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Immunity and Autoimmunity

Ailsa Marsh MNIMH MBANT CNCHMedical Herbalist, Nutritional Therapist

Today we will cover…

• What is the immune system? (Its anatomy and physiology)

• When the immune system goes wrong:

oCommon pathologies of the immune system

oAutoimmunity - what we know, what we don’t know, what we can do about it…

• Atopy

• A range of autoimmune conditions

What is the Immune System?

• An integrated defence system composed of several different components…

• Protects the body from invasion (concept: ‘self’ and ‘non-self’…)

• Destroys and disposes of organisms trying to harm the body

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Components• A complex, intricate collection of both diffuse and highly specialised cells,

organs and mechanisms…

• Organs: Thymus, spleen, bone marrow, tonsils, lymph nodes…

• Cells: Granulocytes, agranulocytes…

• Mechanisms: Inflammation, fever…

• Types: Innate/non-specific; acquired/specific…

Organs associated with the Immune System

• Skin! - expansive external barrier• Adenoids and tonsils - ‘catch’ incoming infections. Contain

antibody-making lymphocytes (later…) to attack pathogens• Spleen - produces and stores lymphocytes• Thymus - processes and matures T-cells (lymphocyte)• Bone marrow - matures B-cells (lymphocyte)• Appendix - stores ‘good’ gut bacteria• Lymph nodes - stores lymphocytes• Peyer’s patches in ileum - ‘aggregated lymphoid nodules’. Monitor intestinal

bacteria populations and prevent the growth of pathogenic bacteria in gut

Types of ImmunityInnate/non-specific (humoral)• From birth• Physical and chemical barriers…• Cells…• Mechanisms…

Acquired/adaptive/specific (cellular)• Not from birth - acquired over time• Cells…• Mechanisms…

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Innate/Non-specific (humoral)

• External - ‘First lines of defence’

o Physical barriers - skin, mucous membranes, cilia

o Chemical barriers - saliva (antibacterial enzymes), tears (antibacterial enzymes), cerumen (ear wax), oil and sweat by sebaceous glands, stomach acid, ‘good’ gut bacteria, urine and vaginal and anal bacteria

• Internal - ‘Second lines of defence’

o Non-specific proteins - ‘complement system’, phagocytic cells (phagocytosis), interferons, NK cells, inflammatory mechanisms, fever

Later we’ll talk about …

• Acquired / adaptive / specific (cellular) - ‘Third lines of defence’

o T1, T2 and B-cells - specific cells with specific actions…

External - ‘First lines of Defence’

Plus: Oil and sweat (sebaceous glands)

Internal – ‘Second Lines of Defence’

Cells:• Non-specific proteins - ‘complement system’• Phagocytes (phagocytosis)• Interferons• NK cells

Mechanisms:• Inflammation• Fever

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Complement System

• Over 30 non-specific proteins produced by the liver, circulating around the body…

• Identified by a letter with a number (e.g. C1, C2, C3)

• Normally inactive but, when activated, these proteins act in a cascade to ‘complement’ immune processes:

oPromote phagocytosis

oContribute to inflammation

oCause cytolysis - destroying (bursting) microbes

Cytolysis

Compliment system may be activated in 3 ways:

1. Classical pathway - activation of complement system when antigen-antibody complexes are formed (later…)

2. Alternative pathway - direct activation of complement by lipid-carbohydrate markers already on invading cells’ surface (pathogen surface markers)

3. Lectin pathway - macrophages digest microbes, releasing chemicals that cause the LECTIN production by the liver, which help to activate complement

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Phagocytosis

• Phagocytic cells - cell-eating, non-specific, antimicrobial cells

• Examples - monocytes (blood), macrophages (tissues), Kupffer cells (liver), microglial cells (CNS)…

• Attracted to sites of inflammation by chemotaxis

• Non-selective in their targets: They engulf and digestany foreign matter

• Five stages of phagocytosis…

1. Chemotaxis - release of chemicals by microbes, WBCs, damaged tissue and by activated complement that attract macrophages

