Test 2 (Immune Lecture) Flashcards
Causes of Kidney Hypoperfusion
1) Intravascular Volume Depletion
2) Reduced Cardiac Output
3) Systemic Vasodilation
4) Renal Vasoconstriction
Pathogenesis of Ischemic AKI
1) Epithelial Cell Injury
a) Necrosis
b) Cytoskeleton Disruption
2a) INFLAMMATION:
- White Blood Cell Recruitment along with Neutrophils, Macrophages, Lymphocytes, and DC Cells
2b) ENDOTHELIAL CELL INJURY:
- Activation, Dysfunction, Detachment, Apoptosis, Necrosis
3a) LEUKOCYTE ACTIVATION
- Cytokine Release, Margination,, Tissue Migration, and Reduced Flow
3b) VASOCONSTRICTION
- Cytokine Release, INCR Permeability, INCR Leukocyte Adhesion Molecules, Reuleaux formation, Reduced Flow
4) RESULTS:
- Cellular Shedding
- Cellular Debris
- Loss of Polarity
- Loss of Tight Junctions
- Cytokine Release
- Tubular Obstruction, Backless, TGF-Beta!!!!!!!!!!!!!
5) DEFECTIVE FUNCTION:
- Reduced GFR
- High FENa
- Concentrating Defect
Cell Activation, Injury, and Reduced Microvascular Flow
1) Loss of Endothelial Cell to Cell Contacts due to HYPOXIA
2) Expression of Adhesion Molecules
3) Cytokines, Chemokines, and ROS released
Impaired Flow
Sterile Inflammation and DAMPs
Sterile Inflammation is induced by Intrinsic DAMAGE- ASSOCIATED MOLECULER PATTERNS (DAMPs):
- Released from dying Parenchymal Cells
- Generated during Extracellular Matrix remodeling
- Kidney cells express a subset of TOLL-LIKE RECEPTORS (TLRs)
- Cells can respond to DAMPs and induce INNATE IMMUNE RESPONSES and subsequent RENAL INFLAMMATION
DAMPs:
1) HMGB1 (Nucleolus)
2) Uric Acid
3) HSPs (Exosomes)—> Renal Tubular Cells
4) HYALURONANS in ECM
5) S100 PROTEIN (Cytoplasm)
- **DAMPs cause COMPLEMENT ACTIVATION!!!!!!!!
- CRP helps activate them
Inflammation caused by PAMPs and DAMPs
Innate Immunity (PAMPs): 1) Nucleic Acid: CpG and ds RNA
2) Lipid: Lipid A
3) Protein (PGN)
Homeostatic Inflammation:
1) Nucleic Acid (ATP)
2) Lipid: oxLDL and Saturated Fatty Acids
3) Protein: HSP and HMGB1
- ***RESULT:
- Toll Like Receptors
- NOD like Receptors
- Protein (PGN)
- ***ARE ALL ACTIVATED!!!!!!!!
———–>
CAUSE:
- TNF alpha
- IL-6
- IL1 Beta
Ischemia Repercussion Induced TLR-4 Expression in Kidney
1) HMGB-1 ECM Components HSPs
2) TLR-4
3) NF-kB!!!!!!! (MyD 88 Dependent/ Independent Pathway)
- major Transcription Factor in promotion for Inflammatory Response
***TLR-4 activation leads to Increased Productions of Proinflammatory Cytokines and Adhesion Molecules, which elicits a strong Inflammatory Response in RENAL TISSUE
- **Ischmia Repercussion Injury
- This exacerbates the Kidney Damage already initiated during the Ischemic Phase through MASSIVE LEUKOCYTE INFILTRATION and Cytotoxicities!!!
Complement in AKI, Inflammation, and Fibrosis
1) DAMPs
- Classical
- Lectin
- Alternatives
2) C3 and C5 Activation
3) MAC
4) APOPTOSIS
5) Macrophages can cause Inflammatory Cytokines to be produced
6) TGF-Beta is released —–> FIBROSIS!!!!!!
