Abnormal immune response Hypersensitivity & Autoimmunity · Abnormal immune response Hypersensitivity & Autoimmunity ... •Secondary responses ... –Remission with growth and

Abnormal immune response

Hypersensitivity & Autoimmunity

Lecture 7

Pathology and Clinical

Science 1 (BIOC211)

Department of BioscienceText Reference:

Grossman, S.C. & Porth, C.M. (2014). Porth’s Pathophysiology: concepts of

altered health states, (9th ed.). Philadelphia, U.S.A. Walters Kluwer Health -

Lippincott, Williams & Wilkins.

© endeavour.edu.au

© Endeavour College of Natural Health endeavour.edu.au 2

Session Learning Outcomes:

This session aims to understand and describe

o The mechanism of hypersensitivity

o Understand the difference between type I to IV

hypersensitivity

o Auto-immunity

o The inflammatory pathway that occurs in

autoimmunity

o The immunodeficiency


REVISION - THE NORMAL

IMMUNE RESPONSE• The immune system is organised into lines of

defence to protect the body from microbial invasion

First

(non specific)

Physical and chemical defences (skin and mucous membranes)

Second

(non specific)

Complement, neutrophils, macrophages, inflammation, fever

Third

(specific)

Antibodies – B-cells

Cell Mediated – T-cells


THE NORMAL IMMUNE RESPONSE:

SPECIFIC IMMUNITY

Antibody Immunity:

• Primary responses

– IgM

• Secondary responses

– IgG and/or IgA

• Specific antigens will

stimulate

– IgE (parasites in

particular)

Cellular Immunity:

• Killer T cells:

– lyse infected body

cells


TYPES OF IMMUNITY THAT DEVELOPS UPON

ENCOUNTER WITH VARIOUS TYPES OF ANTIGENS


ABNORMAL IMMUNE

RESPONSES• The immune system can responds in an abnormal way

such that the response elicited may be

– Unnecessary

– Excessive

• Normal immune reactions will cause some damage to the body which is necessary to rid the body of a greater threat (unchecked infection-fatal)

– Normal immunity causes damage but has long term benefit

• Abnormal immunity causes damage with no benefit to the body

• Hypersensitivity is an abnormal immune response


WHAT IS HYPERSENSITIVITY

• Unusual and often damaging immune responses to normally harmless substances

• There are four basic types of hypersensitivity reactions

– Type I, II, III, IV

• These differ in ways in which they cause tissue injury


TYPE I HYPERSENSITIVITY

(ALLERGY AND ANAPHYLAXIS)

• Allergy is a type I hypersensitivity reaction

– A local reaction

• Anaphylaxis is a type I hypersensitivity

reaction

– Added to local effects, there are

extreme severe systemic effects



(ALLERGY)• Also known as immediate hypersensitivity reaction

• Occurs within 5-10 minutes of exposure to a specific

allergen

• Must be previously sensitised to the allergen

• Predisposed genetic tendency (atopic) for IgE production

to variable allergens (normally harmless in others)

• The specific allergen can be:

– Food – nuts, shellfish, strawberries

– Chemicals

– Drugs – Aspirin, penicillin, local anaesthetics

– Pollen


MECHANISM OF TYPE I

HYPERSENSITIVITY REACTIONS

Un-needed immune response involving the

development of IgE antibodies

• Primary exposure(s) to the allergen

- IgE produced and sensitises mast cells and

basophils

• Secondary (re)exposure to the allergen

stimulates sensitised mast cells

- Degranulation and histamine release (phase l)


Mechanism of

Type I

Hypersensitivity

Reactions

From Porth’s Pathophysiology: concepts of altered health states, (9th ed., p. 342), by Grossman, S.C. & Porth, C.M. (2014), Philadelphia, U.S.A. Walters Kluwer Health - Lippincott, Williams & Wilkins.


