Type 4 Hypersensitivity and Autoimmunity Chang Kim

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Type 4 Hypersensitivity and AutoimmunityChang
Kim
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19. Type IV (Delayed-type or Cell-mediated)
Hypersensitivity
CORE

• a. Classification of Type IV reactions Contact
  hypersensitivity, tuberculin, NK and
  T-cytotoxicity, granulomatous
• b. Contact hypersensitivity (allergic contact
  dermatitis)
• (1) Immunologic mechanisms
• Types of allergens sensitization and elicitation
  phases role of Langerhans cells and
  keratinocytes role of antigen-specific TH1 cells
  and their cytokines mechanisms of down
  regulation.
• (2) Signs, symptoms, incidence and treatment
• c. Tuberculin-type hypersensitivity (recall
  response to antigen encountered during infection)
  
• (1) Immunologic mechanisms
• Infections associated with this response role of
  antigen-specific TH1 cells and their cytokines
  role of macrophages role of endothelium
  adhesion molecule expression and regulation of
  the influx of cells PMN first, followed by
  monocytes and T cells macrophages the main cell
  type mechanisms of down regulation (e.g. IL10
  from macrophages, limited presence of antigen).

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Type IV
CORE

• d. TC and NK cell reactions see previous
  section on T cell activation and cell mediated
  immunity
• e. Granulomatous hypersensitivity (associated
  with many pathologic effects seen in T
  cell-mediated immune reactions)
• (1) Immunologic mechanisms
• cells (antigen-specific TH1 cells, macrophages
  epithelioid cells, giant cells)
• cytokines IFN-gamma TNF-alpha, IL-3, IL-12,
  GM-CSF
• (2) Diseases associated with granulomatous
  hypersensitivity (brief descriptions)
• (a) Leprosy
• (b) Tuberculosis
• (c) Schistosomiasis (the second most prevalent
  tropical parasitic disease)
• (d) Sarcoidosis (A multisystem granulomatous
  disorder of unknown etiology involves
  inflammation that produces tiny lumps of cells in
  various organs in your body.)
• (e) Crohn's disease
• (f) Hypersensitivity pneumonitis (early form
  involves Type III an inflammation in the lungs
  caused by exposure to an (foreign substance),
  usually organic dust)
• f. Evaluation of DTH
• (1) Patch test (to help determine the
  contactant)
• (2) Skin test to evaluate CMI (injection of an
  antigen to see if this is a reactant e.g. a
  tuberculin skin test for tuberculosis)

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Classification of Hypersensitivity Reactions
1o Reactant types
Reaction types
Major Mediators
Antigens
Most DTH
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Figure 10-36
Pentadecacatechol the causative agent of contact
sensitivity to poison ivy.
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Sensitization during the first encounter
Asymptomatic
Penetration into skin
Lymph nodes
Generation and expansion of poison ivy-specific T
cells
Activate naive T cells
Modification of self proteins
protein
Captured by antigen presenting cells
Presentation in LNs
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Hypersensitivity reactions occur during the later
encounters
Activation of downstream effector
cells, Phagocyte recruitment inflammation
Penetration into skin
Modification of self proteins
Memory T cell activation
protein
Captured by antigen presenting cells
Presentation in LNs
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Figure 10-35
Activation of downstream effector cells by
antigens-specific Th1 cells
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Treatment of contact hypersensitivity Corticost
eroids suppress inflammation and activation of
immune cells
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Figure 10-2
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Diseases mediated by Type IV Hypersensitivity
Reactions
All involve T cells
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• Autoimmunity Lecture Objectives
• How do we get autoimmune diseases?
• What are the common autoimmune diseases in
  humans?
• What are their clinical and immunological
  features (hypersensitivity types, reactive
  antigens, and symptoms/pathology)?

