Lecture 4 & 5: Innate and Adaptive Immunity Flashcards
Describe the uniques characteristics of the innate immune system
The innate immune system is an imediate, but nonspecific response to pathogens mounted by phagocytic cells and natural killer cells
Epithelial barriers protect as a barrier and certain cells can secrete antimicrobial peptides called defensins
The small and large intestine also have defensins, lysozymes, mucus secreting goblet cells, and paneth cellls
There is no memory of the innate immune system - if the same pathogen infects the host months in the future, the innate response and time of response will be the same
Cells of the innate immune system
- Phagocytic Cells
- NK Cells
- Mediator Releasers
Phagocytic Cells
Cells containing azurophilic and specific granules with anti-pathogen molecule and enzymes to lower cytoplasmic pH and generate oxidizing agents that are leathal to pathogens and surrounding tissues
Includes neutrophils, monocytes, dendritic cells, and eosinophils
Neutrophils
FIRST RESPONDER
60% of all circulating white blood cells
Short lived - die once they release granules to kill the invading molecule (6-24hrs)
Rapid exit from circulation to tissue sites of injury or infection
Inductive process draws the neutrophils out of circulation into the tissue where the neutrophils phagocytize the invadding microbe and DIE
NEUTROPHILS DIE
NEUTROPHILS DIE - after release of granules
Monocytes
Monocytes become long lived macrophages in many tissues and organs
5% of all circulating leukocytes
Among the first cells to encounter a pathogen, comming in after the neutrophils
Digest a pathogen and display the peptide fragment on the cell surface in the context of a MHC receptor
Has an indented nucleus
Dendritic Cells
Most dendritic cells are probabbly derived from monocytes
Reside within or just below the epithilial
Major gaurds against invading pathogens
After phagocytosis of pathogen the dendritic cell migrates to the regional lymph node where itpresents a peptide fragment in the context of a MHC receptor to activate a T cell - IMPORTANT INDUCERS OF T CELL IMMUNITY
Most efficent antigen presenting cell in the body (100x more efficent)
Eosinophils
Granues stain red with most blood stains
Granules are antiparasitic
Prominent meddiators of allergic reactions - levels in peripherial blood can increase with an allergic response
2-4% of circulating leukocytes
Phagocytosis of an antigen-antibody complex
NK Cells
Large mononuclear cells with azurophillic granules
1-2% of all circulating leukocytes
Sample the surface of virally infected cells or tumor cells for evidence of abnomality (lack of MHC receptor) and if an abnomality is dected, the NK cell kills the infected cell
NK cells secretes molecules which activates members of the adaptive immune system (INFy)
Mediator Releasers
Include basophils and mast cells
Function in immediate hypersensitivity release of histamine, heparin, and peroxidase from granules - Allergic reactions
Basophils are found circulating in peripheral blood and represent .5% of white blood cells
Mast cells are only found in tissue
Have receptors for IgE on the surface
PAMPs
Pathogen associated Mononuclear Paterns
Phagocytic cells must recognize PAMPs
Very chemoatractive to neutrophils
PAMPS include:
- Terminal mannose residues
- Double stranded RNA in viruses
- Short sequence unmethylated CPG motif in bacteria
- LPS - lipids in lipopolysacharide of microbes
TLR
Toll Like Receptor
When a TLR is bound to a PAMP on a pathogen, it activates a signaling pathway so that phagocytic cells can release infamitory mediators to further activate the immune system
TLR activation leads to translocation of NFkB to the nucleus, where NFkB activates the transcription of genes that produce cytokines that activate the immune response
Humans have at least 10 TLRs which lead to the translocation of NFkB into the nucleus
Activation of TLR4
- LPS (a PAMP) binds to TLR4
- Activated TLR4 releases the activated form of MyD88
- MyD88 activates NFkB translocation to the nucleus
- NFkB transcibes INF (interferon) inducible genes
- Accute inflamation occurs and adaptive immunity is stimulated
TLR4 activation can also promote the transcription of proinflamatory genes through IRF5 and Jun/Fos creating an antiviral like state
There are also TLRs that can be activated within the cell located in endosomes
Activation of IL1
- After NFkB is activated and induces the transcription of the inactive form of IL1 (ProIL1) it is cleaved and eleased into circulation, which can cause accute inflamation
- The NLRP3 inflamasome is activated through ion concentration, and does not require a TLR. The inflamasome cleaves Pro-IL1 by releasing casoase and activating IL1 to be released into circulation
Secreted IL1 cause Accute Inflamation
Phagocytic Cells Engulf and Destroy Pathogens
- A microbe identified by an antibody or complement binds to the Fc receptor or complement receptor of the macrophage
- The microbe is endocytosed
- Cytoplasmic NADPH oxidase on the phagosomal membrane catalyzes the production of O2 and HOCl - resulting in a respiratory burst killing the microbe