MECHANISM OF TYPE I

HYPERSENSITIVITY REACTIONS• Vasodilation and vascular leakage

• Results in itching and mild pain

• Duration 5-30 mins induction of the inflammatory

response (phase ll)

• Prostaglandins and leukotrienes

• Increased vasodilation, increased permeability, tissue

destruction

• Increased inflammation and clinical features

• Duration starts 2-8 hours post exposure – can last for

several days

• Induction of bronchoconstriction if in the lungs (asthma)



REACTIONS

• Skin rashes

• Extrinsic asthma (wet asthma)

• Eczema (some forms)

• Hay fever (allergic rhinitis)

• Allergic conjunctivitis

• Vomiting (food allergies)

• Anaphylaxis



http://www.dermnet.com/dn2/allJPGThumb3/eczema-acute-1.jpg

Eczema Allergic Conjunctivitis

Anaphylaxis - Drug ReactionContact Dermatitis

http://www.dermnet.com/dn2/allJPGThumb3/eczema-acute-1.jpg



• Clinical Features of second exposure

– pruritus (itchy)

– vesicles (blisters)

– redness

– Swelling

• Testing for Type I

– Skin prick testing

• Weal and flare reaction in response to pricking

skin with allergen solution

– Measuring specific IgE in serum


SKIN-PRICK TESTINGThe skin prick test introduces a tiny amount of allergen into the skin. These

tests can be carried out on all age groups, including babies, although the

response will be considerably smaller than in an adult.

o Skin testing is usually carried out on the inner forearm or larger areas on the

back.

o The test allergens are selected in accordance with the patient’s history

o As few as 3 or 4 or up to about 25 allergens can be tested

o The prick area is coded with a marker pen for the allergens to be tested

o A drop of the allergen (extract) solution is placed by the relevant name or

number

o The skin is then pricked through the drop using the tip of a lancet – this can feel

a little uncomfortable but should not be painful

o The patient needs to avoid taking anti-histamines and certain other medications

for 48 hours before the test


Skin Prick Testing

http://www.mitchellzhomes.com/AZAPAA/skintest.bmp



• Treatment options include:

– Allergy testing to identify and avoid the

allergen

– Drugs

• Antihistamine drugs

• Glucocorticoids and steroidal derivatives to

stabilise the vascular system

• New drugs include leukotriene receptor blockers

for asthma

– Desensitisation treatment


COMMON HYPERSENSITIVITIES

http://dermimages.med.jhmi.edu/images/Papular_Urticaria_1_100606.jpg

Urticaria (Hives)

• Allergic rhinitis– Nasal mucosa

– Sneezing, copious watery secretion, itching

– Eyes often affected also

– Often seasonal due to increases in allergen exposure (pollen)

• Food allergies– Digestive tract mucosa

– Nausea, vomiting, diarrhoea

– Skin rashes (hives), pruritic

– If severe hives can occur in pharyngeal mucosa obstructing airflow

http://dermimages.med.jhmi.edu/images/Papular_Urticaria_1_100606.jpg



http://www.sciencephoto.com/image/256384/530wm/M1500252-Atopic_eczema-SPL.jpg

• Atopic eczema

– Chronic skin condition

– Often a genetic component

– Common in infants and young

children

– Skin rash can occur anywhere

– Associated with ingested foods,

irritating fabrics, dry

atmosphere

– Remission with growth and

development

– Reoccurrences can occur in

adulthood

Atopic Eczema

http://www.sciencephoto.com/image/256384/530wm/M1500252-Atopic_eczema-SPL.jpg



Image Source:http://trialx.com/curetalk/wp-

content/blogs.dir/7/files/2011/05/diseases/Asthma_Bronchial-3.jpg

• Asthma (extrinsic)• Lung disorder

• May result from allergic response in

bronchial mucosa

• Severe but reversible bronchial

obstruction

• Long term can lead to irreversible

damage (COPD)

