Reasons why there is a high incidence of septic shock

1
Immune responses
Dr Kathy Triantafilou University of Sussex School
of Life Sciences
2
Bacterial infections

• Bacteria enter the body through either
• a number of natural routes
• respiratory track
• gastrointestinal track
• genitourinary track
• unnatural routes
• openings by breaks in the skin
• openings by breaks in mucous membranes

3
Host defense

• Different levels of host defense are enlisted
  depending on
• the number of organisms
• if the inoculum size and virulence are low, then
  localised tissue phagocytes maybe able to
  eliminate the bacteria (innate immune system)
• virulence of the organisms
• Larger inoculums or organisms with greater
  virulence tend to induce and adaptive, specific
  immune response

4
Extracellular bacteria

• Extracellular bacteria are pathogenic because
• they induce a localised inflammatory response
• they produce toxins
• the toxins, endotoxin (LPS) or exotoxin can be
  cytotoxic
• may cause pathogenesis by other ways
• endotoxins (LPS) which are components of
  bacterial cell wall stimulate can cause
  oversecretion of cytokines (septic shock)
• toxin secreted by diphtheria blocks protein
  biosynthesis by the cell

5
Extracellular bacteria

• Humoral immune response is the main protective
  response against extracellular bacteria
• Antibodies that bind to antigens on the surface
  of a bacterium can together with C3b component of
  complement increase phagocytosis and enhance
  clearance of the bacterium
• Complement activation can lead directly to lysis
  of the organism
• Complement activation can induce production
  effector molecules that help in developing an
  inflammatory reponse (complement split products)

6
Intracellular bacteria

• Innate immunity is not effective against
  intracellular bacterial pathogens
• Intracellular bacteria can activate NK cells
• NK cells provide an early defense against these
  bacteria
• Intracellular bacteria induce cell-mediated
  immune response (delayed-type hypersensitivity)
• Cytokines are secreted by CD4 T-cells, notably
  IFN-g which activates macrophages to kill
  ingested pathogens

7
Steps in bacterial infection

• Attachment to host cells
• Proliferation
• Invasion of host tissue
• Toxin-induced damage to host cells

8
Attachment

• Bacteria have surface structures that enhance
  their ability to attach to host cells (pili-long
  hairlike projections)
• Bordetella pertussis secrete adhesion molecules
  that attach to both the bacterium and the
  epithelial cells of the upper respiratory track
• Secretory IgA antibodies specific for such
  bacterial structures can block bacterial
  attachment to mucosal epithelial cells (main host
  defense against bacterial attachment)

9
Bacterial Evasion

• Some bacteria (e.g. Neisseria gonorrhoea,
  Haemophilus influenzae, and Neisseria
  meningitidis) evade the IgA response by secreting
  proteases that cleave secretory IgA at the hinge
  region
• Some bacteria evade the IgA response of the host
  by changing their surface antigens (e.g. in N.
  gonorrhoeae the protein component of pilin has a
  highly variable structure)
• variation in the pilin amino acid sequence is
  generated by gene rearrangement
• this contributes to the pahtogenicity of N.
  gonorrhoeae by allowing it to bind to epithelial
  cells

10
Bacterial Evasion

• Some bacteria possess surface structures that
  serve to inhibit phagocytosis
• Streptococcus pneumoniae has a polysaccharide
  capsule that prevents phagocytosis (there are 84
  serotypes that differ in the capsular
  polysaccharide)
• Streptococcus pyogenes has a surface projection
  called the M protein which inhibits phagocytosis
• Some staphyloccoci are able to assemble a
  protective coat from host proteins. These
  bacteria secrete a coagulase enzyme that
  precipitates a fibrin coat around them, shielding
  them from phagocytic cells

11
Bacterial evasion

• In some gram-negative bacteria long side chains
  on the lipid A of the LPS help to resist
  complement-mediated lysis
• Pseudomonas secretes an enzyme, elastase, that
  inactivates both the C3a and C5a anaphylatoxins,
  thus diminishing localised inflammatory reactions
• Some bacteria escape host defense mechanisms by
  their ability to survive within phagocytic cells