***C3a and C5a promote Inflammatory Cell Recruitment and release of Pro-Inflammatory Cytokines/ Chemokines and REACTIVE OXYGEN SPECIES, thereby intensifying the Immune response and further amplifying the level of tubular Necrosis and Apoptosis
Cell Responses Mediated by DAMPs
Renal Cell Necrosis results in Release of DAMPs
Activation of:
1) DENDRITIC CELLS:
- Antigen Presentation
- Migration
- Type I IFNs, CXCL2, IL1Beta, and IL-12
* ACUTE KIDNEY INJURY and INFECTIONS
2) MACROPHAGE:
- ROS, IL1Beta, TNF, IL-6 and Chemokines
* MOST KIDNEY DISEASES*
3) ENDOTHELIAL CELLS:
- TNF, IL-6, Chemokines, and IFN alpha
* IC-GN Diabetes and Sepsis****
Macrophages in Renal Diseases
1) M1: (TLR- Ligands, and IFN-alpha)
- Increase TNF-alpha
- Increase IL6
* **AKI!!!!!!
Release:
- ROS, NO, Lysosomal Enzymes
- IL1, IL12, IL23, Chemokines
Job:
- Microbial Actions; Phagocytosis and killing of Bacteria dn Fungi
- Inflammation
2) M2: (IL13, IL4)
- Increase Arginase-1
- Increase IL10
- Increase MgL-6
* **CKD!!!!!!! (Fibrosis)
Release:
- IL10 and TGF Beta
- Proline, Polyamines, TGF-Beta
- Il4, IL10
Job:
- Anti Inflammatory Effects
- Wound Repair, Fibrosis
TH17 Cell
1) Activated T Cell —- (IL-23) —->
2) Th17 Cell ——- (IL-17) —–>
3) Tissue Inflammation!!!!!!!
- Leads to recruitment of Neutrophils, Th1, and Monocytes
Cytokines Released:
1) IL-8 (Recruitment of Neutrophils)
2) MCP-1 (Attracts Blood Monocytes)
Role of Treg Cells
- Anti Inflammatory CELLS!!!!!
- Make sure there is not too much of an Immune Response!!!!!!
Cytokines:
1) IL10
2) TGF-Bets
**Help to GENERATE FIBROBLASTS!!!!!
Host Verses Graft Reponses cause Transplant Rejection
1) HISTOCOMPATABILITY AGs are the target for Rejection
2) HYPERACUTE REJECTION is immediate and caused by Antibody
3) ACUTE REJECTION occurs days to weeks after Transplantation and caused by T Cell and maybe Abs
4) CHRONIC REJECTION is seen months or years after transplantation and caused by Vascular Trauma, Inflammatory products of T Cells, Abs
Graft Verses Host Reactions
1) DONOR Lymphocytes ATTACK the Graft recipient
2) The Mechanism of GVHD can be ACUTE or CHRONIC
***Successful Organ Transplantion depends on the use of IMMUNOSUPPRESSIVE DRUGS!!!!
Autografts
- Grafts changed from one part to another of the same inidivudal
Isografts
- Grafts exchanged between different individuals of identical genetic Constitutions (Identical Twins)
Allografts (Allogeneic)
- Grafts changed between nonidentical members of the same species (Ex: What happens in Humans)
Xenografts (Xenogeneic)
- Graft changed between members of DIFFERENT species
Key Concepts
1) The condition of the Allograft
2) Donor-Host Antigenic Disparity
3) Strength of Host Anti-Donor Disparity
4) Immunosuppressive Regimen
Overview of Immune Events
1) APCs trigger CD4+ and CD8+ T Cells
2) Both a LOCAL and SYSTEMIC Immune Response develop
3) Cytokines recruit and activate Immune Cells
4) Development of specific T Cells, NK Cells, or Macrophages (MEDIATED CYTOTOXICITY)
5) Allograft Rejection
ABO matching is not Important for:
1) Corneal Transplantation
2) Heart Valve Transplantation
3) Bone and Tendon Grafts
Blood Group Antigens (ABO)
Group AB:
- No Abs Present
- A and B Ags Present
Group O:
- Anti A and B Abs Present
- No Ags Present
**Abs + Complement = MAC
HLA: Matching Donor and Recipient
- The success of Transplantation is dependent on Matching of the MHC Ags
- These Ags are encoded by the Major Histocompatibility Complex, MHC Class I and Class II
- In humans, the MHC is termed the Human Leukocyte Antigen Complex, HLA COMPLEX
- HLA COMPATABILITY between Donor and Recipient is REQUIRED due to the EXTREME POLYMORPHISM of HLA!!!!!!!!!!!!!!!