• Familial history of other allergic

conditions, onset common in children

• Remission can occur with

development to adulthood

Asthma


ANAPHYLAXIS

http://dccdn.de/pictures.doccheck.com/photos/e/d/7fd15798ce17750_m.jpg

Wasp Sting

• Is an extreme, life threatening,

systemic manifestation of type

I hypersensitivity

• Occurs within minutes of

exposure

• Common causes include:

– Insect stings

– Food allergies (nuts,

shellfish)

– Administration of drugs

(penicillin, anaesthetics)

http://dccdn.de/pictures.doccheck.com/photos/e/d/7fd15798ce17750_m.jpg


ANAPHYLAXIS

• Pathophysiology of Anaphylaxis

– Release of large amounts of chemical

mediators

– General or systemic vasodilation

– Oedema of the lungs

– Bronchoconstriction

– Respiratory and circulatory impairment

– Loss of consciousness

– May be fatal if untreated


Anaphylaxsis


ANAPHYLAXIS• Clinical Features

– Generalised itching or tingling sensation over the body

– Coughing and difficulty breathing

– Weakness, dizziness or fainting

– Fear and panic

– Oedema may be present around eyes, lips, tongue, hands and feet

– Skin may break out in hives

– Collapse and loss of consciousness in minutes


ANAPHYLAXIS

http://www.emergency.com.au/flex/course-in-first-aid-management-of-anaphylaxis/546/1

• Emergency Treatment

– Call an ambulance

– Epinephrine immediately (sufferers often carry Epipens)

– Administer oxygen if available

– Treat for shock

– Administer CPR if needed

http://www.emergency.com.au/flex/course-in-first-aid-management-of-anaphylaxis/546/1


TYPE II HYPERSENSITIVITY

(CYTOTOXIC)

• Location of the antigen is on the surface of cells or other tissue components

• Involvement of IgG, and IgM antibodies

• Involves complement dependent mechanisms

– Lysis via membrane attack complex (MAC)

– Opsonisation via macrophages

• Involves antibody dependent mechanisms

– Antibody dependent cell mediated cytotoxicity (ADCC). This involves lysis of target cell expressing the antigen.


Type II

Hypersensitivity

(Cytotoxic)

From Porth’s Pathophysiology: concepts of altered health states, (9th ed., p. 345), by Grossman, S.C. & Porth, C.M. (2014), Philadelphia, U.S.A. Walters Kluwer Health - Lippincott, Williams & Wilkins.


OUTCOMES OF TYPE II

RESPONSES• Death of cell

• Common type II reactions:

– Transfusion reactions from incompatible donor

– Erythroblastosis fetalis (rhesus incompatibility)

– Drug reactions (where drug is adsorbed to cell surface)

– Auto immune reactions : Grave’s disease, Myathenia Gravis

• Treatment

– Exchange transfusion

– Immunosuppressive drugs

– Cytotoxic drugs

– Plasmapheresis

– Surgery


TYPE III HYPERSENSITIVITY

(IMMUNE COMPLEX)

• Abnormal or persistent antibody- antigen

complex formation which has not been cleared

by normal mechanisms

• Deposits of immune complexes in tissues

– Localised inflammation caused by activation

of complement and neutrophils by the

immune complex

– Can lead to vasodilation and oedema

– Can lead to necrosis


Type III

Hypersensitivity (Immune Complex)

From Porth’s Pathophysiology: concepts of altered health states, (9th ed., p. 347), by Grossman, S.C. & Porth, C.M. (2014), Philadelphia, U.S.A. Walters Kluwer Health -Lippincott, Williams & Wilkins.