12
Bacterial evasion

• Listeria monocytogenes escapes from the
  phagolysosome to the cytoplasm, which is a more
  favorable environment for their growth
• Mycobacterium avium blocks lysosomal fusion with
  the phagolysosome, and some mycobacteria are
  resistant to the oxidative attack that takes
  place within the phagolysosome
• Salmonella has evolved the ability to enter into
  cells that are normally nonphagocytic. On contact
  with the cells Salmonella delivers a number of
  bacterial effector proteins into the host cell
  cytosol, interfering with the actin cytoskeleton
  of the cell and thus gains entry (Galan and Zhou,
  2000)

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Contribution of the immune system to bacterial
pathogenesis

• In some cases, disease is not caused by the
  bacterial pathogens, but by the immune response
  to the pathogen
• septic shock (oversecretion of cytokines)
• food poisoning
• toxic-shock syndrome
• exotoxins produced by the pathogens function as
  superantigens which can activate all T-cells
  leading to overproduction of cytokines

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General characteristics

• Multiply within living cells by using the
  biosynthetic machinery of the host
• Contain a single type of nucleic acid, either DNA
  or RNA
• Contain a protein coat (the capsid) consisting of
  individual protein units (capsomeres)
• May contain a host derived lipid membrane (the
  envelope) through which may be inserted viral
  proteins (spikes)
• Small filterable through bacteriological filters

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Virus morphology

• Helical (e.g. bacteriophage M13)
• Polyhedral/Cubic (e.g. poliovirus)
• Enveloped (e.g. HIV)
• Complex (e.g. poxviruses)

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Major virus families
Family Envelope
Example Adenoviridae No
Adenovirus Arenaviridae
Yes Lassa fever
virus Bunyaviridae Yes
Hantaan Calicividae No
Norwalk
virus Coronaviridae Yes
229E Filoviridae
Yes
Marburg Flaviviridae Yes
Hepatitis C virus Hepadnaviridae
No Hepatitis B
virus Herpesviridae Yes
Cytomegalovirus Orthomyxoviridae
Yes Influenza Papovaviri
dae No
Papillomavirus Paramyxoviridae Yes
Respiratory syncytial
virus Parvoviridae No
RA1
Picornaviridae No
Coxsackievirus Poxviridae
Yes Monkeypox virus

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Major virus families
Family Envelope
Example Reoviridae No
Rotavirus Retroviridae
Yes
HIV Rhabdoviridae Yes
Rabies Togaviridae Yes
Rubella

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Infectious cycle of viruses

• Attachment, using cell surface receptors
• Cell entry
• Nucleic acid and protein synthesis
• Assembly of virions
• release of virus particles from host cell

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Virus Receptors

• It has been clear for many years that viruses
  which propagate within vertebrate hosts have
  adapted many strategies in order to infect host
  cells
• One of the first steps in a viral infection is
  the binding of the virus to cell surface
  molecules.This interaction plays a key role in
  the multiplication cycle.
• Entry of viruses into cells is a complex
  multi-step process and for several viruses cell
  attachment and internalisation are distinct steps

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Entry of viruses into cells is a complex
multi-step process

• HIV-1
• -CD4, CXCR4, CCR5
• Coxsackie B viruses
• -CD55, CAR protein, 100kDa nucleolin protein
• HSV
• - Heparan sulphate, PRR1 and PRR2
• CAV-21
• CD55, ICAM1
• Adenovirus
• -CAR protein, avb3, avb5, b2 integrins

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Virus evasive strategies

• The evolution to use multiple complexes of
  receptors for their cell attachment and entry
• provides viruses with cell tropism for
  different
• tissues and organs
• -HIV1 initially binds CD4 while CXCR4 or CCR5
  are required for cell entry in T cells or
  macrophages respectively
• - Adenovirus binds CAR protein, while uses b2
  integrins for entry into blood cells,and avb3 or
  avb5 integrins for entry in other tissues.

