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The Immune System

BIOL/BMSC 114
Dr Joy McIntosh, Reproduction Group VUW
(Refs: Chapter 43 Campbell and Reece)
Lecture overview:

• What is innate immunity?

• Compare innate immune mechanisms between


invertebrates and vertebrates.

• What is acquired immunity?


- lymphocyte specificity
- clonal selection
- immune memory.
Recognition and response by the immune system

• Animal encounter many dangerous pathogens


=infectious agents that cause disease

• Defence = recognition + response

• 2 major types of immune system defense:


1) innate immunity – recognises a few common traits
of all pathogens (occurs in all animals).
2) acquired (adaptive) immunity – specific to each
pathogen and has memory (only in vertebrates).
Evolution of Immunity
Bacteria – INNATE Immunity
Invertebrates – INNATE Immunity

Immunological Big Bang?

Vertebrates (cartilaginous fish onwards) –


INNATE + ACQUIRED Immunity
Fig. 43.2 in text book
Innate immunity

• Innate immunity is present before any exposure to


pathogens and is effective from the time of birth.

• It involves general, non-self responses to pathogens.

• Innate immunity consists of 5 main defenses:


1) external barrier defenses
2) phagocytic cells
3) antimicrobial peptides (defensins, interferons, complement)
4) inflammatory response
5) natural killer cells
1) Vertebrate External Barrier Defenses

• Skin and mucous membranes = physical barriers to entry


by microorganisms and viruses.

• Mucous membrane cells (digestive, respiratory, urinary,


reproductive tracts) produce secretions including mucus,
to trap and kill microbes and other particles.

• Mucous membrane secretions wash microbes away and


provide conditions hostile to microbes eg. lysozyme in
saliva, mucus and tears, acid in stomach, acid secretions to
keep skin acidic.

• Often cells are ciliated to keep mucus moving.


LE 43-3
10 µm

In the trachea, ciliated epithelial cells sweep mucus and any


trapped microbes upward away from the lungs.
macrophage
2) Phagocytic cells

• Innate internal cellular defenses


depend mainly on phagocytosis
(ingestion of a foreign body) by phagocytic cells.

• Phagocytic cells have membrane Toll-like receptors


that bind to common microbial components, eg.
lipopolysaccharides (LPS), dsRNA, flagellin.

• Several white blood cells (leukocytes) are phagocytic


e.g. neutrophils, monocytes, macrophages and
dendritic cells
Fig:LE42.17
42-16
in text book
Pluripotent stem cells
(in bone marrow)

•All the cells Lymphoid Myeloid


here are stem cells stem cells
leukocytes
(white blood
cells), except
erythrocytes
and platelets
Basophils
NK
•Leukocytes B cells
cells T cells
are found in
blood, lymph Lymphocytes

and Eosinophils
interstitial
fluid
systems. *
Neutrophils
Erythrocytes
Macrophages
*
Dendritic cells
Platelets Monocytes
* *
Leukocytes and type of immunity

• Eosinophils
• Basophils (blood)
• Neutrophils Innate,
• Monocytes (blood) in all
phagocytes animals

• Macrophages, dendritic cells (tissue)
• Lymphocytes ---- natural killer cells
---- B cells Acquired
---- T cells only,
vertebrates
LE 43-5
The Lymph System Interstitial Lymphatic
fluid capillary
Adenoid
1. Blood
3.Lymph Tonsil
to lymph
returns
to blood Blood
Lymph capillary
nodes

Spleen Tissue Lymphatic


cells vessel
Peyer’s patches
(small intestine)

Appendix
2. Cells
group at
nodes
Lymphatic
vessels Lymph Masses of
node lymphocytes and
macrophages
Phagocytic leukocytes:

• Neutrophils: most abundant phagocytes,


first responders to inflammation signals by
migrating to tissue for phagocytosis of
microbes.

• Macrophages: ‘big eaters’, some are


migratory, some are tissue-specific.
Especially useful in spleen, lymph nodes
and other lymph tissue.