TYPE III HYPERSENSITIVITY• Types

– Serum sickness

– Raynaud's phenomena - cryoglobulins deposition

– Arthus reaction

• injection, ingestion or inhalation of allergens, egallergic alveolitis ( farmers lung, pigeons disease coeliac reaction)

• Treatment

– Corticosteroids


– Environmental removal or avoidance of antigen if possible

– Plasmapheresis


TYPE IV HYPERSENSITIVITY

(CELL MEDIATED DELAYED)

• Activation of T cells over time

• 48-72 hours for reaction to develop

• Results in inflammation, cell lysis and tissue destruction

• Common Type IV Activators

– Cosmetics

– Dyes

– Soaps

– Metals

– Rubber and latex

– Elastoplast

– Plant toxins (poison ivy)


TYPE IV HYPERSENSITIVITYMechanism

• Antigens are cell or tissue bound

• Two mechanisms involved- both involving T cells:

• First mechanism:

– Subsets of CD4 T cells are activated (first exposure)

– On second exposure activated CD4 T cells secrete cytokines which in turn activate macrophages

– Associated with inflammation and granuloma formation

• Second mechanism:

– Direct cell cytotoxicity via sensitised CD8 T cells

– T cells become sensitised over time

– CD8 T cells lyse cells bearing antigen


Type IV

Hypersensitivity

From Porth’s Pathophysiology: concepts of altered health states, (9th ed., p. 348), by Grossman, S.C. & Porth, C.M. (2014), Philadelphia, U.S.A. Walters Kluwer Health -Lippincott, Williams & Wilkins.

Cell-mediated

Delayed Hypersensitivity Response


TYPE IV HYPERSENSITIVITY

• Clinical Features - generally do not occur immediately after direct contact

– Localised rash

– Pruritis

– Redness

– Vesicles

– Serous exudate

• Treatment


– Corticosteroids

– Removal of the antigen


POISON IVY REACTION

http://www.babymd.net/poisonivy4.jpg


AUTOIMMUNITY


WHAT IS AUTOIMMUNITY?o 7o A sustained adaptive immune response to a self

antigen which causes tissue damage

o Influenced by both environmental and genetic factors

Environmental

• Occupation

• UV light

• Drugs

• Infections

(viruses, bacteria, mycoplasmas

Genetic

• Inherited chromosomal mutations

• Presence of particular genes such as HLA B2


GENETIC BIAS OF COMMON

AUTOIMMUNE DISEASES

o Ankylosing spondylitis HLA-B27 (90%)

o Myasthenia gravis HLA-DR3 (5%)

o Graves disease HLA-DR3 (5%)

o SLE HLA-DR3 (5%)

o IDDM HLA-DR3 (20%)

HLA-DR4

o RA HLA-DR4 (5%)


AUTOIMMUNITYNormal immune Response1. Invading antigen

2. Antibodies form

3. Antibodies remove antigen

4. Antibodies remain for future

protection

Autoimmune Response1. Antibodies form to SELF antigens

2. SELF antigens attacked – immune

complexes deposited

3. Inflammation & tissue damage


AUTOIMMUNITYImmunological Tolerance

− “a state in which an individual is incapable of developing

an immune response against a specific antigen. Self

tolerance specifically refers to a lack of immune

responsiveness to one’s own tissue antigens.”- Kumar, Cotran and Robbins. Robbins Basic Pathology, 7th Ed, Saunders,

Philadelphia. 2003

o Exact processes of the development of autoimmunity

have not been established

o Self antigens are usually tolerated by the immune

system (the immune system does not react to them)

o When self tolerance is lost the immune system is unable

to differentiate self antigens from foreign antigens


AUTOIMMUNE REACTIONSSome immune reactions are known to be involved

o After self tolerance is broken down different components of the immune system can be activated

o Mediated by either antibodies or T cells

o The antigen cannot be eradicated from the body as it is part of the body

o The antigen involved and the mechanism of action determines the clinical expression of the disease

o The immune reaction may be local or systemic


AUTOIMMUNITY REACTIONSo Autoimmunity reactions have similar mechanism/

processes as the hypersensitivity reactions

o The difference is that autoimmune mechanisms involve self antigens not foreign antigens

o Absence of type I responses

o Reactions involving type II hypersensitivity are common where reactions involve the induction of IgG or IgM

o Reactions involving type III autoimmunity are common where immune complexes form

o In organ specific autoimmunity T cell responses are directly involved in causing the tissue damage (type IV)