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Viral evasion strategies

• Infection of sites not accessible to the immune
  system
• -Infection of central nervous system (neurons do
  not express MHC)
• - Epithelial surfaces with limited T cell access
• Antigenic Variation
• -Viruses undergo mutations at high frequency
• Viral escape of T cell recognition
• -Mutations of the sequences encoding the epitope
  seen by the TCR
• Suppression of MHC molecules
• -Interference with the presentation of viral
  peptides by the host

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Strategies to induce immunosuppression

• Infect T and B cells and abrogate their function
  (e.g. HBV infects B and T cells, HSV infects T
  cells, EBV infects B cells)
• Destroy antigen presentation cells
• (e.g. CMV, HIV)
• Down regulate viral protein expression (e.g. HSV)
• Infect cells lacking MHC class I (e.g. measles
  virus)
• Production of viral proteins that interfere with
  MHC class I (e.g. CMV, HSV)

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Diphtheria (Corynebacterium diptheriae)

• Diptheria is an example of bacterial disease
  caused by a secreted exotoxin (immunity can be
  induced by immunization with an inactivated
  toxoid)
• It was first described by Klebs in 1883 and was
  shown a year later by Loeffler to cause
  diphtheria in guinea pigs and rabbits
• Autopsies of the infected animals revealed that
  the damage from the bacterium was widespread.
  This led Loeffler to speculate that the
  manifestations of the disease were caused by a
  toxic substance secreted by the organism

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Diphtheria

• The disease is spread from one individual to
  another by airborne respiratory droplets
• The bacteria colonises the nasopharyngeal tract,
  remaining in the superficial layers of the mucosa
• Growth of the bacterium causes little tissue
  damage
• The virulence of the organism is due completely
  to its potent exotoxin
• The toxin causes destruction of the underlying
  tissue, resulting in the formation of a tough
  fibrinous membrane (pseudomembrane)

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Diphtheria

• The pseudomembrane is composed of fibrin, white
  blood cells, and dead respiratory epithelial
  cells
• The membrane itself can cause suffocation
• The exotoxin also is responsible for widespread
  systemic manifestations (pronounces myocardial
  damage and neurologic damage)
• The toxoid is administered together with tetanus
  toxoid and inactivated Bordetella pertussis in a
  combined vaccine that is given to children of 6-8
  weeks

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Tuberculosis (Mycobacterium tuberculosis)

• Tuberculosis is the leading cause of death in the
  world from a single infectious agent (killing
  about 3 million people every year)
• About 1.79 billion people (1/3 of the worlds
  population) are infected with M. tuberculosis
• Re-emerged in the 1990s particularly in the
  cities where HIV-infection levels are high
• Infection usually results from inhalation of
  small droplets of respiratory secretions
  containing a few bacilli

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Tuberculosis

• The inhaled bacilli are ingested by macrophages
  and are able to survive and multiply
  intracellularly by inhibiting formation of
  phagolysosomes, when the infected macrophaes
  lyse, large numbers of bacilli are released
• A cell-mediated CD4 T-cell response is
  responsible for much of the tissue damage in the
  disease
• CD4 T-cell activity is the basis for the
  tuberculin skin test to the purified protein
  derivative (PPD) from M. tuberculosis

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Tuberculosis

• In pulmonary infection, CD4 T-cells are
  activated within 2-6 weeks after infection
  inducing the infiltration of activated
  macrophages
• These cells wall off the bacteria inside a
  granulomatous lesion called the tubercle
• A tubercle consists of lymphocytes and a
  collection of activated macrophages
• The massive activation of macrophages that occurs
  within tubercles often results in the
  concentrated release of lytic enzymes

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Tuberculosis

• These enzymes destroy nearby healthy cells,
  resulting in circular regions of necrotic tissue,
  which eventually form a lesion with a caseous
  (cheese-like) constistency
• As these lesions heal, they become calcified and
  are readily visible by X-rays, where they are
  called Ghon complexes
• The activated macrophages suppress proliferation
  of the phagocytosed bacilli and thus the
  infection is contained

