Khan Hypersensitivity Reactions Final 2011

8/3/2019 Khan Hypersensitivity Reactions Final 2011

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KhanNUHS.



Hypersensitivity Reactions Outline

Introduction

Type I Hypersensitivity Type II Hypersensitivity

Type III Hypersensitivity

Type IV Hypersensitivity



Introduction

Normal immune reactions do their job withouthurting the host.

Sometimes, immune reactions can beexcessive, resulting in disease.

People who mount normal immune responsesare sensitized to that antigen.

People who have excessive responses arehypersensitive.



Introduction

Bugs

Environmental antigens

Self antigens

What antigens initiate these “hypersensitivity reactions”?



Introduction

The immune response is triggered andmaintained inappropriately.

Hard to eliminate stimulus!

Hard to stop response once it starts!

So hypersensitivity diseases are often chronic,

debilitating, hard to treat.



Mechanisms of HypersensitivityReactions

These reactions give rise to immunologic injury in variety ofdiseases and causing damage to tissues due to :

A. Exogenous antigens (Dust, pollens, foods, drugs,

microbiologic agents, chemicals, and many blood products.) .

B. Endogenous tissue Antigens. Against Self antigens (causeAutoimmune diseases)

C. Often associated with the Inheritance of Susceptible Genes

(HLA Genes).



Mechanisms of HypersensitivityReactions

Tissue injury may be caused by Humoral or Cellmediated.

Reactions takes “ VARIETY OF FORMS”:

Such as itching of skin . Swelling ,spasm, narrowing of lumen leading to

fatal diseases (like bronchial asthma ,anaphylaxis.)



Classification

They are classified as: Based on immunologic mechanism thatmediates :

Type I ( Immediate ) hypersensitivity reactions. The immune response is mediated by TH2 cells, IgE antibodies and

mast cells . Mast cells release vasoactive and spasmogenic substances(LIKE

histamine or like substances) Which are acting on vessels and smooth muscle and with

inflammatory cells. Type II (Antibody Mediated ) hypersensitivity reactions.

Antibodies(IgG and IgM) directly causing injury to the cells byphagocytosis or lysis and inflammation.

Antibodies may also interfere with cellular function and causedisease.



Continue- Hypersensitivity reactions

Type III (Immune complex mediated) . Antibody ( IgG, IgM) binds to antigen,induce

inflammation directly or with complements. Neutrophils and Macrophages cause tissue damage.

Type IV ( Cells (T) mediated ) hypersensitivity reactions, cause tissue injury.



Type I Hypersensitivity

ALLERGY: Is an example of “Immediate” hypersensitivity. Antigen (allergen) binds to IgE antibodies on

surface of mast cell Mast cell releases nasty mediators. End result: dilation of vessels, contraction of

smooth muscles.




Allergen isinhaled/eaten/injected

Allergen stimulates TH2production

TH2 cell secretes cytokines:• IL-4 stimulates B cells to

make IgE.• IL-5 recruits eosinophils• IL-13 stimulates mucous

secretion.

Mast cell binds IgE. Allergen bridges IgE on mast

cell.

Mast cell degranulates.

Release of mediators.

Sequence of events






What nasty stuff does the mast cellrelease?

Granule contents• histamine

• some chemotactic factors

Membrane phospholipid metabolites• prostaglandin D2 • leukotrienes

Cytokines• TNF

• interleukins• IL-13




What do these nasty substances do? Act on blood vessels, smooth muscle, and WBCs.

Immediate response (minutes)

• vasodilation, vascular leakage, smooth muscle spasm• granule contents, prostaglandin, leukotrienes

Late phase reaction (hours)

• inflammation, tissue destruction

• cytokines




Act on blood vessels, smooth muscle, andWBCs.

Immediate response (minutes)

• vasodilation, vascular leakage, smooth musclespasm

• granule contents, prostaglandin, leukotrienes

Late phase reaction (hours)• inflammation, tissue destruction

• cytokines

What do these nasty substances do?



