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Chapter 1: Overview of the Immune System. Innate (Non-Specific) Immunity Anatomic barriers Physiologic barriers Endocytic barriers Phagocytic barriers Inflammatory response barriers Adaptive (Specific) Immunity Properties Specificity Diversity Memory Self/non-self recognition.

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chapter 1 overview of the immune system
Chapter 1:Overview of the Immune System
  • Innate (Non-Specific) Immunity
  • Anatomic barriers
  • Physiologic barriers
  • Endocytic barriers
  • Phagocytic barriers
  • Inflammatory response barriers
  • Adaptive (Specific) Immunity
  • Properties
      • Specificity
      • Diversity
      • Memory
      • Self/non-self recognition
slide2

Major organs of the immune system

1° organs

2° organs

Major cells of the immune system

B lymphocytes

T lymphocytes

Antigen presenting cells (APCs)

Humoral immunity

Cell-mediated immunity

Compare and Contrast

Cell-mediated vs. humoral immunity

Acquired vs. innate immunity

slide3

Recognition of Ag by B and T lymphocytes

  • Lymphocyte specificity and diversity
  • Role of the major histocompatibility complex (MHC)
  • Processing and presentation of Ags
  • Specificity of receptors
    • Instructional theory
    • Clonal selection theory
  • 1° immune response
  • 2° immune response
  • Cellular interactions required for generation of IRs
  • Generation of the humoral response
  • Generation of the cell-mediated response
  • end of outline
overview of the immune system
OVERVIEW OF THE IMMUNE SYSTEM

IS = immune system IR = immune response

Definitions

Immunity state of protection from infectious disease

Immune Latin immunis (exempt)

antigen foreign substance (non-self) (Ag)

Two Types of Immunity

Innate (non-specific)

Adaptive (specific)

innate immunity non specific
INNATE IMMUNITY(NON-SPECIFIC)
  • {Review Table 1-2 next }
  •   Anatomic Barriers
  • Skin
  • Mucous Membranes
  • Physiologic Barriers
  • Temperature
  • pH
  • Endocytic barriers {Figure 1-3}
  • Phagocytic barriers
  • Inflammatory response barriers {Figure 1-4}
  • Collaboration between Innate and Adaptive Immunity
slide6

Endocytic barriers

    • -  pinocytosis - macromolecules internalized via non-specific membrane envagination (sipping)
    • - receptor-mediated endocytosis - macromolecules selectively internalized via specific receptors
  • endocytic vesicles
  • (fuse)
          • endosome + 1° lysosome
  • (fuse)
  • 2° lysosome
  • (endolysosome)
  • digestion

Figure 1.3 next

figure 1 3
Figure 1.3

phagosome + 1° lysosome

 (fuse)

2° lysosome

(phagolysosome)

digestion

  {Fig. 1-3*}

slide8

Phagocytic barriers

  • - foreign material ingested
  • - cell membrane expands to form phagosome
  • -specialized cells only
  • - neutrophils
  • - blood monocytes
  • - tissue macrophages
inflammatory response barriers
Inflammatory Response Barriers
  • inflammation regulated by cytokines
  • cardinal signs of inflammation
  • 1. rubor(redness)
  • 2. tumor (swelling)
  • 3. calor(heat)
  • 4. dolor (pain)
slide11

major events of inflammation

  • 1. vasodilation
  • - redness
  • -  temperature
  • 2. capillary permeability
  • - influx of fluid (exudate)
  • - swelling
  • 3. influx of phagocytes
  • - phagocytose bacteria
  • - release lytic enzymes
  • - can damage healthy cells (pain)
collaboration between innate and adaptive immunity
Collaboration between Innate and Adaptive Immunity
  • Innate
  • Microbes generate “danger or warning” signals (LPS, microbial products etc.)
  • Increase ability of macrophages of macrophages to take up and present antigens to IS.
  • Stimulate secretion of cytokines.
  • Adaptive
  • When activated produce cytokines to increase effectiveness of innate immunity
  • Antibodies mark pathogens for destruction by complement
adaptive immunity specific
Adaptive IMMUNITY(SPECIFIC)

