Lecture 6 Flashcards
The innate immune response is mediated by…
PMNS (Type of white blood cell) and Phagocytes
The adaptive immune response is mediated by…
Lymphocytes (B and T cells)
ANTIGEN
Protein or carbohydrate that engages the immune system and initiates an immune response.
Proteins
Majority of antigens, may be pure proteins, glycoproteins or lipoproteins
Polysaccharides
Pure polysaccharides or lipopolysaccharides (sugar chains); type of antigen
Lipids
Non-immunogenic may assist in antigen-mediated immune activation
Nucleic acid
Usually poorly immunogenic, most effective when single-stranded or complexed with proteins
What recognizes antigens?
Specific antibody proteins or T-cell receptors
Epitope
Antigen determinant; interacts with a single antibody or T-cell receptor (Binds to the antibody)
Types of Epitopes
Linear (Short and continuous and formed by a specific sequence; after denaturation, it may still be able to bind to the antibody)
Conformational (3D structure, domains of proteins composed of specific regions of protein chains; after denaturation, it can no longer bind to the antibody)
B-cell epitopes
Region of the antigen recognized by immunoglobulins/antibodies 3-20 a.a. or sugar residues
T-cell epitopes
Region of the antigen recognized by T-cell receptor
8-15 a.a. long; only recognized after the antigen is processed and presented with an MHC protein
True or False: One antigen can have many different epitodes
True
Which are the professional APCs that present antigens to CD4 T-cells
Macrophages, dendritic cells, and B-cells
3 stages of APC Sentinels
The resting stage, Activated by cytokines or PRR (AP mode), and the attacking mode
Antigen-presenting molecules
MHC I/II
What cell is produced when cytokines attract monocytes
Dendritic cells
Types of Pattern/Pathogen Recognition Receptors (PRR)
TLR-Toll-like receptor, RLR-Rig-like receptor (IFNα/β), NLR-NOD-like receptor (inflammatory), Lectin-like receptors
Which microbes bind with TLRs (extra-cellular and endosomal) and NLRs (cytosolic)
Bacterial cell wall lipids
Which microbes bind with RLRs (cytosolic)
Viral RNA
Which microbes bind with lectin (extra-cellular)
Fungal polysaccharide
Peripheral Dendritic cells role
Travel from peripheral site to LN to present antigens to
T cells
Resident/ Follicular Dendritic cells role
Stay in LN to sample lymph for opsonized
antigens to present to B cells
Macrophages role
Stay at sites of infection/inflammation and support the fight at the site of infection, also re-stimulate T cells that have arrived from LN at peripheral sites of inflammation
B-cell role
Stay in LN and stimulate CD4 T cells to support antibody production. They sample antigen specifically through BCR and present it to CD4 T cells.
What are the 2 states of APCs?
Immature/quiescent state and the mature state
Characteristics of the immature state of APCs
Routinely process and present antigen, Express PRRs, Express low levels of MHC I and II
Characteristics of the mature state of APCs
Present antigen to naïve T-cells and activate them, Increase antigen processing and presentation, Increase MHC expression, Express co-stimulatory molecules for T-cells, and produce cytokines
Where do the antigens that MHC I present come from?
Intracellularly (present the antigen extracellularly to CD8+ T-Cells)
Where do the antigens that MHC II present come from?
Extracellularly (present the antigen extracellularly to CD4 T-cells
MHC II binds with…
Macrophages (intravesicular pathogens) and B-cells (extracellular pathogens)
Major Histocompatibility complex (MHC)
Control graft rejection and control the immune response to all protein antigens
Polygenic
Several different MHC I and II genes, therefore every individual has a set of MHC molecules with different ranges of peptide binding specificities
Polymorphic
Variability at a gene locus within the population
Human Leukocyte antigens (HLA)
Called MHC in humans and is controlled by genes located on chromosome 6 (MHC are co-dominantly expressed - half from mother, half from father)
HLA in MHC I
Bind to CD8+ T-cells; HLA-A, HLA-B, HLA-C
HLA in MHC II
Bind o CD4+ T-cells; HLA-DR, HLA-DQ, HLA-DP
MHC haplotype
Set of maternally- and paternally-derived MHC genes on each chromosome (3 MHCI, 3 MHCII from each parent)
Parts of a T-cell receptor
membrane-bound, a/b chains, disulphide bond, carbohydrate, variable region, constant region, stalk segment, a transmembrane region, cytoplasmic tail (1 antigen binding site)
Where does T-cell receptor diversity occur?
The thymus
Where do Mature and activated T-cells go?
Mature: Lymphoid organs
Activated: Sites of infection
VDJ Recombination - segments
V: Variable, J: Joining, D: Diversity
a-chain gene rearrangement
Germline DNA –>(recombination) rearranged DNA –>(transcription splicing translation)–> protein T-cell receptor
b-chain gene rearrangement
Protein T-cell receptor (translation splicing transcription) <–rearranged DNA (recombination) <–germline DNA
How does germline DNA produce genetic diversity in the antigen binding site of the receptor?
