An undergraduate lecture on the biological aspect of human immunity

1. The Immune System
Aurnab Ghose
200304, 200305, 200311

2. Overview
• Immunis – Latin meaning exempt
• Immunology – refers to the mechanisms used by the body as
protection against infections

3. Unusual combination of features:
- Not anatomically well defined and circumscribed
- Is resting in the ideal state – has to be activated
- Following activation – undergoes maturation
- DNA rearrangement during development & maturation

4. Why is the immune system required?
True multicellularity necessitates keeping the
component cells integrated and division of labour
Many groups of cells are not free-living and require
support
Controlled internal environment rich in nutrients
Therefore, freeloaders (other organisms/rogue cells)
Need to defend the body against infections

6. Invasion of infectious agents can come from anywhere
- immune defense has to be be everywhere too
( not a well circumscribed system)
Needed only when infection occurs – not a continuous
function
(at rest when there is no infection)

7. How to deal with infections?
Detection and Action
Simplest: Immune cell with a special invader recognition
receptor, which upon activation takes necessary action
Huge variety of infectious agents – one tag for all
pathogens will not work.
- array of receptors
Wide range of evasion strategies – one response will fail
Same tag but different evasion strategies – detection and
response has to be decoupled.

8. How to generate an array of receptors - I?
1. Clonal uniformity (innate immunity): all cells in population
copies of each other
- bear the same receptor
- recognize molecules that are classified as foreign
(unique to ‘expected’ pathogens. E.g., lipopolysaccharide)
- macrophages bear such receptors
- these have limited and fixed range and recognize a
few conserved, frequently occurring ligands
- evolutionary info; coded in genes; innate immunity

9. Clonally Uniform
receptor expressing immune cells (innate immunity)
InvadersClonally
uniform
defenders
Clonally
diverse
defenders
Bal&Rath1997

10. How to generate an array of receptors - I?
Problems:
Stop making or change tag sufficiently to avoid recognition
- false negative
Commensal organisms
– false positive
Works best: Relatively constant environment ; sedentary;
hard shell; restricted range of potential invaders
1. Clonal uniformity (innate immunity):

11. Clonally Uniform
receptor expressing immune cells (innate immunity)
InvadersClonally
uniform
defenders
Clonally
diverse
defenders
Bal&Rath1997

12. How to generate an array of receptors - II?
2. Clonal diversity (adaptive immunity): all cells descend
from the parent cell but express unique receptors
- bear unique receptors recognizing an extremely large
diversity of unique molecular shapes
- only a small subset of these cells will be triggered
- therefore has to proliferate so that there is enough
to deal with the infection (resting – activated upon
engaging with specific target)

13. Clonally Uniform (innate) and Clonally Diverse (adaptive)
receptor expressing immune cells
InvadersClonally
uniform
defenders
Clonally
diverse
defenders
Bal&Rath1997

14. How to generate an array of receptors - II?
2. Clonal diversity (adaptive immunity):
If an extremely large repertoire of receptors are needed:
- how to generate these (not enough genes)?
- also not enough cells – only a few cells will express a
particular receptor. Will not be enough to control the
infection
- as only a few cells will be triggered, there is a need
to proliferate so that there is enough to deal with the
infection
(resting – activated upon engaging with specific target)

15. How to generate an array of receptors II?
2. Clonal diversity (adaptive immunity): unique
receptors – one for each likely molecular conformation
Bal & Rath 1997
1 week 1 week 1 year1 month 2 days

16. How to generate an array of receptors II?
2. Clonal diversity (adaptive immunity):
1 week 1 week 1 year1 month 2 days
Bal & Rath 1997
1 week 1 week 1 year1 month 2 days
Following one infection, the activate cell type is now slightly
expanded and more sensitive – immune memory/immunity

17. Advantages:
Trigger only a small subset of immune cells
Will require amplification – cell division
Effector cells needs activation and then maturation
This allows for memory
Adaptive immunity
How to generate an array of receptors II?
2. Clonal diversity (adaptive immunity): unique
receptors – one for each likely molecular conformation