TYPE II AUTOIMMUNITYo Auto-antigen is cell bound

o Immune reaction to the auto-antigen results in type II hypersensitivity mechanisms becoming activated:

• Complement dependent lysis

• Antibody dependent cellular cytotoxicity

• Anti-receptor antibodies

o Common Type II Autoimmune Reactions

• Autoimmune haemolytic anaemia

• Part of Hashimoto’s thyroiditis

• Binding of antibodies to a receptor-

–Graves disease

–Myasthenia gravis


TYPE III AUTOIMMUNITYo Auto-antigen is free

o Immune reaction to the auto-antigen results in type III hypersensitivity mechanisms becoming activated:

• Antibodies are produced to the auto-antigen

• Immune complex formation can occur locally or systemically

o Common Type III Autoimmune Reactions

• Rheumatoid Arthritis

• Systemic Lupus Erythematosus (SLE)


RHEUMATOID ARTHRITIS STAGES

http://emedicine.medscape.com/article/401271-overview

Early

MidLate

MidA B

C D


RHEUMATOID ARTHRITIS

http://images.rheumatology.org/image_dir/album75692/md_99-05-0020.tif.jpg


SYSTEMIC LUPUS

ERYTHEMATOSUS (SLE)

http://imaging.ubmmedica.com/consultantlive/images/articles/2003/07012003/0307ConPERheum1A.jpg


TREATMENT OF AUTOIMMUNITY

oGlucocorticoids (only in non-organ

specific conditions)

oPrednisone (high dose during

exacerbation)

oSystem specific therapy

oSymptom relief


IMMUNODEFICIENCYo A partial or total loss of function of one or more

components of the immune system

o Can be inherited or acquired

o Can be transient or permanent

o Can be induced by immunosuppression

o Most common form of immunodeficiency worldwide is malnutrition

o However, in developed countries most immunodeficiency's are inherited

o Certain immunodeficiency's correlate to an individuals susceptibility to particular infections or diseases

o Two forms / types - Primary and Secondary


PRIMARY IMMUNODEFICIENCY'So A basic developmental failure somewhere in the

immune system

• Inherited or congenital

• Genetic basis

o Congenital hypoglobulinemia

• Affect B cell

o Thymic aplasia

• Low T cell

o DiGeorge’s syndrome

• Low mature T cells

o Inherited combined immunodeficiency syndromes

• Affect B & T cell

o Inherited deficit of one or more components

• Affect complement


THYMIC APLASIA

Failure of the Thymus Gland to develop Low T-Lymphocyte count

http://histology.med.umich.edu/sites/default/files/lymph_pq_3.jpg


SECONDARY IMMUNODEFICIENCYo Secondary

• Acquired

• Loss of immune function due to specific causes

• May occur at any time in the lifespan

o Causes

• Infection (particularly viral)

• Malnutrition

• Liver disease (hypoproteinemia)

• Cancer

• as a result of malnutrition and blood loss and commonly effects of treatment (decreased bone marrow production)

• Immunosuppressive drugs

• Severe stress (prolonged glucocorticoid secretion)


SECONDARY

IMMUNODEFICIENCY'So Kidney disease with globulin loss

• Affects Humoral immunity

o Hodgkin's disease (cancer of the lymph nodes)

• Affect T Cell

o AIDS

• T Cell

o Immunosuppression, radiation, chemotherapy

• Loss of phagocytes

o Malnutrition

• complement

o Cirrhosis of the liver

• Complement


HODGKIN’S LYMPHOMA

http://www.healthoma.com/hodgkins-lymphoma-and-its-symptoms/

Reed Sternberg

cells in Hodgkin’s

Lymphomas

http://www.healthoma.com/hodgkins-lymphoma-and-its-symptoms/


LIVER CIRRHOSIS

http://medicalpicturesinfo.com/wp-content/uploads/2011/09/Cirrhosis-2.jpg


SECONDARY

IMMUNODEFICIENCY'S

http://theness.com/neurologicablog/wp-

content/uploads/2011/10/malaria.jpg

Insect Image: http://www.gossipjackal.com/wp-

content/uploads/2010/07/malaria-proof-

mosquitoes.jpg

Malaria

As anaemia worsens, liver and

spleen start lysing ALL blood cells

and platelets leading to:

