Lecture: Introduction to Immunology Flashcards
(38 cards)
Innate immunity
“the ability to recognize self from non-self”
The innate response is based on non-specific recognition of foreign substances and their removal by various mechanisms including activation of the inflammatory response, through opsonization and subsequent activation of the complement system, destruction by NK cells and neutrophils, and phagocytosis by macrophages (mφ).
Major Components of innate immune system
Complement proteins
Neutrophil
Macrophage
- (professional phagocytes)
Innate Lymphoid Cells (incl. NK-cells)
Major Mechanisms of innate immune system
Invaders may be destroyed directly through recognition of foreign molecules or lack of self-MHCs.
The signaling action of cytokines ramps up the cellular response.
Phagocytes recognize opsonizing “tags” and opsonized antibodies & destroy “marked” cells.
3 pathways to activate the Complement Cascade
Classical - recognition of antigens by antibodies produced by B lymphocytes. “recognition of antigens from antibodies”
Lectin (mannose-binding) - recognition of foreign sugars in cell membrane. “relies on the fact that bacteria have mannose on their cell membranes. Easy for a complement protein to look for mannose which means there is a foreign cell membrane”
Alternative - automatic destruction of cells that can’t inactivate C3. “we have C3 circulating all the time which is a protein that chooses to attack everything. For cells to exist, they have to be able to prevent C3 from attacking it. The onus is on the individual cell to prevent it from getting destroyed”
Opsonization
stick a circulating antibody onto something = opsonization
antibodies can opsonize things, but complement proteins themselves can also opsonize things. Complement proteins (C3b and C4b) if they stick onto something, it is a signal to other complement proteins/cells that we should get rid of that thing. like antibodies, C3C4b can stick to something and mark it for removal (opsonization)
Neutrophils
born in marrow
“marginal pool” stored in marrow, usually in adult form, but possibly as band cells
released in circulation, usually in adult form, but possibly as band cell
enters connective tissue via rolling adhesion and diapedesis
“dies” after being used
Macrophages
Formed in marrow as a monocyte
Migrates via diapedesis through endothelium to connective tissue & differentiates to become a macrophage
Macrophages also normally sit in peripheral CT, and in many organs, e.g.:
lung - alveolar macrophage
liver - Kupffer cell
brain - microglial cell
Macrophages kill by:
1 - recognizing a foreign substance
2 - engulfing it in a phagosome
3 - killing it by attaching lysosomes
Macrophages are also APCs (antigen presenting cells) for the adaptive immune system
Adaptive Immune Response
-phagocytosis of IgG-tagged
-structuresAPC for T-cells
-‘hyperactivation’ response to T-cell cytokin
2 types of macrophages
M1 and M2
M1 macrophages
classical activation pathway
for phagocytosis. You want the macrophage to eat something
type 1 inflammation
TH1 response
M2 macrophages
alternative activation
more subtle nuanced version of macrophage response. You may not want to get rid of everything at the expense of ruining the organ (ie heart attack)
type 2 inflammation
TH2 responses
Innate Lymphoid Cells (ILC)
From Lecture Syllabus:
Other important cells include the innate lymphoid cells (ILCs). These are cells derived from the lymphocytic lineage that do not have specific recognition as their primary function. They instead function in the innate immune response. NK (natural killer) cells were the first ILCs to be discovered (in 1975). Now, five separate subtypes of ILCs are defined.
Lecture slides:
Lymphocytes, non-B, non-T, CLP derived.
They promote inflammation and tissue repair.
Group I:
-NK cells (CD56+) are one type
-intracellular pathogens
Group II:
-enriched in lung, skin, adipose tissue
-parasites
Group III:
-ILC3: skin, lamina propria
-LTi: intestine, lymphoid tissue
-bacteria & fungi
cytokines
Cells produced an induced immune response through signalling via inflammatory cytokines, small molecules which, through their interaction with cytokine receptors, specifically call other cells and instruct their actions. As an example, here are some the most significant inflammation-producing cytokines secreted by resident macrophages in response to and infection:
TNF-α : increases permeability of endothelium
Il-6 : induces thermogenesis via fat and muscle metabolism
CXCL8 : recruits neutrophils
CCL2 : recruits monocytes
Il-12 : recruits NK cells
Cells of the Adaptive Immune System
Antibodies (Ig (immunoglobulin) molecules). “Can be surface molecules on membranes, or free in the extracellular space”
Cells that make antibodies
- B-cells
- Plasma cells (activated B cell)
Antigen-presenting cells (APCs)- cells that help the T cells
Cells that are designed to be very specific recognizers of intracellular invaders like viruses.
