Lecture 1. Immunology. Introduction & Innate immunity

1.

Lecture 1
Immunology
Introduction & Innate immunity

2.

What is immunity?
“Protection” from infection, tumors, etc.
Innate immunity is always available
Adaptive immunity distinguishes “self” from
“non-self” and involves immune system
“education”
Responses that may result in host tissue
damage

3.

Two types of immunity
Innate immunity (not antigen-specific)
Anatomical barriers
Mechanical
Biochemical
Non-specific (eg. Low pH in stomach)
Receptor-driven (eg. PAMP-recognition)
Adaptive immunity (antigen-specific)
Receptor-driven
Pre-existing clones programmed to make a specific
immune response (humoral/cellular)

4.

Antigen
A substance (antigen) that is capable of
reacting with the products of a specific immune
response, e.g., antibody or specific sensitized Tlymphocytes.
A “self” component may be considered an
antigen even though one does not generally
make immune responses against those
components.

5.

Characteristics of Adaptive Immunity
Immune response is highly specific for the antigen that triggered
it.
Receptors on surface of immune cells have same specificity as
the antibody/effector activity that will be generated
Exposure to antigen creates an immunologic “memory.”
Due to clonal expansion and creation of a large pool of cells
committed to that antigen
Subsequent exposure to the same antigen results in a rapid and
vigorous response

6.

Components of the immune
system

7.

platelets
Cells eosinophil megakaryocyte
T Lymphocyte
Pluripotent
involved
hematopoietic
neutrophil
stem cell
in
B Lymphocyte
immunity
basophil
common
myeloid
progenitor
common
lymphoid
progenitor
plasma cell
mast cell
Natural
Killer cell
monocyte
macrophage

8.

Lymphoid Organs
Primary or central lymphoid organs
bone marrow and thymus
where lymphocytes are generated
Secondary or peripheral lymphoid organs
where adaptive immune responses are initiated

9.

Distribution of Lymphoid Tissues

10.

Innate Host Defense Mechanisms
Anatomic Factors
Mechanical Factors
Biochemical Factors

11.

Skin
Stratified and cornified epithelium provides a
mechanical barrier
Indigenous microbiota competes with pathogens
Acid pH inhibits growth of disease producing
bacteria
Bactericidal long chain fatty acids in sebaceous
gland secretions

12.

Respiratory Tract
Upper Respiratory Tract
Nasal hairs induce turbulence
Mucous secretions trap particles
Mucous stream to the base of tongue where material is
swallowed
Nasal secretions contain antimicrobial substances
Upper respiratory tract contains large resident flora
y smallest particles (<10µ in diameter) reach alveoli
Alveoli

13.

Respiratory Tract
Lower Respiratory Tract
Particles trapped on mucous membranes of bronchi
and bronchioles
Beating action of cilia causes mucociliary stream to
flow up into the pharynx where it is swallowed
90% of particles removed this way.
Alveolar macrophage rapidly phagocytize small particles

14.

Alimentary Tract
General defense mechanisms
Mucous secretions
Integrity of of mucosal epithelium
Peristaltic motions of the gut propel
contents downward
Secretory antibody and phagocytic cells
Stomach
Generally sterile due to low pH
bacteria

15.

Alimentary Tract
Small Intestine
Upper portion contains few bacteria
As distal end of ilieum is reached flora increases
Colon
Enormous numbers of microorganisms
50-60% of fecal dry weight is

16.

Genitourinary Tract
Male
No bacteria above urethrovesicular junction
Frequent flushing action of urine
Bactericidal substances from prostatic fluid
pH of urine
Bladder mucosal cells may be phagocytic
Urinary sIgA

17.

Genitourinary Tract
Female (Vagina)
Large microbial population (lactobacilli)
Microorganisms produce low pH due to breakdown
of glycogen produced by mucosal cells

18.

Eye
Flushing action of tears which drain through the
lacrimal duct and deposit bacteria in nasopharynx
Tears contain a high concentration of lysozyme
(effective against gram positive microorganisms

19.

Receptors
Almost all of biology occurs because recognition
Enzymatic action
Interactions between cells (cooperation/activation)
Communication between cells
Innate and adaptive immunity requires it

20.

