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Alterations in Immune Function
Excessive Immune Responses
Immune system
Defends body against invasion or infection by antigens Patrols for and destroys infected,
abnormal or damaged cells
Autoimmune and/or hypersensitivity System is over or hyperfunctioning Primarygenetic
Secondaryacquired
Disorders are either
. Excessive immune response . Deficit immune responses
Excessive Immune Responses Cont.
Effect of functional increase in immune system activity involves multiple, interacting immune
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
Describes the mechanism of injury May or may not involve autoimmunity
Hypersensitivity
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
increase risk of autoimmune disorders
Gender an issue females at higher risk of autoimmune disorders
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
Hypersensitivity
Normal immune response that is either
Inappropriately triggered Excessive Produces undesirable effects on the body
Basic mechanism
Hypersensitivity types I, II, and III Hypersensitivity type IV
Mediated by T cells
Specific antigenantibody reaction or specific antigenlymphocyte interaction Mediated by
antibodies produced by B lymphocytes
TYPES OF HYPERSENSITIVITY
The four types of hypersensitivity are . Type I Hypersensitivity IgE mediated . Type II
Hypersensitivity Antibody mediated . Type III Hypersensitivity immune complex . Type IV
Hypersensitivity cell mediated The first three are mediated by antibody, the fourth by T cells.
TYPES OF HYPERSENSITIVITY
Immediate
Most immediate within minutes of exposure
Anaphylaxis systemic
shellfish, antibiotics airway obstruction Shock, death
Delayed
Memory T Cell mediated response Skin irritant
poison ivy or oak adhesive tape sunburn PPD response Graph rejection
Allergy
Mast cell degranulation Asthma, eczema, uritcaria Vasodilation gt vascular permeability
Inflammation
clinical manifestation
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
Type I Hypersensitivity Cont.
Pathogenesis Also known as immediate hypersensitivity
Reaction occurs minutes after exposure to antigen
First exposure to antigen triggers B cell production of IgE
IgE binds to Fc receptors on mast cells Subsequent exposure antigen binds to IgE and
causes crosslinking of IgEFc 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
Follows stimulation by cytokines from TH cell activation by allergen
MOLECULE
EFFECTS PRIMARY MEDIATORS
HISTAMINE
VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION VASCULAR
PERMEABILITY, SMOOTH MUSCLE CONTRACTION
SEROTONIN
ECFA NCFA PROTEASES
EOSINOPHIL CHEMOTAXIS NEUTROPHIL CHEMOTAXIS
MUCUS SECRETION, CONNECTIVE TISSUE DEGRADATION
SECONDARY MEDIATORS LEUKOTRIENES PROSTAGLANDINS BRADYKININ
CYTOKINES
VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION VASCULAR
PERMEABILITY, SMOOTH MUSCLE CONTRACTION AND PLATELET ACTIVATION
VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION NUMEROUS EFFECTS
INC. ACTIVATION OF VASCULAR ENDOTHELIUM, EOSINOPHIL RECRUITMENT AND
ACTIVATION
Pathogenic mechanisms
Three classes of mediators derived from mast cells Preformed mediators stored in granules
histamine Newly sensitized mediators leukotrienes, prostaglandins, platelets activating factor
Cytokines produced by activated mast cells, basophils e.g. TNF, IL, IL, IL IL, chemokines
These mediators cause smooth muscle contraction, mucous secretion and bronchial spasm,
vasodilatation, vascular permeability and edema
Elsevier items and derived items , by Saunders, an imprint of Elsevier Inc.
Type I Hypersensitivity Cont.
Clinical manifestations
Mild
Hives Seasonal Eczema
allergic rhinitis
More problematic symptoms
Throat
constriction edema amp bronchoconstr Localized edema Wheezing Tachycardia to increase
blood flow
Anaphylaxis
Most
lifethreatening reaction occurs in very small number of highly allergic individuals
Type I Hypersensitivity Manifestations
. 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
Pooled secretions can often result in opportunist infections Histamine receptor blockers i.e.
Antihistamines, H antagonists often
provide symptomatic relief
. Atopic Asthma
Sensitized mast cells in the respiratory tract, or from the nasal mucosa that
have 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 amp
hypoxemia
Type I Hypersensitivity Manifestations Contd
. 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
. Atopic Dermatitis Eczema
eczema is a rash associated with a type I
hypersensitivity
often caused by foods, irritating fabrics, or
a dry environment
often is a family history
lesions often dry, scaly and itchy treatment hydration, baking soda or
oatmeals soaks, corticosteroids
Figure Porth
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,
this condition is called anaphylactic shock organs start to fail
TYPE I HYPERSENSITIVITY ANAPHYLAXIS CONTD
Treatment
injected epinephrine increases the HR and myocardial contractility, causes vasoconstriction
and bronchodilation histamine receptor blockers
Type I Hypersensitivity Cont.
Pharmacologic management
Antihistamines B
etaadrenergics epinephrine Corticosteroids Anticholinergics IgE therapy Epinephrine
adrenergic agent given subQ or IV during acute allergic reactions
Type II Hypersensitivity
Also known as tissuespecific, cytotoxic, or cytolytic hypersensitivity Antibodies attack normal
antigens on surface of specific cells or tissues Often immediate reaction, but some occur
over time mins 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
TYPE II HYPERSENSITIVITY CONT.