18. What are the parasite niches?
- Extracellular niche
(Pneumococcus – pneumonia)
-Intacellular niche
vesicular or endosomal
(Mycobacterium – TB; Salmonella – typhoid)
Cytoplasmic
(Viruses; Shigella – dysentery)

19. upon exposure. When the
l invasion by a Gram-neg-
onse results in elimination
roy Pathogens
rier to Infection
mechanism is the inges-
material by phagocytosis.
tosis, the general term for
rom its environment. In
rane expands around the
nclude whole pathogenic
sicles called phagosomes
conducted by specialized
neutrophils, and tissue
t cell types are capable of
s receptor-mediated endo-
ules are internalized after
tors, and pinocytosis, the
id from the surrounding
contained in it.
a Complex
timulates
or by an invading patho-
mplex sequence of events
matory response. As de-
nent of a microbe, such as
Bacterium becomes attached
to membrane evaginations
called pseudopodia
Bacterium is ingested,
forming phagosome
Phagosome fuses with
lysosome
Lysosomal enzymes digest
captured material
Digestion products are
released from cell
3
2
4
5
1
(b)
of inflammation” as rubor (redness), tumor (swelling),
calor (heat), and dolor (pain). In the second century AD, an-
other physician, Galen, added a fifth sign: functio laesa (loss
Phagocytosis
If in vesicles/endosomes, normally the pathogen is destroyed
But pathogens have evolved ways of trying to avoid this fate

20. Intracellular invader bugs,drilling holes and
getting into the cytoplasm of infected cells
Extracellular invader bugs, sitting both
inside and outside blood vessels between cells
Intracellular invader bugs, sitting in
bubbles inside infected cells
Various locations of pathogens Bal & Rath 1997

21. Different solutions (responses) for different niches
~
~
~
~
~~
~~
~~
*# #
*
*
*
#
*
#
#
*
*
Free molecules help tag
extracellular invaders
to be eaten by phagocytes
May also directly destroy them
Helper cells signal
infected cells to kill
intracellular parasites
lurking in bubbles
Killer cells signal
cells infected with
intracellular parasites
in their cytoplasm
to die
Bal & Rath 1997

22. Sites of action of the immune system
Tissue or interstitial fluid
Drained into the lymphatics
and lymph nodes
Finally connects to the
circulatory system

23. Travels of an immune cell:
Bone marrow – maturation (thymus for T-cells) – lymph nodes
or circulating between blood vessels, tissue fluids and back.

24. Pathogens in the extracellular niche

25. Dealing with Pathogens in the extracellular niche
Recognition by clonally uniform immune cells like
macrophages (phagocytosis)
Circulating free molecules
(complement system ; C-reactive protein)
Strategy: common molecular shapes found in pathogens
that are rarely encountered in the body
(PAMPs: Pathogen-associated molecular patterns)
Circulating free molecules
(Antibodies – produced by B-cells)
Innate Immunity
Adaptive Immunity

26. Pathogen-associated molecular patterns, or PAMPs,
are small molecular motifs consistently found on
pathogens.
They are recognized by pattern recognition
receptors (PRRs) (all metazoans - plants and animals)
Recognition by Innate immunity:
Innate immunity

27. Consequences of PAMP: PRR interaction:
Ellicit other components of the immune system:
Activation of other members of the immune system
Activation of the cell s own degradation machinery
Innate immunityToll-like receptor – a PRR family

28. Conservation of Innate Immunity through Evolution
Innate immunity

29. Innate immunity
es-
is.
or
In
he
nic
mes
ed
ue
of
do-
ter
he
ng
Bacterium becomes attached
to membrane evaginations
called pseudopodia
Bacterium is ingested,
forming phagosome
Phagosome fuses with
lysosome
Lysosomal enzymes digest
captured material
Digestion products are
released from cell
3
2
4
5
1
(b)
Phagocytosis

