Explain the Importance of Immunology for Human Health

Immunology 1: Introduction to Immunology

Explain the importance of immunology for human health

Function of the immune system: to identify and eliminate harmful microorganisms and substances

Mechanisms of action:

Distinguishing ‘self’ from ‘non-self’ proteins
Identifying ‘danger’ signals (e.g. from inflammation)

The immune system must make a compromise between removing the pathogen and causing accidental damage to the host (immunopathology)

Failure of proper function of the immune system function may lead to:

Persistent/fatal infections
Allergy
Autoimmune disease
Transplant rejection

The advent of vaccines resulted in a significant increase in human health(e.g. vaccines for diphtheria, polio and measles)

Generation times: time taken for reproduction

Pathogens have much shorter generation times than hosts (i.e. humans)
The host exerts selection on the pathogen and the pathogen exerts selection on the host
The pathogen replicates and can evolve much faster than the host
The host relies on a flexible and rapid immune response with a degree of non-specificity

Outline the basic principles of immune responses, and the timescales in which they occur

Innate immunity / Acquired immunity
Involves pre-formed cells and molecules / Involves clonal selection
Fast response / Slow response
Non-antigen specific: i.e. limited specificity / Antigen specific: i.e. high degree of specificity

Innate immunity: an early phase of the response of the body to possible pathogens, characterised by a variety of non-specific mechanisms and pattern recognition receptors; it does not generate memory

Anatomical/physical barriers:

Skin
Mucous membranes: produce mucous; cilia propel the mucous along epithelia

Physiological barriers:

Low pH (in the stomach)
Secretion of lysozyme (in the tears)
Interferons
Antimicrobial peptides
Complement

Components of the innate immune system
Cellular components: granular leukocytes / Humoral components
Natural killer cells (NK) / Acute-phase proteins
Macrophages (mononuclear phagocytes) / Cytokines
Neutrophils (polymorphonuclear leukocytes or PMN) / Complement
Basophils/mast cells
Eosinophils

Granulocytes:

Neutrophils (PMN): multi-lobed nucleus; phagocytic; 50-70% of circulating leukocytes
Eosinophils: bi-lobed nucleus; act against parasites; 1-3% of circulating leukocytes
Basophils: release granules containing histamines, serotonin or prostaglandins; not phagocytic; less than 1% of circulating leukocytes

Cytokines: small proteins whichcarry messages between cells

Mechanism of cytokine action:

A stimulus induces cytokine-producing cells to secrete cytokines
Cytokines bind to a receptor on the surface of a target cell
This stimulates gene activation which has biological effects: cytokines stimulate proliferation of lymphocytes

Functions of the innate immune system:

Buys time while the acquired immune system is mobilised
Stimulates the acquired immune response (e.g. via cytokines and complement)

Acute phase inflammatory response: occurs in response to tissue damage (e.g. due to infection or trauma)

Effects:

Fever (rise in body temperature)
Increased production of acute phase proteins, mainly by the liver:

C-reactive protein and serum amyloid protein: bind to molecules found on the cell wall of some bacteria and fungi
Mannan-binding lectin: binds to mannose residues- these are not found on mammalian cells
These acute phase proteins direct phagocytes and complement to combat the infectious agent as part of the innate immune response

Acquired/adaptive immunity: the response of antigen-specific lymphocytes to antigen; it involves the development of immunological memory; adaptive responses can increase upon repeated exposure to the potential pathogen

Antigen specific
Can form memory
Requires priming

Effector arms: include B lymphocytes, T lymphocytes and antibodies

Components of the acquired immune system
Cellular components / Humoral component
T lymphocytes / Antibodies
B lymphocytes
Dendritic cells
(Basophils/mast cells)
(Eosinophils)

Define the terms antigen, antibody, B lymphocyte, T lymphocyte, active and passive immunity, primary and secondary immune responses

Antigen: a molecule which reacts with antibodies or T cells

Antibodies bind to the epitope region of the antigen
T cell receptors bind to peptide fragments of the antigen

Immunogen: an antigen which is sufficient to induce an immune response by itself

Antibody: an immunoglobulin molecule which binds specifically to the immunogen that induced its synthesis

