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68 Cards in this Set
- Front
- Back
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Relationship between Innate and Acquired Immunity
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Innate: Acute Inflammation, nonspecific, skin, mucous membranes, temperature, complement, intensity does not increase
Acquires: humoral and cell mediated, reacts quickly after subsequent exposure, specific, chronic inflammation, self regulate, distinguish from self Intensified inflammation leads to cytokine production that can activate the acquired response. |
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Humoral and Cell Mediated Responses are separate but overlapping
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Start with a t helper cell that makes cytokines:
1. activate B cells to make Abs 2. activate cytoxic Tcells, NKS, LAKS |
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Clonal Selection
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Applies to B and T cells
Cells that react with a certain Ag expand and proliferate The specificity for Ag is determined before it even encounters the Ag, due to rearrangement |
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Different Cell Types in blood and function
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1.Granulocytes : N, E, B : N and E phagocytose the Ags, and use their granules to kill
2. Mast Cell: release histamine due to IgE mediated reaction 3. Monocytes: precursors to Macrophages : Phagocytosis, secrete cytokines, present Ag 4. Lymphoid Cells a. B Cells : makes abs, important for extracellular pathogens b. T cells : many functions, important for intracellular pathogens 5. Dendritic Cell: bring Ags from infected tissues to lymphoid organ and activate T Cells (adaptive) |
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Cell Membrane Molecules associated with Lymphocytes
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T Cell: CD3
CD4 on helper CD8 on cytoxic cells B Cell: CD 19 CD40 Ligand : found B T and M cells, important for the interaction between B and T Cells, activations of MOs, and class switching CD56: Natural Killer |
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Immune Organs and Functions
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1. Thymus : where T cells develop, in cortex with stromal, epithelial, and dendritic cells. Mature T cells are found in the medulla
2. Lymph Nodes: Filter, have cortex and medulla, outter part of cortex has B cells in primary follicles which become germinal centers when make Abs, T cells are more toward center 3. Spleen: monitors blood 4. MALT - Appendix, tonsil, etc.. |
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How Cells Leave the blood and enter tissues
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Accomplished by selectins, integrins, and cytokines.
1.Selectin bind addressin - rolling 2. Cytokines will PO4 integrin - adhesion 3. Binding of integrin to CAM - diapedesis Certain selectins, addressins, etc are expressed on different tissues |
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What is an Immunoglobulin
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Ab - heavy and light chains
Heavy: Constant Light and Heavy: Variable Regions Light: either kappa or gamma, kappa greater variability in humans thus more frequent Difference in AA sequences in the variable regions of the H and L chain lead to hypervariable regions Different splicing in constant region leads to different isotypes |
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Classes of Abs from most to least frequent
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1. IgG: Opsonization, Placental Transfer
2. IgM: first in everything 3. IgA: Neutralizes Bacteria 4. IgD 5. IgE: involved with mast cells and basophils |
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Allotype versus Idiotype
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Allotype: aa sequence differences in individuals in the constant region
Idiotype: on variable regions |
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Antibody Regions
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Fab: hypervariable sites that form Ag binding site
Fc: binds to cell membrane |
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What makes a good AG?
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1. MW > 100,000
2. Not self 3. More complex chemical structure, conformation 4. Susceptibility to processing: able to be degraded etc 5. Epitope: part of the Ag that the B or T cell binds to |
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Define Hapten
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Can react with Ab's but done produce an immune response unless bound to carrier proteins
Ex: Penicillin breakdown and poison Ivy |
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Genetic arrangements of Igs
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Heavy and two light chains are all on separate chromosomes
Lambda organized in cassetes: J1 then C1 Heavy: Rearrange DJ then V, if successful then rearrange light chain, if not: null Light: Rearrange VJ |
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12/23 Rule
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RAGS can only cut at the 7 and 9 conserved bases with 12 and 23 nonconserved bases in between
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What leads to Immunodiversity
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1. P nucleotides: palindromes formed at the cuts of DNA
2. N nucleotide: added at random to the cut ends 3. Combinations of VJ VDJ 4. Mutation The D region is very diverse and is a hot spot for mutations |
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Isotype Switching
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Between each C segment, their is a switch signal. Depending on where you cut you will get different classes.