30. Complement mediated lysis
~ 20 interacting soluble
proteins
Upon initiation starts
proteolytic cascade
Ultimately lyses the pathogen
or tags it for clearance by
phagocytosis
Innate immunity
C-reactive protein:
recognizes pathogen
motifs, binds and
recruits the complement
system

31. Adaptive
immunity
(Humoral)
Circulating Antibodies produced by B-cells

32. 8 P A R T I Introduction
Tissue damage causes release of
vasoactive and chemotactic factors
that trigger a local increase in blood
flow and capillary permeability
Permeable capillaries allow an
influx of fluid (exudate) and cells
Phagocytes and antibacterial
exudate destroy bacteria
Phagocytes migrate to site of
inflammation (chemotaxis)
2
1
3
4
Exudate
(complement, antibody,
C-reactive protein)
Capillary
Margination Extravasation
Tissue damage
Bacteria
FIGURE 1-4 Major events in the inflammatory response. A bacte-
rial infection causes tissue damage with release of various vasoactive
and chemotactic factors. These factors induce increased blood flow
blood cells, including phagocytes and lymphocytes, from the blood
into the tissues. The serum proteins contained in the exudate have
antibacterial properties, and the phagocytes begin to engulf the bac-
Inflammatory response

33. Pathogens in the intracellular niche

34. Pathogens in the intracellular niche
Adaptive Immunity
Recognition and action by T-cells
Innate Immunity
Natural Killer cells (NK-cells)

35. Pathogens in the intracellular niche
T-cells recognize infected cells and send signals to
infected cells to activate them (Helper T-cells; pathogen
in endosomal vesicles) or to instruct them to die (Killer
T-cells; pathogen in cytoplasm).
Must recognize cells as targets not free molecules
T cells can only recognize antigens associated with certain
molecules (MHC) which expressed on the surface of cells
Adaptive immunity (Cellular)

36. Adaptive immunity (Cellular)
Tc
Virus infected cell, cancer cell
MHC I + peptide
Cytotoxic T lymphocyte
Cytosolic
pathogen
Th
Antigen presenting cell (APC)
MHC II + peptide
Helper T lymphocyte
Vesicular
pathogen

37. Adaptive immunity (Cellular)

38. Adaptive immunity (Cellular)

39. NK-cells (innate immunity and intracellular pathogens)
Natural Killer (NK) cells recognize molecular patterns
common to infected cells and induce cell death
Infected cells are likely to be ‘sick’ and have reduced
levels of certain proteins on their cell surface. NK
cells recognize these (like drop in MHC I levels)
Innate immunity

41. Innate Immunity:
set of components that recognize a class of molecules
typical of commonly encountered pathogens (clonal
uniformity)
less specific than adaptive and acts as the first line of
defense
most components present before onset infection
Adaptive Immunity
high degree of specificity (clonal diversity)
triggered only after antigen challenge
has immunological memory

42. Innate vs. Adaptive Immunity
Innate Adaptive
Specificity Inherited in Genome YES NO
Trigger Immediate Response YES NO
Recognize Pathogens Broadly YES NO
Self/Non-self discrimination PERFECT IMPERFECT
Distribution All metazoans Only vertebrates
Level of response Constitutive Inducible
Innate and Adaptive immunity are a continuum

43. The Adaptive Immune Response
• Cell-mediated immunity Involves T cells
• Humoral immunity Involves Ab produced by
B cells
Adaptive immunity

44. Antibody Structure
Adaptive immunity (Humoral)

45. IgG
• Monomer
• 80% of serum
• In blood, lymph,
intestine
• Cross placenta
• Enhance
phagocytosis;
neutralize toxins &
viruses; protects
fetus & newborn
• Half-life = 23 days
IgM
• Pentamer
• 5-10% of
serum
• In blood,
lymph, on B
cells
• Agglutinates
microbes; first
Ab produced in
response to
infection
• Half-life = 5
days
IgA
• Dimer
• 10-15% of serum
antibodies
• In secretions
• Mucosal
protection
• Half-life = 6 days
IgE
• Monomer
• 0.002% of
serum
antibodies
• On mast cells
and basophils,
in blood
• Allergic
reactions; lysis
of parasitic
worms
• Half-life = 2
days
Adaptive immunity (Humoral)