- Neutrophils die, while macrophages process the peptide of the microbe and ppresent it in the context of a MHC class 2 molecule
Respiratory Burst
After the engulfment of a foreing particle NADPH oxidase is released from the phagosomal membrane and the production the following compounds is catalize resulting in the destruction of the forgien particle:
O2
HOCl
Hydroxyl Radicals
NO
*Mammals defficent in NADPH oxidase are very suceptible to bacterial infection
NETs
Neutraphil Extracellular Traps
After a respiratory burst and the death of the invading pathogen, the nuclear membrane of the neutrophil is dirupted forming punctate granules
The death of a neutrophil forms an extracellular trap that contains DNA and products of the azurophillic granules which continue to help destroy pathogens
Production of the inflammatory response due to activated macrophages
Activated macrophages produce chemokines and cytokines that contribute to the production of the inflamitory response
Chemokines are chemoattractants for neutrophils monocytes, and dendritic cells
Cytokines such as IL1 cause fever and TNFa can cause septic shock
Important for the inflamitory response - recruit an army of phagocytic cells
Production of the inflammatory response due to activated NK Cells
NK cells are activated by INFa and INFb
Kill virally infected cels and some tumor cells via apoptosis
Also secrete cytollines (INFy) which helps induce adaptive Immunity
Macrophages with phagoocytosed microbes secrete IL12 stimulating NK cells to release INFy which results in the macrophage killing the microbe
NK cells monitor the level of MHC class 1 molecules on host cells - when the levels of MHC class 1 molecules are low, the inhibitory receptor of NK cells is not engaged and the NK cell is activated resulting in the death of the cell
Unique Characterisics of the Adaptive Immune System
CAlled in by the innate immune system when it cannot handle the pathogen
Specific antigen recognition by specific receptors on T and B lymphocytes and clonal expansion (3-5 days)
Tolerance to self antigens
Memory of response such that subsequent exposure to the same antigen results in a much more rapid response
Highly specific due to recombination of genes on TCR and BCR
T Lymphocytes
Origin: Develop in the thymus and precursors come from the bone marrow
Location: Bone Marrow, Thymus, Spleen, Lymph Nodes, Tonsils, Pyers Patches, connective tissue and blood and lymph vessles
Function: When stimulated by antigen T cells develop into effector T cells (Th1, Th2, Th17, T reg) and can also develop into cytotoxic T lymohocytes
*Must see an antigen in the context of a MHC molecule on the surface of an APC
* Depends on the microbe which T cell develops
B Lymphocytes
Origin: Develop in the bone marrow with surface Ig receptors to an antigen they have never seen before
Location: Bone Marrow, Thymus, Spleen, Lymph Nodes, Tonsils, Pyers Patches, connective tissue and blood and lymph vessles
Function: Upon antigen stimulation they develop into antibody secreting plasma cells with cytokine help from T cells
Th1
Make INFy, IL2, TNFa
Important in delayed type hypersensitivity and other cell mediated immune responses
Macrophage activation and IgG production (to increas the uptake of bacteria)
Targets Intracellular pathogens
Activated by IL12 from dendritic cells
Th2
Make IL4, IL5, IL10, and IL13
Important in humoral immunity- B cell activation
IL4 - activates B cells that produce neutralizing antibodies (IgE causes the release of granules from mast cells)
IL5 - activates eosinophils involved in parasitic infections and allergic response
Th17
Makes IL17 which induces tissue fibroblasts and epithelial cells to make IL6, chemotactic cytokines, and growth factors (GCSF, GMCSF) for the stimulation of neutrophils
Target is extracellular bacteria
Implicated in various autoimmune disease
*Th17 cells also release IL22 which stimulates epithelial cells to grow and increase barier function
T Reg
Downregulate Immune responses via cytokines and cell surave contact
Cytotoxic T Cells
Make TNFa and cytotoxic effector molecules
Perforin and granzymes
Perforin makes a tube that allows granzymes to enter the cell and activate the caspase cascade, killing the cell
Clonal Selection
B cells and T cells develop Ig or receptors for an antigen even before being exposed to it
Antigen stimulation of a complimentary, antigen specific receptorresults in the prolliferation and differentiation of the stimulated cell
10^5 increase in 1 week of that specific cell after being exposed to the antigen
Monoclonal - a single B and T cell clone activation
Polyclonal - antigenic molecules that have many sites or antigenic determinants (epitopes) that can stimulate B cells and T cells
Immunological Memory
Secondary exposure to an antigen is specific and has a shorter lag time, and the response is more robust
A primary responce produces IgM, while a secondary response produces IgG (or A/E depending on the circumstances)
Phases of the immune response
- Antigen recognition
- Clonal Expansion
- Differentiation of plasma cells and effector T cells
- Elimination of antigen
- Memory
How do cells lean not to respond to self-antigens?