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20. Autoimmunity and autoimmune diseases
CORE

• a. Origins of autoimmune diseases
• (1) Genetic factors familial incidence
  association with specific HLA (or MHC)
  haplotypes
• (2) Failure to maintain self-tolerance (either
  central or peripheral)
• (3) Loss of regulatory T cells (dysregulation
  of the cytokine network)
• (4) Expression of cryptic self epitopes
• (5) Inappropriate expression of MHC II
  molecules or co-receptors on specific tissue
• (6) Cross-reacting antigens and antigenic
  mimicry
• (7) Polyclonal B cell activation
• (8) Association of certain infectious diseases
  with the onset of autoimmunity
• (9) Hormonal influences

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• Pathogenic mechanisms of autoimmune diseases (see
  individual diseases)
• c. Examples of autoimmune diseases (prevalence,
  signs, symptoms, pathologic consequences of
  autoimmune mechanisms, examples of treatments
  some key features of the diseases are given
  below)

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Figure 11-17
How do we gain immune tolerance to self
antigens? B cells Autoreactive B cells are
anergized or deleted in bone marrow, periphery
and germinal centers in response to soluble
antigens. T cells Autoreactive T cells are
deleted in the thymus. Autoreactive T cells are
anergized or deleted in the periphery. Regulatory
CD4CD25 T cells suppress autoreactive
cells. Physical separation separation of tissue
antigens from immune cells. Limited expression
of MHC II and B7 molecules
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Figure 11-37
Autoimmune diseases result from defective
self-tolerance.
Requirement of T cell help in B cell responses
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• Influencing factors of autoimmune diseases
• HLA (MHC) genotype/ Genetic background
• Microbial infection
• Adjuvant effect recruitment and activation of
  immune cells
• Induction of MHC molecules and B7
• Molecular mimicry
• Injury
• Reveals cryptic auto-antigens from
  immune-privileged organs
• Environmental factors and behavior
• e.g. smoking and hygiene
• Gender and sex hormones

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Sympathetic ophthalmia Physical trauma in one
eye can initiate autoimmune response to both eyes

• Eye anterior chamber is an immune-privileged
  site. Normally, auto-antigens in this site are
  not exposed to the immune system
• Injury in one eye ? drain of eye proteins to the
  local lymph nodes ? immune responses ? on
  occasion, this causes blindness in the both
  damaged and undamaged eyes

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Sex and autoimmunity Roles of sex hormones?
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Figure 11-19
AutoImmune REgulator (AIRE) gene defect causes a
wide range of autoimmune diseases Defective
thymic deletion of autoreactive T cells due to
inability to express peripheral antigens in the
thymus. Autoimmune PolyEndocrynology Candidiasis
Ectodermal Dystrophy
Defective negative selection leads to autoimmunity
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IPEX (immune dysregulation, polyendocrinopathy,
enteropathy, X-linked syndrome)

• Mutations in the T cell transcription regulator
  FOXP3
• FOXP3 is expressed by regulatory T cells
  (Tregs)
• FOXP3 is essential for generation of Tregs.
• Tregs suppress the activation of other immune
  cells.

