Chapter 11 -I Flashcards
Immune Response to pathogens
For a successful adaptive immune response 2 key events must occurs
- Innate immune response must sense danger - dendritic cells recruited to the sire of infection, mature and move into lymph node
- Innate immune system must sense danger and activate - TH cells must be activated - a dendritic cell must present a peptide complexed with MHC class 2 protein to the TH cell
- Innate immune system must activate adaptive immune system
Extracellular bacterial Infections
Appropriate response: Antibody response
Goals of Antibody Response: depending on the class of antibodies they can: - Neutralize - Opsonize - Activate complement to MAC and kill bacteria
Main cell types involved:
- B cells to synthesize and secrete antibody
- TH cells to provide signals 2 and 3 to B cells to fully activate them
- Dendritic cells to activate TH cells
Once infected
- adaptive immune response starts at the nearest lymph node
- innate response starts at site of injury
The Immune response to infection
- pathogen enters the body
- innate responses: pathogen overwhelms innate response, immature dendritic cell engulfs bacteria- senses danger
- dendritic cells mature and moves to the lymph node
- Activation of TH cells by dendritic cells
- at the same times pathogen binds to BCR of B cells
- Interaction of B cell with TH cell
- Proliferation and differentiation of B cell
- Secretion of antibody into body fluids
- antibody function
Early Innate Response
starts within a few minutes
Mast cells release histamine causing vasodilation
Activation of complement via alternative complement activation
phagocytosis of bacteria by resident macrophages
a bit later, the production of alarm cytokines by resident macrophages to start the induced innate response
Immediate Innate response: complement
Complement component C3 is always spontaneously breaking down to C3a and C3b
The alternative complement pathway is activated as a result of the binding of c3b to the pathogen surface
Formation of the C3 convertase is followed by the formation of C5 convertase and ultimately to the formation of MAC
Immediate Innate Response: Mast cells
Mast cells are found in mucosal and epithelial tissue, and in the connective tissues below the epithelium
Mast cells express receptors for complement fragmentsC3a and C5a
(c3a and c5a bind to mast cells)
When complement receptors are engages, histamine and other inflammatory mediators are released (degranulise)
together these act to increase vascular permeability, increase fluid accumulation in tissue
Immediate Innate Response: Phagocytosis
Opsonic receptors recognize pathogens indirectly - they bind to complement fragments of IgG that is bound to the pathogen
- eg receptors that identify host-derived proteins on phagocytic cells
Non-opsonic receptors identify distinct molecular patterns to induce phagocytosis include:
- C types lectins, scavenger receptors (proteins that recognize a variety of negatively charged microbial ligands)
Induced Innate Response
- Start within a few hours
Recruitment of neutrophils, monocytes, and dendritic cells to the site of infection
Phagocytosis of bacteria by newly arrived neutrophils
Maturation of newly arrived monocytes into macrophages
Phagocytosis of bacteria by macrophages and dendritic cells
Induced phase of the innate response
The pro-inflammatory cytokines (IL-Ib, IL -6, TNF-a)
produced by resident macrophages act on the endothelial cells of the blood vessels
leukotrienes help recruit neutrophils, promote cytokine production
Prostaglandins have various functions (eg vasodilation)
- NSAIDs prevent prostaglandin production
The Inflammatory response
Histamine released by resident mast cells result in vasodilation
cytokines released by resident macrophages cause changes in the blood vessel wall that allows neutrophils and monocytes to slow down, stop and be recruited to the site of infection
Presence of bacteria and chemokine IL-8 act as chemoattractants
Dendritic Cells - link between innate and adaptive immune response
Dendritic cells are in the tissue constantly sampling what is in its local environment
If dendritic cell phagocytoses pathogens, TLR signaling imitates its maturation pathways
Cytokines from other innate immune cells may also drive the dendritic cells towards the maturation pathway
The dendritic cells start to migrate towards the lymphatic vessels and into the lymphoid vessel
it will then begin to migrate to the nearest lymph node where they meet naive T cells to activate them
Dendritic cells
All dendritic cells move to the lymph node, it digests pathogen
It uses the exogenous pathway to display a peptide on the MHC class 2 protein
The ingested bacterium is digested in a phagolysosome, and peptides derived from it are loaded on MHC 2
Results in a dendritic cell displaying MHC class 2 and migrate to lymph node to find the T cell
Dendritic cells activate naive tH cells
