Immunology Immunology, an overview Dermatology BM2023 Dr Tim Scott-Taylor Health and Human Sciences.
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Immunology Immunology, an overview Dermatology BM2023
Dr Tim Scott-Taylor Health and Human Sciences
Innate Immunity Acquired Immunity
Phagocytosis Antigen Presentation Inflammatory Response Types and functions of white blood cells
Tutorial: Innate vs Acquired Immunity
Topics
Learning Objectives to know the important structures that make up
innate immunity to understand how a specific immune response
is generated to know some of the processes in a secondary
immune response to know (a little) about antibody structure and
function to list examples of white blood cells To understand the sequence of events in an
immune response
derived from immunitas: Latin for exemption
A system of cells and molecules that together
formulate resistance and an immune response
Recognition of foreign antigen
Tolerance of self
Can be pathological; allergy
autoimmunity
The Immune System
The Immune System
Innate immunity; is present continuously from birth. the initial, always on, quick-response defense
system consists of physical, chemical and cellular
defenses does not distinguish between different
pathogens, non specific.
Host defense against foreign bodies can be divided into Innate Immunity and Acquired Immunity.
Acquired Immunity
induced by the presence of foreign material and forms a specific response against a particular antigen.
The fundamental properties are:
1. Specificity
2. Adaptiveness
3. Discrimination between self and non-self
4. Memory
Innate Immunity
physical barriers; obstructions
physiological barriers; conditions
biochemical barriers; anti-microbial secretions
non-specific cellular activities
Consists of a series of
Innate Immunity
Physical Barriers Skin keratinization acts as a physical barrier
Mucous membranes in the respiratory, gastrointestinal, urogenital tract trap bacteria with mucous
Trapped bacteria are removed by ciliated cells.
Saliva flush microbes from the teeth tears eyes urine urethra
Physiological Barriers Fatty acids from sebaceous glands provide a
detergent-like activity on skin
Bile in the small intestine inhibits bacterial growth
Acid pH on skin, in stomach, and in the urogenital tract inhibit bacterial growth
Commensal flora provide competition to inhibit gut infection and skin colonisation
Biochemical Barriers Lysozyme in tears, saliva and vaginal
secretions; hydrolytic action on bacterial cell walls
Complement; a series of blood proteins that activate blood cells and lyse foreign cells
C-reactive protein; produced by the liver, opsonises bacteria
Interferons; anti-viral proteins produced by infected cells
Lysozyme Enzyme present in mucosal secretions eg tears and saliva
cytoplasmic granules of the neutrophils egg white
functions by attacking cells walls of bacteria
hydrolyzing the bond that connects N-acetyl muramic acid
N-acetylglucosamine
non-specific innate opsonin; binds to the bacterial surfacereduces the negative charge facilitates phagocytosis of bacteria
peptidoglycan
Bacterial Cell Walls
Gram-positive Gram-negative
Lipid bilayer plasma membrane with integral proteins
Lipid bilayer plasma membrane with integral proteins
peptidoglycan
cell wall
lipoprotein
Lipoteichoic acids traversing wall and anchored in basement membrane
porin
polysaccharide (O antigen)
lLipid A
Bacterial cell walls
Peptidoglycan is an important feature of gram positive cell walls.
Composed of a polymer of sugar residues, muramic acid and n- acetyl glucosamine, linked by a peptide bridge.
