18 Autoimmunity 2009

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					     Autoimmunity
    Dr. Prakash Nagarkatti
Associate Dean for Basic Science
           733-3180
   pnagark@gw.med.sc.edu
                Autoimmunity
 Immune response to self antigens.
 Tolerance to self Ags is maintained by central
  and peripheral mechanisms.
 Dysregulation in these mechanisms will
  trigger autoimmune disease.
 A family of 80 chronic and disabling diseases
 Affects about 15-23 million people in the
  USA.
Effector mechanisms of autoimmune
damage
   Specific components:
     Antibodies   (majority)
    T   cells
   Nonspecific components:
     Complement
     Phagocytes(PMN and macrophages)
     NK and other cells
    Tissues and organs involved

 Organ-specific diseases
   Damage is confined to the organ against
    which the immune response is mounted
 Non-organ-specific diseases
   Immune response against antigens
    which are not associated with the organ
    involved
Tissues and organs involved
Role of genetic factors in
     autoimmunity
          Myasthenia gravis
A   Schwann cell                      B
         ACh at nerve endings         Y    ACh
                           Y
          post synaptic Y Y       Y         Auto Abs
          membrane      Y         Y
         ACh receptors                    ACh receptor
             Muscle fiber

                     ACh        No sodium influx
     C
                                No muscle
                                Contraction
                         Internalized vesicles
                         with ACh receptors
   Myasthenia gravis
(A) In normal individuals, acetyl choline(ACh) is
produced at motor nerve terminals. When released,
it interacts with ACh receptors on post synaptic
membrane of the muscle, ultimately activating
contractile machinery. In Myasthenia gravis (B and
 C), Auto Abs are produced against ACh receptors
which can activate complement and cause damage to
post synaptic membrane(B) or the ACh receptors are
internalized and destroyed (C). The net result is that
there is loss of ACh receptors.
             Myasthenia Gravis
 Neuromuscular disorder.
 Caused by autoAbs
  against acetylcholine
  receptors.
 Weakness and fatigue of
  voluntary muscles.
 Difficulty in swallowing,
  breathing, can lead to
  death.
                          Diabetes
   An estimated 20.8 million people in the United
    States—7.0 percent of the population have diabetes.
   Mainly two types: Type 1 and type 2.
   Insulin-dependent (Type 1) Accounts for 5-10% of
    diagnosed cases.
   Type 1 starts in childhood or young adult but can
    occur at any age.
   In type 1, CD4+ and CD8+T cells destroy pancreatic
    beta cells. AutoAbs specific for islet cell proteins are
    detected and have diagnostic value but may not play
    a role in pathogenesis.
    Diabetes
 In type 2 diabetes, Several mechanisms
  have been proposed:
 Increased non-esterified fatty acids,
  inflammatory cytokines (TNF, IL-6), and
  mitochondrial dysfunction for insulin
  resistance, and glucotoxicity, lipotoxicity,
  and amyloid formation for β-cell
  dysfunction.
 Anti-insulin receptor Abs (see next slide)
      Insulin-resistant Diabetes
         Adipocyte
                        Insulin receptor
various intracellular        Insulin in blood
processes
                                           Pancreaticcells

         Adipocyte
                        Insulin receptor
                                 Insulin Pancreaticcells
                        YY


         YYYY        Auto Ab against
                     insulin receptors
                   Sjogren’s syndrome
                                                          Immune cells
Infiltration of lymphoid cells in a lesion
                                                          attack and destroy
The secretory duct from a patient with
                                                          the glands that
Sjogren’s syndrome                                        produce tears and
                                                          saliva.




                                    Immunofluorescent detection of
                                    Anti-duct mitochondrial antibody
                                    in a patient with Sjogren’s syndrome
             Pemphigus and pemphigoid
                                           Chronic autoimmune skin
                                           disease, leading to skin
                                           blisters and antibodies
  Immunofluorescent detection of anti-skin
                                           against the type XVII
basement membrane antibody in pemphigoid collagen component of

                                           hemidesmosomes



      Immunofluorescent detection of
   anti-desmosome antibody in pemphigus
    Systemic Lupus Erythematosus
               (SLE)
 Auto Abs are produced mainly
  against nucleic acids(dsDNA).
 Ag-Ab complexes are
  deposited in kidneys and
  vascular tissue.
 Trigger Type III
  hypersensitivity.
 Severe damage to kidneys,
  vascular tissue.
   Type III Hypersensitivity--->Lupus
platelets                                      Neutrophil
                    Blood Vessel Wall
        Ag                              Ag
                                                Ab
               Ab
                                  activate C
  activate C               enzyme release
        mediators
                       Basophil
                                               Immune
  Increased vascular                           complexes
  permeability                                 are deposited
         Rheumatoid Arthritis
 Auto  Abs against Fc portion of IgG often
  called rheumatoid factor.
 Abs against collagen.
 Immune complexes deposited in joints.
 Complement activation leads to
  inflammation---Type III
  hypersensitivity.
            Experimental Allergic
           Encephalomyelitis(EAE)
                          Nervous tissue of rat
                          +Freunds Adjuvant



 Hind leg paralysis and death
This disease can also be induced by injecting myelin
basic protein----a major Ag present on myelinated nerve
fibers. Mimics human Multiple Sclerosis(MS).
   nucleated cell body


