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