alterations in immune function

7/29/2019 Alterations in Immune function

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Alterations in Immune Function

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Week 2 Chapter 10


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Excessive Immune Responses

Immune system Defends body against invasion or infection

by antigens

Patrols for and destroys infected, abnormalor damaged cells

Disorders are either:1. Excessive immune response

Autoimmune and/or hypersensitivity System is over or hyper-functioning

2. Deficit immune responses Primary-genetic Secondary-acquired

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Effect of functional increase in immunesystem activity; involves multiple, interactingimmune cells

Autoimmunity Immune system attacks own tissues Describes causes of abnormal excessive immune

responses toward own tissues ~ loss of self tolerance Involves several genetic and environmental factors

Hypersensitivity Describes the mechanism of injury May or may not involve autoimmunity

Excessive Immune Responses

(Cont.)

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Autoimmunity (Cont.)

Genetic Factors

Different cytokine cycles can be

associated with autoimmunity

MHC genes (HLA) Some associated with certain autoimmune

disorders

Some MHC phenotypes appear to increaserisk of autoimmune disorders

Gender an issue; females at higher risk

of autoimmune disorders4


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Autoimmunity (Cont.)

Environmental triggers Chronic or multiple viral or bacterial

infections

Environmental and/or occupational stress,esp. in genetically susceptible individuals

Pharmacotherapies Individualized immunosuppressive therapy

most often used Corticosteroids and cytotoxins

Therapeutic plasmapheresis

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Hypersensitivity

Normal immune response that is either Inappropriately triggered Excessive Produces undesirable effects on the body

Basic mechanism Specific antigen-antibody reaction or specific

antigen-lymphocyte interaction

Hypersensitivity types I, II, and III Mediated by antibodies produced by B

lymphocytes

Hypersensitivity type IV Mediated by T cells

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TYPES OF HYPERSENSITIVITYThe four types of hypersensitivity are:

1.Type I Hypersensitivity- IgE mediated

2.Type II Hypersensitivity-Antibody mediated3.Type III Hypersensitivity- immune complex4.Type IV Hypersensitivity- cell mediated

The first three are mediated by antibody, thefourth by T cells.


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TYPES OF HYPERSENSITIVITY

Immediate Most immediate: within

minutes of exposure

Anaphylaxis: systemic

shellfish, antibiotics

airway obstruction

Shock, death

Allergy

Mast cell degranulation

Asthma, eczema, uritcaria Vasodilation

> vascular permeability

Delayed Memory T- Cell mediated

response

Skin irritant

poison ivy or oak

adhesive tape

sunburn

PPD response

Graph rejection

Inflammation

clinical manifestation


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Type I Hypersensitivity

Etiology Often is a strong genetic or hereditary linkage

regarding IgE response to antigens (i.e. atopic)

Also are nonatopic forms Involves ability to respond to antigen and to

produce an IgE antibody response

High IgE levels (although lower levels do not

exclude type I) Characterized by increased mast cell

degranulation

Triggered by environmental allergens

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Type I Hypersensitivity (Cont.)

Pathogenesis

Also known as immediate hypersensitivity

Reaction occurs 15-30 minutes after exposure to antigen

First exposure to antigen triggers B cell production of IgE

Follows stimulation by cytokines from TH cell activation by allergen IgE binds to Fc receptors on mast cells

Subsequent exposure: antigen binds to IgE and causes cross-linking of

IgE-Fc receptors

Increased intracellular calcium results in immediate, massive, local mast

cell degranulation of proinflammatory mediators

Released mediators cause inflammatory response Histamine, superoxide, PGs, leukotrienes, bradykinin, interleukins


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MOLECULE EFFECTS

PRIMARY MEDIATORS

HISTAMINE VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

SEROTONIN VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

ECF-A EOSINOPHIL CHEMOTAXIS

NCF-A NEUTROPHIL CHEMOTAXIS

PROTEASES MUCUS SECRETION, CONNECTIVE TISSUE DEGRADATION

SECONDARY MEDIATORS

LEUKOTRIENES VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

PROSTAGLANDINS VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTIONAND PLATELET ACTIVATION

BRADYKININ VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

CYTOKINES NUMEROUS EFFECTS INC. ACTIVATION OF VASCULAR ENDOTHELIUM,EOSINOPHIL RECRUITMENT AND ACTIVATION


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Elsevier items and derived items 2010, 2005 by Saunders, an imprint of Elsevier Inc. 12

