which kind of antibodies may also contrubute to vascular injury?
Alloreactive antibodies
How long after the transplant does hyperacute rejection occur?
Less than 24 hours
What are the signs and symptoms of hyperacute rejection?
Fever and anuria
WHat is the immune component of hyperacute rejection?
Antibody and complement
What are the pathological findings of hyperacute rejection?
Polymorphonuclear neutrophil deposition and thrombosis
What is the treatment for hyperacute rejection?
None, success rate –> 0%
How long after transplantation does accelerated rejection occur?
3 to 5 days
What are the signs and symptoms of accelerated rejection?
Fever, graft swelling, oliguria, tenderness
What is the immune component of the accelerated rejection?
Non-complement fixing antibodies
What are the pathological findings of accelerated rejection?
Vascular disrpution hemorrhage
What is the treatment for accelerated rejection?
ALF, ATG and anti-CD3, success rate –> 60%
How long after transplantation does acute reaction occur?
6 to 90 days
What are the signs and symptoms of acute rejection?
Oliguria
Salt retention
Graft swelling
Tenderness
Sometimes fever
What is the immune complement of acute rejection?
T cells and antibodies
What are the pathologic findings of acute rejection?
Tubulitis and endovasculitis
What is the treatment for acute rejection?
Steroids, ALG, ATG and anti-CD3, success rate –> 60 to 90%
How long after tranplantation does chronic rejection occur?
More than 60 days
What are the signs and symptoms of chronic rejection?
Edema
Hypertension
Proteinuria
Occasional hematuria
What is the immune component of chronic rejection?
Antibody
What are the pathologic findings of chronic rejection?
Vascular onion skinning
What is the treatment for chronic rejection?
None, success rate –> 0%
What is operational tolerance?
The specific absence of a destructive immune response to transplanted tissues without maintenance immunosuppression
What are the approaches to tolerance induction?
Microchimerism
T-Regulatory
What are the three essential requirements of Graft vs. Host Disease?
- The graft must contain immune complement cells
- The host must be recognized by the graft as foreign
- The host must be incapable of rejecting the graft before it mounts an effective immune response
What prevents GVHD?
T-cell depletion in donor grafts prevents GvHD and thus decreases morbidity and mortality
What are minor HC Antigens?
Minor histocompatibility antigens are human-leukocyte antigen-presented peptides derived from normal self-proteins that differ in amino acid sequence between donor and recipient due to genetic polymorphisms
Where are minor H antigens expressed?
Epithelial tissue and hematopoietic cells
What happens if donor T cells recognize minor H antigens?
Graft vs Host disease
Graft vs. Leukemia
What can some minor H antigens be used as?
Therapeutic T-cell targets augment the graft vs. leukemia effect in order to prevent or manage leukemia relapse after HCT
What happens to the patient’s normal hematopoietic and leukemia cells with minor H antigens?
They are eliminated by the transplant conditioning regimen and replaced with donor hematopoietic cells
What happens if all of the patient’s normal hematopoietic and leukemia cells with minor H antigens are chimerised?
The patient is cured
What happens if the recipient’s malignant hematopoietic cells present hematopoietic-restricted minor H?
The disease persists or reoccurs and the patient relapses
What do the minor H antigens serve as?
Tumor-specific antigens for donor T cells
How do we match donors to recipients?
HCT: high-resolution HLA matching
Solid organ transplants:
1. Avoid unacceptable incompatibility (ABO Blood group + Avoid preformed HLA antibodies)
2. Maximize HLA compatibility
