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Block 3 Molecular sciences > Autoimmunity > Flashcards

Autoimmunity Flashcards

1
Q

re-edit again after lecture

Define autoimmunity

A
  • Breakdown in tolerance
    • Ability to distinguish between ‘self’ and ‘non-self’
    • Central
    • Peripheral
  • Specific adaptive response against self antigens
    • Impossible to eliminate the antigen completely
    • Sustained immune response
    • Chronic inflammation involving target tissues
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2
Q

Recap self tolerance

A
  • Unresponsiveness to self antigens
  • Mechanisms actively prevent either the maturation or activation of potentially self-reactive lymphocytes
  • Central tolerance
    • Induction of tolerance in generative lymphoid organs
    • Encounter antigen presented by thymic epithelial cells
  • Peripheral tolerance
    • Induction of tolerance in mature lymphocytes in the peripheral tissues
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3
Q

Recap layers of tolerance

A
  • Central tolerance:
    - Deletion
    - Editing
    - Site of Action
    - Thymus
    - Bone marrow
    • Antigen segregation
      • Physical barrier to self-antigen access to lymphoid system
      • Site of action: Peripheral organs (e.g., thyroid, pancreas)
    • Peripheral anergy
      - Cellular inactivation by weak signaling without co-stimulus
      - Secondary lymphoid organ
    • Regulatory T cells
      - Suppression by cytokines, intercellular signals
      - Secondary lymphoid tissue and sites of inflammation
    • Functional deviation
      • Differentiation of regulatory T cells that limit inflammatory cytokine secretion
      • Secondary lymphoid tissue and sites of inflammation
  • Activation- induced cell death
    - apoptosis
    - secondary lymphoid tissue and sites of inflammation- Central tolerance:
    - Deletion
    - Editing
    - Site of Action
    - Thymus
    - Bone marrow
    • Antigen segregation
      • Physical barrier to self-antigen access to lymphoid system
      • Site of action: Peripheral organs (e.g., thyroid, pancreas)
    • Peripheral anergy
      - Cellular inactivation by weak signaling without co-stimulus
      - Secondary lymphoid organ
    • Regulatory T cells
      - Suppression by cytokines, intercellular signals
      - Secondary lymphoid tissue and sites of inflammation
    • Functional deviation
      • Differentiation of regulatory T cells that limit inflammatory cytokine secretion
      • Secondary lymphoid tissue and sites of inflammation
  • Activation- induced cell death
    - apoptosis
    - secondary lymphoid tissue and sites of inflammation
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4
Q

Describe the factors influencing susceptibility to autoimmune disease

A

Factors influencing susceptibility to autoimmune disease
- Genetic factors
- Familial clusters, HLA association
- Sex
- Age
- Environmental factors
- Ultraviolet radiation, drugs, viruses, chronic infection, gliadin
- Loss of regulatory T cells

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5
Q

Describe genetic and familial susceptibility to autoimmune disease

A
  • Familial Clusters suggestive of a more generalised heritable defect as seen in:
    - Type I diabetes mellitus
    - Graves’ disease, Hashimoto’s thyroiditis, autoimmune gastritis, hypoadrenalism, vitiligo
    - Systemic lupus erythematosus scleroderma
    - Autoimmune polyendocrinopathy syndromes
  • HLA associations: specific HLA complexes are associated with incidence of autoimmune diseases
    • HLA B27
      • Ankylosing spondylitis
      • Anterior uveitis
      • Reactive arthritis
    • HLA DR3
      • Graves’ disease
      • Myasthenia gravis
      • Systemic lupus erythematosus
    • HLA DR4
      • Diabetes mellitus
      • Rheumatoid arthritis
      • Pemphigus vulgaris
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6
Q

Describe other factors that influence susceptibility to development to autoimmune disease

A
  • Sex
    • More common in female patients, particularly those of childbearing age
  • Age
  • Environmental exposures
    • UV radiation
    • Drugs - alpha methyldopa
    • Certain viral and chronic infections - Chronic inflammation leads to greater chance of exposure to self antigens
    • Gliadin
  • Loss of regulatory T cells
    • May be secondary to other medical conditions and exposures, or perhaps idiopathic.
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7
Q