2. Adherence - binding of phagocyte to target (aided by complement)

3. Ingestion - microbe/foreign matter is engulfed

4. Digestion - lysosomes fuse with ingested matter and release lysozymes. The microbe/foreign matter is broken down and destroyed by the enzymes and chemicals produced in the phagocyte

5. Excretion/presentation - release/presentation of digested material

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Phagocytes in the Body

Cell Types Granulocytes and Agranulocytes

Granulocytes Agranulocytes

Granules in the cytoplasm No granules in the cytoplasm

Cell types:

• Basophils/mast cells• Eosinophils• Neutrophils

• Natural Killer (NK) cells

Cell types:

• Monocytes/macrophages• Dendritic cells• T-lymphocytes• B-lymphocytes

Phagocytic CellsNeutrophils (granulocyte)• Fast action - migrate towards infection site within an hour!• Cannot renew lysosomes used in phagocytosis - die after having phagocytised a few

pathogens• Activity and death in large numbers forms PUS• Raised in strenuous exercise, metabolic disorders and heavy smoking• Also due to microbial infection and tissue damage

Eosinophils (granulocyte)• Chemotactic• Eliminate larger pathogens (e.g. parasites, worms)• Promote inflammation• Migrate due to allergic reaction

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Monocytes (agranulocyte)• ‘Blood-bound macrophage’• Large, mono-nuclear• Involved in antigen presentation (later…)• Some become macrophages…• Increased numbers with microbial infection

Macrophages (agranulocyte)• ‘Tissue-bound monocyte’• Forms: Kupffer cells, microglia, Langerhans cells, Peyer's Patches…• Protection defense via phagocytosis and isolating dangers (walling off)• Release cytokines (e.g. IL1 - pro-inflammatory)• Stimulate lymphocytes and other immune cells to respond to the pathogen• ‘Police Patrols’: Protect, prevent, pick-up-the-pieces

Dendritic Cells (DCs) (agranulocyte)

• Antigen-presenting cells (later…) for T-cells of the adaptive/specific immune system

• So-called as they grow branched projections (‘little trees’) however these structures are not the same as neuronal dendrites

• Found in the skin as well as the linings of the nose, lungs, stomach and intestines

• Specialist skin DCs: Langerhans cells

Basophils/mast cells (granulocyte)

• *Not phagocytic

• Chemotactic

• Pro-inflammatory: Contain pro-inflammatorysubstances (leukotrienes and cytokines)

• Also contain heparin (anticoagulant) and histamine (vasodilator)

• In blood: Basophils

• In tissue: Mast cells

*(Later…) Basophils have IgE protein receptors on their cell surface that bind IgE antibodies very tightly - important RE: allergic reactions

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Natural Killer (NK) Cells• Granular lymphocyte

• Provide rapid response to viral-infected cells and to tumour formation, acting at around 3 days after infection

• Mechanism of action: Specific lymphocytes (T- and B-cells, later…) adapt/learn to recognise antigen (foreign body) with a view to destruction. NK cells can recognise ‘non-self’ cells in the absence of markers, enabling a much faster response leading to lysis/apoptosis…

• Recent research indicates the potential of NK role in adaptive immunity also RE: immunological memory (later…)

Interferons (IFNs)

• Antiviral agents: ‘interfere’ with viral replication

• Part of a group of cytokines: Cellular communication (signalling molecules) to trigger defence against pathogens (e.g. viruses, bacteria, parasites, malignant cells)

• Typical scenario: A virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defences…

• Other functions RE: immune modulation:

oActivation of macrophages and NK cells

oUp-regulation/amplification of antigen presentation

• IFNs (and other cytokines) are responsible for promotion of certain ‘general-infection’ symptoms such as fever, muscle pain and ‘flu-like' symptoms

• Over 20 distinct IFN genes and proteins have been identified and are divided into 3 categories: Type I IFN, Type II IFN and Type III IFN

Molecular structure of an interferon

Interferons (IFNs)

