Microbiology by ert554898

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  Chapter 16
       Part I

Dysfunctions of Immune
• Study of the over-reactivity or under-
  reactivity of the immune system
Overview of Immune Dysfunction
    Overreactions to Antigens
• Allergic and hypersensitive individuals are
  acutely sensitive to repeated contact with
  – Antigens in this case are allergens
  – Allergens do not noticeably affect non-allergic
  Four Main Categories of Allergic
• Type I
  – Common allergy and anaphylaxis
• Type II
  – IgG or IgM mediated cell damage
• Type III
  – Immune complex
• Type IV
  – Delayed hypersensitivity
  Four Main Categories of Allergic
• Generally speaking Types I, II, III involve a
  B cell immunoglobulin response
• Type IV involves a T-cell response
Four Main Categories of Allergic
            Part II

        Type I Reactions:
Reactions to antigens not on cells
  Allergies: Atopic & Systemic
          Involves IgE
                   Type I
• Strong genetic predisposition
• Hereditary is generalized as susceptibility
  and is not allergy specific
• New allergies can appear throughout
  lifetime, especially after new exposures
  – Moving
  – Lifestyle change
            Nature of Allergens
• Proteins are more allergenic than
  carbohydrates, fats, or nucleic acids
• Some allergens are haptens
  – Form complexes with carrier molecules
  – Non-proteinaceous substances with a MV < 1000
     • Organic and inorganic chemicals
        –   Household products
        –   Cosmetics
        –   Food
        –   drugs
 Allergens and Portals of Entry
• Allergens typically enter through epithelial
  portals in the respiratory tract, GI tract,
  and skin
  – GI tract and respiratory tract
     • Mucosal surfaces of the gut and respiratory system
       are thin, moist, and easily penetrated
  – Skin
     • Dry tough keratin of the skin is less permeable
     • Access occurs through tiny breaks, glands, and
       follicles in the skin
Common Allergens Portal of Entry