Describe autoimmune disease, and classification

A
  • Occur in 3-5% of the general population
  • Classification
    • Sites of organ damage
      • Location of the immune response
    • Demonstrable autoantibodies (Ig’s) or autoreactive T cells
      • Specificity for self antigens (autoantigens)
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8
Q

Describe pathogenic autoantibodies, and pathogenic mechanisms of autoantibodies

A

Pathogenic Autoantibodies

  • Introduction of antibodies into man/animal models results in the development of disease
  • Able to cross the placenta causing disease in the foetus or newborn
  • Identification of autoantibodies in the pathological lesion
  • Correlation between antibody levels and disease activity

Pathogenic Mechanisms of Autoantibodies

  • Complement lysis
  • Antibody-dependent cellular cytotoxicity
  • Binding of antibody to cell-surface/tissue antigens followed by complement activation and cell lysis/phagocytosis
  • Formation of circulating immune complexes
    • Deposition in capillary beds, activation of complement, localized inflammatory response
  • Production of stimulating or blocking antibodies
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9
Q

List and describe immunopathogenic mechanisms

A
  • Type I
    • IgE mediated
  • Type II
    • IgG or IgM mediated cytotoxic damage
    • Autoimmune haemolytic anaemia, Goodpasture’s syndrome
  • Type III
    • Immune complex diseases
    • Circulating immune complexes deposit in capillary beds
    • Systemic lupus erythematosus
  • Type IV
    • Delayed type hypersensitivity
    • Cell-mediated
    • Type I diabetes mellitus
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10
Q

List some organ-specific autoimmune diseases by systems

A
  • Endocrine
    • Autoimmune thyroiditis
    • Graves disease (hyperthyroidism)
    • Type I diabetes mellitus
    • Hypoadrenalism (Addison’s disease)
    • Primary ovarian failure
  • Gastrointestinal
    • Autoimmune gastritis (pernicious anaemia)
    • Coeliac disease
  • Haematological
    • Autoimmune haemolytic anemia
    • Autoimmune idiopathic thrombocytopenic purpura
    • Neutropenia
  • Renal
    • Goodpasture’s syndrome
  • Hepatic
    • Autoimmune hepatitis
    • Primary biliary cirrhosis
  • Neurological
    • Myasthenia gravis
    • Guillain Barré syndrome
  • Skin
    • Vitiligo
    • Pemphigus
    • Bullous pemphigoid
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11
Q

List systemic autoimmune diseases

A
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Sjögren’s syndrome
  • Scleroderma
  • Polymyositis/Dermatomyositis
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12
Q

Describe some mechanisms of organ-specific autoimmune disease

A
  • Antibodies and lesions are organ-specific
  • Clinical and serological overlap
  • Antigens present in low concentrations
  • Administration of the antigen evokes organ-specific antibodies and induction of the lesion
  • Familial tendency - clustering of organ-specific autoimmune disease suggestive of a more generalized defect
  • Production of antibodies, cell-mediated destruction
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13
Q

List some diseases mediated by direct cellular damage

A

Direct cellular damage occurs via:
- Cellular lysis and/or inflammatory response in the target organ
- Autoimmune thyroiditis (Hashimoto’s)
- Autoimmune anaemia
- Goodpasture’s syndrome
- Type I diabetes mellitus

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14
Q

Describe Hashimoto’s thyroiditis

A
  • Autoimmune thyroiditis
  • Predominantly middle-aged women
  • Characterized by a lymphocytic infiltrate (thyroid gland)
  • Progressive thyroid destruction and the development of hypothyroidism
  • Up to 95% anti-thyroid peroxidase antibodies (high titre)
  • Association with other autoimmune diseases
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15
Q