-Tc cells (cytotoxic, CD8)
-Th cells (helper, CD4)
More details on cells of the adaptive immune system
Cells that allow us to generate responses to very specific invaders.
B-cells
- extracellular pathogens
- when activated, become Ig producing plasma cells
- also Breg and Bmem
Tc-cells (CD8+) - non-self recognition (ideally)
- MHC1 recognition
- direct killing of cells by lymphotoxins
- also Tc-reg and Tc-mem
Th-cells (CD4+) - MHC2 recognition
- indirect killing of cells by lymphokine signaling
- also Th-reg and Th-mem
Antigen-Presenting Cells
- specialized “dendritic cells”, in many tissues like skin
- macrophages
- B-cells (for their specific antigen)
Anibodies
B cells work by using antibodies
also known as:
- antigen receptors
- Immunoglobulins (Ig) or gamma-globulins
can be soluble, or membrane bound
contain heavy chain, light chain and constant regions
Antibodies consist of a variable
region (Fab, light chain & heavy
chain) and a constant region Fc.
The Fab region allows for close
conformation to the antigen
surface.
The Fc (constant) region allows
easy recognition & binding by
other proteins.
Fab = antigen specificity
Fc = Ig class
Antibodies: Structure & Class Switching
B-cells make IgM antibodies first, but in the presence of cytokines, B-cells can switch the class of antibodies that they make
IgG in presence of IFN-γ
IgE in presence of IL-4 and IL-5
IgA in presence of TGF-β
Antibodies: IgG
- most common antibody in blood and CT
- small, good diffusibility
- complement cascade occurs only with sufficient antigen present
- only antibody that crosses placenta, provides “passive” immunity of fetus
Antibodies: IgD
- the mysterious one
- present on naive B-cells during development, together with IgM
- may regulate B-cell maturation
- does not bind complement
- present at very low levels in blood & secretions
- related to IgW of sharks
Antibodies: IgE
- mast cell IgE receptors trigger degranulation
- great for parasitic infections
- responsible for allergies and anaphylaxis
Antibodies: IgM
- pentamer (sometimes hexamer) of IgGs
- excellent at bringing together multiple C1 complement molecules that will then start the complement cascade
- excellent at early response to infection
- more sensitive to the amount of antigen present “require a lot of foreign invader to bind IgM”
Why first molecule made so complex with all Fc regions together?
“Fc region “are you bound, or are you not bound?” By bringing several molecules together, it’s harder for those antibodies to all bind to any given foreign invader”
Antibodies: IgA
tolerance antibody
two IgG structures clipped together = very difficult to read that Fc domain = prohibits the other arms of immune system form reading whether that antigen is bound or unbound
- protects mucosal surfaces
- secreted in breast milk
- “clip” region confers resistance to acids
- does not bind complement
- passive defender of the gut
B cell
uses antibodies as surface molecules. every B cell makes a specific antibody. each antibody is unique. there are millions of different antibodies that respond to something different.
Fights extracellular substances
Expresses B-cell receptor (BCR) that uses Ig antibodies to recognize antigens. The B cell receptor is sitting in a lipid raft.
Critical density of antigen causes “activation”.
Upon ‘activation’, divides and differentiates into a plasma cell (antibody factory) which secretes antibodies. Plasma cell 1) creates more free antibodies 2) creates more B cells
B–cell life span
Immature B-cells leave the marrow
Mature Naive B-cells express IgD & IgM.
Antigens activate B-cells
B-cells can “class switch” to produce other antibodies (typically IgG) (the “kill this” antibody)
A small population differentiate to memory B-cells, specific to the antigen that caused activation, and persist throughout life
T-cells
“B cells are great, but viruses have evolved to take advantage of the intracellular space. Viruses inject genome into the cell and uses the cell’s machinery to replicate themselves. While they are intracellular, they are invisible to B cells specificity. They would have to be caught in that brief moment when they are extracellular.”
T cells:
Lymphocyte
Fights viruses & phagocytosed material (intracellular invaders)
Expresses T-cell receptor (TCR), which recognizes antigens bound to MHC (major histocompatibility complex)
CD8+ = Tc, “cytotoxic” = MHC1. Destroys things
CD4+ = Th, “helper” = MHC2 (MHC2 is a molecule that only appears on APCs)