                         Myelin sheath



            Axon(conducting zone)

Neuron(communication cells of brain,
spinal cord, and nerves)
Experimental Allergic Encephalomyelitis(EAE)
             (Multiple Sclerosis)
                                                                       Th
                                                                    Th cells
Inject Myelin Basic Protein                                         get activated
                              MBP is processed by dendritic cells
 (MBP) in an adjuvant         and presented to Th cells               Th
T h cells cross blood-brain barrier

           Th cells produce cytokines that attract            Th
           macrophages triggering inflammation,                      Macrophage
           which destroys myelin sheath
                                                        Th
             Myelin Sheath
                   Axon

             hind leg paralysis
            Multiple sclerosis
 One  of the few autoimmune diseases
  caused by T cells. Abs are produced but
  their role is controversial.
 Mediated by Th17 cells.
Role of IL-17 in autoimmunity
 Unique T cells that produce IL-17 have
  been discovered that are distinect from Th1
  and Th2 subsets.
 Such cells are called Th17 cells.
 Th1 cells differentiate in the presence of
  IL-12.
 Th2 cells use IL-4.
 Th17 cells differentiate in the presence of
  TGF-beta and IL-6.
 Mice deficient in IL-17 do not develop
  EAE.
       Spontaneous Infertility
 Exposure of immune system to a self
  Ag absent during ontogeny.
 Production of Abs to spermatozoa
 Immunity to spermatozoa after
  vasectomy.

                             sperm
Vasectomy
APC
       T
            T cell and
            Abs
            to sperm
Abs against spermatozoa can
lead to agglutination and loss of
motility




        I   can’t swim!!
Infertility:
 Can result from Abs to spermatozoa.
 Abs can be seen in both male and
  females.
 Treatment with immunosuppressive
  drugs leads to fertility.
Autoimmune Thyroid Disease
 Immune  response against thyroid tissue
 and hormone receptors can lead to a
 wide range of thyroid diseases,
 including tissue destruction, increased
 or decreased metabolic activity, and
 thyroid cell division.
Hashimoto’s thyroiditis
       Ab response against Thyroid
        Ags.
       Decreased production of
        thyroid hormones.
       Pituitary gland attempts to
        stimulate thyroid to produce
        more thyroid hormones, thus
        causing thyroid gland to
        enlarge (goiter).
Grave’s disease:
(Hyperthyroidism)

 Abs to receptors for thyroid stimulating
  hormone(TSH).
 These Abs mimic TSH and over stimulate
  production of thyroid hormones.
 Increased heart rate, weight loss, agitated,
  nervous.
 Such IgG can cross placenta.
      Pernicious Anemia
Ab against
intrinsic factor
   What causes Autoimmunity?
 Defect  in clonal deletion(-ve
  selection).
 Exposure to Ag absent during
  ontogeny.
    Ex:Following Vasectomy.
 Decreased regulatory T cell function.
 Increased Th17 function.
Autoimmunity:
 Infections---Molecular   mimicry:
 Adenovirus  type 2 mimics myelin
  basic protein.
 Cell wall M protein of Streptococci
  mimics myosin of heart causing
  rheumatic fever.
 M.tuberculosis can cause arthritis.
What causes Autoimmunity?
Defect in Fas and Fas ligand
Activation   Fas(CD95)
of T cells
                         Fas ligand




                 Apoptosis
                 (cell-death)
    ALPS
 Mutations in Fas or Fas ligand genes in humans
  leads to development of Autoimmune
  lymphoproliferative syndrome (ALPS).
 Patients with ALPS have chronic,
  nonmalignant lymphadenopathy and
  splenomegaly of childhood onset and an
  increased risk of B-cell lymphomas,
  autoimmune complications, increased numbers
  of normally rare α/βTCR+ CD3+CD4-CD8- or
  "double negative T cells"
  Treatment of Autoimmunity
 Immunosuppressive    drugs
    Corticosteroids, Azathioprine
    Cyclosporin A
    Anti-inflammatory
 Oral administration of myelin purified
  from cow brains--to treat MS.
 Transfer of regulatory T cells.
Immunotherapy of autoimmune
          disease
   Use of Regulatory T cells
                    Isolate lymphocytes
                    from blood

                            lymphocytes


                               +IL-2

                 Purify regulatory T cells
                 (Foxp3+)
        Treatment of MS
       Th                  APC

                     MBP
              V17 & 5

       Th                     +C
                           Ab against V  17& 5
   In MS, most T cells that respond to MBP use
    V17 and V  5, TCR. Thus Abs against
    such T cells are being tested.
  Treatment of Autoimmunity
 Use of beta-interferon to treat MS
  blocks HLA expression.
 Use of Abs against TNF--->suppresses
  arthritis pain for 5-10 weeks.
 Use of Abs against adhesion molecules--
  -> VLA-4, ICAM-1, etc.
 Use of Abs against CD4 Th.
MS treated with
Abs against CD4




MRI
    Summary of Autoimmunity
 Cause: Multiple—genetic, environmental,
  nutrition, infections, etc
 Breakdown in self-tolerance.
 Organ specific or Systemic.
 Majority are caused by autoAb production
 Treatment: Immunosuppressive drugs, Abs
  against TCR, cytokines, adhesion molecules,
  etc.

				
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