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Inflamed duodenum of IPEX patients
IPEX patients dont have FOXP3 Tregs.
Before
After marrow transplantation
Baud et al. NEJM, Volume 3441758-1762 June 7,
2001 Number 23
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Figure 11-23
Association of HLA allotype with autoimmune
diseases important!
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Ankylosing spondylitis
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Figure 11-28
Food allergy ? Autoimmune disease
Ciliac Disease wheat flour gluten
peptide-specific CD4 T cells. HLA-DQ2/8 presents
the peptide to CD4 T cells.
CD4 T cells ? activate macrophages and B
cells. Development of anti-transglutaminase
auto-antibodies. Destruction of villi structure
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Infection plays an important role in causing
autoimmunity. Molecular mimicry antibodies to
pathogens cross-react against host antigens. e.g.
Rheumatic fever
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Figure 11-31Figure 11-31 part 2 of 2
Molecular mimicry similarity between pathogenic
antigens and self-antigens causes the generation
of auto-reactive T cells
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Figure 11-30
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Figure 11-32
Infection/inflammation induces IFN-g, which
induces MHC class II expression on tissue cells
and facilitates autoimmunity.
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Figure 11-2
Autoimmune hemolytic anemia type 2
Splenectomy is performed to reduce blood cell loss
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Immune Thrombocytopenic Purpura (ITP)
Antibodies attach to blood platelet, cells that
help stop bleeding, and cause their
destruction. Thrombocytopenia refers to
decrease in blood platelet. Purpura refers to the
purplish-looking areas of the skin and mucous
membranes (such as the lining of the mouth) where
bleeding has occurred as a result of decreased
platelet.Some cases of ITP are caused by drugs,
and others are associated with infection,
pregnancy, or immune disorders such as systemic
lupus erythematosus. About half of all cases are
classified as "idiopathic," meaning the cause is
unknown.
type 2
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Goodpastures syndrome
type 2
Autoantibodies
IgG against the alpha3 chain of type IV collagen
in the basement membranes throughout the body
including lung and kidney (hemoptysis, dyspnea,
anemia and nephritis) Renal Glomerulei is most
sensitive to the antibody deposition and
inflammatory response Treatments plasma
exchange and immunosuppressive drugs
Infiltration with neutrophils and MNC
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• (2) Autoimmune Endocrine Diseases
• Insulin-Dependent Diabetes Mellitus (Type II and
  IV auto-antibodies to beta cell surface antigen,
  cytoplasmic antigen, and glutamic acid
  decarboxylase associated with GABA synthesis
  HLA-DR proteins expressed on beta cells HLA-DR3,
  HLA-DR4)
• Chronic Thyroiditis (Hashimoto's Disease Type II
  and IV goiter antithyroglobulin and antithyroid
  peroxidase are prevalent)
• (c) Graves' disease (hyperthyroidism anti-TSH
  receptor autoantibodies MHC II HLA-DR
  expression on thyroid cells HLA-DR3)

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Autoimmune diseases of endocrine glands
e.g. insulin- producing cells are attacked e.g.
anti-insulin Ab
Failure to produce adequate levels of cortisol.
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Autoimmune diseases of endocrine glands Thyroid
gland
Graves disease Agonistic (stimulatory)
autoantibodies against TSH receptor act as a
ligand for the receptor (mimicking the natural
TSH) leading to overproduction of thyroid
hormone. Heat intolerance, nervousness,
irritability, warm moist skin, weight loss,
thyroid enlargement, bulging eyes. A Th2 type
disease. Hyperthyroid disease. Treatment
thyroidectomy or destruction of thyroid by
radioactive 131I
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Figure 11-5
Graves disease
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Autoantibodies can be passed from affected
mothers to their new born babies Graves disease
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Figure 11-6
Hashimotos thyroiditis
Antibodies and effector T cells specific for
thyroid antigens are produced (attacking thyroid
gland), leading to destruction of the thyroid
gland and loss of thyroid hormone production. A
Th1 type disease. Hypothyroid disease. Treatment
oral administration of thyroid hormone
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IDDMinsulin-dependent diabetes mellitus
Normal
Insulitis
Selective destruction of the beta cells of islets
of Langerhans that produce insulin by the immune
system (antibodies and T cells) Treatment daily
injection of insulin
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• (3) Autoimmune Liver and Gastrointestinal
  Diseases
• Inflammatory Bowel Disease Crohn's Disease
  (abnormality of mucosal T cell regulation
  granulomatous reaction characteristic)
  Ulcerative colitis (Possibly Type II continuous
  mucosal ulceration common)
• Pernicious Anemia (antiparietal cell antibodies
  and anti-intrinsic factor antibodies)
• A chronic illness caused by impaired absorption
  of vitamin B-12 because of a lack of intrinsic
  factor (IF) in gastric secretions. VB-12 is a
  component of an enzyme required for thymine
  synthesis.
• (c) Autoimmune Chronic Active Hepatitis
  (HLA-B8/DR3 liver cells express MHC II proteins
  anti-liver cell antibodies are present)