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Type I IFNs

• Two types: IFN-a and IFN-b

• Secreted by fibroblasts and monocytes upon viral infection

• Activated Type I INFs create molecules which prevent the virus from producing and replicating its DNA and RNA

Type II INFs

• Immune/gamma interferon (IFN-g)

• Mainly secreted by T-cells, natural killer (NK) cells and macrophages, once activated by Interleukin-12

• Exert a key influence on the quality of the cellular immune responses

Interferons (IFNs)

Type III IFNs

• Discovered more recently than Type I and Type II IFNs

• Three types of IFN-λ (lambda) molecules: IFN-λ1, IFN-λ2 and IFN-λ3

• Recent research suggests IFN-λ expression more flexible than IFN-alpha/beta expression, which could allow expression of Type III IFNs in response to a wider range of stimuli compared with Type I IFNs…

Interferons (IFNs)

Mechanisms: InflammationComplex biological response of cytokines and vascular tissues to harmful stimuli such as pathogens,

damaged cells, extreme temperatures, irritants, etc.

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• Vasodilatation of the local blood vessels

• Increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues

• Increased permeability of the capillaries

• Clotting of the fluid in the interstitial space

• Migration of large proteins leaking from the capillaries

• Swelling of the tissue cells…

Mechanisms: Inflammation (Continued)

The ‘5 Signs of Inflammation’

• Redness (rubor)

• Heat (calor)

• Pain (dolor)

• Swelling (tumour)

• Loss of function…

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Inflammation has a bit of a bad reputation…

• Positive: Vital for life! Promotes blood coagulation to seal wounds and facilitates influx of infection-fighting white blood cells to the site of damage

• Negative: A part of the pathophysiological picture of many (most..? all..?) chronic diseases. May contribute to the symptomatic burden of many patients (Jones, 2006)

Potential Harmful Effects of Inflammation

• Swelling: May be dangerous if in a confined space - e.g. ICP

• Pain: Occurs when swelling compresses the sensory nerve endings, also as a reaction to chemical mediators - e.g. bradykinin, prostaglandins…

• Suppuration/pus formation: Pus - dead phagocytes, dead cells, debris, fibrin, inflammatory exudate and living/dead microbes

• Abscess formation: Localised, painful accumulation of pus surrounded by inflamed tissue

• Adhesions and scar tissue: Permanently reduces function of area

• Atherosclerosis: Atherosclerotic plaques

Possible Outcomes of Inflammation

• Resolution: Cause is successfully overcome, inflammatory mechanisms shut down

• Granuloma: If the infection cannot be cleared, it may be ‘walled off’ (see picture)

• Fibrosis: Scar tissue formation (collagen fibres secreted by fibroblasts). Loss of tissue, cells do not regenerate, can be a result of chronic inflammation...

• Scar tissue may have damaging effects such as:

oAdhesions

oFibrosis of thrombus or embolus blocking a blood vessel

oTissue shrinkage

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Chronic Inflammation

• Inflammatory mechanisms remain active, more body tissue likely to be damaged (possible cause..?), present in symptomatic burden of many chronic conditions

Mechanisms: Fever• Abnormally high body temperature (above 37 degrees C)

• Occurs because the hypothalamus thermostat is reset

• Common in infection/inflammation

• Can be triggered by bacterial toxins which cause macrophages to release fever-causing cytokines (e.g. interleukin-1)

• High body temperature:

o Makes interferons more effective

o Inhibits growth of some microbes

o Speeds up the reactions that aid repair

Summary So FarInnate/Non-specific (Humoral) Defence

External ‘First lines of defence’A. Physical barriers: Skin, mucous membranes, ciliaB. Chemical barriers: Saliva (antibacterial enzymes), tears (antibacterial enzymes),

cerumen (ear wax), oil and sweat by sebaceous glands, stomach acid, ‘good’ gut bacteria, urine and vaginal and anal bacteria

Internal ‘Second lines of defence’• Cells: Non-specific proteins - ‘complement system’, phagocytosis, interferons, NK

cells• Mechanisms: Inflammation, fever

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Acquired / Adaptive / Specific (Cellular) Immunity‘Third lines of defence’