Focus of course

Properties

antigen specificity

diversity of B and T cells

immunologic memory

self/non-self recognition

Theme of course

Remember

specificity

diversity

memory

self/non-self recognition

antigen specificity
ANTIGEN SPECIFICITY
  • IS can distinguish subtle differences among Ags
  • Sensitive to 1 a.a. difference
  • DIVERSITY
  • ability to recognize billions of foreign Ags
  • B cell diversity via immunoglobulins (Igs)
  • T cell diversity via T cell receptors (TCRs)
immunologic memory
IMMUNOLOGIC MEMORY
  • IMMUNE SYSTEM remembers 1st Ag encounter
  • 2nd encounter with same Ag
  • heightened response
  • can confer life-long immunity
  • SELF/NON-SELF RECOGNITION
  • IS distinguishes self from non-self Ags
  • governed by MHC molecules
  • response to non-self Ags  normal IR
  • response to self Ags  autoimmune disease
major organs of the immune system
MAJOR ORGANS OF THE IMMUNE SYSTEM

1° ORGANS

· Bone Marrow

- gives rise to B and T cells

- B cell maturation

· Thymus

-  T cells migrate from bone marrow

-  T cell maturation

-   thymic selection

2° ORGANS

· Spleen

-  filter for blood

-  traps Ag

-  Ag interacts with Ag-specific cells

·  Lymph Nodes

-  filter for lymph

-  traps Ag

-  Ag interacts with Ag-specific cells

major cells of the immune system
MAJOR CELLS OF THE IMMUNE SYSTEM

{Figure 1-5}

B CELLS

T CELLS

ANTIGEN PRESENTING CELLS (APCs)

NOTE

CD = Cluster of Differentiation

(proteins expressed on cell surface)

(a.k.a. protein “markers”)

b cells
B cells
  •   responsible for humoral IR
  • originate and mature in bone marrow (bursa of Fabricius - chicken)
  • immunoglobulins (Ig) - (Ab is general term)
  • -Ag receptor (“recognition”)
  • -membrane-bound (mIg) » BCR
  • -soluble (sIg)
slide19

maturation

  • - Involves Ig gene rearrangements (>108combinations) (>108combinations)
  • - self-reactive B cells eliminated
  • mature B cells
  • -immunocompetent (Ag-specific)
  • -circulate in blood and lymph
  • -activated by Ag-binding to mIg
slide20

mature B cell + specific Ag

  • ê
  • clonal selection / expansion
  • í î
  • memory B cells plasma cells
  • long-lived - effector B cells
      • - remember Ag - short-lived
      • -2° response faster - secrete sIg
          • sIg + Ag
          •   ê
          • Ag-Ab complex
          • ê
          • elimination
t cells
T CELLS
  • responsible for cell-mediated IR
  • originate in bone marrow
  •   mature in thymus
slide22

·T cell receptor (TCR)

-  associated with CD3

-  Ag receptor (“recognition”)

-   dimer ( or )

slide23

· maturation

-involves TCR gene rearrangements

(>1015 combinations)

-  self-reactive T cells eliminated

  • mature T cells
  • - immunocompetent (Ag-specific)
  • -  circulate in blood and lymph
    • -  activated by TCR recognition of Ag
    • + MHC
slide24

sub-populations

  • T helper cells (TH)
  • - CD3+, CD4+, CD8-
  • - recognize Ag + MHC II
  • - activation leads to cytokines (“help”)
  • T cytotoxic cells (TC)
  • - CD3+, CD4-, CD8+
  • - recognize Ag + MHC I
  • - activation è differentiation to CTL
  • - cytotoxic T lymphocyte
  • - armed effector cell
  • -kills target cell
antigen presenting cells apcs
ANTIGEN PRESENTING CELLS (APCs)
  • internalize Ag by phagocytosis or endocytosis
  • present Ag + MHC II to TH cells
  • {Figure 1-6}
  • TH cells produce cytokines
  • cytokines required by T and B cells
  • T cells (cell-mediated immunity)
  • B cells (humoral immunity)
  • APCs
  • -     macrophages (Ms)
  • -     B cells
  • -     dendritic cells
humoral immunity
HUMORAL IMMUNITY
  • Latin humor (body fluid)
  • B cell response
  • plasma cells are effector cells
slide28

Igs (Abs) are effector molecules

  •   -  neutralize Ag
  •   -  facilitate Ag elimination
  • Ag elimination
  • - Ab-Ag complexes more palatable to Macrophages
  • - Ab-pathogen complexes activate
  • complement (C’) system  pathogen lysis
  •   -Ab-toxin complexes  neutralization
cell mediated immunity
CELL-MEDIATED IMMUNITY
  • T cell response
  • effector cells
  • -THè cytokines
  • -CTL è cell lysis
  • cytokines
  • - activate phagocytes
  • - induce TC differentiation
  • TC è CTL (effector)
  • -support B cell differentiation
  • B cell è plasma cell (effector)
cell mediated vs humoral immunity
CELL-MEDIATED vs HUMORAL IMMUNITY

TH cell cytokine production supports both B cell (humoral) and T cell (cell-mediated) IRs.

