Semester 3 Microbiology

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Semester 3Microbiology ImmunologyAutoimmunity
and Transplantation

• Basic AutoimmunityResponses to Self
  Antigensand Self-Tolerance Its Loss
• Nicholas R. Sinclair, MD PhD
• February 13, 2002 - 900am

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Learning Objectives forBasic Autoimmunity

• Discuss autoimmune disease in terms of
  organ specificity
• Relate clinical autoimmune disease to
  types of hypersensitivity states
• Discuss immunopathogenesis of autoimmune
  disease
• Discuss the genetic basis of clinical
  autoimmunity
• Discuss the environmental triggers of
  clinical autoimmunity

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Three Types of Autoimmune DiseaseType
IIType IIIType IV
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Type II Autoimmune Diseases

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RGCase 24AutoimmuneHemolyticAnemiaMycoplas
ma Pneumonia
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Case 24 Autoimmune Hemolytic
Anemia
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Case 24 Autoimmune Hemolytic
Anemia
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Case 24 Autoimmune Hemolytic
Anemia
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Case 24Autoimmune Hemolytic AnemiaPeripheral B
Cell Tolerance
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Type II Autoimmune Diseases

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Type II Autoimmune Diseases

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Antibodies To Vascular Basement Membranes Cause
Goodpastures Disease That Affects Renal
Glomeruli and Lung Alveoli
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Type II Autoimmune Diseases

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Case 27 Pemphigus Vulgaris
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Case 27 Pemphigus Vulgaris
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Case 27 Pemphigus Vulgaris
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Case 27 Pemphigus Vulgaris
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Case 27PemphigusVulgarisCyclophosphamide and
Active Intermediate
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Type II Autoimmune Diseases

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Type II Autoimmune DiseasesInclude
Autoimmunity Against Cell Surface Receptors

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Mechanism For Thyrotoxicosis (Graves Disease or
Exophthalmic Goiter) Is Anti-TSH Antibody
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Autoimmune Thyroid Disease
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Normal Thyroid
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Normal Thyroid Histology
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Autoimmune Thyroid Disease

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Atrophic Thyroid - Hashimotos
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Hashimotos Histology
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Hashimotos Histology
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Antimicrosomal Antibody
Staining in thyroid epithelial cells No staining
in follicle colloid Antigen is thyroid
peroxidase Seen in Hashimotos thyroiditis
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Anti-thyroglobulin Antibody
Staining in follicle colloid No staining in
thyroid epithelial cells
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Autoimmune Thyroid Disease

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Autoimmune Colloid Goitre
(Euthyroid - cold nodules)
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Euthyroid Nodular Goitre
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Euthyroid Nodular Goitre
Inactive cold nodule - flattened epithelial
cells
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Autoimmune Thyroid Disease

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Diffuse Hyperthyroid Picture
Hyperactive thyroid tissue - infoldings of the
hyperplastic epithelium Thyrotoxicosis - Graves
Disease
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Diffuse Hyperthyroid Picture
Hyperactive thyroid tissue - infoldings of the
hyperplastic epithelium scalloping
(arrow) Thyrotoxicosis - Graves Disease
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Evidence That A Circulating Antibody Can Cause
Autoimmune Disease Involves Transfer Of Serum
From Patient To An Animal
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Circulating IgG Autoantibodies Can Cross Placenta
To Affect Fetus
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IgG Anti-TSH Antibodies Can Go From Mother To
Fetus And Cause Graves Disease In Baby
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Type II Autoimmune DiseasesInclude
Autoimmunity Against Cell Surface Receptors

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In Myasthenia Gravis, Antibodies To The
Acetylcholine Receptor Block Neuromuscular
Transmission Needed Form Muscle Contraction
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Case 20MyastheniaGravisEye Muscle Weakness
Seen When Moving Eyes to Each Side
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Case 20 Myasthenia GravisPlacental Transfer of Ab
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Both Antibodies T Cells Induce Myasthenia Gravis
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Case 20MyastheniaGravisAzathioprine
(Imuran)Is a Purine Analogue
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Case 20 - Myasthenia GravisRelapses after
Infection
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Type II Autoimmune DiseasesInclude
Autoimmunity Against Cell Surface Receptors


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Pernicious Anemia
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Types III/IV Autoimmune Diseases

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Types III/IV Autoimmune Diseases

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H1-Specific T Cells Help H1-Specific B-Cells
FormAnti-H1 Ab ButThey Also HelpAnti-DNA B
Cells
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But Cannot Help Anti-Ribosomal B Cells (Ribosomes
Lack H1 Histone)
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Systemic Lupus ErythematosusB Cell Functions,
More Than Precursors of Ab-Forming Cells
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Systemic Lupus ErythematosusB Cell Functions,
More Than Precursors of Ab-Forming Cells
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Immune Complex Glomerulonephritis Causes Kidney
Failure in Systemic Lupus Erythematosus
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(No Transcript)
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Types III/IV Autoimmune Diseases

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Types III/IV Autoimmune Diseases

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IDDM Is Due to T Cells to b-islet Cells of the
Pancreas
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Certain MHC-II Allotypes Are Associated In
Populations With Autoimmune DiseaseDR3 DR4
(Heterozygous) Occur In IDDM
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MHC-II Association In Families
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Structure Of IDDM MHC-II
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Types III/IV Autoimmune Diseases