Acquired over time…The lymphocytes: T-cells and B-cells

T-lymphocytes: Cell-mediated Immunity

• Immunity provided via production of cytotoxic T-cells/killer T-cells

• Defence against intra-cellular pathogens, cancer cells and transplants

B-lymphocytes: Antibody-mediated / Humoral Immunity

• Immunity provided via production of antibodies (immunoglobulins)

• Defence against extra-cellular pathogens

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• NB: Lymphocyte self-tolerance and self-recognition is vital

• To function properly T-cells must be able to recognise the body’s own immune labels (self-recognition) and own proteins (self-tolerance)

• They learn how to do this in the thymus

• T-cells that don’t display proper self recognition and/or self-tolerance are deleted or inactivated

• Only about 1-5% of T-cells make it through this screening process!

• B-cells undergo a similar screening process in the bone marrow

T- and B-lymphocytes

• Specific: Possess specificity RE: antigens. T- and B-lymphocytes recognise self from non-self molecules, each is able to bind to a particular molecular structure

• Adaptive: Learn to respond to antigens and immune labels…

• …Possess memory for previously encountered antigens. This allows them to produce a quicker and greater attack with the next encounter with the antigen

T- and B-lymphocytes

T-lymphocytes• Made: Bone marrow

• Processed and matured: Thymus (lymphoid organ)

• Most T-cells arise before puberty but continue to mature and leave the thymus throughout life. Numerous in lymph nodes

• Cell-mediated immunity: Attack antigens, also antibody-mediated

• Two types:

• T-helper 1 (Th1): Involved in Cell-mediated Immunity

• T-helper 2 (Th2): Involved in Antibody-mediated Immunity

• Balance between Th1 and Th2 maintained by Regulatory T-cells and Suppressor T-cells

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How Cell-mediated Immunity Works

• Also known as antigen presentation

• Antigen: Foreign body, triggers immune response

• T-lymphocytes have been activated in the thymus and are released into the circulation

• For the T-lymphocytes to get ‘sensitised’ to their antigen, the antigen must be presented to the cell, usually by a dendritic cell or macrophage

• Cancer cells can also present their antigen to T-lymphocytes

Remember!

• Specific T-lymphocytes attack specific antigens…

• Each T-cell is programmed to recognise just one type of antigen: A T-cell produced to recognise a chickenpox virus cell will not respond to a measles virus cell

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B-lymphocytes

• Made: Bone marrow

• Processed: Bone marrow

• Matured: Lymph organs (bone marrow, lymph nodes and lymph glands)

• Numerous in lymph nodes

• Produce antibodies (immunoglobulins): Antibody-mediated immunity

How Antibody-mediated Immunity Works

• B-lymphocytes are fixed in lymphoid tissue (spleen and lymph nodes)

• They can recognise and bind antigens without prior presentation (i.e. no macrophage necessary)

• Once the B-lymphocyte has bonded to an antigen, a helper T-lymphocyte (Th2) stimulates it (by releasing IL-2) to enlarge, then divide, proliferate and differentiate…

• This is called clonal selection

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1. Plasma cells

• Secrete antibodies into the blood

• Only produce one type of antibody

• Short-lived

2. Memory B-cells

• Long-lived

• Remember/recognise antigen for next time. Ready to proliferate and produce more plasma cells for a second immune reaction…

Two types of cells are then produced…

B-cell Secreted Antibodies: Immunoglobulins

• Belong to ‘globulin’ group of proteins

• Think Madonna! Ig…MADGE (sure she’d be pleased!)

• Bind to antigens forming antibody-antigen immune complexes

• Highly specific: Antibody fits to antigen like a lock and key…

Immunoglobulins inactivate antigens in different ways…

1. Neutralising: Neutralise bacterial toxins/prevent viral attachment to cells

2. Immobilising: Bind to antigens on bacterial cilia or flagella

3. Agglutinating and precipitating: Cause antigen carrying matter to clump. Together/become insoluble making it easier to for phagocytic cells to engulf

4. Activate complement: Stimulating antigen lysis…

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Antibody type Where is it found?

