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Immunology > Autoimmune Diseases > Flashcards

Autoimmune Diseases Flashcards

1
Q

Immune Tolerance

A

Lack of response to antigen because it was previously introduced to lymphocytes

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2
Q

Central Tolerance

A

Occurs in Bm and thymus

Mechanisms

Deletion of self reactive

Receptor editing of B cells

Development of regulatory T cells

(Defficieny of T regs –> autoimmune diseases)

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3
Q

Peripheral Tolerance

A

Clonal Anergy: lach signal 2 B7–> inactivate

Deletion

Suppression via T regs secreted IL 10 and TGF-Beta

Supress self-reactive, pathogenic lymphocytes, block MO activation

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4
Q

Mucosal Tolerance

A
  • Ignorance of ag by immune system (anergy)
  • Deletion of T cells that respond to inhaled/ingested AG
  • Generation of T reg cells to control and or modulate inflammatory responses
  • Considerable overlap of mechanisms
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5
Q

Autoimmune Diseases

A
  • Failure of self tolerance and subsequent adaptive immune responses against self antigens
  • Most are complex polygenic traits with inheritance of multiple genetic polymorphisms
  • Interplay of
    • Genetic factors: HLA
    • Infections (molecular mimicry)
    • Enviromental factors (mercury)
  • Leads to break down of self tolerance
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6
Q

Autoimmune diseases initiation and pathophysiology

A
  • Tolerance breakdown
  • Self and non self recognition failure
  • Generation of autoreactive B and T cells
  • Auto-AB or autoreactive T cells attack body
    • Inflammation, tissue damage
    • Hypersensitivities II, III, IV
    • Complement activation
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7
Q

Complement activation and AID development

A
  • Uncontrolled complement activation leads to inflammation
  • common in autoimmune diseases
  • Deficiency in complement proteins
    • C1q, C2, C4
    • seen in 10% SLE
    • Defective immune-complex clearance and apoptotic cells
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8
Q

Ab-dependent Cytotoxic HS (II)

3 mech

A
  • IgG and IgM bind cell surfave antigens
  • activating cytotoxic immune response killing target
  • 3 mechanisms for this cytotoxicity
    • Complement-mediated lysis
    • Cell injury by inflammation
    • Phagocytosis of antibody coated cells
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9
Q

Imm-complex HS (III) Mechanism

A
  • Ab-ag imm complex usually removed by phagocytes and complememnt
  • Persisting complexes percipitate into tissue and organ causing inflammation
  • Immune-Complex Mediated Disease (
    • persistent ag
    • Self ag: SLE and RA
  • Immune complex formation and deposition in blood vessel causes vasculitits causing
    • Platelet aggregation and complement activation
    • Microthrombi formation
    • C5a C3a recruitment of PMNs damage to vessel wall
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10
Q

Type III HS Autoimmune diseases

2 examples

A

SLE

Vasculititis

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11
Q

Type IV DTH

Examples

A
  • T cell mediated, primarily Th CD4
  • Encountered in
    • Contact dermatitis
    • Tuberculin-type Hypersensitivity
    • Granulomatous formation (TB, leprosy)
    • Allergic rxn to bacteria virs fungi
    • Graft rejection
    • Autoimmune diseases
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12
Q

Type II HS autoimmune diseases

A

Idiopathic thrombocytopenic purpura

Autoimmune Hemolytic Anemia

Graves disease

Myasthenia gravis

Insulin receptor Ab syndrome

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13
Q

Type IV Autoimmune diseases

A
  • Insulin-dependent diabetes mellitus
  • Hasimotos disease
  • Rheumatoid Arthritis
  • Multiple sclerosis
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14
Q

How are auto-antibody diseases characterized

A

Presence of autoantibodies in serum

Deposition of autoantibodies in tissue

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15
Q

What dictates how pathogenic autoantibodies are

A

Affinity

Charge

Concentration

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16
Q

Characteristics of Anti-DNA antibodies charge

A

Anti-DNA antibodies are weakly positive

Bind negatively to glomerular of kidney

Anti-DNA Abs are prevalent and diagnostic in SLE

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17
Q

Anti-DNA Ab

A

Lupus Nephritis

18
Q

Complement fixing autoantibodies

A

Autoimmune anemias

thrombocytopenia

19
Q

Tissue-specific autoantibodies

A

SLE

RA

Type 1 diabetes

20
Q

Autoantibodies to cell surface receptors

A

Graves Disease

Myasthenia gravis

21
Q

Autoimmune Hemolytic Anemia

Antigen

Mech

clinical

A
  • Ag- RBC membrane proteins
  • Mech- Opsonization and phagocytosis of RBC
  • Clinical- Hemolysis, anemia
22
Q

Autoimmune thrombocytopenic purpura

Ag

Mech

Clinical

A
  • Ag- Platelet mebrane
  • Mech- Opsonization and phagocytosis of platelets
  • Clinical- bleeding
23
Q

Acute rheumatic fever

Ag

Mech

Clinical

A
  • Ag- Strep Ag cross reacts with myocardial Ag
  • Mech- inflammation, macrophage activation
  • Clinical- Myocarditis, arthritis
24
Q

Myasthenia Gravis

Ag

Mech

Clinical

A
  • Ag- Acetylcholine receptor
  • Mech- Ab inhibits Ach binding
  • Clinical- Muscle weakness, paralysis
25
Q