{Review Figure 1-7}

adaptive vs innate immunity
ADAPTIVE vs INNATE IMMUNITY

(SPECIFIC) (NON-SPECIFIC)

  • work together to eliminate foreign invader
  • examples
  • - phagocytes augment specific IR
  • - cytokines augment non-specific phagocytosis
  • - inflammatory cytokines attract and coordinate cells  specific IR ; more cytokine production
recognition of ag by b and t cells
RECOGNITION OF Ag BY B AND T CELLS
  • Ags- large and complex
  • B and T cells recognize epitopes
  • -  antigenic determinants
  • -  bind to TCRs or BCRs (mIg)
  • B cells
  • -  humoral immunity
  • -  recognize epitopes alone
slide33

T cells

  • - cell-mediated immunity
  • -  recognize epitopes + MHC molecules on the surface of
      • - altered self-cells (virus / cancer) - MHC I
      • - self-cells (APCs) - MHC II
  • - Class II MHC molecules (APCs only)
lymphocyte specificity and diversity
LYMPHOCYTE SPECIFICITY AND DIVERSITY

SPECIFICITY

·B cells  mIg (BCR)

·T cells  TCR

slide35

DIVERSITY

  • B cells
  • - generated by random gene rearrangements
  • during maturation
  • - self-reactive B cells eliminated (clonal deletion)
  • - >108 antigenic specificities
  • - ~105 mIg/B cell with same specificity
  • (“antigenically committed”)
  • T cells
  • - generated by random gene rearrangements
  • during maturation
  • -  self-reactive T cells eliminated (thymic selection)
  • - >1015 antigenic specificities
  • - ~105 TCRs/T cell with same specificity
  • (antigenically committed)
role of major histocompatability complex mhc
ROLE OF MAJOR HISTOCOMPATABILITY COMPLEX (MHC)

{Figure 1-8}

·multi-allelic family of proteins with

multiple loci

·two major classes

-   MHC I

- MHCII

slide37

MHC I- glycoproteins; single chain (a)

  • - always associated with 2-microglobulin
  • - loci
      • - humans (3) - A, B, C
      • - mice (2) - K, D
  • - all nucleated cells
  • - identify unique “self”
  • - Ag + MHC I TC recognition
  • MHC II
  • - heterodimeric glycoproteins ( +  chain)
  • - loci
      • - humans (3) - DR, DP, DQ
      • - mice (2) - IA, IE
  • - APCs only
  • - Ag + MHC II  TH recognition
slide38

MHC and antigen recognition

MHC binds to a “spectrum” of antigenic peptides

  MHC distal regions

-  wide variation in a.a. sequences

-  form cleft that holds antigenic peptides

-  present Ag to T cells

processing and presentation of ags
PROCESSING AND PRESENTATION OF Ags

(Fig. 1-9)

Exogenous

From the outside

Endogenous

From the inside

slide40

Endogenous Ag

  • from within
  •  e.g. cancerous and virally-infected cells (altered self-cells)
  • processed and presented with MHC I via
  • cytosolic pathway
  • TC recognition
  • Exogenous Ag
  • from outside,
  • e.g. bacteria,foreign proteins
  • processed and presented with MHC II via
  • endocytic pathway
  • TH recognition
specificity of receptors
SPECIFICITY OF RECEPTORS

(Ab and TCR)

What is the mechanism?