- Immunodeficiency - WBC’’s

- Worsening anaemia - RBC’s

- Excessive bruising - Platelets


TREATMENT OF

IMMUNODEFICIENCY'S

oReplacement of antibodies with

gammaglobulins

• (blood transfusions)

oBone marrow or thymus transplants

• Limited success

• Not suitable in all cases


HIV AND AIDS

oEpidemiologyoTransmissionoViral structureoMechanism of infectionoProgression of the disease - when

does HIV positive become AIDSoClinical signs and symptomsoTreatment


HIV AND AIDS

From Porth’s Pathophysiology: concepts of altered health states, (9th ed., p. 364), by Grossman, S.C.

& Porth, C.M. (2014), Philadelphia, U.S.A. Walters Kluwer Health - Lippincott, Williams & Wilkins.


HIV LIFE

CYCLE

From Porth’s Pathophysiology: concepts of altered health states, (9th ed., p. 365), by Grossman,

S.C. & Porth, C.M. (2014), Philadelphia, U.S.A. Walters Kluwer Health - Lippincott, Williams &

Wilkins.


Readings and ResourcesResources:

o Set Textbooks:

Colledge, N.R., Walker, B.R. & Ralston S.H. (2014). Davidson’s Principles and Practice of Medicine, (22nd ed.). Edinburgh.

Churchill Livingstone.

Grossman, S.C. & Porth, C.M. (2014). Porth’s Pathophysiology: concepts of altered health states, (9th ed.). Philadelphia,

U.S.A. Walters Kluwer Health - Lippincott, Williams & Wilkins.

o Additional textbooks:

Davies, A. & Moores, C. (2010). The respiratory system: basic science and clinical conditions, (2nd ed.). Edinburgh. Churchill,

Livingstone, Elsevier.

Field, M., Pollock, C., Harris, D. (2010). Systems of the Body: The Renal System; Basic Science and Clinical Conditions. (2nd

ed.). United Kingdom: Churchill Livingstone.

Jamison, J.R. (2006) Differential Diagnosis for Primary Care: a handbook for health care practitioners. (2nd ed.). Edinburgh.

Churchill Livingstone.

Lee, G. & Bishop, P. (2013). Microbiology and Infection Control for Health Professionals, (5th ed.). Frenchs Forest, NSW.

Pearson Education.

McCance, K.L. & Huether, S.E. (2014). Pathophysiology: the biological basis for disease in adults and children, (7th ed.). St.

Louis, MO. Elsevier.

Murphy, K. (2011). Janeway’s immunobiology, (8th ed.). New York. Garland Science.

Noble, A., Johnson, R. & Bass, P. (2010). The cardiovascular system: basic science and clinical conditions, (2nd ed.).

Edinburgh. Churchill, Livingstone, Elsevier.

Pagana, K.D. & Pagana, T.J. (2013). Mosby’s diagnostic and laboratory test reference, (11th ed.). St. Louis, MO. Elsevier.

Smith, M.E. & Morton, D.G. (2010). The digestive system: basic science and clinical conditions, (2nd ed.). Edinburgh.

Churchill, Livingstone, Elsevier.

VanMeter, K.C. & Hubert, R. (2014). Gould’s pathophysiology for health professions, (5th ed.). St. Louis, MO. Elsevier.


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Abnormal immune response Hypersensitivity & Autoimmunity · Abnormal immune response Hypersensitivity & Autoimmunity ... •Secondary responses ... –Remission with growth and

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