Briefly describe T1DM

A
  • Characterized by
    • Pancreatic β cell destruction and ultimately absolute insulin deficiency
    • T cell-mediated
    • Presence of autoantibodies (directed against pancreatic islet cells)
      • Glutamic acid decarboxylase (GAD), protein tyrosine phosphatase (IA2), zinc transporter 8 and insulin (IAA)
    • Presence of one or more antibodies can precede clinical onset by many years (presence of all three close to 100% risk of developing clinical diabetes)
    • No evidence that these autoantibodies are pathogenic
  • Image - Link
  • Inflammatory response within the pancreatic islet cells “insulitis”
    • Mononuclear cell infiltrate with predominantly CD8+ cells (CD4 + T cells and macrophages)
      • observed in early diabetes
    • Increased expression of Class I MHC and aberrant expression of class II MHC on beta cells
  • Progressive pancreatic β cell destruction (size and number)
    • mediated by autoreactive CD4+ T cells
    • lysis by cytotoxic T cells
    • local production of pro-inflammatory cytokines and ROS
  • evidence for defects in Treg function
  • overt diabetes only occurs once most of these cells have been destroyed
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16
Q

Describe Grave’s disease

mediated by stimulating antibodies

A
  • Grave’s disease
    • Present with thyrotoxicosis, diffuse goitre
    • Ophthalmopathy, dermopathy
    • Female predominance
    • Weak HLA association - HLA DR3 (Caucasians)
    • Thyroid-specific autoantibodies including those with stimulating properties
    • Directly involved in the pathogenic process
    • Transplacental transfer can result in neonatal hyperthyroidism

  • autoimmune B cells synthesise and secrete antibodies against thyroid-stimulating hormone receptor that subsequently cause elevated thyroid hormone production
  • Normally, a negative feedback loop would cause a shutdown in the production of thyroid-stimulating hormone to ensure that an appropriate level of thyroid activity is maintained, but no mechanisms exist to shut down the production of auto-antibodies that mimic the effect of thyroid-stimulating hormone.
  • Excessive thyroid hormone production hence causes the symptoms of Graves’ disease.
17
Q

Describe myasthenia gravis

mediated by blocking antibodies

A
  • Fatiguability of muscles leading to profound weakness
    • Association with thymoma, thymic hyperplasia, other autoimmune diseases (including thyroid)
    • HLA association
    • Female preponderance
    • Autoantibodies to the acetylcholine (Ach) receptor on the motor end plates of muscles
    • Blocks binding of ACh leading to complement-mediated destruction
    • Transplacental transfer - neonatal myasthenia
18
Q

Describe some systemic polyendocrine syndromes

A
  • Autoimmune polyendocrine syndrome type 1 (APECED)
    • Mutations in AIRE (autoimmune regulator) gene
    • Deletion of autoreactive T cells does not occur in the thymus, mature and exported to the periphery leading to organ-specific autoimmune disease
    • Onset in early childhood, male predominance
    • Major manifestations
      • Mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency
    • Other associated manifestations
      • Other autoimmune endocrineopathies, chronic active hepatitis, hypogonadism, alopecia, pernicious anemia
  • Autoimmune polyendocrine syndrome type 2 (Schmidt’s syndrome)
    • Females (peak age of onset 20 - 40 years)
    • Addison’s disease and
    • Autoimmune thyroid disease, type I diabetes mellitus
    • Pernicious anemia, chronic active hepatitis, vitiligo, hypogonadism
19
Q

Describe IPEX

A
  • X-linked polyendocrinopathy, immune dysfunction, and diarrhea
    • Rare, lethal disorder
    • Early onset diarrhea, villous atrophy and lymphocytic infiltrates, failure to thrive
    • Early onset (usually neonatal) type I diabetes mellitus
    • Autoimmune cytopenias, eczematous skin rash, recurrent infections
  • Mutations in FOXP3
    • Mediates CD4+CD25+ regulatory T cell development within the thymus
    • In absence, generation of autoreactive T cells responsible for disease manifestations observed in IPEX
20
Q

