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Introduction to the Immune system: Lectures 1 and 2
Hugh [email protected]
Recommended textbook: Janeway’s Immunobiology (7th Ed) 2008, Garland Science
Why study immunology?
Several reasons, most important in terms of numbers:
Infectious diseases are a major burden worldwide
Major challenges are HIV/AIDS, TB and malaria• 42 million people living with HIV and AIDS worldwide
• Malaria causes more than 300 million acute illnesses and at least one million deaths annually
• An estimated two million deaths resulted from tuberculosis in 2002
• We need new strategies or vaccines to prevent or treat infectious disease
Do pathogens “want” to kill us? Does the
immune system (usually) “win” the fight
with pathogens, enabling survival of the
host?
Or does the pathogen evolve to adapt to
the host, including the host immune
response, enabling it to more effectively
persist?
Virulence and evolutionary fitness
Multiple theories:
• Virulence (damage to host) is detrimental to pathogen: a dead
host is less effective at transmission
• Highly virulent pathogens are recently emerged and will
evolve towards lower pathogenicity
• Virulence factors confer increased fitness to pathogen
• Virulence may increase as pathogens evolve. Are both true?
• Perhaps virulence increases to a limit, after which it is
counterproductive to the pathogen
• Must also consider that immune response is often responsible for
host damage
The role of the immune system
To protect us from infection:
• Viruses; 20-400nm (obligate intracellular)
• Bacteria; 1-5 m
• Fungi; 2-20 m
• Protozoan parasites; 1- 50m
• Metazoan parasites (worms) 3mm – 7m
Apart from infectious diseases, why else study immunology?
• Autoimmune disease – eg multiple sclerosis, rheumatoid arthritis
• Allergy – Allergy and asthma prevalence increasing
• 300 million people suffer from asthma and >180 000 die annually
• Asthma deaths are predicted to increase by almost 20% in the next 10 years
• Unwanted responses – transplantation.
The immune system
• Physical barriers
• Cells
• Soluble effector proteins
– complement, antibodies
• Cytokines – communication
Cells of the immune system
Lymphocytes are mostly small and inactive cells
An infection and the response to it can be divided into a series ofstages
Innate immunity
Many barriers prevent pathogens from crossing epithelia and colonizing tissues
Time frame for different stages of immune response
The innate immune response
• Mediated (initiated) by phagocytes, NK cells and soluble proteins
• Phagocytes• Cells specialized in the process of phagocytosis
» Macrophages Reside in tissues and recruit neutrophils
» Neutrophils Enter infected tissues in large numbers
• Recognize common molecules of bacterial cell surface using a few surface receptors
• Phagocytosis• Capture, engulfment and breakdown of bacterial pathogen
• The largest cells in the blood
• Monocytes are the precursors to macrophages in the tissue
• Can be tissue resident or recruited to sites of inflammation
• Engulf and kill viruses and bacteria
• Important for antigen presentation to T cells
Monocyte / macrophage
Macrophages are activated by pathogens and both engulf them and initiate inflammatory responses
Pattern recognition in innate immunity
Microrganisms have repeating patterns of molecular structure on their surface
in cell walls of Gram-positive and Gram-negative bacteria
Peptidoglycan molecules
Other microbial elements with repetitive structure
Bacterial DNA with unmethylated CpG dinucleotide repeats
The repetitive structures are known as pathogen-associated molecular patterns (PAMPs) and the receptors that recognise them as pattern recognition receptors (PRRs)
Phagocytes
• Most common leukocyte (white blood cell) in blood (up to 80%)
• Distinctive lobed nucleus and intracellular granules
• Highly motile, they respond rapidly to inflammatory stimuli by migrating out of the blood and into tissues in large numbers.
• Recognise, engulf and kill viruses and bacteria
• Short life span – about 24hrs
• Dead neutrophils are a major constituent of pus!
Neutrophils
The innate immune response
• Inflammatory response enhances phagocytosis through acute phase proteins• Mannose-binding lectin (MBL)
» Binds to bacterial surface with particular spatial arrangement of mannose or fucose
• C-reactive protein (CRP)
» Binds to phosphorylcholine on bacterial surface
• Complement
» Set of proteins which bind to bacterial surface
• Inflammatory response• Accumulation of fluid and cells at infection site (swelling, redness, heat and
pain)
Complement system
Complement system
Pre-formed protein cascade:
• Punches holes in pathogen membranes
• Alerts and recruits other components of immune system to danger
• Coats pathogens for uptake by phagocytes: ‘opsonisation’
Innate immunity
• First line of defence against infection
• Pre-existing or very rapid response (hrs)
• Recognition of pathogens is based upon pattern recognition (PAMPs) using germline encoded receptors (PRRs) or proteins.