46. Antigenic Determinants
(Antigens = Antibody Generators)
• Antibodies recognize and react with antigenic determinants or
epitopes.
Adaptive immunity (Humoral)

47. Antibodies function
Adaptive
immunity
(Humoral)

48. B-cell
Antigen
Antibody secreting B cell
(plasma cell)
Soluble antibodies, circulate in the body
Surface bound antibody
B cells
Adaptive immunity (Humoral)

49. B-cell
Virus killed
Antibody secreting B
cell (plasma cell)
Adaptive immunity (Humoral)

50. Antibody titer
(amount of Ab in serum)
Adaptive immunity (Humoral)

51. • recognize trillions of possible Ags, individually and
specifically.
• to use only one receptor per cell (a given lymphocyte can
not carry receptors, for say, 1000 Ags) to do so
• to have sufficient cells specific for the Ag in question to
mount an effective response. (ie need 100,000s to millions of
Ag-sp cells for a given Ag)
Insufficient space!
Problem to solve:
Adaptive immunity (Humoral)

52. Clonal Selection
• The immune system has an extremely low frequency of
cells specific for each of trillions of possible specificities.
• These cells continuously recirculate.
• If a cell does not meet its correct antigen within 2-3
days, it dies.
• When a cell encounters its specific Ag, it replicates
extensively, turning ~5-10 cells into millions of progeny.
Adaptive immunity (Humoral)
1 week 1 week 1 year1 month 2 days

53. Clonal Selection
Adaptive immunity (Humoral)

54. • that a given Ag find a lymphocyte
expressing a specific receptor for that Ag
• that those cells multiply to provide enough
cells to be effective
• an off signal once Ag is removed, to limit
pathology
B-Lymphocyte activation requires…
Adaptive immunity (Humoral)

55. Adaptive immunity (Humoral)

56. How does one generate adaptive diversity of Abs
to match the large number of antigens possible?
…by shuffling immunoglobulin gene segments !!!
Adaptive immunity (Humoral)

57. vH dH jH = VH
Mouse heavy chain gene expression
Adaptive immunity (Humoral)
Undifferentiated
B-lymphocyte
Differentiated
B-lymphocyte
lH-vH ~ 300
dH ~ 10-50
jH ~ 4
ck = 8

58. 5 cap-
Mouse (kappa) light chain gene expression
5 cap
—
N- - C
N- - C
vk jk = Vk
Adaptive immunity (Humoral)
Undifferentiated
B-lymphocyte
Differentiated
B-lymphocyte
lk-vk ~ 300
jk ~ 5
ck = 1

59. • true randomness comes from “errors” in
recombination at the v-d-j/v-j junctions
• affinity for antigen can be increased during
maturation (affinity maturation) by processes
such as “somatic hypermutation”
SIMILAR MECHANISM GENERATE THE
DIVERSITY OF T-Cell RECEPTORS

60. • If something is ubiquitous and not associated with the
functional hallmarks of an invader, it is likely to be self.
• Ubiquitous targets are likely to be encountered almost
immediately after B & T cells are born
•If young B & T cells encounter antigens at their juvenille
stage they are turned “off”.
• Self is not normally associated with functional hallmarks
of invaders (‘context’)
•Co-stimulatory “contextual” information is required for B-
and T-cells to mount a response
Self – Non-self recognition

61. Self – Non-self
recognition
*****
B cell
*target
quiescent
phagocyte target
T cell
**
***
T cell
*
target
contextual
signals
activated
phagocyte
RESPONSE!
* infections
DANGER signals!
B cell
RESPONSE!
*target
contextual signals
*
no
response
*
Bal & Rath 1997

62. Acquired Immunity
• Naturally acquired active immunity
– Resulting from infection
• Naturally acquired passive immunity
– Transplacental or via colostrum
• Artificially acquired active immunity
– Injection of Ag (vaccination)
• Artificially acquired passive immunity
– Injection of Ab