Mast cells intact (left) and degranulated (right) Mast cell. Type I hypersensitivity. In a type Ihypersenstivity reaction, the mast cell has IgE on its surface. When an allergen comes along, itbinds to the IgE, and the mast cell busts open, releasing its contents, mostly histamine



Type I Hypersensitivity Reaction (Allergy)

Immediate Reaction. within minutes,after

combination ofantigen with antibodybound to mast cells(also Basophils).

In individuals

previously sensitizedto an antigens ,Systemic or localreactions can occur.

Begin within 30minutes and subsidewithin 60 min.

Infiltration of tissues

with eosinophils,neutrophils,basophils, monocytescells(CD4+T)



Type I Hypersensitivity Reaction (Allergy)

What happens to the patient? Local reactions

• skin: itching, hives

• GI: diarrhea

• lung: bronchoconstriction Anaphylaxis

• itching, hives, erythema• constriction of bronchioles, wheezing

• laryngeal edema, hoarseness

• vomiting, cramps, diarrhea• laryngeal obstruction

• shock

• DEATH




“Atopy” – predisposition to react toallergens.

Atopy refers to predisposition to developlocalized immediate hypersensitivityreactions.

Family history of allergy is found in 50%of atopic individuals

Atopic patientshave higher IgE levels, moreTH2 cells

Candidate genes:• 5q31 (bunch of cytokine genes here)• 6p (close to HLA complex)

Why do some people have allergies, whileothers don’t?



Type II Hypersensitivity

ANTIBODIES.

“Antibody-mediated” hypersensitivity.

Antibodies bind to antigens on cell surface.

Macrophages eat up cells, complement getsactivated, inflammation comes in.

End result: cells die, inflammation har.ms tissue




Disease Antigen Symptoms

Autoimmune

hemolytic anemiaRBC antigens, drugs Hemolysis

Pemphigus vulgarisProteins between

epithelial cellsBullae

Goodpasture syndrome Proteins in glomeruliand alveoli

Nephritis, lunghemorrhage

Myasthenia gravis Acetylcholine receptor Muscle weakness

Graves disease TSH receptor Hyperthyroidism

What kinds of diseases involve type IIhypersensitivity?




Antibodies bind tocell-surfaceantigens

One of three thingshappens:

• 1.Opsonizationand phagocytosis

• 2.Inflammation

• 3.Cellulardysfunction

Sequence of events

Type II hypersensitivity. Antibodies bind to fixed antigens on cell surfaces.

One of three things happens: 1) opsonization and phagocytosis, 2) inflammation(shown here), 3) cellular dysfunction.

Diseases that have type II hypersensitivity include autoimmune hemolytic anemia,myasthenia gravis, and Graves disease.( important for exam.)



Type II Hypersensitivity Reaction There are Three types of antibody dependant

mechanisms.

1. Detection and removal of cells : By Opsonizatio and Phagocytosis: Cells are Targeted by Antibodies ,This is

called opsonized that make them attractive

for phagocytes( Phagocytosis). This may be due to complement activation,

which tags antigens with its byproducts andmakes them recognizable by phagocytes.

2. Antibody mediated destruction of

cells : A process-Antibody dependant cellularcytotoxicity(ADCC) may lead to destruction of cells .

Does not involve complement but requiresleukocytes.

Cells are coated with IgG antibody.



Type II Hypersensitivity Reaction

3.Antibody Mediated CellularDysfunction.

Antibody is directed against cell surfacereceptors, impair or dysregulate function“without causing cell injury or

inflammation.” Example: Myashthenia Gravis and Grave’s

disease. Antibodies in MG are directed against

Post-synaptic Ach receptors. Antibodies in Grave’s disease are directed

against TSH receptors on Thyroid Follicles.



Summary . Draw this picture twice




IMMUNE COMPLEXES

“Immune complex-mediated” hypersensitivity

Antibodies bind to antigens, forming complexes

Complexes circulate, get stuck in vessels,stimulate inflammation

End result: bad inflammation, necrotizingvasculitis




Disease Antigen Symptoms

Systemic lupuserythematosus

Nuclear antigens Nephritis, skin lesions,arthritis…

Post-streptococcal

glomerulonephritisStreptococcal antigen Nephritis

Polyarteritis nodosa Hepatitis B antigen Systemic vasculitis

Serum sickness Foreign proteinsArthritis, vasculitis,

nephritis

Arthus reaction Foreign proteins Cutaneous vasculitis

What kinds of diseases involve type IIIhypersensitivity?