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Therapy

• Several drugs (sometimes used in combination),
  isoniazid, rifampin, streptomycin, pyrazinamide
  and ethambutol
• The intracellular growth of M. tuberculosis makes
  it difficult for drugs to reach the bacilli
• Drug therapy must be continued for at least 9
  months to eradicate the bacteria
• The vaccine for M. tuberculosis is the attenuated
  strain of M. bovis called BCG (Bacillus
  Calmetter-Guerin)

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Lyme Disease (Borrelia burgdorferi)

• In 1975, about 60 cases of a newly observed
  disease were reported in Lyme, Connecticut
• The disease symptoms included unexplained bulls
  eye rashes, headaches, and arthritis
• In some cases, severe neurologic complications
  developed excruciating headaches, meningitis,
  loss of memory, and mood swings
• No causative agent was isolated until 1977, Willy
  Burgdofer found that the patients were bitten by
  ticks

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Lyme Disease

• It was found that the tick was teeming with a new
  species of gram-negative spirochete, which was
  subsequently named Borrelia burgdorferi
• Since the tick takes a blood meal, B. burgdoferi
  enters the bloodstream
• Lyme disease begins with a characteristic rash,
  appears as a bulls eye 10-50 cm in diameter
• After the rash, arthritic and neurologic symptoms
  develop
• The disease can be successfully treated with
  broad-spectrum antibiotics such as penicillin

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Meningitis

• Caused by Neisseria meningitidis, Haemophilus
  influenzae, and Streptococci
• Usually bacteria colonize the throat (sore
  throat), where they gain access into the
  bloodstream (septicemia). After replication in
  the bloodstream, they reach the meninges (lining
  of the brain)
• Therapy vaccine against Haemophilus influenzae
  (very effective)

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Vaccines

• Neisseria has five main Groups - A,B,C, W135 and
  Y
• Most UK meningococcal disease is caused by groups
  B and C
• There are combined vaccines for group A and C,
  that can give some protection
• Effective vaccines for Group B are still some
  years away (which accounts for 65-70 of the
  cases)

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Autoimmunity

• Inappropriate response of the immune system
  against self-components
• First observed by Paul Ehrlich early in this
  century, and he termed the condition horror
  autotoxicus
• Not all self-reactive lymphocytes are deleted
  during T and B-cell development
• Self-reactive lymphocytes are re-circulating,
  their activity regulated by clonal anergy or
  clonal suppression

39
Autoimmunity

• The damage to self-cells or organs is caused by
• antibodies
• Autoimmune hemolytic disease (antigens on red
  blood cells are recognised by auto-antibodies)
• Hashimotos thyroiditis (antibodies attack
  thyroid peroxidase or thyroglobulin and cause
  severe tissue destruction
• T-cells
• rheumatoid arthritis
• insulin-dependent diabetes mellitus

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Hashimotos thyroiditis

• An individual produces auto-antibodies and
  sensitised TDTH cells specific for thyroid
  antigens
• The DTH response is characterised by an intense
  infiltration of the thyroid gland by lymphocytes,
  macrophages and plasma cells which form germinal
  centers
• Antibodies are formed to a number of thyroid
  proteins, including thyroglobulin and thyroid
  peroxidase
• Binding of these antibodies to thyroid tissue
  interferes with the iodine uptake and leads to
  decreased production of thyroid hormones

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Autoimmune anemias

• Include pernicious anemia, autoimmune hymolytic
  anemia and drug-induced hemolytic anemia
• Pernicious anemia is caused by auto-antibodies to
  a membrane bound intestinal protein on gastric
  cells (intrinsic factor), that facilitates the
  uptake of vitamin B12 from the small intestine
• In the absence of B12, which is necessary for
  hematopoiesis, the number of functional mature
  red blood cells decreases below normal
• It is treated by injections with B12