Antibodies are produced by B lymphocytes and found in the bloodstream and body fluids
Antibodies are the humoral component of the acquired immune response

Types of immunoglobulin (Ig): IgG, IgA, IgM, IgE, IgD

IgG: monomer

75% of serum Ig
Bivalent
Can be transferred across the placenta
Longest serum half-life
Contributes to the secondary immune response

IgA: dimer

Tetravalent: 2 molecules are held together by a J chain
Found in body secretions
Contains a secretory piece to protect it from the action of hydrolytic enzymes in secretions

IgM: pentamer (star-shaped)

10% of serum Ig
Multivalent (decovalent): 5 molecules are held together by a J chain

IgE: monomer

Bivalent
Involved in allergic response and defence against parasites
Bound to basophils/mast cells: it triggers the release of histamines

IgD: monomer

Antibodies are specific to a particular antigen since the antigen-binding region (Fab region) on the antibody is complementary to the epitope (antibody-binding region) on the antigen

Mechanisms of antibody action against viruses:

Neutralisation: the antibody binds to a virus and prevents its attachment to the host cell
Opsonisation: the virus-antibody complex is phagocytosed by macrophages
Complement-mediated lysis of enveloped viruses
Antibody-dependent cell-mediated cytotoxicity (ADCC): this is mediated by NK cells

Lymphocytes: mononuclear agranular leukocytes

Antigen-specific: lymphocytes express antigen receptors on their surface which are specific to a particular antigen
Form 20-40% of circulating leukocytes and 99% of cells in lymph fluid
Lymphocyte precursors are produced in the bone marrow by self-renewing haematopoietic stem cells
Lymphocytes consist of bone marrow-derived and thymus-derived cells
Subsets of lymphocytes are distinguished by unique cell-surface markers

B lymphocytes: bone marrow-derived lymphocytes

Maturein the bone marrow
Recognise free antigen in the body fluids
Surface markers include: CD19 and class II MHC molecules
B cells produce 1 clone of antibody
The antibody may be bound to the surface of the B cells or it may be secreted by the B cells
The Fab (antigen-binding)region of an antibody is unique to a particular antigen
When an antigen binds to a surface antibody, this promotes the B cell to secrete antibodies

T lymphocytes: thymus-derivedlymphocytes

Mature in the thymus
Recognise antigen presented at the cell surface by MHC molecules
Surface markers include: CD3, CD4 and CD8
TH cells (helper T cells): express the CD4 co-receptor on their surface
TC cells (cytotoxic T cells or CTLs): express the CD8 co-receptor on their surface
Regulatory T cells: a subset of TH cells which suppress the immune response

Naïve lymphocytes: have never encountered their cognate antigen and hence have never responded to it

Memory lymphocytes: the product of an immune response; they allow their specific receptor to remain in the pool of lymphocytes in the body

Active immunity: the induction of an immune response by the introduction of antigen

Passive immunity: immunity gained without antigen introduction (i.e. by transfer of antibody or immune serum into a naïve recipient)

Primary response: the response made by naïve lymphocytes when they first encounter their cognate antigen

Naïve lymphocytes are activated by antigen to ensure proliferation of a lymphocyte with the appropriate receptor for the antigen

After the antigen has been removed, a few lymphocytes with the cognate antigen remain as memory cells; the remaining lymphocytes die

Secondary response: the response made by memory lymphocytes when the reencounter their cognate antigen

The secondary response is more effective than the primary immune response: it is quicker, greater in magnitude and lasts longer than the primary response

Outline the concept of clonal selection, and its role in immune responses

Immune memory (secondary response): a response which occurs upon the 2nd or subsequent exposure to a particular antigen

Lymphocyte antigen receptors:

T and B lymphocytes express unique surface antigen receptors which bind to proteins
Each cell has aparticular antigen receptor which recognises and binds to the epitope of its cognate (associated) antigen
There are many copies of the antigen receptor on the cell surface
Lymphocytes circulate constantly between the blood and tissues via the lymph

The thoracic duct is the final lymphatic vessel which reintroduces lymph into the subclavian vein