Graves Disease

Ag

Mech

Clinical

A
  • Ag- Thyroid Stimulating Hormone (TSH) receptor
  • Mech- Ab- mediated stimulation of TSH receptors
  • Clinical- Hyperthyroidism
26
Q

How does tissue-specific autoantibodies destroy tissue

A

Autoantibodies are depositied in tissue

Complement is activated (C3 and C5) resulting in inflammation

Phagocytes are recruited to tissue with Auto-ab-Ag complex

Phagocytes release proteolytic enzymes and toxic radicals

27
Q

Autoimmune Hemolytic Anemia

Mech

A
  • Complement-fixing Autoantibody
  • IgG or IgM autoantibodies activates complement
  • Complement occurs on RBC where autoantigen are
  • May cause RBC lysis by Membrane Attack Complex
  • Induce phagocytosis of RBC via C3b on RBC
  • (Type II)
    *
28
Q

How do autoantibodies to receptors work and examples

A

Bind to cell membrane receptors and interfere with endogenous ligand binding to receptor

Graves disease: TSH to TSH receptor

Myasthenia: Ach to Ach receptors

29
Q

Mechanisms of T cell mediated Tissue Injury and autoimmune disease

A
  • Self ag activates T cells to cause tissue damage and autoimmune disease
  • Cell injury mediated by T helper T cells via DTH is seen in
    • Type 1 diabetes, RA and MS
  • Cell killing via CD8 T cells
  • Autoimmune diseases with T cell mediation may also include auto-abs and immune complexes, it is the T cell mediation that plays a dominant role
30
Q

Type 1 Diabetes

Ag

Clinical

A

T cell mediated

Ag- Islet cell

Clinical- impaired glucose metabolism, vascular diseases

31
Q

Rheumatoid Arthritis

Ag

Clinical

A

T cell mediated

Ag- Synovial fluid Ag

Clinical- Inflammation and erosion or joints and bones

32
Q

Multiple Sclerosis

Ag

Clinical

A

T cell mediated

Ag- Myelin protein

Clinical- Demyelination of CNS, sensory and motor dysfunction

33
Q

Hasimotos Disease

Ag

Clinical

A

T cell mediated

Ag- Thyroglobulin

Clinical- Destruction of thyroid gland, hypothyroidism

34
Q

Molecular Mimicry

A
  • Induction of autoantibodies by cross-reactive antigens
  • Autoreactive B cells recognize both self-ag and cross reactive foreign ag
  • Cross-reactive foreign ag triggers Th cell activation and cytokine production
  • B cells proliferate, differntiate and secrete autoantibodies
  • the antibodies bind to the pathogenic structures and control infection
  • Residual auto-abs bind to self ag and trigger autoimmune disease
35
Q

Molecular Mimicry in Rheumatic Fever

A

Auto-Abs to heart valve Ag is developed after group A Streptococcal infection of throat

Carb Ags on strep cell wall cross-react with a heart valve Ag

Strep infection is controlled via Abs

Later these Ab then bind the heart valve ag

Leading to inflammatory disease of the heart valves: rheumatic fever

36
Q

Other Molecular Mimicry Diseases

A

Coxsackie virus B4 nuclear protein similar to pancreatic islet cell Ag glumate decarboxylase: Causes Type 1 Diabetes

Campylobacter jejuni glycoproteins similar to myelin-associated gangliosides:causes Guillain-Barre syndrome

37
Q

Link between RA and Periodontitis

A

Link established through protein citullination or deamination in host

Patients with periodontitis have citullinated proteins in gingiva

This is due to post translational modification of arginine to citruline

P. gingivalis generates citrullinated peptides

Host creates antibodies against CCP

Citrullinated auto antigens are found in the synovial fluid of RA

Therefore infection with P. gingivalis leads to generation of CCP, loss of self-tolerance, anti-CCP Abs, development of RA

38
Q

Periodontitis and autoimmune atherosclerosis

A

Heat shock protein from P. gingivalis may have a link between the two

HSP causes TNF production

Anti-TNF treatment in RA patients benefited RA and periodontal condition

Omega-3-fatty acids reduces swollen, tender joints in RA, may be beneficial for periodontitis

Dietary polyphenols may also be useful

39
Q

How does an autoimmune disease develop?

A
  • Self ag is not expressed in thymus or at low concentration
  • Affinity of TCR for self-Ag: MHC complex is too low
  • Concentration of self-ag: MHC complex in the thymus is too low
  • Allow autoreactive T cells to leave thymus
  • Once in periphery can induce immune response to self-ag
  • Genetic predisposition
40
Q

How to diagnose autoimmune disease

A
  • Involves determination of auto-ab
    • Anti-DNA Ab in SLE, anti-Rh factor Ab in RA
    • Examination of tissue biopsies for deposits of Ab and complement proteins
41
Q

Treatment of Autoimmune diseases

A

NSAIDS, COX-2 inhibitors and corticosterids: Block inflammation

Cyclophosphamide prevents proliferation B cells: reduces auto-Ab producetion, used in SLE

Anti-TNF-a mAb: control inflammation, used in Chrons disease and RA

Anti-CD20 mAb: eliminates B cells used in RA, SLE

42
Q
A

Immunology (11 decks)

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