Innate Immune Recognition
All multi-cellular organisms are able to recognize
and eliminate pathogens
Despite their extreme heterogeneity, pathogens
share highly conserved molecules, called
“pathogen-associated molecular patterns”
(PAMPs)
Host cells do not share PAMPs with pathogens
PAMPs are recognized by innate immune
recognition receptors called pattern-recognition
molecules/receptors (PRMs/PRRs)

21.

Typical PAMPs
Lipopolysaccharides
Peptidoglycans
Certain nucleotide sequences unique to bacteria
Other bacterial components

22.

Endogenous Signals Induced by PAMPs
Mediate inflammatory cytokines
Antigen-presenting cells recognize PAMPs
Same APC processes pathogens into specific
pathogen-derived antigens and presents them with
MHC encoded receptors to T-cells
T-cell responds only when presented with both
signals
Different Effector Cytokines in Response to Different
Pathogens (Th1 vs. Th2)

23.

Antimicrobial Peptides/Defensins
Four hundred peptides described to date
Defensins (3- 5-kD, four families in eukaryotes)
a-defensins (neutrophils and intestinal Paneth cells)
b-defensins (epithelial cells)
Insect defensins
Plant defensins
Defensins appear to act by binding to outer membrane
of bacteria, resulting in increased membrane
permeability.
May also play a role in inflammation and wound repair

24.

Complement System
Three pathways now known
Classical
Alternative
Lectin or MBL pathway (binding to mannose-
containing carbohydrates)
Host cells have complement regulatory proteins
on their surface that protect them from
spontaneous activation of C3 molecules

25.

Inflammatory Mediators in Innate Immunity
Cytokines secreted by phagocytes in response to infection include:
IL-1
activates vascular endothelium and lymphocytes
Increases adhesiveness of leukocytes
IL-6
Induces B-cell terminal maturation into Ig-producing plasma
cells
IL-8
Induces expression of b2 integrin adhesion molecules on
neutrophils, leading to neutrophil migration to infection site
IL-12
Activates NK cells and induces Th1-cell differentiation
IL-18
TNF-a
Activates vascular endothelium and increases vascular

26.

Other Mediators and Molecules
Phagocytes
Toxic oxygen radicals
Peroxides
Nitric oxide (NO)
Lipid mediators of inflammation
Prostaglandins
LTB4
Platelet activating factor
Complement component C5a
Stimulates mast cells to release histamine, serotonin and LTB4
IL-1, IL-6 and TNF-a
Induce acute-phase response in liver
Induce fever
IL-1 and IL-18 signaling pathways activate NF-kB, important in
innate immunity

27.

Immune Cells and Innate Immunity
Phagocytes
Neutrophils
Moncyte/macrophage
Eosinophils (to a lesser extent)
NK cells (large granular lymphocytes)
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Have two major functions
Lysis of target cells
Production of cytokines (IFN-g and TNF-a)
Act against intracellular pathogens
Herpesviruses
Leishmania
Listeria monocytogenes
Act against protozoa
Toxoplasma
Trypanasoma

28.

Immune Cells and Innate Immunity (cont’d)
g/d T cells
Two types of T cell receptors
One composed of a and b chains (basic T cell antigen receptor)
One composed of g and d chains (minor population of T cells)
Two groups of g/d T cells
One group found in lymphoid tissues
One group located in paracellular space between epithelial cells
Recognizes unprocessed target antigen in absence of APC help
B-1 cells (minor fraction of B cells, do not require T-cell help)
Mast cells
Located in serosa, under epithelial surfaces and adjacent to blood
vessels, nerves and glands
Capable of phagocytosis
Process and present antigen using MHC class I or II receptors
LPS can directly induce release of mast cell mediators
Complement (C3a and C5a) induce mast cells to release mediators
Chemotaxis, complement activation, inflammation
TNF-a secreted by mast cells results in neutrophil influx into infected site

29.

Summary of Innate Immunity
External and mechanical barriers
Receptors for pathogen motifs
Soluble antimicrobial proteins
Pattern of cytokines produced influences
adaptive response