Describe features of systemic autoimmune disease

A
  • Antibodies and lesions non-organ specific
  • Overlap of systemic autoimmune features possible
  • Higher levels of antigen present
  • Reflect generalised immune dysfunction
    • Cell-mediated destruction
    • Direct cellular damage mediated by autoantibodies
    • Deposition of immune complexes
21
Q

Describe the features of SLE

A
  • Wide-ranging effects, multiorgan involvement
    • Rash
    • Cytopenias
    • Glomerulonephritis
    • Sicca symptoms
    • Neurological syndromes
    • Thrombosis, recurrent miscarriage
    • Neonatal syndromes (photosensitivity rash, congenital heart block)
  • Presence of autoantibodies
22
Q

Describe the pathogenic mechanisms of SLE

A
  • Multiple factors
    • Genetic and environmental influences
    • Abnormal responses to self-antigens
    • Production of autoantibodies - play a role in complement fixation and activation, deposition of immune complexes
    • Defects in clearance of immune complexes (related to complement deficiency)
    • Defects in apoptosis
23
Q

Recall mechanisms of T cell tolerance

A
  • Central tolerance in T cells: normally induced in the thymus
    • Newly formed immature T cells migrate to the thymus
    • There, they encounter self-antigens presented by thymic epithelial cells.
    • At the thymus, naïve T cells that are unable to recognise MHC are removed from the repertoire, as such T cells will be unable to confer immunologic advantage.
    • Next, naïve T cells that are strongly auto-reactive (as determined by self-antigen expression through the action of the AIRE gene) are removed from the repertoire, with some of these autoreactive T cells exposed to signals that encourage their differentiation into regulatory T (Treg) cells.
  • Peripheral tolerance: normally induced after central tolerance to limit the effect of autoreactive T cells.
    • Immature dendritic cells collect self-antigens and present them to naïve T cells.
    • If self-reactive naïve T cells recognise the self-antigens presented by dendritic cells, they may once again be converted into regulatory T (Treg) cells, or may be deleted.
    • Another method of peripheral tolerance is the suppression of self-reactive T cells by Treg cells, or the induction of anergy, where self-reactive T cells are made non-responsive.
24
Q

Recall mechanisms of B cell tolerance

A

B cell tolerance
- Central tolerance for B cells:
- Immature B cells in the bone marrow are negatively selected when they recognise self antigen. Initially, they undergo further light chain rearrangement to express a new receptor specificity, but those B cells that remain self-reactive after this point:
- Undergo apoptosis
- Are made anergic

  • Peripheral B cell tolerance
    • B cells that have migrated to the periphery, yet recognise self-antigen in the absence of T cell help are made non-responsive.
25
Q

Revise Type I hypersensitivity reactions

A
  • IgE mediated
    • Soluble antigen
    • Mechanism: allergen specific IgE antibodies bind to mast cell via their Fc receptor. When the specific allergen binds to IgE, cross-linking of IgE results in degranulation of mast cells
    • local and systemic aaphyalaxs, hayfever, food and drug allergies
26
Q

Revise type II hypersensitivity reactions

A
  • IgG or IgM mediated cytotoxic damage
    • Cell bound antigen
    • Autoimmune haemolytic anaemia, Goodpasture’s syndrome
    • Mechanism: IgG or IgM binds to cellular antigen, leading to complement activation and cell lysis. IgG can also mediate ADCC with cytotoxic T cells, NK cells, macrophages and neutrophils
27
Q

Revise type III hypersensitivity reactions

A
  • Immune complex diseases
    • IgG and IgM
    • Soluble antigen
    • Circulating immune complexes deposit in capillary beds. Complement activation provides inflammatory mediators and recruits neutrophils. Enzymes are released from neutrophils and damage tissue
    • Systemic lupus erythematosus, PSGN, RA
28
Q

Revise type IV hypersensitivity reactions

A
  • Delayed type hypersensitivity
    • Cell-mediated (T cells)
    • Soluble or cell-bound antigen
    • Th1 cells secrete cytokines, activating macrophages and cytotoxic T cells
    • Type I diabetes mellitus, MS and contact dermatitis

Block 3 Molecular sciences (7 decks)

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