• Non-adaptive
• No memory
• Evolutionarily early
Acquired / adaptive immunity
• Specific to a particular antigen – detected by specific receptors on T and B cells
• Response improves with time
• Results in MEMORY =Protection against re-infection with the same pathogen
• Evolutionarily late – only present in vertebrates
• Involves T and B lymphocytes
B cells
• Produce antibodies
• Sometimes called “humoral immunity”
Proliferation Differentiation
B cell receptors
Long lived
T cells
T cell receptor (TCR)
only recognises foreign antigen as a peptide on an MHC molecule presented by an antigen presenting cell (APC)
Pathogen Recognition: T and B cell receptors
• T and B cells have receptors specific for only one antigen
• Genes for the antigen receptors are re-arranged in each cell – every cell is different
• Gene rearrangement results in receptors that can recognise a huge variety of antigens (108 different specificities in a human at one time)
T and B cell responses are initiated in secondary lymphoid organs - lymph nodes and spleen
HaematopoiesisB cellsNeutrophils etc
T cell development
Primary and secondary immune responses
Smallpox - an immunology success story
Evolution of smallpox lesions on proximal upper
extremity on days 3, 5, and 7 of lesions
1796 Exposure to cowpox protects against smallpox
Jenner
SmallpoxVaccinationwell known in16th centuryChina
Smallpox is the only major human disease to have been eradicated.
The Adaptive Immune response
• Creates millions of different B and T cells for specific antibody-mediated and cell-mediated immunity
• Antibody-Mediated Immunity (AMI)• Involves B lymphocytes, plasma cells and antibodies
• Humoral immunity
» Name derives from antibodies found in body fluids (humors - old medical term)
• Cell-Mediated Immunity (CMI)• Involves T lymphocytes, antigen-presenting cells and MHC (major
histocompatibility complex) molecules
• Cellular immunity
Antibody-mediated (humoral) immunity
Directed against extracellular microorganisms
and toxins
B-lymphocytes (B cells)• Differentiate into plasma cells which produce antibodies
• Function as antigen-presenting cells (APC’s)
Classification of Antibodies (Immunoglobulins)• Immunoglobulin M (IgM)
• Immunoglobulin G (IgG)
• Immunoglobulin A (IgA)
• Immunoglobulin D (IgD)
• Immunoglobulin E (IgE)
Cell-mediated immunity
• Directed against intracellular microorganisms • Phagocytic cells and nonphagocytic cells
• T-lymphocytes (T cells)• Differentiate into effector cells following antigen presentation by
antigen presenting cells (APC’s)
• Activate B lymphocytes
• Functional types of T cells• Helper (CD4 T cells)
» TH1 and TH2 cells
• Cytotoxic (CD8 T cells)
• Regulatory (Suppressor)
» CD4 Tregs
» CD8 Tregs
The nature of antigens
• Historically named as antibody generators• Molecule which stimulates production of and binds specifically to an
antibody
• Contemporary view distinguishes between• Antigen
» Molecule which can bind to specific antibody but cannot elicit adaptive immune response
• Immunogen
» Molecule which can stimulate adaptive immune response
• Best immunogens are proteins with MW > 10,000
The nature of antigens
• Carbohydrates, nucleic acids and lipids are also potential antigens / immunogens
• Hapten• Small (low MW) molecule unable to elicit immune response
• Combines with larger carrier molecule which together function as immunogen
• Antibody may react independently with hapten following hapten/carrier adaptive immune response
• Example
» Penicillin G (MW of 372)
» Albumin (MW of 66,000)
Antigens are the molecules
recognized by the immune
response
Epitopes are sites within
antigens to which antigen
receptors bind
An antibody binds an antigen directly whereas a T-cell receptor binds
a complex of antigen fragment and self molecule
The nature of antibodies
• Antibodies are glycoproteins• Exist as monomers, dimers or pentamers of
basic structure• Basic antibody structure has 4 polypeptide
chains• 2 identical light chains
• 2 identical heavy chains
• Regions of heavy and light chains• Variable
• Constant
The nature of antibodies
• Also referred to as• Immune globulins / Immunoglobulins (IG)
• Immune serum globulins (ISG)
• Gamma globulins
• Contemporary immunology• Antibody
»Secreted form of IG made by plasma cells
• Immunoglobulin»Antigen binding molecules of B cells
(B cell antigen receptors)
Classification of Antibodies (Immunoglobulins)