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Types III/IV Autoimmune Diseases

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Experimental Autoimmune Encephalomyelitis A Model
For Multiple Sclerosis
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Autoimmune Diseases Are Organ-Specific (Mainly
Types II IV) Non-Organ Specific (Systemic
Mainly Type III)
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(No Transcript)
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Antibodies Against Cell Surface Receptors Cause
Various Autoimmune Diseases
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Tolerance To Self Is Based Partly On Deletion
IgnoranceButAlso On Other Mechanisms
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TransplantTolerance Induction By Bone Marrow
Cell Chimerism, Established Neonatally, Is
Antigen Specific
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Self Level Sets Tolerance Degree
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Tolerance Induced By Feeding
Oral Tolerance
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Tolerance Induced By Feeding
Oral ToleranceRegulation
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These Sites Sequester Self Antigens, But Few
Autoimmune Diseases Are Due to Release Of Hidden
Self Antigens
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Sympathetic Ophthalmia
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Auto-B Cells Are Excluded From GC By Other B Cells
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Peripheral Deletionof Auto-immuneB Cells
byFas-type Apoptosis
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Somatic Hypermutation Produces B Cells With Low
Affinity For Antigen (Die By Neglect), High
Affinity For Antigen (Selected) and Reactivity To
Self (Death After Activation)
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Antigen-Induced Active Regulation
By Regulatory T Cells - Treg
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Virus Infection Breaks Tolerance
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Infections Break Tolerance
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Infections Break Tolerance
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Infections And Tissue Damage
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Anti-Neutrophil Cytoplasmic Antibodies (ANCA) In
Wegeners GranulomatosisTriggered by Infection
that Releases Proteinase-3
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Antibodies To Vascular Basement Membranes Cause
Goodpastures Disease That Affects Renal
Glomeruli and Lung Alveoli (Smoking!!)
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Newer Mechanisms for Autoimmunity

• ? Coinhibition (genetic risk factors)
• knockout mice human defects in-
• CTLA-4, CD22, Lyn, FcgRIIB
• inhibitory protein tyrosine lipid phosphatases
  (bind to ITIMs)
• inflammatory cytokines - also regulatory
• apoptosis signals Fas (lpr) FasL (gld)
• transgenic mice
• bcl-2 - prevents apoptosis
• ? Costimulation (environment risk f.)
• mainly the association with infection
• ? dendritic cell antigen presentation (B7CD28)
  stimulation by T cells (BAFF BCMA/TACI)

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New Way that B Cells Are Stimulated in SLE (which
Produce High Levels of BAFF)
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Decoy Approach to Treatment of Autoimmune Disease
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3-Signal Model (2000)
Ag
CIL
CSL
CIR
CSR
(-)
()
ITIMs
(ITIM)
(I?SM)
AgR
Signal 1 (new) Coinhibition Quiescence
Signal 2 Costimulation Danger
(ITAM)
Activation
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Learning Objectives forBasic Autoimmunity

• Discuss autoimmune disease in terms of
  organ specificity
• Relate clinical autoimmune disease to
  types of hypersensitivity states
• Discuss immunopathogenesis of autoimmune
  disease
• Discuss the genetic basis of clinical
  autoimmunity
• Discuss the environmental triggers of
  clinical autoimmunity

92
Semester 3Microbiology ImmunologyAutoimmunity
and Transplantation

• Basic Clinical TransplantationResponses to
  Alloantigens
• Nicholas R. Sinclair, MD PhD
• February 25, 2002 - 800am

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Learning Objectives forBasic Transplantation

• Describe the histocompatibility barriers
  to successful transplantation
• Describe direct and indirect antigen
  presentation
• List types of transplants that are carried
  out reasons for these
• Describe types of graft rejection and graft
  rejection episodes

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Graft Rejection Is Mediated By T Cells
TargetMHC
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Graft Rejection is Immunologic
CD3 T Cells
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Acute Cellular Tubular Interstitial Rejection
Normal Glomerulus
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Acute Cellular Rejection - Heart
Anti-CD3 Peroxidase Stain of T cells in Myocardium
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Chronic Vascular Rejectionof a Kidney Graft
renal artery
interstitial fibrosischronic inflammation
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Graft Rejection Is Mediated By T Cells
TargetMinors (MiHC Ag)
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Polymorphic Proteins Are Minors
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Two Types of Alloantigen Presentation Direct
Indirect
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Donor APC Play An Important Role In Starting
Graft Rejection
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Hyperacute Rejection Is A Tragedy To Be Avoided
At All Costs
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Tissue TypingMicro-cytotoxicity Assay
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Testing For MHC-II/I Differences
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Transplant Score Card 5-Year Survival Rates Are
Good But Longer Times Still Have Problems
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1-Year ?, gt1-Year Unchanged
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Natures Most Successful And Important Graft
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Hoops for Xenotransplantation
PERVs
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Learning Objectives forBasic Transplantation

• Describe the histocompatibility barriers
  to successful transplantation
• Describe direct and indirect antigen
  presentation
• List types of transplants that are carried
  out reasons for these
• Describe types of graft rejection and graft
  rejection episodes