How common is it?

What does it do?

IgGBlood, lymph and intestines

Most common:Makes up 80% of all antibodies in

the blood

Protects against bacteria and viruses by neutralising toxins, enhancing phagocytosis and activating

complement. It is the only antibody that can cross the placenta

IgA

Sweat, tears, saliva, breast milk, GI-

secretions.Smaller amounts in blood and lymph

10-15% of antibodies in

blood

Localised protection of mucous membranes against bacteria and viruses.

Levels are decreased during stress!

IgMBlood, B-cell

surface

5-10% of antibodies in

blood

Activates complement to cause lysis of microbes.Antigen receptors on B-cells.

Anti-A and anti-B antibodies of the ABO blood grouping system

IgDB-cell surface

0.2% of antibodies in

bloodB-cell antigen receptors – involved in B-cell activation

IgELocated on mast

cells and basophils

Less than 0.1%of antibodies in

blood

Involved in allergic reactions.Provide protection against parasites. Serum IgE levels rise in

parasitic diseases, thus measuring IgE levels is helpful in diagnosing parasitic infections

Interdependence of T- and B-cells

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Active and Passive Immunity

• It is possible to acquire immunity both actively and passively, by either natural or artificial means

Naturally-acquired active immunity

• Natural exposure to a disease either clinical presentation or sub-clinically

Naturally-acquired passive immunity

• Transfer of IgG antibodies across the placenta from mother to child. Transfer of IgA antibodies from mother to child via the breast milk

Artificially-acquired active immunity

• Vaccination

• Artificial manipulation of immunological memory…

Artificially acquired passive immunity

• Injection with immunoglobulin (antibodies) - e.g. snake anti-venom

Active and Passive Immunity

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When it all goes wrong…

• Innate/adaptive immune mechanisms overwhelmed leading to bacterial/viral/fungal/parasitic infections…

• Acute/chronic…

• Inflammation…

• Hypersensitivity/allergy…

• Autoimmunity!

Allergies: Hypersensitivity

• Allergy: A powerful immune response to an antigen

• Antigen often harmless but over-reaction by the immune system may cause damage to the body

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What Happens?• Initial exposure to allergen sensitises individual

• Subsequent exposure leads to an elevated response, disproportionate to perceived threat

4 types of allergic reaction:

• Type 1: Anaphylactic (IgE-mediated)

• Type 2: Cytotoxic (autoimmune)

• Type 3: Immune complex disease

• Type 4: Delayed-type hypersensitivity

Type 1: Anaphylactic (IgE-mediated)

Long term dangers:Inflammation, atopy, anaphylaxis

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Atopy• A syndrome characterized by a tendency to be

‘hyperallergic’ (‘atopic syndrome’)

• A person with atopy typically presents with one or more of the following: Eczema (atopic dermatitis), hay fever (allergic rhinitis), allergic asthma

• ‘Allergic Triad’: Presentation of all three conditions

• Food allergies also common

• Often familial...

• Highly atopic leads to risk of anaphylaxis

Hygiene Hypothesis

• Lack of early childhood exposure to infectious agents, symbiotic microorganisms (e.g. gut flora) and parasites increases susceptibility to allergic diseases by suppressing the natural development of the immune system

• Originally RE: Type I hypersensitivity (particularly atopy) but now increasingly considered in relation to dysregulation of all types of immune reaction

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Type 2: Cytotoxic Autoimmunity

• When the immune system turns against the body

• Failure to distinguish between ‘self’ and ‘non-self’ leads to immune response against ‘self’ (Failure RE: self-tolerance and self-recognition)

• Formation of auto-antibodies: Antibodies/immunoglobulins (B-cells) and cytotoxic T-cells formed against self-antigens, ordinary markers on host cells

• The antibody-antigen reaction leads to complement activation, inflammation and tissue damage

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• Like Type 1 - often has a genetic link, tends to run in families

• Some disorders effect specific tissues, others are generalised…

Examples:

• Grave's Disease (TSH receptors)

• Myasthenia Gravis (acetylcholine receptors)• Haemolytic Anaemia

Type 3: Immune Complex Disease

• Antibody-antigen immune complexes usually cleared by phagocytosis

• Large complexes easily cleared by macrophages, smaller complexes more difficult. Phagocytosis disposal failure leads to collection of complexes in small blood vessels, joints, skin, eye, glomeruli etc.