IgM and IgD are coexpressed. Then G E AND A Alternate RNA splicing leads to membrane or solube Ig forms. |
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Somatic Hypermutation
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Mutations that occur in activated B Cells (CDR) resulting in different antibodies, some which may be higher affinity and other lower affinity for the Ag.
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Gene Rearrangement in T cell versus B Cell
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Same except T Cell does not show somatic hypermutation
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Describe MHC
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Gene complex with many different allelles
Class 1: on all nucleated cells, involved in graft rejection Class 2: On B cells, involved in adaptive immunity Class 3: Non HLA, genes for complement Bottom Line: Different Alleles either bind different peptides or they bind the same peptide in different conformations All diversity resides in the peptide binding groove |
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Class 1 MHC versus Class 2
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Class 1: one polypeptide, with B2 microglobulin, on all nucleated cells, HLA A B C, thus 6 proteins per cell
Class 2: 2 polypeptides, HLA DQ, DR, DP, each locus contains several different alpha and beta chains: alpha mom can bind alpha dad or mom. |
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Cis and trans of MHC Class 2
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MHC consists of 2 alpha and 2 beta chains, an alpha pairs with a beta
Both parental alleles are expressed Maternal alpha with maternal beta: cis |
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Endogenous versus Exogenous Pathways
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Endogenous (CD8): inside the cell, MHC I and degraded peptides (transported by TAP) in the ER are shuttled to the membrane
Exogenous Pathway: (CD4) from outside the cell, MHC II is made in ER, complexed with an invariant chain to protect the binding site, then fuses with phagosome and is picks up peptide |
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MHC Restriction
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TCRS dont bind epitopes or full Ags, they bind peptides presented by MHC molecule. They are specific for Ag and MHC!
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Two signals required to activate a T Cell
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1. Signal from binding of TCR and CD4/8 with MHC
2. Costimulatory signals delivered by accessory molecules (CD28) or cytokines |
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Accessory Molecules for TCR and their functions
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1. CD3- Signaling- On all T cells
2. CD4/CD8 3. CD2 - adhesion 4. LFA-1 - Binds ICAM 1 and 2 5. CD28 AND CTLA 4 - both bind to B7, CTLA-4 inhibitory 6. CD40 L : Only expressed on ACTIVATED T cells 7. CD45 : on all hematopoetic cells, used to distinguish naive from memory Tcells, may function as T Cell activator by dephosphorlating : different isoforms a. CD45RA/RB/RC/R0 - Refers to expression of the exons : Memory and activated T Cells display high CD45R0 |
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T Cell Clonal Selection and Expansion
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1. Cognitive: recognize Ag
2. Signals activate T cell 3. Increase adhesion molecules - recpetors for cytokines appear - IL-2 drives the proliferation |
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T Cell Lineages
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Alpha beta: Expressed later, 4 different maturational stages
Gamma Delta : Expressed earlier, populate mucosal and cutaneous surfaces (IE Innate physical Barrier) |
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Divergence of CD4/CD8 during development
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Start with ALL negative cells (CD8.CD4.CD3.TCR) - the thymic nurse cells drive proliferation and maturation by IL-7 - leads to all four positive - if the T cells can not interact with the cortical epithelial cells, because of MHC, do not receive a survival signal - if they correctly interact the will become CD4 or CD8 based upon the MHC they are reacting with
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Negative and Positive Selection
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Positive Selection : CD4 or CD8 molecules that interact with MHC molecules are saved
Negative Selection: those that bind too strongly to self antigens are eliminated |
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Naive versus TH1 versus TH2
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Naive T Cell will migrate to lymph nodes where it is presented with Ag - this causes activation, and depending upon which cytokines are present go to TH1 or TH2
TH1: secrete IL-2, IFN, TNF - thus they play a role in cell mediated responses TH2: secrete IL4 IL5 play a role in humoral responeses |
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Pre B cells, immature B cells, and mature B Cells
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Pre B: Heavy chain expressed
Immature B: IgM, Light chain is rearranging, This cell is committed to a specific Ag since its Ag binding site has been determined Mature B: IgM and IgD, both chains are rearranged, has not come into contact with Ag |
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B1 versus B2
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T Dependent: B2 Cells
T Independent: B1, CD5 +, do not undergo somatic mutation so the affinity of Ab is low and high cross reactive with related epitopes |
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Primary Antibody Response
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1. Lag phase: where Ags are carried to the lymph nodes and bind to B Cells. B Cells are activated by TH2 and are stimulated to proliferate and differentiate. B cells make IgM, no class switching.