  Airborne mite feces
and mite particles cause
   numerous allergies

                                   Single pollen spore
                           One flower releases millions of these
Type I: Atopy and Anaphylaxis
• Atopy
  – Chronic local allergy
  – Hay fever
  – asthma
• Anaphylaxis
  – Systemic
  – Sometimes fatal
     • Airway obstruction
     • Circulatory collapse
 Mechanism of Action of Type I
• Sensitizing dose
  – Allergen penetrates portal of entry
  – Lymphatics carry allergen to lymph nodes
  – B cell activation forming plasma cell
     • Class switching leads to IgE production
     • Fc region of IgE high affinity for mast cells and basophils
• Provocative dose (Secondary Exposure)
  – Allergen binds to IgE bound to mast cells and
  – Degranulation of mast cells and basophils
Mechanism of Action – Type I
 Role of Mast Cells and Basophils
• Ubiquitous location in all tissues
• High concentrations in
  – Lungs
  – Skin
  – GI tract
• Capacity to bind IgE during sensitization
  – Cells cell has 30,000 to 100,000 receptors
  – Bind 10,000 to 40,000 IgE antibodies
         Degranulation Targets
• Targets
  –   Skin
  –   Upper respiratory tract
  –   GI tract
  –   Conjunctiva
• General responses
  –   Rashes
  –   Itching
  –   Rhinitis
  –   Sneezing
  –   Diarrhea
  –   tears
      Degranulation Targets
• Systemic targets
  – Smooth muscle
    • Smooth muscle is responsible for regulating the
      size of blood vessels and respiratory airways
    • Changes can profoundly alter blood flow, blood
      pressure and respiration
  – Mucous glands
  – Nervous tissue
    • Pain, anxiety, agitation and lethargy
• The principal chemical mediators
  produced by mast cells and basophils
  – Histamine
  – Serotonin
  – Leukotriene
  – Platelet-activation factor
  – Prostaglandins
  – Bradykinin
• Most profuse and fastest acting
• Acts on
  – Smooth muscles
     • Constricts
         – Bronchioles – labored breathing
         – Intestine – increased peristalsis
     • Relaxes
         – Vascular smooth muscle
         – Dilates arterioles and venules
  – Glands
  – Eosinophils
      More Severe Reactions of
• Anaphylaxis can be accompanied by
  edema and vascular dilation
• Leads to
  – Hypotension
  – Tachycardia
  – Circulatory failure
  – shock
• Uncertain role in allergies
• Appears to complement those of histamine
• Increases
  –   Vascular permeability
  –   Capillary dilation
  –   Smooth muscle contraction
  –   Intestinal peristalsis
  –   Respiratory rate
• Inhibits
• CNS activity
• Slow acting substance of anaphylaxis
• This type of leukotriene is responsible for
  – Prolonged bronchospasm
  – Vascular permeability
  – Mucous secretion of asthmatic individual
     Platelet-Activating Factor
• Lipid released by basophils, neutrophils,
  monocytes, and macrophages
• Physiological response similar to
• Powerful inflammatory agents and also
  important in signaling pain
• Many biological roles
• In allergic reactions
  –   Vasodilatation
  –   Increased vascular permeability
  –   Increased sensitivity to pain
  –   Bronchoconstriction
• Certain drugs act by preventing actions of
  prostaglandins including aspirin
Atopic Diseases Caused by Type I
• Hay fever is a generic term for allergic rhinitis
• Dermatitis is an inflammatory condition of the
  skin known as eczema
• Sensitization occurs through ingestion,
  inhalation, and contact
• In infants
   – Reddened, vesicular, weeping, encrusted lesions
• In adults
   – Dry, scaly, thickened skin condition
  Atopic Dermatitis or Eczema
• Itchy, painful lesions cause considerable
• Can cause a predisposition to secondary
  bacterial infections
• Respiratory disease characterized by
  episodes of impaired breathing due to
  severe bronchoconstriction
• Respiratory tract of an asthmatic person is
  chronically inflamed and severely over
  reactive to allergic chemical
  – Especially leukotrienes and serotonin from
    pulmonary mast cells
•   Other pathologic components
•   Thick mucous plugs in the air sacs
•   Lung damage due to chronic inflamation
•   Imbalance in the nervous system control
    over smooth muscles as episodes are
    influenced by psychological states
         Other Type I Allergies
• Food
  – Peanuts, fish, milk, eggs, shellfish & soybeans
• Drug
  – Cutaneous anaphylaxis – wheal and flare
  – Systemic anaphylaxis – sudden respiratory and
    circulatory disruption can be fatal in few minutes
  – Actual allergy is usually not intact drug but a hapten
    given off during liver processing
  – The physiological events in systemic anaphylaxis
    parallel those of atopy but the response are greatly
 Diagnosis of
• Skin Testing
  – Not reliable in
    most cases for
    food allergies
      Treatment & Prevention
• Avoiding the allergen
• Drugs – goal is to block the progress of
  the allergic response somewhere along
  the route between IgE production and
  appearance of symptoms
  – Block degranulation
  – Block histamine effects on target organs
     • Anti – histamine drugs
• Desensitization therapy
Circumventing Allergic Attacks

           Other Treatments
• Inhalers with adrenaline – rapid
  vasodilatation of airways
• Desensitization – Controlled injection of
  specific allergens
  – Not effective for food
  – Immunological bases for this treatment not
    well understood
     • One theory suggests that injected allergens
       stimulate IgG not IgE
         Part III

