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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
Type I Hypersensitivity (Cont.)
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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
Type I Hypersensitivity (Cont.)
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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
CTOTOXIC T CELLS INDUCED
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
CTOTOXIC T CELLS INDUCED
STEP 3
PERFORINS FORM PORES
GRANZYMES PASS THROUGH PORES
ACTIVATE ENZYMES OF CELLS
APOPTOSIS
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MECHANISM OF ACTION
CTOTOXIC T CELLS INDUCED
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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.)
49
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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
53
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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
problems54
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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
Recommended