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Autoimmune anemias

• An individual with autoimmune hemolytic anemia
  makes auto-antibodies to RBC antigens
• This triggers complement-mediated lysis or
  antibody-mediated opsonization and phagocytosis
  of RBCs
• One form of autoimmune anemia is drug-induced
  certain drugs (such as penicillin) interact with
  RBCs and the cells become antigenic

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Goodpastures syndrome

• Auto-antibodies specific for certain
  basement-membrane antigens bind to the basement
  of the membranes of the kidney and the alveoli of
  the lungs
• This leads to complement activation and direct
  cellular damage as well as an inflammatory
  response mediated by the build-up of complement
  split products
• Tissue damage leads to kidney damage and
  pulmonary hemorrhage
• Death ensues often within several months

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Insulin-dependent Diabetes Mellitus (IDDM)

• Autoimmune attack of the pancreas
• The attack is directed against specialised
  insulin-producing cells (beta cells) that are
  located in spherical clusters called the islets
  of Langerhans
• The autoimmune attack destroys the beta cells,
  resulting in decreased production of insulin and
  consequently increased levels of blood glucose

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Insulin-dependent Diabetes Mellitus (IDDM)

• Several factors are important in the destruction
  of beta cells
• activated CTLs migrate into the islets and begin
  to attack the beta cells
• local cytokine production released during this
  response IFN-g, TNF-a, and IL-1
• auto-antibody production also can be a
  contributing factor in IDDM
• Coxasckievirus group B

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Coxsackieviruses

• Coxsackie B viruses can cause IDDM (25 of the
  cases)
• It could result from direct destruction of the
  beta cells by the virus
• It could result from molecular mimicry

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Diseases mediated by stimulating or blocking
auto-antibodies

• Auto-antibodies can act as agonists, binding to
  hormone receptors instead of the normal ligand
  and stimulating inappropriate activity
• This leads to overproduction of mediators or
  increase in cell growth
• Auto-antibodies can bind to hormone receptors and
  act as antagonists (blocking receptor function)
• This causes impaired secretion of mediators and
  gradual atrophy of the affected organ

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Graves Disease

• The production of thyroid hormones is regulated
  by thyroid-stimulating hormone (TSH), which is
  produced by the pituitary gland
• Binding of TSH to a receptor on thyroid cells
  stimulates synthesis of two thyroid hormones
• thyroxine
• triiodothyronine
• A patient with Graves disease produces
  auto-antibodies to the receptor for TSH
• Binding of these auto-antibodies to the receptor
  mimics the normal action of TSH, resulting in the
  production of thyroid hormones

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Graves Disease

• Unlike TSH, the auto-antibodies are not regulated
  and they overstimulate the thyroid
• Thus, these auto-antibodies are called
  long-acting-thyroid-stimulating (LATS) antibodies

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Myasthenia Gravis

• Myasthenia Gravis is a classic example of an
  autoimmune disease mediated by blocking
  antibodies
• A patient with the disease produces
  auto-antibodies to the acetylcholine receptors on
  the motor end-plates of muscles
• Binding of these auto-antibodies to the receptors
  blocks the normal binding of acetylcholine and
  also mediates complement mediated degradation of
  the receptors (resulting in progressive weakening
  of the skeletal muscles)

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Myasthenia Gravis

• Ultimately the antibodies destroy the TSH
  receptors
• The early signs of the disease include
• drooping eyelids
• inability to retract the corners of the mouth

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Systemic Autoimmune Diseases

• In systemic autoimmune diseases, the response is
  directed toward a broad range of target antigens
  and involves a number of organs
• These disease reflect a general defect in immune
  regulation
• Tissue damage is widespread by
• cell-mediated immune responses
• direct cellular damage caused by auto-antibodies
• accumulation of immune complexes

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Systemic Lupus Erythematosus

• Systemic lupus erythematosus (SLE) is a systemic
  autoimmune disease
• It appears in women between 20-40 years of age
• The ratio of female to male patients is 101
• SLE is characterised by fever, weakness,
  arthritis, skin rashes, and kidney disfunction
• Lupus is more frequent in African-American and
  Hispanic women than in Caucasians