 Type II Immune Reactions:
Reactions Against Foreign Cells
     Involves IgG & IgM
          Type II Reactions
• Complement assisted destruction of cells
  by antibodies (IgG & IgM)
• Two types
  – Transfusions reactions
    • These reactions are not immune dysfunctions as
      allergies and autoimmunity
  – Auto Immune disorders
Human Blood Types
         Human Blood Types
• ABO are inherited as two of three alleles
  – Co-dominant genetics between A & B
  – A & B are dominant over O
• A & B sugar groups
  – A has enzyme adds
     • N-acetylgalactosamine
  – B has enzyme adds
     • D-galactose
• AB has both enzymes
• O lacks both enzymes
   Antibodies Against A and B
• Blood serum contains antibodies that react with
  blood of another antigenic type
• Exposure is not necessary for these antibodies
  to be present
• Type A Blood
  – Anti B antibodies
• Type B Blood
  – Anti A antibodies
• Type O Blood
  – No antibodies
Interpretation of Blood Typing
Source of Anti A & B Antibodies
• Develop early in infancy
• Due to exposure from certain antigens that
  are widely distributed in nature
• Antigens are from surface molecules on
  bacteria and plant cells that mimic
  structure of A and B antigens
• Exposure of these stimulates production of
  corresponding antibodies
               Clinical Concerns
•   Reactions from incompatible types leads to
•   Destruction of RBCs
•   Systemic shock
•   Kidney failure
    – Blockage of glomeruli
      by cell debris
•   Fever
•   Anemia
•   Jaundice
•   Death
                    Rh Factor
• Genetics
• Two alleles involved
  – Dominant – 85% of population
     • Rh+/+ or Rh+/-
  – Recessive – 15% of population
     • Rh-/-
               Rh Factor
• Environmental antigens does not sensitize
  Rh-/- person
• Only way to develop antibodies against
  this factor are through placental
 Hemolytic disease of Newborn
• First pregnancy
  – Rh-/- Mother
  – Rh+/+ or Rh+/- Fetus
  – During childbirth blood mixing
• Rh+/+ or Rh+/- blood of fetus causes mother to
  make antibodies against Rh positive antigen
• Second pregnancy
  – Antibodies (IgG) made during first pregnancy can
    cross placenta and cause massive cell death of fetal
 Hemolytic disease of Newborn
• Prevention
• Rh-/- mother must receive RhoGAM shot
  – This antiserum reacts with any fetal RBCs that
    have escaped into maternal circulation and
    prevents sensitization of the mother
  – Ineffective if mother has already been
    sensitized by a prior Rh+ fetus
  – Sensitivity can be detected by serological test
                Part IV

       Type III Immune Reactions
      Immune Complex Reactions:
Therapy – related disorders from immunization
            Autoimmune diseases
        Involves IgG, IgM, & IgA
                Not IgE
          Type III Reactions
• Soluble antigen with antibody complexes
  are deposited in the basement
  membranes of epithelial tissue
• Similar to type II in that IgG and IgM are
• Requires repeated exposure to antigens
  and complement activation
• Differs from type II in that antigens are not
  attached to cell surfaces
         Type III Reactions
• Repeated interaction between antigen and
  antibodies produces free floating
  complexes that can be deposited in the
• Known as immune complex reaction
          Type III Reactions
• Two categories
  – Therapy related disorders
    • Serum sickness
    • Arthus reaction
  – Autoimmune diseases
    • Glomerulonephritis
    • Lupus erythematosus
 Mechanisms of Immune Complex
• Initial exposure
   – Large amount of antigen
   – Large quantities of antibodies produced
• Second exposure
   – Antigen reacts with antibodies to form Ag-Ab
      • These complexes are part of normal immune response
   – In disease state these complexes are so numerous
     they are deposited onto basement membranes of
     epithelial tissues
 Mechanisms of Immune Complex
• Deposits on basement membranes
  attracts neutraphils
• Neutraphils release
  – Lysosomal granules
    • Lysosomal granules digest tissue
    • Leads to a destructive inflammatory condition
Mechanisms of Immune Complex
    Therapy – Related Disorders
• During the early years of immunological
  testing these types of reactions were
• Arthus reaction and serum sickness are
  associated with passive immunization
  – IgG, IgM, or IgA not IgE
  – Require large doses of antigen
  – Symptoms are delayed
    Therapy – Related Disorders
• Arthus reaction
  – Localized dermal injury – acute
  – Caused by second injection of vaccines or
    drugs at the same site as the first injection
• Serum sickness
  – Systemic injury
  – Ag-Ab complexes that circulate in the blood
    and settle into membranes
        Autoimmune Disorder -
• Kidney Failure
• Many causes
  – immune disease
  – Infections
  – inflammation of the blood vessels (vasculitis)
  – conditions that scar the glomeruli
• IgA nephropathy
• Characterized by recurrent episodes of
  blood in the urine
• Deposits of IgA in the glomeruli
  – Leads to immune complex formation and
    tissue damage
• IgA nephropathy can progress for years
  with no noticeable symptoms
• More common in men than in women.
       Autoimmune Disorder -
       Lupus Erythematosus
• All patients produce auto Ab against a
  great variety of organs and tissues
• Major organs involved
  – Skin
  – Nervous system
  – Kidney
  – Heart
  – joints
                       Characteristic Face Rash
       Lupus Erythematosus
• Auto Ab – auto Ag complexes are
  deposited in basement membranes of
  various organs
• Not known how such a large general loss
  of self tolerance arises
  – Viral infection (broad host cell range)
  – Loss of T suppressor cell function
  – Hormones
     • 90% of cases are women in child bearing years
             Part V