Transfusion reaction
Individual
receives blood from someone with a different blood group type
Preformed
Abs in recipients blood attach to donated RBCs
Hemolytic disease of the newborn
Occurs
during pregnancy Rh negative mother is sensitized to her fetuss Rhpositive red cell group
antigens Mothers exposure occurs when fetal and maternal blood are mixed
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
Type III Hypersensitivity
Also known as immune complex reaction Immune and phagocytic systems fail to effectively
remove antigenantibody immune complexes not tissue specific Deposit of antigenantibody
complexes in tissues results in
Activation of complement Subsequent tissue inflammation Destruction
CAUSE OF TYPE HYPERSENSITIVITY
NORMALLY SOLUBLE ANTIGENANTIBODY COMPLEX FORMATION REMOVED BY
MACROPHAGES IN SPLEEN AND LIVER
CAUSE OF TYPE HYPERSENSITIVITY
ABNORMALLY INCREASED SOLUBLE ANTIGENANTIBODY COMPLEX FORMATION
NOT ALL REMOVED BY MACROPHAGES IN SPLEEN AND LIVER DEPOSITION OF
COMPLEXES VIA BLOOD VESSELS
MECHANISM OF ACTION
STEP
Large quantities of soluble antigenantibody complexes form in the blood and are not
completely removed by macrophages.
MECHANISM OF ACTION
STEP
These antigenantibody complexes lodge in the blood vessels between the endothelial cells
and the basement membrane.
MECHANISM OF ACTION
STEP These antigenantibody complexes activate the classical complement pathway leading
to vasodilation
MECHANISM OF ACTION
STEP The complement proteins and antigenantibody complexes attract leukocytes to the
area.
MECHANISM OF ACTION
STEP The leukocytes discharge their killing agents and promote massive inflammation. This
can lead to tissue death and hemorrhage.
TYPE III HYPERSENSITIVITY CONT.
Immune complex glomerulonephritis
Inflammatory renal disorder Typically occurs days to weeks after Streptococcus infection
Autoimmune attack own cell Occurs more frequently in women, ages Etiology unknown
genetic or hormonerelated Individual develops antibodies against nuclear antigens such as
DNA and RNA antinuclear antibodies, ANAs
Systemic lupus erythematosus
Immune complexes deposit in connective tissue throughout the body Causes inflammation
and tissue destruction Vasuculitis in many organs ischemia and tissue destruction
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
TYPE IV HYPERSENSITIVITY
Delayed hypersensitivity
Tissue damage resulting from a delayed cellular reaction to an antigen
No primary antibody involvement Principal mediators
Lymphocytes Lymphocytes Macrophages
Principal effector cells
Sensitized T cells react with altered or foreign cells and initiate inflammation
CAUSE OF TYPE HYPERSENSITIVITY
CAUSED BY TCELLS . THELPER CELLS BY SECRETION OF CYTOKINES . MAINLY BY
CYTOTOXIC TCELLS BY DIRECT DAMAGE
MECHANISM OF ACTION
TH CELLS INDUCED
STEP
ANTIGEN ENTERS THE BODY
ENGULFED BY MACROPHAGES PRESENTED TO TH CELLS TH CELLS BECOMES
ACTIVATED AND INCREASED IN NUMBER
MECHANISM OF ACTION
TH CELLS INDUCED
STEP
SECOND EXPOSURE
ENGULFED BY MACROPHAGES PRESENTED TO TH CELLS TH CELLS RELEASE
CYTOKINES
MECHANISM OF ACTION
TH CELLS INDUCED
STEP TH or TD CELLS RELEASE CYTOKINES TH CELLS RELEASE IL AND IL
ATTRACTION FOR MORE MACROPHAGES AT THE SITE OF ATTACK PROMOTE
EXTRACELLULAR KILLING BY EOSINOPHILS MORE INFLAMMATION SKIN LESIONS
TISSUE DAMAGE
MECHANISM OF ACTION
CTOTOXIC T CELLS INDUCED
STEP
ANTIGEN BINDS TO NORMAL CELL
EPITOPE PRESENTED WITH MHC CTL ATTACHED BY TCR/CD ACTIVATION OF TCELL
MECHANISM OF ACTION
CTOTOXIC T CELLS INDUCED
STEP ACTIVATION OF CYTOTOXIC TCELL
RELEASE OF . POREFORMING PROTEINS CALLED PERFORINS . PROTEOLYTIC
ENZYMES CALLED GRANZYMES . CHEMOKINES
MECHANISM OF ACTION
CTOTOXIC T CELLS INDUCED
STEP PERFORINS FORM PORES
GRANZYMES PASS THROUGH PORES
ACTIVATE ENZYMES OF CELLS APOPTOSIS
MECHANISM OF ACTION
CTOTOXIC T CELLS INDUCED
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
Tuberculintype 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 incompatible MHC 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
Type IV Hypersensitivity Cont.
Mechanisms of Hypersensitivity
Elsevier items and derived items , by Saunders, an imprint of Elsevier Inc.
Deficient Immune Responses
Result from
Functional decrease in one or more components of immune system Diseasecausing
genotypes Secondary/acquired dysfunction
Can affect
Lymphocytes Antibodies Phagocytes Complement proteins
Primary Immunodeficiency Disorders
May be from congenital, genetic, or acquired defects that directly affect immune cell function
First clinical indicators signs and symptoms of infection Most cause moderate immune
impairment that may not be diagnosed
Severe congenital immunodeficiency disorders less common
Suspected with severe recurrent, unusual, or unmanageable infections
BCELL AND TCELL COMBINED DISORDERS
Severe combined immunodeficiency disorders SCID
Result from embryonic defects Characterized by severe immune system dysfunction and a
variety of clinical features Most severe form reticular dysgenesis Also known as thymic
hypoplasia Associated with total or partial loss of thymus gland function Often associated
with other congenital problems
DiGeorge syndrome
Secondary Immunodeficiency Disorders
Problems in neuroendocrine and immune system interaction Excessive neuroendocrine
response to stress increased corticosteroid production increases susceptibility to infection
Immune function impaired as a result of other nonimmune system disorders that secondarily
suppress immune function
Poor nutrition proteins Stress Drugs