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Autoimmune Rheumatic Diseases Rheumatoid
Arthritis (Type III and IV hypersensitive
reactions rheumatoid factors vasculitis,
synovitis HLA-DR4 cellular and chemical
effectors PMN, TH1, TC, IL-1, TNF-alpha, IL-8,
PGE2, LTB4) Systemic Lupus Erythematosus (Type
II and III multiple auto-antibodies HLA-DR2,
HLA-DR3 multiple organ involvement) Polymyositis
/Dermatomyositis (HLA-DR3, HLA-DR Type IV serum
muscle enzymes elevated)
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Figure 11-11
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Systemic Lupus (wolf) Erythematosus (skin rash)
This facial rash is found in some SLE
patients Affects 1 in 500 African or Asian
women Abs to histone and DNA
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SLE (Systemic Lupus Erythematosus) deposition of
immune complexes

• IgG against a wide variety of cellular
  constituents (e.g. nucleic acids).
• Binding of antibodies to cell surface antigens
  causes inflammatory responses leading to cell and
  tissue destruction.
• Immune complexes, deposited in blood vessels,
  kidney, joints and other tissues, causing tissue
  inflammation and destruction.

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Figure 11-12
Rheumatoid arthritis immune response to joints

• Rheumatoid factor IgM/G/A against the Fc region
  of IgG
• Leukocyte infiltration in the joint synovium CD4
  T, CD8 T, B cells, neutrophils and macrophages
• Plasma B cells produce rheumatoid factor
• Inflammatory cells produce prostaglandins and
  leukotrienes, lysosomal enzymes, proteinases and
  collagenases
• Treatment anti-inflammatory and
  immunosuppressive drugs.
• e.g. anti-TNF-a

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Smoking ?Injury? generation of citruline
residues? activation of CD4 T cells? RA
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Anti-CD20 to treat RA
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• Autoimmune Neurologic Diseases
• (a) Multiple Sclerosis (abnormal T cell
  regulation Type II and IV inflammatory
  demyelination in CNS white matter resulting in
  "plaques" auto-antibodies to MBP and PLP of
  myelin)
• (b) Acute Disseminated Encephalomyelitis
  (follows infection or vaccination Type IV
  directed at MBP and other myelin antigens)
• (c) Acute Inflammatory Polyneuropathy
  (Guillain-Barre Syndrome follows viral or
  Campylobacter infection Type II and IV reaction
  to peripheral nerve antigens)
• (d) Myasthenia gravis (Type II autoimmune Abs
  directed at acetylcholine receptors)

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• Guillain Barre Syndrome (acute idiopathic
  polyneuritis)
• Guillain-Barrè (ghee-yan bah-ray) syndrome is a
  disorder in which the body's immune system
  attacks the peripheral nervous system.
• The immune system starts to destroy the myelin
  sheath that surrounds the axons of many
  peripheral nerves
• Initially, weakness or tingling sensations in the
  legs
• Symptoms can increase in intensity until certain
  muscles cannot be used at all ? problems with
  breathing and heart beating
• Plasmapheresis (to remove autoreactive Abs) and
  high-dose immunoglobulin therapy (mechanism
  unclear)

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Multiple Sclerosis

• An autoimmune response against myelin sheath of
  the CNS
• Motor weakness, impaired vision, lack of
  coordination and spasticity
• Activated T cells (e.g. Th17 cells or Th1 cells)
  are implicated. They induce expression of
  chemokines and cytokines that recruit
  inflammatory cells to cause demyelination.

• Treatment Regular subcutaneous injection of
  IFN-beta (which suppresses Th17 ells)
  immunosuppressive drugs

J Clin Invest. 2008 Apr 1, The type I IFN
induction pathway constrains Th17-mediated
autoimmune inflammation in mice.
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Myasthenia (muscle weakness) Gravis (severe)

• Antagonistic (suppressive) auto-antibodies
  against the acetylcholine receptor
• Treatments Pyridostigmine (an inhibitor of
  cholinesterase, increases AC) Azathioprine
  (immunosuppressive drug, suppresses auto-antibody
  production) Thymectomy

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Figure 11-1 part 1 of 3
Autoimmune diseases mediated by Type II
hypersensitivity mechanism
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Figure 11-1 part 2 of 3
Autoimmune diseases mediated by Type III and IV