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Primary versus Secondary Antibody Responses
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1. Secondary occurs much quicker because already have Abs to those Ags
2. Other antibodies besides IgM are found in secondary 3. The affinity of Abs is much greater in secondary responses due to competition and somatic recombination during class switching 4. For primary response: Dendritic Cell activates the naive T Cell which then can activate the B cell |
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How B cells present Ag to T Cells
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At least 2 IgM/IgD on the surface of the B cell must bind Ag, which is then endocytosed and presented to the T Cell by MHC II
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T Cells activate B Cells
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T Cell must first become activated by dendritic cells carrying Ag. Then the T cell can express the necessary CD40L for B cell activation
CD40 binding to CD40L is essential for class switching |
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Role of cytokines in Ab responses and Isotype Switching
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Activated T cells secrete cytokines which drive the differentiation and proliferation of B Cells. Which Cytokine is present determines which class it will be switched to.
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Progression of the Ab Response In Vivo
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1. Antigen enters the lymph and travels to the lymph node where it is phagocytosed by MOs or FDS.
2. B Cells Bind the Ag and binds the T cell, which leads to activation of the B cell. 3. As B Cells proliferate the move to germinal centers. Cells that are stimulated to differentiate into plasma cells go to the medulla where it leaves the node 4. B cells that were activated to undergo class switching but did not differentiate into plasma cells are memory cells 3. |
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T Cell Dependent versus T Cell Independent Ab Responses
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Independent: No class switching or affinity maturation, no memory express CD5
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Sequence of activation of cytotoxic T Cells
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1. Directly by a Dendritic Cell
2. Cytokines such as IL-2 which comes from TH1 Cells 3. APC activates CD4 which activates the APC to express B7 which can then bind and activate CD8 Cells |
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How cytotoxic T Cells kill
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Bind target cell - PO4 of LFA-1 to strengthen interaction- directional exocytosis of granules that contain perforin and granzmes
Perforin: Puts a pore in the cell Granzymes: initiate apoptosis Fas also induce apoptosis (member of TNF alpha family |
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Natural Killer Cells versus CD8 Cells
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Natural Killer Cells recognize carbohydrates on membranes NOT ASSOCIATED with MHC
Both use perforin mechanisms to kill |
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Antibody Dependent Cell mediated Cytotoxicity
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Cytotoxic T Cells have receptors for the Fc portion of Ab's
Thus the specificity is Ab dependent |
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How Macrophages are activated by TH1 Cells
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LPS is a strong activator of MOs, but in their absence TH1 cells can secrete IFN y and others to activate them. IFN y can be membrane form (contact) or secreted
Contact dependent activation of MOs requires co-accessory signals |
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What is a granulomatous reaction?
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Continuous activation of MOs results in MOs forming giant cells
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What is Complement?