Pathogenic mechanisms

* Three classes of mediators derived from mast cells:

!) Preformed mediators stored in granules (histamine)

2) Newly sensitized mediators:

leukotrienes, prostaglandins, platelets activating factor

3) Cytokines produced by activated mast cells, basophils

e.g. TNF, IL3, IL-4, IL-5 IL-13, chemokines

* These mediators cause: smooth muscle contraction,

mucous secretion and bronchial spasm, vasodilatation,

vascular permeability and edema


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Clinical manifestations Mild

HivesSeasonal allergic rhinitis

Eczema More problematic symptoms

Throat constriction; edema &bronchoconstr

Localized edemaWheezing Tachycardia; to increase blood flow

AnaphylaxisMost life-threatening reaction; occurs in

very small number of highly allergicindividuals


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Type I Hypersensitivity: Manifestations

1. Allergic Rhinitis:

activation of mast cells within the nasal mucosa results in sneezing, watery

nasal secretions, and pruritus (itching)

inflammation often spreads to the mucosa of the sinuses and the conjuctiva

sinusitis and conjuctivitis (i.e. red, itchy, watery eyes)

Pooledsecretions can often result in opportunist infections

Histamine receptor blockers (i.e. Antihistamines, H1 antagonists) often

provide symptomatic relief

2. Atopic Asthma:

Sensitized mast cells in the respiratory tract, or from the nasal mucosa thathave pooled in the airways can produce extrinsic asthma

mucous is secreted into the airways

inflammatory chemical mediators cause bronchoconstriction

ultimately obstruction, air trapping poor blood oxygenation &

hypoxemia


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Type I Hypersensitivity: Manifestations Contd

3. Food Allergies:

food allergens activate mast cells in the GI tract

the resulting inflammation nausea, vomiting, and diarrhea

food allergies may also cause systemic effects e.g. hives or anaphylaxis

allergens: milk, eggs, peanuts, tree nuts, shellfish, fish

4. Atopic Dermatitis (Eczema):

eczema is a rash associated with a type I

hypersensitivity

often caused by foods, irritating fabrics, ora dry environment

often is a family history

lesions often dry, scaly and itchy

treatment: hydration, baking soda oroatmeals soaks, corticosteroids Figure 61-18 Porth


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TYPE I HYPERSENSITIVITY: ANAPHYLAXIS

Anaphylaxis is a systemic type I hypersensitivity- Allergens introduced by injection, insect sting or

absorption across epithelial surface of the skin or GI tract chemical mediators from mast cells enter general

circulation Manifestations

- Skin erythema (red) with warm or burning sensation

- Itching and hives (urticaria)- Apprehension, tachycardia and tachypnea

- Edema around the eyes, lips, tongue, hands, feet

- In the lungs, mucus, edema and bronchconstriction obstruct the

airways

Triggers wheezing, chest tightness, dyspnea

Leads to hypoxemia

- Systemic vasodilation and increased capillary permeability result in

a rapid decrease in blood pressure (dizziness, LOC)

- When the blood pressure is insufficient to perfuse the tissue, thiscondition is called anaphylactic shock; organs start to fail


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TYPE I HYPERSENSITIVITY: ANAPHYLAXIS

CONTD

Treatment- injected epinephrine:

increases the HR and

myocardial contractility,

causes vasoconstrictionand bronchodilation

- histamine receptor

blockers


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Pharmacologic managementAntihistamines

B eta-adrenergics epinephrine

CorticosteroidsAnticholinergics

IgE therapy

Epinephrine: adrenergic agent given

subQ or IV during acute allergic

reactions


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Also known as tissue-specific, cytotoxic, orcytolytic hypersensitivity

Antibodies attack (normal) antigens on surface ofspecific cells or tissues

Often immediate reaction, but some occur overtime (15-30mins)

Cell lysis may be mediated by Activated complement fragments (membrane

attack complex) Phagocytic cells that are attracted to target cells by

attached antibodies

Type II Hypersensitivity

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Type II Hypersensitivity

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TYPE II HYPERSENSITIVITY (CONT.)