Two Major Theories

Instructional Theory

Clonal Selection Theory

instructional theory
INSTRUCTIONAL THEORY
  • (supported by Linus Pauling)
  • Ag exists prior to Ab
  •  Ag acts as template
  • Ag instructs formation of specific Abs 
clonal selection theory
CLONAL SELECTION THEORY
  • {Figure 1-10}
  • early version: side chain theory (lock & key) (Paul Erlich ~1900)
  • Ag-specific B cells exist prior to Ag
  • Ag encounter causes proliferation of specific B cell clones
1 immune response
1° IMMUNE RESPONSE
  • {Figure 1-11}
  • ·1st encounter with Ag
  • selection of B cell clones
  •   clonal expansion (proliferation/differentiation)
  • ê î
  • plasma cells memory B cells
  • ê
  • IgM
  • (low affinity)
  • lag period ~ 5-7 days
  • peaks @ ~14 days
2 immune response
2° IMMUNE RESPONSE
  • Figure 1-11a
  •   2nd encounter with Ag
  • activation of memory B cells
  • clonal expansion (proliferation/differentiation)
  • 
  • plasma cells more memory B cells
  • IgG
  • (high affinity)
  • lag period ~ 1-2 days
  • peaks @ ~7 days
cellular interactions required for generation of immune responses
CELLULAR INTERACTIONS REQUIRED FOR GENERATION OF IMMUNE RESPONSES
  • TH cells required for both humoral and cell-mediated Irs
  • Ag + MHC II  TH activation
  • activated TH cells  cytokines necessary for activation of B cells and TC cells
  • TH cytokines also regulate proliferation and differentiation of non-specific effector cells(e.g. NK cells and Ms)
  • memory TH cells important for 2° IR 

{Figure 1-13}

generation of the humoral response
GENERATION OF THE HUMORAL RESPONSE

B cell recognizes soluble Ag

AND

some Ag internalized, processed, and

presented with MHC II by APC

ê

soluble Ag cross-links mIgs (BCRs) on B cell

AND

Ag-MHC II binds TCR on Ag-specific TH cell

ê

Ag-specific TH activation, proliferation,

differentiation, and cytokine secretion

memory TH cells

ê

TH cytokines support B cell

proliferation and differentiation

í î

sIg producing memory B cells

plasma cells

generation of the cell mediated response
GENERATION OF THE CELL-MEDIATED RESPONSE

endogenous Ag processed and presented

as Ag-MHC I

AND

some soluble Ag internalized, processed, and

presented as Ag-MHC II by APCs

ê

Ag-MHC I binds TCR on Ag-specific TC cell

AND

Ag-MHC II binds TCR on Ag-specific TH cell

ê

Ag-specific TH cell activation, proliferation,

differentiation and cytokine secretion (esp. IL-2)

memory TH cells

ê

TH cytokines (esp. IL-2) support TC cell

proliferation and differentiation

í î

cytotoxic T lymphocytes memory TC cells

(CTLs)

cell mediated vs humoral immunity50
CELL-MEDIATED vs HUMORAL IMMUNITY

TH cell cytokine production supports both B cell (humoral)

and T cell (cell-mediated) IRs.

{Review Figure 1-7}

fig 1 11a
Fig. 1-11a

IgM

Long lag

fig 1 11a ii
Fig. 1-11a(ii)

IgG

Short lag

major organs of the immune system69
MAJOR ORGANS OF THE IMMUNE SYSTEM

1° ORGANS

· Bone Marrow

- gives rise to B and T cells

- B cell maturation

· Thymus

-  T cells migrate from bone marrow

-  T cell maturation

-   thymic selection

2° ORGANS

· Spleen

-  filter for blood

-  traps Ag

-  Ag interacts with Ag-specific cells

·  Lymph Nodes

-  filter for lymph

-  traps Ag

-  Ag interacts with Ag-specific cells

major cells of the immune system70
MAJOR CELLS OF THE IMMUNE SYSTEM

{Figure 1-5}

B CELLS

T CELLS

ANTIGEN PRESENTING CELLS (APCs)

NOTE

CD = Cluster of Differentiation

(proteins expressed on cell surface)

(a.k.a. protein “markers”)

antigen presenting cells apcs71
ANTIGEN PRESENTING CELLS (APCs)
  • internalize Ag by phagocytosis or endocytosis
  • present Ag + MHC II to TH cells
  • {Figure 1-6}
  • TH cells produce cytokines
  • cytokines required by T and B cells
  • T cells (cell-mediated immunity)
  • B cells (humoral immunity)
  • APCs
  • -     macrophages (Ms)
  • -     B cells
  • -     dendritic cells