Autoreactive B cells and T cells are normally deleted in the bone marroww or thymus
hHgh affinity to a self antigen results in the deletion of the cell
Weak affinity to self antigens allow the cell to mature
Only a couple of % of cells make it to the periphery where they can react with an antigen
Lymphocyte Circulation and Recirculation
Lymphocytes leave the blood by adhering to and squeezing between the endothelial cells of the High endothelial venule in the para cortex of the lymph node
The lymphocytes stay in the lymph node for abount 12 hours unless they encounter antigen
When lymphocytes leave the lymph node they exit through the efferent lymphatic whic empties into the thoraci duct and then into circulation
Pathway
- Antigen enters through the afferent lymphatic (generally picked up by dendrtitic cells)
- Lymphocytes enter the lymh node in the HEV located in the deep cortex
- B cells are found in the follicles, superficial cortex
- T cells are found in the para cortex
- If not activated the cells migrate through the medulla and leave through the efferent lymphatic
S1P
If there is no antigen for an immune response T and B cells leave the node in response to a high S1P gradient in the lymph
If there is an immune response they downregulate the S1P receptor and stay in the node until they beome effector cells
Receptor for S1P is located on the surface of lymphocytes
A recenly activated T cell will have low levels of S1P expressed and will stay in the lymph node
An effector T cell days after innoculation or unactivated t cell will have high S1P receptors and leave the node
*TO KEEP A MOLECULE IN THE NODE, use a molecule that blocks the S1P receptor and downregulates the S1P receptor
Important Chemokines for T lymphocyte location
CCL19 is made by the stromal cells of the paracortex and keeps T cells in the paracortex
The paracortex is where mature antigen laden dendritic cells are found to activate the appropriate T cell
*once activated T cells loose receptors for CCL19 and develop receptors for CXCL13 (of B Cells) and move into the follicle to help B cells
Important Chemokines for B lymphocyte location
B cell lymphocyte chemoatracant CXCL13 is made in lymphoid follicles and draws B cells there
Located in the supperficial cortex
Consequences of loosing chemokine receptors on the immune system
HEV
High Endothelial Venule
Venule that allows for the import of lymphocytes from the blood into the paracortex of the lymph node
Migration of lymphocytes from the blood through the HEV into the lymph node
- L selectin on the surface of the lymphocyte must bind to the GlyCam1 receptor on the endothelial cells of the HEV
- The chemokine receptor on the lymphocyte must bind to the chemokin CCL21 - on the enothelial cells of the HEV
- Activation of LFA1 receptor on lymphocytes by binding to ICAM1 on endothelial cells of the HEV allows the lymphocyte to move throgh the epithelial cells and migrate into the node
What is the difference between the surface of naive cells and activated effector cells
Naive Cells
- L Selectin
- Chemoline Receptor for either CCL19 (T cell) or CXCL21 (B Cell)
- LAF1/ ICAM
- Allows for the migration of the naive cell to come into the node
Effector Cell
- E or P selectin ligan to bind to the inflamed lining of the blood vessles
- LFA1/ ICAM1
- CXCR3 or CCR3