At the lymph node, the dendritic cell finds a naive TH cell to activate
Signal 1 - TCR complex of mature naive t cell binds to MHC class 2 foreign peptide complex on the dendritic cell, CD4 strengthens this bonds and CD3 delivers a signal to the nucleus
Signal 2 - involves binding of CD28 of T cell to B7 of the dendritic cell
Signal 3 -T cell makes and secretes IL-2 for itself. IL2 binds to IL2R on itself
the dendritic cell provides other cytokines for signal 3
Meanwhile:
bacteria in the tissue are pushed into the lymph fluid and are carried away to the nearest lymph node where they encounter B cells
Lymphatic
Flow of lymph fluid towards lymph node
the lymph vessel drain into the thoracic duct near the heat, returning fluid to the blood circulatory system
B cell Activation - I
In the lymph nodes, the bacterium encounters a B Cell that has. BCR that is complementary to a structure on the bacterium - it is recognized by B cell
Signal 1 - mature naive B cells bind the bacterium by its BCR, Iga/Igb relays a signal to the nucleus
THe BCR may be a IgM type of IgD type on the B cell
the different classes of mIg have the same antigen specificity
The BCR-Ag complex is brought into cell as an endosome to be digested
- Lysosome fuses with the endosome containing the BCR - Ag complex to form the endolysosome
- the bacterium is digested to form peptide fragments
- peptide fragments from the bacterium are loaded onto MHC class 2 - and the new MHC class 1 - peptide complex is displayed on the surface
B cell Activation - II
The partially activated B cell seeks a previously activated TH cell ( activated by same pathogen)
Signal 2 is the binding of CD40 on the B cell to CD40L on the T cell
The TH cells knows that it has to help this particular B cell because of the peptide being displayed on MHC class2 proteins
Signal 3 TH cells secrete cytokines that help support N cell division and differentiation into effect cell : Plasma cells or memory B cells
(plasma cells secrete antibodies)
B cell activation in lymph node
Naive B cells are activated by the intact antigen that is transported into the follicle (B area ) of the lymph node
After activation, the B cells and the CD4 T cells migrate towards the edge of the follicle where they interact with each other forming cognate pairs
How do the antigen activated B cells and CD4 TH cells know that they are meant for each other
B cells and CD4 cells know they are meant for each other because they present the same linear epitope in the same MHC class 2 peptide that the dendritic cell had when it activated TH cell (same antigen used)
B cell activation
TH helper cell secretes cytokines that help support B cell division and differentiation into effector cells called plasma B cells or memory B cells
The secreted antibody lasts a few months
some plasma cells live a few months while memory B cells are long lived
is plasma migrate back to the bone marrow they become long lived plasma cells
Immune response to pathogens
the antibodies secreted by B cells enter body fluids seeking out bacteria
Neutralization
IgM, IgG, IgA
Opsonization -
IgG
Complement activation - IgM, IgG
Antibody response to Infection
Primary antibody response takes 7-10 days to fully develop
- most of the lag time is accounted fro by the changes in gene expression and proliferation of the naiver TH cells and Naive B cells
the proliferation of TH cells and B cells may cause swelling n lymph nodes
IgM wll be main antibody produced early in the response by short lived plasma cells
IgG may be produced late in the response by long lived plasma cells
Immune response to Infection
When the pathogen is eliminated, the effector TH cells die, as do the short-lived plasma cells
The Member TH and memory B cells remain
Antibodies remain in circulation for ~ 6 months
Memory B cells may have class-switched before developing into memory cells, or they may class switch at the time of re-activation - these cells are expected to secrete IgG or IgA antibodies (depending on the instruction from TH cells)
the secondary response takes only 2-3 days to develop
- memory cells are much easier to activate than naive
Clonal Expansion - T cells
Proliferation of CD4 TH cells are B cells are impressive
the expansion of antigen-specific clones result from proliferation converts small pools of naive antigen specific lymphocytes into large numbers of cell required to eliminate the antigen
Before antigen is exposed, the frequency of naive T cells specific for any antigen is 1 in 10^5 -10^6 lymphocytes
this is why they need to constantly migrate trhoguh the lymph node - to increase chance at being activated by antigen
many of the progeny of the antigen stimulated T cells differentiate into effector cells: others differentiate into memory
Clonal Expansion - b cells
The activation of B cells by antigen results in their proliferation and differentiation into antibody-secreting plasma cells and memory cells