          Type IV Reactions:
           Diagnostic Tool
          Contact Dermatitis
  T Cell Mediated Organ and Graft
T cells involved not any antibodies
 Mechanism of Action – Diagnostic
• Diagnostic tests – extremely useful
  – Person sensitized to disease you are testing for will
    have memory TH1 cells which will react to injected
    antigens of disease of choice
  – TH1 cells will induce an acute inflammatory reaction at
    injection site involving macrophages and TC cells
  – Reaction is delayed usually occurs in 24 to 48 hours
     •   Tuberculosis
     •   Leprosy
     •   Syphilis
     •   Toxoplasmosis
  Mechanism of Action – Contact
• Sensitizing dose
  – Allergen penetrates outer skin layer
  – Processed by langerhans cells (skin
    macrophages) and presented to TH1 cells
• Secondary exposure
  – TH1 cells will induce an acute inflammatory
    reaction at injection site involving
    macrophages and TC cells
  – Reaction is delayed usually occurs in 24 to 48
         Contact Dermatitis
• Contact dermatitis
  from poison oak
• Sensitivity varies
  among individuals
Mechanism of Action Type IV
             Organ Transplant
• Bulk of damage done in graft rejections is due to
  cytotoxic T cells
• Genetic Bases
  – Not matching class I MHC
     • Each person has variability patterns to cell surface molecules
     • Similar patterns in siblings and parents
     • More distant relationship less likely MHC genes will be
• Causes CD8 cells to react to the tissue as
             Host Rejection
• When class I MHC as seen as foreign by
  CD8 cells:
  – CD8 cells kill foreign cells
  – CD8 also releases interleukin-2 (IL-2) as part
    of a general immune mobilizaion
  – IL2 amplifies TH and TC cells specific to
    foreign cells
  – Later antibody production begins
  – Tissue death
            Classes of Grafts
•   Autograft – within same person
•   Isograft – between identical twins
•   Allografts – between two people
•   Xenograft – between species
•   In any grafts host may reject the graft
•   Also the graft can reject the host
    – Graft versus host disease (GVHD)
    – Common in bone marrow transplants
     Part VI

Autoimmune Diseases
       Autoimmune Diseases
• Scope
  – Systemic – several major organs
  – Specific
• Either
  – Type II
  – Type III
• Type depends upon how the auto Ab bring
  about the injury
Autoimmune Diseases
     Origins of Auto Immunity
• Clonal selection theory
  – For reasons not completely understood during
    clonal selection of T and B cells forbidden
    “self” reacting clones survive
• Theory of immune deficiency
  – Mutations arise in the receptors of
    lymphocytes which render them reactive to
  – General breakdown in the normal T
    suppressor function
      Origins of Auto Immunity
• Inappropriate expression of MHC II markers
• Remember only the professional immune cells
  have MHC II receptors
  – Macrophages
  – Dendritic cells
  – B cells
• Suggested that these cells with the inappropriate
  expression of MHC II activate TH2 cells which
  activate B cells which then react to self
     Origins of Auto Immunity
• Molecular mimicry
  – Microbes bear molecular antigens similar to
    human cells
  – Infection causes formation of Ab which can
    cross react with normal tissue
     Origins of Auto Immunity
• Viral mediated autoimmunity
• Viral infections may cause
  – Type I diabetes
  – Multiple sclerosis
• Mechanism
  – Viral alteration of cell surface proteins allows
    the immune system to “see” these cells as
     Origins of Auto Immunity
• Some researchers believe that many, if
  not most, autoimmune diseases will
  someday be discovered to have an
  underlying microbial etiology, either
  through molecular mimicry or viral
  alteration of host antigens due to the
  presence of undetectable microbes in the
  sites affected by autoimmunity
           Rheumatoid Arthritis
• Progressive debilitating damage to joints
  – Auto Ab form immune complexes that bind to synovial
    membranes of the joints
  – Activates phagocytes and promotes cytokine release
• Symptoms
  –   Chronic inflammation
  –   Scar tissue
  –   Joint destruction
  –   Symptoms can be complicated by type IV
 Autoimmunities of Endocrine Glands