B cell antigen receptor (BCR):a surface immunoglobulin (i.e. a membrane-bound antibody)
T cell antigen receptor: the T cell receptor (TCR)consists of 2 protein chains

Generation of clonal diversity in lymphocytes:

During development of T and B lymphocyte precursors in the bone marrow: random genetic recombinations occur within each cell among multiple copies of immunoglobulin genes or TCR genes
This generates diversity of clones of lymphocytes
Each clone of lymphocytes has a different antigenic specificity (i.e. it is unique to a particular antigen)
Each naïve lymphocyte is the precursor of a genetically identical clone of daughter lymphocytes

Principle of clonal selection: when the surface antigen receptor of a T or B lymphocyte recognises and binds to its cognate antigen, it stimulates that particular clone of cells to proliferate

The surface antigen receptor of a T or B lymphocyte recognises and binds to its cognate antigen
This leads to selection and activation of a lymphocyte clone
Clonal expansion occurs:a clone of lymphocytes with identical antigenic specificitiesis produced
Most of the recently proliferated lymphocytes die at the end of the primary immune response due to lack of antigen, lack of cytokines or activation-induced cell death
Some proliferated lymphocytes survive as memory cells

In other words:

T and B cells produced in the primary lymphoid organs are released into the peripheral lymphoid pool
Those that meet their cognate antigen proliferate and produce effector and memory cells; those that do not meet their cognate antigen die
The size of the peripheral lymphoid pool is regulated by homeostatic mechanisms

Antigen presentation:

Antibodies and BCRs bind directly to the antigen
TCRs can only recognise processed antigen (peptide) which is bound to major histocompatibility complex (MHC) proteins on the cell surface
Human leukocyte antigens (HLA): the MHC molecules which occur in human cells
2 types of MHC molecules: class I MHC and class II MHC
Class I MHC molecules: occur on the surface of all cells
Class II MHC molecules: only occur on the surface of antigen presenting cells (APCs)

APCs include: dendritic cells, macrophages and B lymphocytes

Immune response:

T cell activation: occurs in the secondary lymphoid organs (e.g. lymph nodes)

Antigens are taken up by APCs and transported from tissues into secondary lymphoid organs where they meet T cells

TC cells (CTLs): kill infected cells

TC cells recognise virally infected cells via the peptides presented by class I MHC molecules
They kill infected cells by injecting granules containing lethal enzymes into the cells

Antibodies: recognise and label infected cells for destruction

Understand the roles of natural selection and the physical organization of the immune system in its function

Organisation of the lymphatic system:

Lymphatic vessels: venules, veins and ducts
Lymphatic tissues: nodules, nodes, tonsils and Peyer’s patches
Lymphatic organs: spleen and thymus

Lymphoid organs: organised tissue where lymphocytes interact with non-lymphoid cells; site of initiation and maturation of the adaptive immune response

Primary lymphoid organs: site of maturation of lymphocytes

Bone marrow: site of B cell maturation
Thymus: site of T cell maturation

Secondary lymphoid organs: lymph nodes, spleen (white pulp) and mucosa-associated lymphoid tissue (MALT)

Lymphocytes and APCs recirculate through lymphatic vessels from tissues via lymph nodes or the spleen into the blood

Immunology 2:Immune Cells and Organs

Name the primary and secondary lymphoid organs and briefly differentiate between their functions

Primary lymphoid organs: the site of lymphopoiesis (production of lymphocytes)

Bone marrow: the site of haematopoiesis and B cell maturation
Thymus: the site of T cell maturation

Secondary lymphoid organs: the site where antigen, antigen presenting cells and mature lymphocytes come together to initiate an immune response

Spleen
Lymph nodes
MALT (mucosal-associated lymphoid tissue)

Secondary lymphoid organs have special vascular adaptations to recruit lymphocytes from the blood

Draw simple diagrams to illustrate the structure of the thymus, lymph node, spleen, Peyer’s patch, and indicate the changes that occur after stimulation by antigen

Thymus:

A bi-lobed structure which is located in the thorax
Each lobe is organised into lobules

Each lobule contains histologically defined regions of cortex and medulla
Cortex: contains immature thymocytes, some of which undergo selection to become mature thymocytes in the medulla
Medulla: contains mature thymocytes
Only ~5% of cells exit the thymus and enter the peripheral T cell pool
Atrophies with age: areas of active T cell maturation are replaced by adipose tissue