• Five (5) classes (isotypes)IgA IgG IgM IgD IgE
• Based on structural differences in constant regions of heavy chains
• Classes have specialized effector functions
High affinity IgG and IgA antibodies neutralize bacterial
toxins and can inhibit infectivity of viruses
IgE has specialized role activating Mast Cells
B cells and antibody-mediated immunity
• B lymphocytes originate from stem cells in bone marrow
• Maturation takes place in bone marrow followed by migration to secondary lymphoid tissue
• Antigen exposure in secondary lymphoid tissue
• Following exposure to antigen, B lymphocytes differentiate into plasma cells and memory cells
• Plasma cells produce antibodies of all IG classes
1. Neutralisation
Antibodies block the interaction of the virus with its receptor
2. Opsonisation
Antibodies label the virus and it is now recognised by phagocytes
NB Abs can also label the whole virally infected cell for phagocytosis
3. Complement activation
Membrane Attack Complex damage to the viral envelope, MAC contains activated complement proteins, forms pore
Activation of antibody producing cells by clonal selection
• B lymphocytes recognize intact pathogenic microorganisms and toxins
• B lymphocytes possess specific surface receptors for recognition of specific antigen
• IgM and IgD
• Binding of specific antigen results in proliferation of a clonal population of cells
• Antigen determines clonal proliferation
T and B cell responses are clonal
Receptor diversity;• T and B cells have
receptors specific for only one antigen
• Each cell is unique
Specific antigen recognition
Precursors
Clonal Proliferation
Memory cells ‘Effector cells’
Activation of antibody producing cells by clonal selection
• Proliferation of activated cells is followed by differentiation into
• Plasma cells
»Life span of
4 to 5 days
1 to 2 months
»Produce 2,000 antibody molecules / second
• Memory cells
»Life span of years to decades
»Differentiate into plasma cells following stimulation by same antigen
Primary and secondary immune responses
Primary and secondary antibody response
• Primary Response
• Following exposure to an antigen, there is a slow rise in IgM followed by a slow rise in IgG
• Secondary Response
• Following exposure to previously encountered antigen, there is a rapid rise in IgG and slow or no rise in IgM
»Memory response
T cells and cell-mediated immunity
• T lymphocytes originate from stem cells in bone marrow followed by migration to thymus gland
• Maturation takes place in thymus gland followed by migration to secondary lymphoid tissue
• T lymphocytes respond to antigens on the surface of antigen presenting cells (APC’s)
• Antigen presenting cells (APC’s)
• Macrophages
• Dendritic cells
• B lymphocytes
T cells and cell-mediated immunity
• Antigen presenting cells (APCs)• Ingest and process antigens then display fragments (short
peptides) on their surface in association with molecules of major histocompatibility complex (MHC)
• Major histocompatibility (MHC) molecules• MHC class I molecules
» Present antigens to CD8 T cells
• MHC class II molecules
» Present antigens to CD4 T cells
• T cells which encounter antigen differentiate into effector T cells
Pathogen Recognition: T and B cell receptors
• T and B cells have receptors specific for only one antigen
• Genes for the antigen receptors are re-arranged in each cell – every cell is different
• Gene rearrangement results in receptors that can recognise a huge variety of antigens (108 different specificities in a human at one time)
How T-cells are made
Mechanism of host defence against intracellular infection by viruses
Mechanism of host defence against intracellular infection by Bacterium
MHC class I molecules present antigen derived from proteins in the cytosol
Cytotoxic T cells
• CD8+ cells
• Kill by releasing granzymes and perforin or
• by engagement of Fas on target cells by Fas Ligand
• Granule contents cause apoptosis in the target cell
MHC class II molecules present antigen originating in intracellular
vesicles
Summary
The immune system protects us against a huge variety of different pathogens
Innate immunity is our first line of defence
• Physical barriers
• Complement
• Phagocytes
Acquired / Adaptive immunity
Involves T and B lymphocytes
Responses are antigen specific and clonal
Memory responses
Secondary responses are faster and better (more and higher affinity antibody) than primary responses – the basis of vaccination