• Dendritic cells: mostly in tissues in contact


with the environment. Phagocytose
microbes, then present antigens to
stimulate acquired immunity. Also can
migrate to lymph nodes.
Phagocytosis Phagocytes:
- recognise and attach to
microbe/pathogen via their own
surface receptors eg. Toll-like
receptors on dendritic cells and
neutrophils, or IgG receptors on B
cells
- microbe and receptor are engulfed
into phagocyte cell using cytoskeleton
driven extensions of membrane called
pseudopodia
- pseudopodia form a vacuole that
fuses with a lysosome containing
nitric oxide (NO), lysozyme and
peroxidase, to degrade the microbe
- fragments of the engulfed microbe
may then initiate other innate or
acquired mechanisms, or else be
Fig. 43.4 in text
released from the cell
LE 43-1

macrophage

yeast cell
3 µm
3) Anti-microbial peptides and proteins:
• Cell membrane Toll-like receptors recognise
and bind to pathogen, triggering synthesis and
release of anti-microbial peptides and proteins.
• These proteins lyse/burst pathogens and/or
limit their reproduction.
• 3 main groups of anti-microbial proteins:
1) Defensins released after Toll-like receptor Found in all
binding. Pathogen cell membranes are animals.
damaged, causing their lysis.
2) interferons found only in
3) complement proteins vertebrates.
Interferons = glycoprotein cytokines
• are cytokine hormones that regulate activity of immune cells
locally.
• stimulate defense against viruses, tumours and parasites.

• 3 main mechanisms of interferon action:


1) induces production of substances to reduce viral reproduction

Viral interferons Proteins made to inhibit any


dsRNA viral reproduction

Virus-infected cell Non-infected cell

2) activates natural killer cells and macrophages.


3) helps presentation of antigen in acquired immunity
Complement System Complement

• consists of 30 blood plasma proteins


that act together in a cascade to fight
pathogens.
Membrane
attack
• Complement proteins circulate in an complex
inactive state until molecules on
microbe cell surface are recognised
and cascade initiated.
• Complement cascade results in pore
formation (membrane attack complex,
MAC) and lysis of invading cell.
• Complement also plays a role in
inflammation and acquired immunity.
4) Local Inflammatory Response

Fig. 43.8 in text


1) Mast cells release histamines that, together with signals from activated
macrophages, signal for increased blood flow to the site.
2) Capillaries widen and permeabilise, increasing transport of antimicrobial
peptides around injury.
3) Signals from immune cells and activated complement attract extra phagocytic
cells (neutrophils and macrophages).
4) These phagocytic cells digest pathogens, debris forms pus.
5) Natural Killer (NK) Cells

• Are lymphocytes

• Natural killer cells attack diseased cells (eg.virus-


infected body cells and cancer cells) in vertebrates.

• All cells (except red blood cells) have class 1 Major


Histocompatability Complex (MHC) surface proteins.
NK cells recognise altered or lack of class 1 MHC protein
on body cells that occurs in cancer or disease.

• NK cells then attach to infected/diseased cells and


release chemicals that lead to diseased cell lysis and
death. Equivalent to cytotoxic cells in acquired immunity
Innate immunity

• Innate immunity is present before any exposure to


pathogens and is effective from the time of birth.
• It involves non-self responses to pathogens.

• Innate immunity consists of external barriers plus internal


cellular and chemical defenses:
1) barrier defenses
2) phagocytosis Vertebrates and
invertebrates
3) antimicrobial peptides – defensins
- interferons and complement
4) inflammatory response Vertebrates only
5) natural killer cells
Innate Immunity in Invertebrates
Bacteria – cell wall, restriction endonucleases

Invertebrates eg. insects


• Barriers: exoskeleton, digestive system with chitin barrier and
lysozyme.
• Internal mechanisms - hemocytes in hemolymph:
1) secrete lectins that tag ‘non-self’ sugars on pathogen cell
walls, for later recognition by hemocytes.
2) some hemocytes are phagocytic
3) some produce antimicrobial peptide defensins and
complement-like proteins.
eg. when fungus N. crassa infects fruit fly, the fly’s immune cells
recognise infection, Toll receptors are stimulated and initiate
production of a range of defensins.
Acquired (Adaptive) Immunity

• Unique to vertebrates, acquired immunity relies on:


B and T cells (lymphocytes)
in humoral (fluid-based) and cell-based immunity

• Main characteristics of acquired immunity:

1) specifically recognises diverse range of foreign cells

2) self-tolerant ie. own cells not recognised as foreign

3) response to a previously-encountered antigen is


stronger and faster than before,
resulting in immunological memory that is long-lasting
B and T cell lymphocyte development
• Lymphocytes arise from
hemopoietic lymphoid
stem cells in bone
marrow.