Transfusion reaction Individual receives blood from

someone with a different blood group

typePre-formedAbsin recipients blood attachto donated RBCs

Hemolytic disease of the newbornOccurs during pregnancyRh negative mother is sensitized to her

fetuss Rh-positive red cell groupantigens

Mothers exposure occurs when fetal

and maternal blood are mixed 21


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Type II Hypersensitivity (Cont.)

Myasthenia gravis

Graves disease

Lymphocytic thyroiditis (Hashimoto

thyroditis)

Hyperacute graft rejection Transplanted donor tissue has an antigen to

which recipient has preformed antibodies Rarely occurs

Tissue and blood typing prevent most cases

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Type III Hypersensitivity

Also known as immune complex reaction Immune and phagocytic systems fail to effectively remove

antigen-antibody immune complexes; not tissue specific Deposit of antigen-antibody complexes in tissues results in

Activation of complement

Subsequent tissue inflammation Destruction

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CAUSE OF TYPE 3 HYPERSENSITIVITY

NORMALLY

SOLUBLE ANTIGEN-ANTIBODY COMPLEX

FORMATION

REMOVED BY MACROPHAGES IN SPLEEN AND

LIVER


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CAUSE OF TYPE 3 HYPERSENSITIVITY

ABNORMALLY

INCREASED SOLUBLE ANTIGEN-ANTIBODY

COMPLEX FORMATION

NOT ALL REMOVED BY MACROPHAGES IN SPLEEN

AND LIVER

DEPOSITION OF COMPLEXES VIA BLOOD VESSELS


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MECHANISM OF ACTION

STEP 1Large quantities of soluble antigen-antibody complexes form

in the blood and are not completely removed by

macrophages.


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MECHANISM OF ACTION

STEP 2These antigen-antibody complexes lodge in the blood vessels

between the endothelial cells and the basement membrane.


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MECHANISM OF ACTION

STEP 3These antigen-antibody complexes activate the

classical complement pathway leading to

vasodilation


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MECHANISM OF ACTION

STEP 4

The complement proteins and antigen-antibody

complexes attract leukocytes to the area.


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MECHANISM OF ACTION

STEP 5

The leukocytes discharge their killing agents andpromote massive inflammation. This can lead

to tissue death and hemorrhage.


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TYPE III HYPERSENSITIVITY (CONT.)

Immune complex glomerulonephritis Inflammatory renal disorder

Typically occurs 10 days to 2 weeks afterStreptococcusinfection

Systemic lupus erythematosus Autoimmune (attack own cell)

Occurs more frequently in women, ages 20-40

Etiology unknown; genetic or hormone-related

Individual develops antibodies against nuclear antigenssuch as DNA and RNA (antinuclear antibodies, ANAs)

Immune complexes deposit in connective tissue throughout thebody

Causes inflammation and tissue destruction

Vasuculitis in many organs ischemia and tissue destruction 34


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TYPE III HYPERSENSITIVITY (CONT.)

Systemic lupus erythematosus Variety of signs and symptoms

- Diagnosis may be difficult

- Follow a pattern of exacerbations and remissions

- Ranges from mild episodes to fatal Rash

Alopecia

Arthritis

Fever, anorexia, malaise, increased ESR ~ chronic

inflammation

Lungs, heart and GI tract also affected

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TYPE IV HYPERSENSITIVITY

Delayed hypersensitivity Tissue damage resulting from a delayed

cellular reaction to an antigen

No primary antibody involvement Principal mediators Lymphocytes

Principal effector cells

Lymphocytes Macrophages

Sensitized T cells react with altered orforeign cells and initiate inflammation

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CAUSE OF TYPE 4 HYPER-SENSITIVITY