HLA System
- Each individual inherits only 10 to 12 alleles/ person
- HLA Ags are CO-DOMINANTLY EXPRESSED
- The CLASS I HLA Ags (HLA-A and HLA-B) are particularly STRONG BARRIERS to TRANSPLANTATION
- There are thee Most IMPORTANT for transplantation pairs of the CLASS I HLA Ags (HLA-DR, HLA-DP, HLA-DQ) —> Only present on Professional APC
**Lymphocytes LYSIS can be detected by STAINING the CELLS with Acridine Orange, Ethidium Bromide or HEMOTAXIN Stain!!!
Microcytotoxicity Test (Class I MHC)
1) Add Abs
2) Add Complement to for MAC
3) Add Dye
***If dye accumulates on the Donor Cell and Recipient Cell then the HLA Ags are IDENTICAL!!!!
***If dye accumulates on the Donor Cell but NOT on the Recipient Cell then the HLA Ags are NOT IDENTICAL!!!!
Normally:
- Usually this test is done on a Panel where multiple HLA Ags can be matched. The Mismatches are just as important as the Matches are
Microcytotocicity Test for PREFORMED Abs
1) Add Patient Serum
2) Add Complement
3) Add Dye
***If Dye accumulates in the Cell then there are PREFORMED Abs PRESENT!!!!
Mixed Lymphocyte Response (Class II HLA Typing)
1) Add Radiation that is supposed to prevent PROLIFERATION is the Class II MHC are Identical
2) Add Recipient Cells
3) Add H3 Thymidine
***If there is Activation and Proliferation of Recipient cells then the Recipient cells do NOT SHADE Class II MHC of Donor (High Radioactivity Present)
***If there is No Proliferation, and a LOW Amount of Radioactivity, then there is a Class II Match!!!!
Host vs Graft Response
- The Immune System attack the DONOR Tissue
0 ADAPTIVE IMMUNE RESPONSE against a Graft
- This is due to a HIGHER FREQUENCY of T Cells that recognize the Graft as Foreign:
a) Immunized individuals has
Direct vs Indirect Allorecognition
Direct:
- T Cell recognizes UNPROCESSED Allogenic MHC Molecules on Graft APCs
Indirect:
- T Cell recognizes PROCESSED peptides on Allogeneic MHC Molecule bound to Self MHC Molecule on Host APC
Host vs Graft Response
- Up to 2% of the HOST T CELLS are capable of recognizing and responding to sing FOREIGN MHC
- NON IMMUNE INJURY of the GRAFT (Danger Signals) activates Endothelial Cells,a dn T Cells enter the Allograft
Effector Mechanisms of Graft Rejection:
1) HUMORAL:
- TH2 (IL4, IL5, IL10)
2) CELLULAR:
- TH1 (IL2, IFN Gamma)
Hyperacute Rejection
- Takes Minutes to Hours
- Performed Antidonor Abs and Complement
Accelerated Rejection
- Takes Days
- Reactivation of Sensitized T Cells
- Complement activation, Endothelial Damage, Inflammation, and Thrombosis
Acute Rejection
- Takes Days to Weeks
- Primary activation of T Cells
- Activation of CD8+ cells or Abs
Chronic Rejection
- Takes Months to Years
- Both Immunologic and Nonimmunologic Factors
- Results in OCCLUSION (Ischemia)
Mechanism of Rejections
1) Hyperacute = HUMORAL
2) Accelerated = HUMORAL
3a) Acute Cellular = CELLULAR (Th1)
3b) Acute Vascular = HUMORAL (Th2)
4) Chronic = HUMORAL
Graft vs Host Disease
- Occurs in IMMUNOCOMPROMISED Recipients because their immune system is UNABEL TO REJECT THE ALLOGENEIC CELLS IN THE GRAFT!!!!!
- Often occurs when transplants are Small Bowel, Lung, or Liver
Acute GVHD: Epithelial Cell Death in Skin, Liver, and GI
Chronic GVHD: Fibrosis and Atrophy of Affected Organs
***Donor APCs can activate Donor CD8+ T Cells by Cross-Presenting recipient Ags on MHC Class I Molecules
