Hypersensitivity, Tolerance and autoimmunity

Based Upon Warren Levinson 1

Autoimmune Diseases, Tolerance and Hypersensitivity

Dr. Muhammad Yahya NooriBDS


Hypersensitivity

An exaggerated or inappropriate immune reaction harmful to the host

• The clinical manifestations of these reactions are typical in a given individual.• They occur on contact with the specific antigen to which the individual is

hypersensitive. • The first contact of the individual with the antigen sensitizes, i.e., induces the

antibody and the subsequent contacts elicit the allergic response.


Classification of Immune Reactions


Type 1 Hypersensitivity Reactions• Atopy • Anaphylaxis • Asthma


Type I Hypersensitivity(Anaphylactic) Reactions/Allergy

• Occur within minutes of exposure to antigen• Antigens combine with IgE antibodies• IgE binds to mast cells and basophils, causing them to undergo degranulation and release several mediators:• Histamine• Prostaglandins• Leukotrienes

• Exposure to an allergen activates B cells to form IgE secreting plasma cells

• Secreted IgE molecules bind to Fce receptors on mast cells• A subsequent exposure to the allergen results in crosslinking of

the bound IgE which triggers the release of various compounds


Type I Hypersensitivity Reaction


Clinical Aspects of Hypersensitivity


Allergens • Allergens are non-parasite antigens that can stimulate a

type I hypersensitivity response.• Allergens bind to IgE and trigger degranulation of

chemical mediators. • Small 15-40,000 MW proteins. • Specific protein components • Often enzymes.

• Low dose of allergen • Mucosal exposure. • Most allergens promote a Th2 immune.


In the US ---36 million people said to have hay fever!


Atopy

• Atopy is the term for the genetic trait to have a predisposition for localized anaphylaxis.

• Atopic individuals have higher levels of IgE and eosinophils.


Mechanisms of allergic response Sensitization

Repeated exposure to allergens initiates immune response that generates IgE isotype.

• The IgE can attach to Mast cells by Fc receptor, which increases the life span of the IgE. • Half-life of IgE in serum is days whereas attached to

FceR it is increased to months.


Mast Cells and the Allergic Response


Type II Hypersensitivity (Cytotoxic) Reactions/antibody-dependent • Involve activation of complement by IgG or IgM binding

to an antigenic cell.• Antigenic cell is lysed


Type II Hypersensitivity Reactions• Transfusion Reactions

• Occurs with ABO blood antigen groups• Complement mediated lysis

• Drug Induced Hemolytic Anemia• Occurs when an antibiotic forms a complex with red blood cell membrane

protein (similar to hapten carrier complex)• Induces formation of antibodies• Complement

• Hemolytic Disease of the Newborn• Autoimmune hemolytic anemia • Thrombocytopenia • Erythroblastosis fetalis • Goodpasture's syndrome


ABO Blood Groups


Drug reactions • Drug binds to RBC surface and antibody against

drug binds and causes lysis of rbcs. • Immune system sees antibody bound to "foreign

antigen" on cell. ADCC

TYPE II Antibody mediated cytotoxicity


Rh factor incompatibility • IgG abs to Rh an innocuous rbc antigen • Rh+ baby born to Rh- mother first time fine. 2nd time

can have abs to Rh from 1st pregnancy.• Ab crosses placenta and baby kills its own rbcs. • Treat mother with ab to Rh antigen right after birth and

mother never makes its own immune response.

TYPE II Hemolytic disease of newborn


Hemolytic disease of the newborn is caused by type II hypersensitivity reactions When an Rh- mother carries an Rh+ fetus


Generalized Type III Hypersensitivity Reactions: Serum Sickness Occurs when antigen enters bloodstream,

circulating immune complexes form Symptoms include:• Fever • Weakness• Rashes• And many others


TYPE III Antigen antibody immune complexes. IgG mediated

Immune Complex Disease• Large amount of antigen and antibodies form

complexes in blood.

• If not eliminated can deposit in capillaries or joints and trigger inflammation.


TYPE III Immune Complexes

• PMNs and macrophages bind to immune complexes via FcR and phagocytize the complexes.

BUT• If unable to phagocytize the immune complexes can

cause inflammation via C’ activation ---> C3a C4a, C5a and "frustrated phagocytes".


TYPE III Immune Complex Disease"Frustrated Phagocytes"

• If neutrophils and macrophages are unable to phagocytize the immune complexes these cells will degranulate in the area of immune complex deposition and trigger inflammation. • Unable to eat -------try to digest outside cell.


TYPE III Immune Complex Disease

Localized disease

• Deposited in joints causing local inflammation = arthritis. • Deposited in kidneys = glomerulonephritis.


TYPE III Immune Complex Disease

• Serum sickness from large amounts of antigen such as injection of foreign serum. • Serum sickness is usually transient immune complex disease with

removal of antigen source.


Type III Hypersensitivity (Immune Complex) Reactions• Involve reactions against soluble antigens circulating in

serum.• Usually involve IgA antibodies.• Antibody-Antigen immune complexes are deposited in

organs, activate complement, and cause inflammatory damage.• Glomerulonephritis: Inflammatory kidney damage.

• Occurs with slightly high antigen-antibody ratio is present.


Immune Complex Mediated Hypersensitivity


Examples of type III• Serum sickness • Arthus reaction • Systemic lupus erythematosus (SLE)


Type IV Hypersensitivity Reaction• The response is "delayed," i.e., it starts hours (or

days) after contact with the antigen and often lasts for days.• Delayed hypersensitivity is a function of T

lymphocytes, not antibody (Figure 65–4). It can be transferred by immunologically committed (sensitized) T cells, not by serum.