• Graves Disease
  – Auto Ab attach to receptors on follicles of cells
    that secrete hormone thyroxin
  – Abnormal stimulation causes hyperthyroidism
• Hashimoto’s thyroiditis
  – Auto Ab decrease levels of thyroxin by
    destroying follicles cells and inactivating
  – hypothyroidism
 Autoimmunities of Endocrine Glands
• Type I diabetes mellitus
  – Beta cells of pancreas (endocrine) secrete
    insulin (blood sugar regulator)
  – Auto Ab and sensitized T cells attack beta
  – Leads to chronic increase in blood sugar
    levels which is toxic to the body
Neuromuscular Autoimmunities
• Myasthenia graves
• Pronounced muscle weakness
  – Auto Ab bind receptor for acetylcholine Ach
    • Ach is required to transmit nerve impulse across
      synaptic junction to a muscle causing muscle
  – Immune attack severely damages muscle cell
    membranes and leads to paralysis
• Treatment
  – Immunosuppressive drugs
Myasthenia graves
Neuromuscular Autoimmunities
• Multiple Sclerosis
• Paralyzing disease
• Auto Ab and T cells attack myelin sheath
  creating lesions in the sheath
  – Myelin sheath are membranes that surround neurons
  – Required for proper conduction of nerve signal
  – Lesions severely limits capacity of neurons to send
• Strong connection has been made between MS
  and herpesvirus
Hyposensitivity of Immune System
• Recurrent overwhelming infections often
  from an opportunistic microbes
• Primary
  – Present at birth usually due to genetic factors
• Secondary
  – Acquired after birth caused by natural or
    artifical agens
Hyposensitivity of Immune System
Deficiencies in B-Cell Development
• Appear as abnormalities in immunoglobulin
• Some or all Ig are absent or reduced
• Many diseases of this type are X-linked
• Agammaglobulinemia
  – Absence of gamma globulin
  – T cell function is usually normal
• Treatment
  – Passive immunotherapy
  – Continuous antibiotic therapy
Deficiencies in T-Cell Development
• Dysfunctional T-cell line more devastating
  than a defective B-cell line because T
  helper cells are required to assist in most
  specific immune reactions
• Deficiency can occur anywhere along
  developmental T cells spectrum
  – Thymus to mature circulating T cells
Deficiencies in T-Cell Development
• DiGeorge syndrome
• Children are highly susceptible to persistent infections
   – Congenital absence or immaturity of the thymus
• Other symptoms
   –   Reduced growth
   –   Wasting of the body
   –   Unusual facial characteristics
   –   Lymphatic cancer
   –   Reduced antibody levels
• Treatment
   – Thymus transplant
   – Thyroid hormone therapy
           Severe Combined
• Bubble Boy
  – Mutation to receptors for IL2, IL4, IL7
  – Prevented T and B cells from receiving
    interleukin signals for growth, development
    and reactivity
  – Both cytotoxic immunities and antibody
    producing systems are shut down
• Dysfunction in both B and T cells
• Some are due to complete absence of
  lymphocytes stem cells in the marrow
• Two most common forms
  – Swiss type agammaglobulinemia
  – Thymic alymphoplasia
  – Both diseases are due to genetic defect in the
    development of lymphoid cell line
  – Numbers of all lymphocytes in low
  – Blood antibody content low
  – Thymus and cell mediated immunity are poorly
• Bare lymphocyte syndrome
  – Lack of genes that code for class II MHC
• Rare case adenosine deaminase
  deficiency (ADA)
  – Autosomal recessive defect in adenosine
• Treatment
  – 50% successful transplanting compatible
    bone marrow, but it is complicated by GVHD
   Secondary Immunodeficiency
• Secondary acquired deficiencies in B and
  T cells are caused by:
  – Infection
     • AIDS
  – Organic disease
  – Cancer treatments
     • Chemotherapy
     • Radiation
  – Lymphoid cancers
       Part VII

Immune system and Cancer
 Changes in
• Proto-oncogene
  – Normal gene
  – Mutation changes
    normal function of
  – Becomes an
    oncogene which is
    improperly regulated
            Viral Oncogenes
• Many viruses are
  known to have the
  ability to transform
  normal cells into
  cancer cells
• The viral gene causes
  the normal cell to grow
  and divide without the
  proper cellular
  regulation and signals

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