Two kinds of type III hypersensitivity reactions.

Systemic immune complex disease Complexes formed in circulation

Deposited in several organs Example: serum sickness Local immune complex disease

To specific organs such as Kidney- Glomerulonephritis,Joints-Arthritis

Complexes formed at site of antigen injection. Precipitated at injection site.

Example: Arthus reaction.






How do the complexes causeinflammation?

Immune complexes activatecomplement, which:

attracts and activates neutrophils and

monocytes. Neutrophils and monocytes release

bad stuff (PG, tissue-dissolvingenzymes, etc.)

makes vessels leaky. Immune complexes also activate

clotting, causing microthrombi. Outcomes: vasculitis, glomerulonephritis,

arthritis,other –itises.Immune-complex-mediated vasculitis




C3b: promotes phagocytosis of complexes (and bugs!) C3a, C5a (anaphylatoxins): increase permeability

C5a: chemotactic for neutrophils, monocytes

C5-9: membrane damage or cytolysis

What are the important complementfractions to know?




Serum sickness Due to large amounts of foreign serum for passive

immunization (Antidiphtherial Toxin).

In olden days: used horse serum for immunization

Inject foreign protein (antigen).

Antibodies are made; they form complexes withantigens.

Complexes lodge in kidney, joints, small vessels.

Inflammation causes fever, joint pain, proteinuria.




Arthus reaction

“Arthus reaction” = localized area of skin necrosisresulting from immune complex vasculitis

Inject antigen into skin of previously-immunizedperson

Pre-existing antibodies form complexes with antigen

Complexes precipitate at site of infection Inflammation causes edema, hemorrhage,

ulceration






“T-cell-mediated” hypersensitivity

Activated T cells do one of two things:• release cytokines that activate macrophages, or

• kill cells directly This process is normally useful against intracellular

organisms (viruses, fungi, parasites)

Here, it causes bad stuff: inflammation, cell destruction,

granuloma formation




Two kinds of type IV hypersensitivity

Delayed-type hypersensitivity (DTH):• CD4+ T cells secrete cytokines

• macrophages come and kill cells Direct cell cytotoxicity:

• CD8+ T cells kill targeted cells




Delayed-typehypersensitivity (DTH)

Patient exposed to antigen• Antigen presenting cells (APC)

presents antigen to CD4+ T cell

•T cells differentiate into effector andmemory TH1 cells

Patient exposed to antigen again• TH1 cells come to site of antigen

exposure• Release cytokines that activate

macrophages, increase inflammation

Results• Macrophages eat antigen (good)• Lots of inflammation and tissue

damage (bad)



Perivascular cuffing by CD4+ cells




Prolonged DTH can lead togranulomatous inflammation

Perivascular CD4+ T cells

replaced by macrophages• Macrophages are activated,look “epithelioid”

• Macrophages sometimesfuse into “giant cells”

Granuloma = collection ofepithelioid macrophages




Good example of DTH: positive Mantoux test

Patient previously exposed to TB

Inject (inactive) TB antigen into skinSee reddening, induration. Peaks in 1-3 days




Why, yes it does. The same mechanisms underlie

both. Cell-mediated immunity is the major defense we have

against intracellular bugs (like TB and fungi).

Cell-mediated immunity (good) can coexist with DTH(bad)!

Patients with AIDS:• Lack CD4+ cells• So have poor cell-mediated immune response!• Macrophages sit there unactivated; can’t kill bugs.

DTH sounds a lot like cell-mediatedimmunity!




CD8+ T cell recognize antigens onthe surface of cells

T cells differentiate into cytotoxic Tlymphocytes (CTLs) which killantigen-bearing cells

CTLs normally kill viruses and tumorcells

In T-cell mediated cytotoxicity, CTLskill other things:

• Transplanted organ cells• Pancreatic islet cells (Type I

diabetes)

T-cell-mediated cytotoxicity



Summary

Type I• Allergy• TH2 cells, IgE on mast cells, nasty mediators

Type II

• Antibodies• Opsonization, complement activation, or cell dysfunction

Type III• Immune complexes

• Lodge, cause inflammation, tissue injury

Type IV• CD4+ or CD8+ T cells• DTH or T-cell-mediated cytotoxicity



Clinical

Type II reactions occur in the following situations:

Transfusion reactions. Erythroblastosis fetalis (blood-type mismatch)

Autoimmune hemolytic anemia, thrombocytopenia,

agranulocytosis Certain drug reactions.