Lysozyme attacks the bond between the sugar residues
C-reactive Protein• produced by liver, collects in serum• early defense system against infection• reacts with pneumococcus C polysaccharide
• opsonification, assists phagocytic binding• splits C1 (classical pathway)
• baseline levels low, increases
10,000-fold • binds a wide array of; bacteria fungus
parasiteplant
Pentraxin; flattened β-jellyroll
structure
ligandschromatin histones apoptotic membranes damaged cell components
within hours of inflammation
Complement
Classical (adaptive) and alternative (innate) pathways
A system of ~20 serum proteins that sequentially cascade forming a lytic pore complex
Initiated by
(i) cross-linking of C1q by antibody
(ii) LPS, teichoic acids, zymosan
(i)
(ii)
ComplementThree main actions;
• opsonization marking of invading cells, bacteria, antigen for elimination by phagocytotic cells; C1q, C3b
• inflammatory signals activation of basophils, mast cells, eosinophils; C4a, C3a, C5a
• cytolysis formation of the membrane attack complex; C5b6789
Complement Punctures Cells
Interferon *********8Types and Properties of Interferon
Interferon
Property Alpha Beta Gamma
designations Type I Type I Type II
Genes >20 1 1Principal
sourceLeukocytes, Epithelium Fibroblasts Lymphocytes
Interferon Gamma
IFNγ is mainly secreted by lymphocytic cells
Acts on;
B cells: antibody Helper T: TH2 cytokines NK cells: activation Macrophages: MHC II
Interferons α and βInterferon α and β protects cells from viruses
Viral infection stimulates interferon production which induces resistance in surrounding cells
Interferon Products "translation
inhibitory protein" or "TIP“
complexes with preexisting ribosomes. Modified ribosomes check mRNA's caps. Only correct autologous mRNA's are translated
Interferons act on a wide variety of cell types
to induce the synthesis of a series of proteins which interfere with viral replication both by degrading RNA and by inhibiting protein synthesis. They also potently activate NK cells.
Innate Cellular Activities Bacteria and fungi recognised by broadly specific
receptors (to sugar residues) eg manose receptor Non-specific killing by NK cells Phagocytes include monocytes, neutrophils,
macrophages, and dendritic cells. Have complement and antibody receptors (CD3;
CD35, CD21, CD16) ; uptake greatly enhanced by opsonification
Ingestion of foreign material leads to digestion, antigen presentation to lymphocytes; acquired immunity
Cells of the Immune System
Immune Cells
• Blood is mostly made up of RBCs and platlets
•Leukocytes can be distinguished by nucleus shape and granules
• Most immune cells remain in the blood
• During inflammation cells are attracted into the skin and organs
Non-Specific Immune Cells
White Blood Cell Type Function Immune System Category
Monocytes Exit blood vessels and turn into macrophages. Engulf invaders and debris by phagocytosis
Non-specific
Neutrophils Stay in blood vessels and engulf invaders and debris by phagocytosis
Mainly non-specific but can be specific when directed by antibody targeting.
Basophils Release histamines and participate in the inflammatory and allergic reactions
Non-specific
Eosinophils Chemically attack parasitic invaders similar to natural killer cells
Non-specific
Lymphocytes Form T-cells and B-cells Specific except for Natural killer cells
NK Cells Natural Killer cells Large granular lymphocytes; abundant ER and
granules lack TCR, CD3 or Ig; null cells do express CD16 (FcγRIII) and CD56 (NCAM)
1. CD942. Ly493. KIR
Detect ‘altered self’ Cell lysis; porphorins, granzymes apoptosis
receptors for MHC I
Phagocytosis
Encapsulation of a pneumococcus
chemotaxis, pseudopodia, phagocytosis
Phagocytosis
Modes of ingestion are:
Pinocytosis: ingestion of fluid surrounding cells
Receptor-mediated: internalization of molecules bound endocytosis to membrane receptors
Phagocytosis: internalization of intact particles eg bacteria
Phagocytosis• the phagosome fuses with lysosomes
• killing occurs by a) hydrolytic enzymes b) reactive oxygen species eg. superoxide anion eg. hydrogen peroxide c) reactive nitrogen species
eg. nitrous acid • Digested material is exocytosed out of the cell.
• peptides bind to antigens receptors are presented on the surface of the cell to lymphocytes
Positions of Phagocytes
Various mononuclear phagocytes form the
Reticulo-Endothelial System
tissue phagocytes prominent in brain; microglia lungs; alveolar mǿ dermis; histiocytes
liver; kupffer cells
Derived from myeloid cells
Visualisation of the RESInjection of carbon particles leads to uptake by phagocytes in many prominent areas of the circulation.