CAUSED BY T-CELLS

1. T-HELPER CELLS BY SECRETION OF CYTOKINES

2. MAINLY BY CYTOTOXIC T-CELLS BY DIRECT

DAMAGE


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MECHANISM OF ACTION

T-H CELLS INDUCED

STEP 1

ANTIGEN ENTERS THE BODY

ENGULFED BY MACROPHAGES

PRESENTED TO T-H CELLS

T-H CELLS BECOMES ACTIVATED AND INCREASEDIN NUMBER


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MECHANISM OF ACTION

T-H CELLS INDUCED

STEP 2SECOND EXPOSURE

ENGULFED BY MACROPHAGES

PRESENTED TO T-H CELLS

T-H CELLS RELEASE CYTOKINES


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MECHANISM OF ACTIONT-H CELLS INDUCED

STEP 3T-H1 or TD CELLS RELEASE

CYTOKINES

ATTRACTION FOR MOREMACROPHAGES AT THE

SITE OF ATTACK

MORE INFLAMMATION

SKIN LESIONS

T-H2 CELLS RELEASE

IL-4 AND IL-5

PROMOTE EXTRACELLULAR

KILLING BY EOSINOPHILS

TISSUE DAMAGE


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MECHANISM OF ACTION

CTOTOXIC T CELLS INDUCED

STEP 1

ANTIGEN BINDS TO NORMAL CELL

EPITOPE PRESENTED WITH MHC-1

CTL ATTACHED BY TCR/CD8+

ACTIVATION OF T-CELL


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MECHANISM OF ACTION


STEP 2

ACTIVATION OF CYTOTOXIC T-CELL

RELEASE OF

1. PORE-FORMING PROTEINS CALLED

PERFORINS2. PROTEOLYTIC ENZYMES CALLED GRANZYMES

3. CHEMOKINES


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MECHANISM OF ACTION


STEP 3

PERFORINS FORM PORES

GRANZYMES PASS THROUGH PORES

ACTIVATE ENZYMES OF CELLS

APOPTOSIS


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MECHANISM OF ACTION



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Type IV Hypersensitivity (Cont.)

Contact hypersensitivity

Most familiar type

Epidermal phenomenon

Slow reaction; hapten very small, incomplete; must combine with

endogenous carrier protein to become antigenic

E.g. latex, cosmetics, dyes, adhesives

Tuberculin-type hypersensitivity

Individual (previously infected by tuberculosis) is exposed to tuberculin

antigen in a tuberculin test

Rejection of Transplanted Tissue

Recipients immune system damages donated tissue with incompatibleMHC (HLA) profile

Rejection can be hyperacute or acute (Type II hypersensitivity) or

chronic (Type IV)

Immunosuppressive drugs delay rejection but leave client susceptible to

infection 48


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Type IV Hypersensitivity (Cont.)

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Elsevier items and derived items 2010, 2005 by Saunders, an imprint of Elsevier Inc. 51

Mechanisms of Hypersensitivity


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Deficient Immune Responses

Result from Functional decrease in one or more

components of immune system

Disease-causing genotypes Secondary/acquired dysfunction

Can affect Lymphocytes

Antibodies

Phagocytes

Complement proteins

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Primary Immunodeficiency Disorders

May be from congenital, genetic, oracquired defects that directly affectimmune cell function

First clinical indicators: signs and symptomsof infection Suspected with severe recurrent, unusual, or

unmanageable infections

Most cause moderate immune impairmentthat may not be diagnosed Severe congenital immunodeficiency disorders

less common

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B-CELL AND T-CELL COMBINED

DISORDERS

Severe combined immunodeficiency

disorders (SCID)

Result from embryonic defects

Characterized by severe immune systemdysfunction and a variety of clinical features

Most severe form: reticular dysgenesis

DiGeorge syndrome

Also known as thymic hypoplasia

Associated with total or partial loss of thymus

gland function

Often associated with other congenital

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Secondary Immunodeficiency Disorders

Problems in neuroendocrine and immunesystem interaction

Excessive neuroendocrine response to

stress; increased corticosteroid productionincreases susceptibility to infection

Immune function impaired as a result ofother nonimmune system disorders that

secondarily suppress immune function Poor nutrition proteins

Stress

Drugs

alterations in immune function

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