Exam cheatsheet - Summary Immunology PDF

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Summary

Formation of Germinal Centers Requires interaction respectively. Cytokines from FDCs TFH help differentiate B cells. TFH bind MHC:peptide, and cause upregulation of AID for CSR SHM B cell activation an extra signal besides binding Ag. Extra signal can be 3 things: T dependent: from T helper cell T i...

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Formation of Germinal Centers Requires CD40/CD40L interaction b/w B&T-cell, respectively. Cytokines from FDCs & TFH help differentiate B cells. - TFH bind MHC:peptide, and cause upregulation of AID for CSR & SHM B cell activation req’s an extra signal besides binding Ag. Extra signal can be 3 things: T dependent: from T helper cell T independent 1: PRR on B cell surface T independent 2: Co-receptor binds complement molecule - TI-1 & TI-2 tend to be used when Ag is a carbohydrate.

Max MHC II (i.e. heterozygous at every loci): 12//Max MHC I (i.e. heterozygous at every loci): 6

Naïve B cells express CXCR5+, which is attracted to CXCL13 secreted by follicular DCs. Naïve T cells express CCR7+, attracted to paracortex cells secreting CCL21/19 After activation, T cells express CTLA-4. A negative CSR that outcompetes CD28 for CD80/86 binding, preventing reactivation

Delayed (Type IV) Hypersensitivity

Type II

Purely cell mediated - Requires a sensitization phase where you’ve made memory cells to an antigen - Upon re-exposure to the antigen, after a few days, you will see signs of an immune response.

(Ag on cell surfaces) Hyperacute transplant rejection - req’s host has preexisting Abs to an Ag - Abs bind Ag immediately and initiate an immune response involving: complement, inflammation, NK cells - e.g. blood transfusions - can lead to destruction of vasculature in organ transplant From TB: women can have pre-existing Abs against paternal alloantigens of the fetus, as a result of fetal blood passing into the mother’s bloodstream.

Similar response in acute transplant rejection - Recipient T cells get activated against donor dendritic cell’s MHC. - Can be circumvented by giving the recipient immunosuppressants until the donor’s dendritic cells all die. - Years later, as the donor organs peptides break apart, any of its foreign peptides may trigger a response.

Type III – Immune Complex (Mainly IgG) Binds soluble Ag, forming AbAg complexes that elicit similar response to Type II (complement activation, tissue damage, inflammation) - diffuse targeting, not specific.

Family Name

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IL-1

Pro-inflammatory - secreted by MAST cells, increase vascular permeability, act in endocrine on liver. Diverse functions, grouped into receptor based subfamilies - γ-bearing is on naïve T cells & exhibits pleiotropy in response to IL-2. - β-γ (intermediate affinity) binding → survival signals. α-β-γ (high affinity) binding → boost in cell proliferation Antiviral - use JAK-STAT pathway Soluble or membrane bound, homeostasis & cell death - can be either pro or anti-apoptotic - TC cells have a TNF called Fas in their membrane which binds Fas receptor (expressed in sick cells) to cause death. Pro-inflammatory, neutrophil recruitment

Hematopoietin (Class I cytokines)

Interferon (Class II cytokines) Tumor Necrosis Factor (TNF)

Interleukin 17 family Chemokines

Chemoattractant - use GPCRs, GDP gets swapped for GTP upon activation

Classical pathway Initiation step: C1 complex has to bind to at least 2 IgG antibodies that are bound to antigen, or 1 IgM bound to antigen. 1. C1 is now active! It can cleave C4 2. C4b binds to membrane 3. C2 binds to C4b 4. C1 cleaves C2, C2a stays bound to C4b.…. (note: C2a is the larger piece, this is just a historical mis-naming). C4b2a = C3 convertase (enzyme that can cleave C3). 5. C3 convertase cleaves C3 a. A lot of C3b sticks to water molecules nearby and will simply be excreted, it's now waste. 6. C3b can bind to the cell membrane acting as an opsonin, OR 7. C3b binds C3 convertase, forming C4b2a3b AKA C5 convertase 8. And so on, so forth….. Immunological synapse: what’s holding them together? T cells: TCR is binding MHCII:peptide, CD28 is binding CD80/86, and CD40L is binding CD40 on B cell.