Simple diagram of a human thymic lobe:

Bone marrow:

Produces haematopoietic stem cells and B cells
Haematopoietic stem cells destined to become T cells migrate to the thymus
Differentiation of B cells is centripetal with stem cells under the bone; the most mature B cells are found towards the centre of the bone marrow
In the foetus: the liver and spleen are the first active sites of haematopoiesis; bones become active subsequently to the liver and spleen
In adults: active sites of haematopoiesis include spongy regions at the end of long bones, vertebral bones, the sternum, ribs and flat bones of the cranium and pelvis

Lymph nodes:

Diameter: 1-15 mm
Round or kidney-shaped
Have an indentation at the hilus where blood vessels (BV) enter and leave the lymph node
Lymph enters the lymph node through several afferent vessels (A)
Lymph leaves the lymph node through one efferent vessel (E) at the hilus
As lymph passes through a lymph node, phagocytes remove free antigens
Cortex: rich in B cells
Paracortex: rich in T cells

Simple diagram of a lymph node:

A: afferent

E: efferent

BV: blood vessel

Spleen:

Contains 2 main types of tissue:

Red pulp: acts as a general filter for antigens in the blood
White pulp: the lymphoid tissue; it initiates the major responses to blood-borne antigens

Periarterial lymphatic sheath (PALS): concentric areas of lymphoid tissue which surround the central arteriole

The PALS region nearest the central arteriole is rich in T cells
Lymphoid follicles: rich in B cells; occur periodically along the PALS
Marginal zone: the primary entry site of B and T cells into the white pulp;surrounds the PALS

Simple diagram of a part of the spleen:

Diagram of a part of the spleen:

Individuals who do not have a spleen are highly susceptible to infections with encapsulated bacteria

Epithelium: the first line of defence against infection

The skin and mucosal layers form a physical barrier with a very large surface area
Epithelia are heavily defended by MALT and the cutaneous immune system

MALT: an aggregate of lymphoid tissue which does not have a tough outer capsule

Occur predominantly in the lamina propria and submucosal areas of the GI, respiratory and genito-urinary tracts
Examples of MALT: tonsils; appendix; Peyer’s patches

Peyer’s patches: organised regions of lymphoid tissue found in the wall of the gut

Predominantly contain B cells
Contain germinal centres during immune responses

Simple diagram of a Peyer’s patch:

Cutaneous immune system:

Consists of 2 parts: the epidermis and the dermis

Epidermis: contains Langerhans cells (epidermal dendritic cells) and intraepidermal lymphocytes
Dermis: contains T lymphocytes, macrophages and dermal dendritic cells

Outline the re-circulation of lymphocytes

Naïve lymphocytes: lymphocytes which have matured and have not yet encountered antigen

There are many naïve T and B lymphocytes with different specificities (i.e. they recognise different antigens); however there may only be a limited amount of antigen

Lymphocyte recirculation increases the likelihood that naïve lymphocytes will encounter their cognate antigen

Recirculation of naïve lymphocytes:

Naïve lymphocytes constantly circulate from the blood into secondary lymphoid organs: they leave blood vessels through high endothelial venules (HEVs)

HEVs: specialised sections of post-capillary venules

Naïve lymphocytes migrate from lymph nodes into efferent lymphatic vessels
They eventually return to the blood via the thoracic duct
In case of an infection: lymphocytes which recognise the infectious agent remain in the lymphoid tissue in lymph nodes, where they proliferate and differentiate

Explain the use of CD (cluster of differentiation)markers for discrimination between lymphocytes

Lymphocytes: small cells with agranular cytoplasm and a large nucleus

Subdivided into 2 groups:

B lymphocytes: mature in the bone marrow
T lymphocytes: mature in the thymus

B cells and T cells cannot be differentiated under a microscope using conventional stains

CD markers: an internationally recognised systematic nomenclature for cell surface molecules which is used to discriminate between haematopoietic cells; more than 300 CD markers exist

Compare and contrast phenotypic characteristics of B and T cells