• Newly formed
lymphocytes are alike
but later develop into B
cells or T cells,
depending on where
they mature.

• B cells mature in the


bone marrow, while T
cells mature in the
thymus.
Specific recognition of Acquired Immunity

Pathogenic cell
presenting different
(
B antigens on its cell
surface.
Binding
lymphocytes and
T ( Response

• B and T cells each have about 100,000 cell surface receptors that
bind to foreign molecules = antigens on pathogens.
• Receptors bind only to a small portion of the antigen (about 4 amino
acids) called an epitope. Each antigen usually has many epitopes.
• Lymphocyte receptors are actually antibodies
• All receptors on one lymphocyte are the same, recognising only one
epitope, but other lymphocytes have other receptors.
Antibodies, antigens and epitopes
• antibodies = immunoglobulin proteins exist as:
-- antigen receptors on cell surfaces of B and T cells
-- free, soluble antibodies secreted by plasma B cells.

• antigens (antibody-generating substances):


mostly large molecules (proteins, polysaccharides) either
on pathogen/infected cell surface or secreted as toxins

epitope
Antigen molecule

• epitopes: small accessible region of an antigen that is recognised by a


receptor eg. 4-5 amino acids of a protein, may not be in sequence
but in folded protein.
B Cell Receptor T Cell Receptor

Fig. 43.9 in text


B lymphocyte receptor or free immunoglobulin
Immunoglobulin diversity – generated by gene
rearrangement.

• Question:
How does the diversity seen in the known 1014
different B cell antibodies and 1017 different T cell
antibodies arise from the 20,500 protein-coding genes
in the human genome?

• Answer: diversity is built by the recombination


‘shuffling’ that alternatively splices, rearranges and
mutates the immunoglobulin light and heavy chain
genes.
Diversity from Gene Rearrangements on Antibody Molecules
1) Multiple variable
and joining genes,
so alternative
splicing (1 V with
1 J with 1 C)
result in 200
combinations
generated for a
light chain
2) and for heavy
chain.
3) Recombinases
(RAGs) randomly V J
alter splice sites. C

4) Mutation of
hypervariable
regions. Fig. 43.13 in text
2) Origin of self-tolerance

• Gene rearrangement does result in some receptors


being specific for ‘self’ molecules.

• In the bone marrow or thymus, immature


lymphocytes are tested for self-recognition.
Lymphocytes that self-recognise are destroyed or
inactivated.

• This enables the immune system to be self-tolerant.


3) Amplification of response and lymphocyte memory

• Only a few antigen receptors will be specific for any one


antigen, so the response to binding must be amplified for it to
be so effective.
• This is achieved by clonal selection:
1) Binding of lymphocyte receptor to its specific antigen
results in activation of the B or T lymphocyte.

2) Activated B or T cells then divide many times as clones ie.


clonal selection, amplifying the response

3) form 2 populations of daughter cells both with same


receptors:
- effector = active cells to produce antibodies, attack antigen
- memory = inactive cells ready for future attack
Clonal Selection

Fig. 43.14
in text
Primary and secondary immune responses

• Primary immune response:


during first exposure to antigen, active effector cells are
produced.
- T cells are activated to effector forms in 7-10 days.
- B cells take 10-17 days to peak, to generate plasma cells
that secrete antibodies
T and B memory cells also produced at this time.

• Secondary immune response:


during a repeated exposure to an antigen, the response is
quicker (takes only 2-7 days for B cells), and is stronger and
longer.
- This secondary response relies on the reservoir of T and B
memory cells from first exposure to be activated into effector
forms.
Primary and Secondary Responses to Antigen

Fig. 43.15 in text