Alternative Pathway 1. C3 binds water: C3(H2O) 2. Factor B binds: C3(H2O)B 3. Factor D cleaves factor B: C3(H2O)Bb a. "fluid phase C3 convertase" 4. This cleaves other C3, C3b can bind to a membrane 5. Factor B binds: C3bB 6. Factor D cleaves Factor B: C3bBb a. "membrane-bound C3 convertase" 7. Properdin stabilizes this C3 convertase, which can then cleave C3, etc. to form C5 convertase… and so on.

Vitronetin/S protein and Protectin prevent C9 binding to host cell membrane. - These are host cell membrane proteins… therefore it only prevents MAC formation on our own cells C1 inhibitor (C1 INH) breaks up the C1 complex, doesn't even give the classical complement pathway a chance to start. C4b2a = Classical C3 convertase JAK-STAT pathways: pretty common signalling pathway for cytokines 1. Ligand binds receptor 2. Receptor chains dimerize (brought together) 3. Cytoplasmic portion of chain holds JAKs. JAKS Phosphorylate the chains and each other 4. P'd receptor chains recruit STATs a. JAKs P the STATs 5. P'd STATs dimerize and enter nucleus - (yes, STATs are transcription factors)

DAF (CD55)

Prod. by self-cells & is membrane bound

CR1

Prod. by self-cells & is membrane bound

C4BP

Soluble, but preferentially binds self-cells

C3bBb = Alternative membrane-bound C3 convertase DAF (CD55)

Prod. by self-cells & is membrane bound

CR1

Prod. by self-cells & is membrane bound

Factor H

Soluble, but preferentially binds self-cells

Factor I degrades C4b & C3b to prevent reformation of C3 convertases. - Requires host membrane proteins MCP & CR1 to be active.

Endogenous pathway of antigen processing is used by Class 1 MHC - Antigen processed by proteases, the little protein pieces are moved into the ER using TAP - Class I MHC is placed right next to TAP. - If a peptide binds strongly to Class I, ur blessed, and the MHC buds out of the ER as a vesicle and is sent to the membrane. - If you lacked TAP, you would be lacking Class I MHC Exogenous pathway of antigen processing is used by Class 2 MHC - Class II MHC buds out of ER and fuses with an endosome that contains digested antigens. - Now they're in close proximity, binding may happen. Q: Both Class I and Class II are in the RER together, why doesn't Class II pick up peptides here? A: Class II's binding site is blocked w/ invariant chain. The invariant chain gets partially degraded when it buds out of ER, but there's a piece that stays in the binding site that binds really tightly called CLIP. - This ensures the peptide that ends up binding to MHC actually has a really strong bond with the anchor points.

Function of Antibodies IgA = found in secretions (saliva, tears.), bad at causing inflammation (therefore good for gut b/c foreign material is always present, and constant inflammation would be bad). Sux @ complement. Toxin neutralizing IgM = primary response, pentavalent, complement IgD = function unknown IgG = memory, mediates ADCC (NK interaction), IgG1/3 good @ complement IgE = inflammation, allergic responses Final Maturation Steps and Exit from the Thymus. 1. Upregulation of Foxo1 Tc'n factor a. Expression of sphingosine receptor (SIPR) which aids in leaving the thymus b. Expression of IL-7R which gives survival signals and CCR7 which also helps cells exit thymus and head towards lymph nodes Mature T-cells that just exit the thymus are referred to as recent thymic emigrants

B CELL DEVELOPMENT Pre-Pro B cells: - Express B-cell specific markers B220 and EBF1 - IL-7R signalling enhances prod. of EBF1, EBF1 is a Tc'n factor that promotes accessibility - "Pre" simply means before Pro B-cells Pro-B cells: marked by expression of PAX5 Tc'n factor. Non B-cell lineage genes permanently blocked. - Early pro-B: DJH recombined first, cell prepares for V-DJH - Late pro-B: PAX5 contracts/bends IgH locus promoting VH to DJH recombination. - no PAX5 = no heavy chain (cell will fail at 1st checkpoint) 1st checkpoint: after V(D)J recomb. At the IgH locus, can the heavy chain fold properly w/ the aid of the a surrogate light chain? Yes. Alright GREAT you've now made a pre-BCR and a pre-B cell. Pre-B cells: cells express a pre-BCR (heavy chain with surrogate light chain) - Large pre-B: transient downregulation of RAG 1/2 and TdT. Pre-BCR negatively regulates prod. of surrogate light chain. (i.e. more pre-BCR leads to less preBCR)… This transitions into small pre-B stage. - Small pre-B: decreased levels of pre-BCR. RAG levels increase. Light chain rearrangement initiated. How is it initiated? Light chain loci opens up, basal level of Tc'n, RAG levels increased. 2nd checkpoint: if light chain is productive, you've passed the checkpoint and have IgM on surface