• Setting up and prolonging of inflammatory response, bringing ever-increasing inflammatory cells to the area

Examples:

• Rheumatoid arthritis• SLE (lupus)• Vasculitis• Ankylosing spondylosis• MS? • ME? • Others…

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Rheumatoid Arthritis

• Chronic, systemic inflammation of many tissues, primarily the synovium (potentially all organs except brain)

• Affects 1% of people worldwide - approximately 400,000 affected in the UK (F:M = 3:1)

• Inflammatory, autoimmune type III condition: IgM-IgG/IgG-IgG complexes

• Rheumatoid factor (RF) may also be involved: An auto-antibody which can bind to other antibodies, then directed against a portion of IgG

• The resultant immune complex activates complement proteins, leading to inflammation and damage

• RF is present in approx. 70-80% of suffers (not all) - RF may also be present in other conditions

Signs and Symptoms

• Joint swelling, starting with proximal and interphalangeal joints (wrists, hips)

• Impaired extra-capsule joint function: Bursitis, tenosynovitis (the sheath that encases the tendons)

• Prolonged morning stiffness

• Insidious onset (not always - some cases aggressive, sudden onset)

• Late stage: Deformity of hands – ‘swan-neck fingers’. Other complications…

Investigations

• Rheumatoid Factor - 70%

• C-Reactive Protein (CRP) - Peaks at beginning of autoimmune disease, then drops. ‘Normal count’: 0

• Erythrocyte Sedimentation Rate (ESR) - normal range: 10-20, RA: 40-60

• Serum immunoglobulin levels

• Plasma viscosity - immunoglobulins stick together leading to increased blood plasma viscosity

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Allopathic treatment

• Pain relief: OTC NSAIDs (problems: COX I and II…)

• DMARDS: Methotrexate - Danger: Liver, lung and bone marrow damage with long-term use

• Hydrocortisone (But…)

• Gold (s/e nausea, skin rashes)

• HM/NT/acupuncture support…

Systemic Lupus Erythematosus (SLE)

• Chronic autoimmune, connective tissue disease. May effect any part of the body

Signs and Symptoms

• Wide-ranging, varied symptoms: Butterfly rash, fever, depression, photosensitivity, vasculitis, purpura, urticarial, pleurisy, Raynaud’s, NS damage, heart damage, abdominal pain, renal disease, anaemia, etc.

• Unpredictable disease course: Flare-ups frequently alternate with remissions

• Investigations

• Full blood count, antinuclear antibody test, RF, complement levels, immunoglobulin levels (IgG and IgE), ESR

• Allopathic treatment

• Immunosuppressives, NSAIDS

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Type 4: Delayed-type Hypersensitivity (DTH) Reaction

• DTH reactions take 2-3 days to develop

• Unlike the other types, it is not antibody-mediated but is a type of cell-mediated response

• Initiated and mediated by monocytes/macrophages and T-lymphocytes - they become dysregulated. Function becomes abnormal, response to pathogens markedly impaired

• Monocyte/macrophage impairment: Bacteria engulfed during phagocytosis are not killed

• T-cell impairment: Antigens are not destroyed

• Result: Undesirable consequences include illness such as contact dermatitis and allograft rejection (drugs: immunosuppressives…)

• Very serious! The patient may present with opportunistic infections which cause vastly more serious complications than would normally be seen (as illustrated in patients with HIV and AIDS)

Type 4: Delayed-type Hypersensitivity (DTH) Reaction

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Nothing in isolation…• An aside: Organ/hormonal systems throughout body are inter-related, impacting

on each other…

• Prolonged stress response can be immunosuppressive