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SLE

• Affected individuals produce auto-antibodies to a
  vast array of tissue antigens, such as DNA,
  histones, RBCs, platelets, leukocytes and
  clotting factors
• Auto-antibodies against RBCs and platelets can
  cause hemolytic anemia and thrombocytopenia
• When immune complexes of auto-antibodies with
  various nuclear antigens are deposited along the
  walls of small blood vessels, a type III
  hypersensitivity reaction develops

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SLE

• Excessive complement activation in patients with
  severe SLE produces elevated serum levels of
  complement split products (such as C3a, C5a, 3-4
  times higher than normal)
• This facilitates neutrophil aggregation and
  attachment to the vascular endothelium (the
  circulating neutrophils decrease and various
  occlusions of the small blood vessels develop
• Diagnosis of SLE focuses on characterisation of
  antinuclear antibodies, which are directed
  against DNA, nucleoprotein, histones, and
  nucleolar RNA (indirect immunofluorescence)

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Multiple sclerosis (MS)

• MS is an autoimmune disease that affects the
  central nervous system
• Symptoms may be mild such as numbness in the
  limbs, or severe, such as paralysis or loss of
  vision
• Most people are diagnosed between the ages of 20
  and 40
• Individuals produce autoreactive T-cells that
  participate in the formation of inflammatory
  lesions along the myelin sheath of nerve fibers
• The cerebrospinal fluid contains activated
  T-cells which infiltrate the brain tissue and
  destroy the myelin

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MS

• MS is more common in the Northern Hemisphere
  (mostly in the USA)
• It has been suggested that there is an
  environmental component of the risk of
  contracting MS
• Genetic influences are also important (siblings
  have 1 in 50 chance in developing MS)
• The cause is not well understood, but it has been
  suggested some viruses can cause demyelinating
  disease
• There is no definite data to implicate a
  particular virus

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Rheumatoid Arthritis

• A common autoimmune disease, most often affecting
  women from 40 to 60 years old
• Major symptom is chronic inflammation of the
  joints
• Many individual with rheumatoid arthritis produce
  a group of auto-antibodies, called rheumatoid
  factors that are reactive with determinants of
  the Fc region of IgG
• Such auto-antibodies bind to normal circulating
  IgG, forming IgM-IgG complexes, that are
  deposited at the joints

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Rheumatoid Arthritis

• IgM-IgG immune complexes deposited at the joints
  activate the complement cascade
• This results in a type III hypersensitivity
  reaction, which leads to chronic inflammation of
  the joints

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Proposed mechanisms for induction of autoimmunity

• Association with MHC
• expression of a particular MHC allele renders the
  individual susceptible to autoimmunity
• In ankylosing spondylitis, is an inflammatory
  disease of vertebral joints
• Individuals who have HLA-B27 have a 90 times
  greater likelihood of developing spondylitis
• 90 of the cases of ankylosing spondylitis are
  male

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Release of sequestered antigen

• The induction of self-tolerance in T-cells is
  thought to result from
• exposure of immature thymocytes to self-antigens
• subsequent clonal deletion of those that are
  self-reactive
• any antigens that are not seen by immature
  T-cells will not induce self-tolerance
• exposure of mature T-cells to those antigens at a
  later time might result in activation

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Sequestered antigens

• Myelin basic protein (MBP) is an example of an
  antigen that is normally sequestered from the
  immune system due to the blood-brain barrier

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Molecular mimicry

• Microbial or viral agents might play a role in
  autoimmunity is very attractive
• Some viruses and bacteria have been shown to
  possess antigenic determinants that are identical
  or similar to normal host-cell components (a
  pathogen may express a region of protein that
  resembles a particular self-component
• More than 3 of the virus-specific antibodies
  tested also bound to normal tissue