The RES screens lymph and blood for microorganisms and antigen
• important response especially of skin to cellular injury or infection
• has both a rapid innate component and prolonged acquired immunity phase.
• injury or infection releases proteins causing; swelling redness
pain heat
Inflammation
• increases blood flow and attracts cells to local area to restrict the spread of infection
Causes mechanical trauma chemical injury ionising radiation
ultra-violet light thermal injury ischaemia infarction infection
A variety of infectious and mechanical causes initiate inflammation
The extent and duration of inflammation depend on the type and amount of tissue damage
Inflammatory MediatorsReleased by variety of leukocytes
endothelium liverplasma
Trigger and enhance particular inflammatory aspectsvasodilationvascular permeabiliitypain feverchemotaxis
RednessRedness rubor
calor
tumour
dolor
Histaminesfibrinkinins cytokines
Inflammation
increase vascular permeabiityinduce adhesion molecules stimulate nerves, leading to pain attract leukocytes phagocytosisT and B cell activation increase immunoglobulin synthesis
If inflammation persists for more than a few hours then macrophages and lymphocytes are recruited to the site. Macrophages also present foreign peptides, promoting antibodies production and acquired immunity to infection
Inflammation
Vasodilation Increase capillary diameter Tissue redness and temperature rise
Increased vascular permeability Plasma exudate Swelling and pain
Influx of leukocytes Margination, diapedisis, chemotaxis Cytotoxic and phagocytic activity Pus and tissue repair
Innate Leads to Adaptive Immunity
Phagocytosis
Complement activation
Inflammation
ultimately lead to induction of adaptive immunity
Adaptive Immunity
Adaptive immunity increases in strength and effectiveness with each encounter.
Antigen specific; foreign antigen is recognised in a specific manner and memory is acquired to it by lymphocytes
Naïve lymphocyte; ~ 0.001% of circulating population
antigen presentation activation induction of cytokines receptors proliferation
Memory cells; 0.1 to 0.5% of circulating population
The first encounter with an antigen is known as the primary response. Re-encounter with the same antigen causes a secondary response that is more rapid and powerful.
Secondary Response
Speed Of Immune Response
• The rapidity of response is often the difference between an infection and a symptomatic disease
• Secondary immune response much quicker than primary response
• Rapid accumulation of immune responses and activated immune cells intervenes before microbial multiplication reaches critical levels
• Persistence of antigen specific, memory B and T lymphocytes gives head start on microbes on reinfection
Adaptive Immune System Antibody; specific recognition of antigen
B cells; clonal induction of specific cells
T cells; activated by presentation of specific antigen by dendritic cells and mǿ
Antigen A foreign substance visible to the immune
system anything that can be bound by an antibody small antigens may not be immunogenic and
need to be coupled to a carrier, a hapten, to elicit an immune response.
antibodies interact specifically with relatively small parts of molecules; antigenic determinants or epitopes
epitopes are 3-dimensional structures, referred to as conformational
AntibodiesAntibodies are y-shaped molecules composed of heavy chains and light chains, connected by S-S bonds. The ends of the Y arms are the bindingsites for antigen
Action of AntibodiesAntibodies work in three ways. Neutralisation; blocking the biological activity of their
target molecule eg toxin binding to receptors Opsonisation; interacting with special receptors on
immune cells, including macrophages, neutrophils, basophils and mast cells allowing them to "recognise" and respond to the antigen
Complement Activation; causing direct lysis by triggereing complement cascade. Complement recruitment also enhances phagocytosis
Antibody Actions
Functions of Immunoglobulins
Immunoglobulin
Major Function
IgM Main Ig during Primary Response Fixes Complement (most effectively).
IgGMain Ig during Secondary Response Opsonization. Fixes Complement.Neutralizes Toxins, Viruses.
IgA Secretory mucosal IgPrevents invasion from gut mucosa.
IgE
Immediate Hypersensitivity.Mast cell and Basophil reactions.Activates Eosinophils in helminth infection.