Mechanism


Delayed type hypersensitivity Th1 cells and macrophages

• DTH response is from:• Th1 cells release cytokines to activate macrophages causing

inflammation and tissue damage. • Continued macrophage activation can cause chronic

inflammation resulting in tissue lesions, scarring, and granuloma formation.

• Delayed is relative because DTH response arise 24-72 hours after exposure rather than within minutes.


Stages of Type IV DTHSensitization stage

• Memory Th1 cells against DTH antigens are generated by dendritic cells during the sensitization stage. • These Th1 cells can activate macrophages and

trigger inflammatory response.


Stages of Type IV DTHEffector stage

• Secondary contact yields what we call DTH. • Th1 memory cells are activated and produce cytokines. • IFN-g, TNF-a, and TNF-b which cause tissue destruction,

inflammation. • IL-2 that activates T cells and CTLs.• Chemokines- for macrophage recruitment. • IL-3, GM-CSF for increased monocyte/macrophage


Stages of Type IV DTHEffector stage

Secondary exposure to antigen• Inflamed area becomes red and fluid filled can form

lesion. • From tissue damage there is activation of clotting cascades and

tissue repair.

• Continued exposure to antigen can cause chronic inflammation and result in granuloma formation.


Type IV DTH Contact dermatitis

• The response to poison oak is a classic Type IV. • Small molecules act as haptens and complex with skin proteins

to be taken up by APCs and presented to Th1 cells to get sensitization. • During secondary exposure Th1 memory cells become activated

to cause DTH.


Contact dermatitis


Delayed type hypersensitivity (DTH)

DTH is a type of immune response classified by Th1 and macrophage activation that results in tissue damage.

DTH can be the result ofChronic infection or Exposure to some antigens.


Type IV MechanismAPC resident in the skin process antigen and migrate to regional lymph nodes where they activate T cellsSensitised T cells migrate back to the the skin where they produce cytokines which attract macrophages which cause tissue damage


Examples of Type IV• Contact dermatitis • Mantoux test • Chronic transplant rejection • Multiple sclerosis


Recap


Autoimmunity

Immune reactions against self antigens


Conditions to be met for diagnosis of an autoimmune disease• The presence of an immune reaction specific for

some self antigen or self tissue• Evidence that such a reaction is not secondary to

tissue damage but is of primarypathogenic significance• The absence of another well-defied cause of the

disease.


Classification of Autoimmune Diseases


Important Autoimmune DiseasesAntibodies to Receptors

Autoimmune Disease Target of the Immune Response

Myasthenia Gravis Acetyl Choline Receptor

Grave’s Disease TSH1 Receptor

Insulin Resistance Diabetes Insulin Receptor


Important Autoimmune DiseasesAntibodies to Cell Components other than Receptors


Systemic Lupus Erythematosis dsDNA, Histones,

Rheumatoid Arthritis IgG in joints

Rheumatic Fever Heart and joint Tissue

Hemolytic Anaemia RBC membrane

ITP Platelet membrane

Good Pastture’s Syndrome Basement Membrane Lungs /Kidneys

IDDM Islet cells


Important Autoimmune DiseasesCell Mediated


Multiple Sclerosis Myelin

Celiac Disease Enterocytes


Tolerance• Tolerance is specific immunologic unresponsiveness, i.e., an immune

response to a certain antigen (or epitope) does not occur, although the immune system is otherwise functioning normally.

• In general, antigens that are present during embryonic life are considered "self" and do not stimulate an immunologic response, i.e., we are tolerant to those antigens. The lack of

• An immune response in the fetus is caused by the deletion of self-reactive T-cell precursors in the thymus.

• On the other hand, antigens that are not present during the process of maturation, i.e., that are encountered first when the body is immunologically mature, are considered "nonself" and usually elicit an immunologic response.

• Although both B cells and T cells participate in tolerance, it is T-cell tolerance that plays the primary role.


T Cell Tolerance• The main process by which T lymphocytes acquire the ability

to distinguish self from nonself occurs in the fetal thymus.• This process, called clonal deletion involves the killing of T

cells ("negative selection") that react against antigens (primarily self MHC proteins) present in the fetus at that time. • The self-reactive cells die by a process of programmed cell

death called apoptosis. • Tolerance to self acquired within the thymus is called central

tolerance, whereas tolerance acquired outside the thymus is called peripheral tolerance.


B Cell Tolerance• B cells also become tolerant to self by two

mechanisms: • (1) clonal deletion, probably while the B-cell precursors

are in the bone marrow and • (2) clonal anergy of B cells in the periphery.


Immunologic Tolerance


Pathogenesis of Autoimmunity


Mechanisms related to autoimmunity• Defective tolerance or regulation• Abnormal display of self antigens.• Inflammation or an initial innate immune response.• Antigen Mimicry• Alteration of Normal Proteins• Release of Sequestered antigens• Epitope spreading• Failure of Regulatory T Cells


Genetic Factors Related to AutoimmunityHLA


Genetic Factors Related to AutoimmunityNon-HLA Genes


Antigen Mimicry


Autoantibodies and their association with different diseases


General Features of Autoimmune Disease• Autoimmune diseases tend to be chronic,

sometimes with relapses and remissions, and the damage is often progressive. • The clinical and pathologic manifestations of an

autoimmune disease are determined by the nature of the underlying immune response.


Thank you

Hypersensitivity, Tolerance and autoimmunity

Health & Medicine

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