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Post-rabies encephalitis

• Developed in individuals who had received a
  rabies vaccine
• Rabies virus was grown in rabbit brain-cell
  cultures, and preparations of the vaccine
  included antigens derived from the rabbit brain
  cells
• In vaccinated people, these rabbit brain-cell
  antigens could induce formation of antibodies and
  activated T-cells, which could cross-react with
  the recipients own brain cells, leading to
  encephalitis

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Rheumatic fever

• Rheumatic fever can develop after a Streptococcus
  infection
• In this case, antibodies against streptococcal
  antigens cross-react with heart muscle

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Molecular mimicry

• Myelin basic protein (MBP) peptides have been
  shown to be mimicked in the P3 protein of the
  measles virus
• Computer analysis revealed sequence homologies
  between this MBP peptide and a number of peptides
  from animal viruses, including influenza,
  polyoma, adenovirus, Rous sarcoma, Abelson
  leukemia, poliomyelitis, Epstein-barr, and
  hepatitis B viruses

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• One peptide from the polymerase enzyme of the
  hepatitis B virus exhibits 60 sequence homology
  with an MBP peptide
• Rabbits were immunised with this hepatitis
  peptide, and it was shown that the peptide was
  immunogenic inducing both antibody formation and
  the proliferation of T-cells that cross-reacted
  with MBP (central nervous system tissue from the
  immunised rabbits showed cellular infiltration)
• Infection with certain viruses expressing
  epitopes that mimic sequestered self-components
  may induce autoimmunity to those components

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Inappropriate expression of MHC class II

• Pancreatic beta cells of individuals with IDDM
  express high levels of both class I and class II
  MHC molecules (healthy beta cells express lower
  levels of class I and do not express class II)
• Thyroid cells from patients with Graves disease
  have been shown to express MHC class II on their
  membranes
• This inappropriate expression of MHC class II,
  which are normally expressed only on APCs, may
  serve to sensitize T-cells to antigens from
  thyroid cells or pancreatic cells

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Polyclonal B-cell activation

• A number of viruses and bacteria can induce
  nonspecific polyclonal B-cell activation
• Gram-negative bacteria, cytomegalovirus and
  Epstein Barr (EBV) are all known to be polyclonal
  activators
• If B-cells reactive with self-antigens are
  activated by this mechanism, auto-antibodies
  appear
• EBV infected individuals display a variety of
  auto-antibodies
• SLE patients produce large quantities of IgM
  polyclonal antibodies

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Treatment

• Aimed to reduce the symptoms rather than cure the
  disease
• Immunosuppressive drugs (e.g corticosteroids,
  cyclophosphamide) are often given with intent to
  slow proliferation of lymphocytes
• Cyclosporin A or FK506 blocks signal transduction
  mediated by the T-cell receptor
• In myasthenia gravis removal of the thymus is
  sometimes useful

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Experimental therapies

• T-cell vaccination
• Peptide-blockade of MHC molecules
• Monoclonal-antibody treatment
• Tolerance by oral antigens

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T-cell vaccination

• When rats were injected with low doses of cloned
  T-cells specific for MBP, they did not develop
  symptoms for EAE
• Instead they became resistant to the development
  of EAE when later challenged with a lethal dose
  of activated MBP-specific T-cells

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Peptide blockade

• Synthetic peptides differing by only one amino
  acid from their MBP counterpart have been shown
  to bind to the appropriate MHC molecule
• When sufficient amounts of such peptides were
  administered the clinical development of
  autoimmunity was blocked
• The synthetic peptide, acts as a competitor,
  occupying the peptide-binding cleft on MHC
  molecules and thus preventing the binding of the
  MBP peptide

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Monoclonal antibodies

• Anti-CD4 monoclonal antibodies block or deplete
  all Th cells, regardless of their specificity
• Antibodies against the IL-2 receptor block
  autoreactive T-cells

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Tolerance by oral antigens

• When antigens are administered orally, they tend
  to induce the state of immunologic
  unresponsiveness called tolerance
• Mice fed with MBP do not develop EAE
• Individuals with MS were fed with bovine myelin
  every day for a year. T-cells specific for myelin
  were reduced in the myelin-fed group