IgD Function Unknown.Mostly on the Surface of B cells.
Clonal Selection
Many B cells
Each with own
receptor
Selection of specific
B cell by antigen
Proliferation of clone
Secretion of specific
anibody in quantity
B Cell Memory Response
LymphoctesPivotal to specific immune responses;
B cells; mature in bone marrow bursa in chickens antibody production
T cells; helper CD4: MHC I self-recognition help for B and cytotoxic cells cytokine production
cytotoxic CD8: MHC II foreign antgen recognition
lysis of infected cells cytokine production
Self Recognition
MHC class I
Endogenous peptide screening
• newly synthesised MHC class I molecules bind to calnexin
• Binding to b2 microglobulin displaces Cx. Peptides are transported into the ER by TAPs.
• Full MHC class I is transported to the cell surface via the Golgi apparatus.
Recognition by the T-cell receptor of a cytotoxic CD8+ T lymphocyte
Foreign Peptide Recognition
MHC class II Presentation of foreign antigen
Recognition by the T-cell receptor of CD4+, CD3+ T-helper lymphocytes
• newly synthesised MHC class II molecules bind the invariant chain
• IC prevents binding of peptides in the endoplasmic reticulum.
• Foreign proteins in endosomes fuses with the Golgi.
• The IC is cleaved and released allowing peptides to bind to the MHC cleft
•Loaded MHC is transported to the surface
T Cells Kill Virus-infected Cells
• Presentation of viral antigen on MHC class I molecules
• Recognition by CD8 molecules on cytotoxic T cell
• Release of porphorins (C9 homology)
• Entry of granzymes leading to apoptosis
Lymphoid Tissue
Central Peripheral
Primary Secondary
Bone marrow
thymus
Lymph nodes
spleen
Immune cells differentiate from progenitor stem cells in marrow. T lymphocytes mature in the thymus
Lymph originates as blood plasma that leaks from the capillaries of the circulatory system becoming interstitial fluid
Secondary lymphoid tissue screens all tissue fluid through concentrations of B and T lymphocytes
Lymph Node• clusters of lymph nodes are scattered throughout the body, particularly GALT
BALT
• local lymph nodes, filter tissue fluid through areas rich in T & B lymphocytes
• lymphocytes enter via capillaries and migrate through nodes being screened for antigen specificity
• dendritic cells carrying antigen from tissues generate focal interactions with specific lymphocytes; germinal centres
Spleen
located in the upper left part of the abdomen, behind the stomach and just below the diaphragm
Screens blood removing or supplying erythrocytes and removing bacteria and generating specific immune responses
divided into red pulp; mostly blood sinuses removes senescent red cells
white pulp; nodules, Malpighian corpuscles lymphoid follicles; rich in B
lymphocytes
periarteriolar lymphoid sheaths;
rich in T lymphocytes
• You receive a cut. Bacteria enter the wound.
• Many are destroyed rapidly by complement and the phagocytes recruited through acute inflammation
• Some dead bacteria or breakdown products are taken up by the tissue resident dendritic cells.
• The combined action of bacterial products and cytokines activate the tissue dendritic cells.
• Dendritic cells migrate to lymph nodes via afferent lymphatics. • Dendritic cells enter the node in the T cell areas. They
become resident there displaying the antigen
A Simplified Immune Response
• T cells enter the node from the blood, trafficking through the T cell area.
• T cells which recognise the bacterial antigenic peptides activate, divide and differentiate, forming cytotoxic , helper and memory T cells.
• B cells entering nodes from the blood cross the T area, have their MHC-peptide complexes recognised by activated T cells and receive help.
• Some become IgM secreting plasma cells. Some move to B areas and form germinal centres. • Plasma cells and B memory cells produce antibodies.
A Simplified Immune Response
• Cytotoxic T cells lyse bacteria opsonized with antibodies. • MemoryT and B lymphocytes persist in the circulation ready to initiate a secondary immune response upon reinfection
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