Tuberculin skin reaction-

Delayed type hypersensitivity- classic example is tuberculin skinreaction-

injection of tuberculin ( protein-lipopollysaccharide component oftuberculous bacillus) in a previously sensitized person-redness+edema occurs 8-12 hours after injection due to

accumulation of T cells around small veins and venules. Eventually in Lungs replaced by macrophages in 2-3 weeks

Epitheloid cells and Giant cells which accumulate and aresurrounded by lymphocytes(Granulomatous inflammation).

1st exposure to protein antigen of Tuberculous bacilli -

Recognition by CD4+T cells+ class II molecules- CD4+T cells to TH1 cells- cytokines, also IL-12 lead to delayed hypersensitivity.



Immunologic Deficiency Syndromes

Divided into Primary and Secondary. Primary are genetically determined

Primary most commonly in children( 6 months a --2yrs.) withrecurrent infections.

Adaptive (Both Humoral-B) and Cellular immunity-T)

Secondary-as a complications of: Malnutrition. Aging. effects of immunosuppression,irradiation, chemotherapy, and

other autoimmune diseases



X-linked Agammaglobulinemia of Burton

One of the more common of Primary immunodeficiency disorders Almost most commonly seen in males.

Seen at age 6 months . It is characterized by failure of B-cell precursors(Immature) to

mature B-cells,Plasma cells.

Genes of light chains immunoglobulins are absent (because ofMutations)

Recurrent bacterial and viral infections(Staph.aureus, Hemophilusinfluenza,Strep.

B-cells are decreased in circulation.

Immunogloulin level is depressed. Germinal centers in lymphoid tissues is underdeveloped. Plasma cells are absent.

T-cell mediated reactions are normal.



Isolated IgA deficiency

A common immunodeficiency disorder.

It is far less in Blacks and Asians.

IgA deficiency- 1:600 European individuals.

Low levels of both serum and secretory IgA present. Familial or aquired ( with Measles, toxoplasmosis and

other viral inf.) Mucosal defenses are weakened . infection occurs in respiratory, GI and urogenital tracts. Antibodies against IgA are present in 40%. If transfused with IgA containing blood .

the immune system will attack the IgA as foreign and killthe person.

Autoimmune diseases.



Immunologic deficiency syndromes

DiGeorge Syndrome (thymic hypoplasia)

T cell deficiency resulting from failure of development ofthird and fourth pharyngeal pouches- thymus, parathyroid,parts of thyroid, parts of CV system.

Result is loss of T cell immunity. Tetany, congenital CV(Defects in heart and great vessels

defects)



Severe combined immunodeficiencydisease

(SCID)- defects in both humoral and cell mediated immunity.

Infants present with Extensive thrush(Oral Candidiasis), diaperrash, failure to thrive.

Death within 1st year occurs if BM transplant is not done.

Most are X-linked. All lymphoid tissue is hypoplastic



Immunodeficiency with thrombocytopenia andEczema(Wiskott-Aldrich Syndrome)

X-linked recessive with Thrombocytopenia, eczema, recurrent infection , ending in early

death Thymus normal, but progressive depletion of T Lymphs Prone to malignant lymphoma .



Summary : Reading assignment



What type of cell is this? In what hypersensitivity reaction does it play a role?What does it have on its surface, and what does it have inside?



This person was frolicking in the bushes (having frolicked in same bushesmonths earlier). He got these lesions on his hands, and perhaps elsewhere.What type of hypersensitivity reaction does this represent?

Reminder: Where do inflammatory



Reminder: Where do inflammatorymediators come from?

Complementproteins

Coagulationfactors

Factors XII, XI, X, etc.



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Khan Hypersensitivity Reactions Final 2011