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Proteins in serum that facilitate:
1. Opsonization via C3b 2. Inflammation C3a 3. Links Innate and Acquired by facilitating uptake and recognition of Ags by lymphocytes 4. Direct lysis of cell |
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3 Pathways of Complement
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Use different initiation techniques but have the same effector molecules
1. Classical : Ag:Ab complex 2. Lectin: Lectin binding to pathogen surfaces 3. Alternative: Pathogen Surface NOTE: All 3 Pathways can be initiated by Ab independent mechaniams |
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Activation of the Classical Pathway of Complement
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1. Activate C1q complex with 1 IgM or 2 IgG (IgM is more effective)
2. C1q will cleave C4 into C4a and C4b 3. C4b will cleave C2: leads to C4bC2b, which is the C3 convertase 4. C4bC2b will then cleave C3b : get C4bC2bC3b which is C5 Convertase |
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Activation of The Mannose Binding Pathway of Complement
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1. MBL binds mannose residues on pathogens
2. MASP1 - MASP2- C4-C2-C3 |
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Activation of the Alternative Pathway
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1. Spontaneous Activation of C3 to C3b
2. Binding of Factor B allows D to cleave B into Bb and Ba. 3. C3bBb forms this distinct C3 Convertase 4. When there is a lot of C3b then can form C5 convertase (C3b)nBb |
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Shared Final Pathway of each Complement Pathway
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C5 C6 C6 C8 C9 from MAC which inserts a pore into the membrane
MAC can only kill Gram Negative bacteria and cannot kill cells with a cell wall |
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Complement Receptors
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* Found on leukocytes, mast cells, erythrocytes, hepatocytes
* Functions: 1.Clear Immune Complexes 2. Initiate Leukocyte Responses 3. Release of materials (chemotaxins) from the activated leukocytes 4. Enhance Ag presentation by facilitating the uptake of Ags |
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Complement in SLE
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Autoimmune Abs are made to normal tissue, DNA, proteins, etc. This leads to activation of the classical pathway and leads to tissue damage
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Complement in Angioedema
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Genetic deficiency of C1 inhibitor resulting in uncontrolled production of C1
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What is a cytokine?
Cytokine Receptor |
1.Soluble protein secreted by cells of the immune system involved in inflammation, immunity, and hemopoiesis
2. Play a central role in Acquired immunity directing which type of response occurs 3. Control class switching in B cells Cytokine Receptors are transmembrane proteins made of 2 subunits. Signaling is initiated once bound |
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What is a chemokine?
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Chemokines are cytokines that act as chemoattract molecules for WBCs
Their receptor is a 7 transmembrane G Protein |
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Cytokines are mediators of Inflammation and Natural Immunity
What are the cytokines involved? |
Pro-inflammatory: TNFa and IL-1
Anti-inflammatory: TGFb and IL-10 |
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Effects of TNFa and IL-1
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TNFa is produced by MOs
1. Increased vascular permeability 2. Adhesion and migration 3. Clotting IL-1 is same as TNFa except it is involved in the activations of B and T cells |
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Effects of TGFb and IL-10
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Anti-inflammatory cytokines
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IL-2
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Cytokine involved in the proliferation and differentiation of T cells
Naive T cells do not express the Ag, but ones that have been presented with Ag do |
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Chemokine Receptors and HIV
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These receptors play an important role for the entry of HIV-1 into the cells
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TH1 versus TH2
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TH1 - cell mediated response
1. Cytokines: IL-2, TNFa (activates phagocytes), IFNy(activation of MOs) TH2- B cell Response 1. Cytokines - IL4 and IL5, IL-4 is involved in B cell activation and differentitation |
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IL-17
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Pro-inflammatory cytokine produced by TH-17 cells
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T reg cells
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Produce TGFb and IL-10. These control proliferation and differentiation on lymphocytes
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Cytokines and their Inhibitors in Therapy
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1. TNFa inhibitor is given for chronic inflammatory diseases
2. IFNs are used to disrupt viral life cycles 3. IL-2 used in immune deficient indivudals |
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Genetic, anatomical, and hormonal involvements in Autoimmune Disease
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Hormonal: More women develop autoimmune diseases, likely due to estrogen, TH1 vs TH2 respone
Genetic: inappropriate MHC expression |
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Explain the Tx of Autoimmune Disease
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1. Block CD28:B7, IL-12,IL-10, IL-2, TH1 responses, TNFa, CD40 etc
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