Use of different gene segments and the addition of nucleotides when forming the antigen receptor mRNAs
How are T-cells activated?
High-affinity TCR engagement with MHC/ peptide
Complexes through Receptor activation: CD4/TCR: MHC class II and co-stimulation through Co-receptor activation: CD28:CD80/86
Licensing
Promotes CD8 T cell activation and promotes survival
of the dendritic cell. CD40L:CD40, cytokines
The signals for T-cell activation
Signal 1: MHC-peptide-TcR recognition (naïve and memory T-cells)
Signal 2: co-stimulation recognition (naïve T-cells)
Signal 3: cytokine signalling recognition (naïve and memory T-cells)
Immunological Synapse
Adhesion molecules bring APC and CD4 T-cells together. Rearrangement of cytoskeleton and
polarization of cell (4-10 hours)
What does the TCR/co-receptor binding result in?
Activating a signalling cascade and the activation of genes that promote cell cycle, survival and activation (inadequate co-activation signals results in cell death or anergy - abnormal immune response)
How can a NAÏVE antigen-specific lymphocyte manage to contact its specific antigen, or encounter a helper cell with the appropriate antigen specificity?
The “dating bars of the body”– the Lymph nodes
Parts of the Lymphatic System
Cervical nodes, lymph nodes(2dary), thymus, axillary nodes, diaphragm, lymph vessels, spleen(2dary), inguinal nodes
GALT (gut-associated lymphoid tissue)
Lamina propria, Peyer’s patches
BALT (bronchial-associated lymphoid tissue)
Respiratory epithelium
MALT (mucosal-associated lymphoid tissue)
Other diffuse mucosal sites, ex reproductive tract, small and large intestine
How many lymphocytes enter lymph nodes?
About 10,000 lymphocytes enter the lymph nodes each second
Langerhans cell
Immature dendritic cells are found in the skin.
Lymph node
A specialized organ that facilitates the presentation of foreign antigens to the immune system.
Lymph node: Structure and function
T-cells and activated APC enter and leave through lymphatic vessels, lymph filter (lined with macrophages that can devour pathogens as they enter the lymph node)
High Endothelial Venule (HEV)
Doorway to enter LN from the blood – special columnar endothelial cells that allow entry.
Paracortex
T-cell suppression
Afferent (substance going in)
Lymphocyte immigration
Cortex
B-cell activation
Medulla
Lymphocyte emigration
Paracortex
T-cell activation
Naïve cells (LN Trafficking)
Surface adhesion molecules for any secondary lymphoid organs (remain in circulation until a match is made; if no match = death by apoptosis)
Activated cells (LN Trafficking)
Surface adhesion molecules that are expressed depending on where they were activated – tend to return to compartments they encountered antigen
Activated CD4 T-cells
Exit LN and recirculate; promote the function of other T-cells and LN stimulates B-cells and CD8 T-cells
Activated CD8 T-cells
Exit LN and go to sites of inflammation and destroy target cells
Activated B cells
Remain in the LN and cycle between germinal and follicular zones; some will mature to plasma cells to produce anti-bodies (locate in intestinal lamina propria)
How is the movement of cells (T & B cells) regulated?
Up and down regulation of receptors that act as “passports” to various compartments
MALT
Gut surveillance
Lamina propria
Connective tissue containing lymphocytes and some
germinal centers
Peyer’s patches
Lymph node-like nodules in ILEUM, have HEV lymphatic drainage, but no incoming lymphatics (recieve antigens sent from endosomes through M-cells)
Spleen
Filters blood (collects antigen from the blood and disposes of old red blood cells)
Th1
CD4 T-cell; Cell-mediated immunity and inflammation, attacks intracellular pathogens, autoimmunity (IL-2, IFN-y, TNF-a)
Th2
CD4 T-cell; Antibody-mediated immunity, extracellular parasites, asthma, allergy (IL-4, IL-5, IL-6, IL-10, IL-13)
Th1 response outcome (cell-mediated)
Microbes (IFN-y)–> Macrophage activation
B-cell (IFN-y)–> Complement-binding and opsonizing antibodies
Neutrophil(LT, TNF)–> Neutrophil activation
Th2 response outcome (humoral)
B-cells (IL-4) –> Production of neutralizing IgG antibodies + IgE
Eosinophil (IL-5) –> eosinophil activation
Activated macrophage (IL-10, IL-4) –> suppression of macrophage activation
Regulatory T-cells function (T-reg)
Control/ dampen the immune response, Maintain tolerance to self-antigens, Prevent autoimmune disease
True or False: CD4 cells are terminal and cannot respond to dynamic change in the immune system
False; They are not terminal and can change with the course of the infection to respond to the needs of the immune system dynamically