MHC1: intracellular pathogen antigens - On all nucleated cells MHC2: APCs, presents extracellular pathogens - Dendritic cells, macrophages, B cells Bare Lymphocyte Syndrome 2 (w/o MHC II) - No memory for infections b/c CD4+ cannot be activated, and thus B-cells cannot be differentiated. - T-helper cells increase toxicity of APCs, and so w/o activated T-cells APCs are less toxic → suppressed innate system - CD8+ cells don’t fxn b/c they req. activation by CD4+ - now susceptible to intracellular infections too - T cells aren’t even made! Why? b/c T cell development has steps that require contact w/ MHC - Treatment: hematopoietic stem cell transplant. Bare Lymphocyte Syndrome 1 (w/o MHC I) - susceptible to intracellular viral infections --- NOT! - why not? b/c MHC I was an inhibitory ligand, inhibiting death by NK cells. - w/o MHC I, a viral infection will be handled pretty efficiently by NK cells alone. - slight autoimmune disease symptoms also result from this ^

The D segments have a 12&23 on opp. sides. - this means D segments can recombine w/ themselves. - viable for δ but not for β **note: δ locus is within the α locus

What is happening? - RAG1 is the main RAG protein, it binds the RSS, and RAG2 stabilizes. - These bring the segments of interest together (synapsis) and cleaves them. - DNA repair proteins come and seal the DNA breaks together. Mutations in any RAG protein will lead to severe combined immune deficiency (SCID) - (no B or T cells) (no adaptive immune system) Junctional Diversity - P nucleotide addition: asymmetrical hairpin opening by Artemis causes nucleotide addition. - N nucleotide addition: untemplated nucleotide addition after hairpin is open (can be blunt) - Exonuclease trimming: enzymes remove nucleotides at hairpin opening *these must all be done in groups of 3 nucleotides, otherwise frameshift mutation*

1. HSC: self-renewing, and multipotential (one daughter is a HSC, one is slightly differentiated). 2. Multipotent progenitor: no longer self-renewing, still are multipotential. Produce CXCR4 chemokine receptor which helps keeps it in the bone marrow. 3. Lymphoid-primed: might become myeloid, so still technically called multipotential. Slight upregulation in RAG1/2. TdT, IL-7R, and B-cell specific tc'n factor EBF1. 4. Early lymphoid progenitor: lymphoid specific genes increase (such as RAG), stem cell factors decrease (e.g. c-kit/sca-1) a. Some cells leave bone marrow and head to thymus to become T-cells. This is where B & T-cell differentiation first splits. 5. Common lymphoid precursor: lost all myeloid potential. Still has potential for any lymphoid cell. a. Chromatin regions open up around Ig (BCR) locus and TCR locus.

DN1: β locus rearrangement occurs first. DN2: T-cell commitment DN3: β selection, just like with the BCR, it uses a surrogate α chain (called "pre-Tα"). - Passing the β chain checkpoint stimulates prod. of CD4 and CD8. DN4: α chain rearrangement & α selection - Passed? The cell is officially a: Double Positive (DP) thymocyte Next, DP undergo Positive & Negative selection - 95% die due to death by neglect if the α/β receptor doesn't bind to anything. - Positive selection: DP thymocyte bind MHC with low/intaffinity interaction. - Negative selection: DP thymocyte binds MHC with too high affinity (will die) **Note: throughout this process the cells are DP meaning they can receive signals from either class 1 or class 2 MHC Receiving a signal from one will result in signalling that upregulates that class and downregulates the other....