IMS: Immunology > Autoimmunity > Flashcards

Autoimmunity Flashcards

(19 cards)

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1
Q

Autoimmune Diseases

Characteristics

A

Situations where adaptive immunity inappropriately targets self-antigens due to loss of self-tolerance.

  • Chronic, progressive, and self-perpetuating
    • If autoreactive reaction crosses threshold, resulting tissue damage can further up-regulate immune response
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2
Q

Factors Leading To

Autoimmunity

A
  • Breakdown or failure of tolerance mechanisms
  • Genetic susceptibility
  • Uncontrolled or misdirected response to foreign antigen
  • Injury
  • Hormonal influences
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3
Q

Genetic Susceptibility

to

Autoimmunity

A
  • MHC Alleles
    • Most associated with class II MHC
    • Alkylosing spondylitis shows strongest correlation
    • Most encode residues in the peptide binding groove or regions near the groove
      • Determines peptide binding, T cell recognition, and selection during thymic maturation
  • Non-MHC Alleles
    • Genes with role in development and regulation of immune responses
    • Most in noncoding regions of the gen e
  • Few single-gene abnormalities identified that cause autoimmunity
    • High penetrance
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4
Q

Infection

&

Autoimmunity

A
  1. Release of sequestered Ag
    • Break cell/tissue barriers
    • Increasing concentration of specific self-Ag
    • Triggers activation of un-tolerized (ignorant) lymphocytes
  2. Triggering a bystander effect
    • Infection upregulates costimulators on APCs
    • Naive non-tolerant T-cells accidently provided both signals by APC presenting self-Ag
  3. Altering self-proteins
    • Infectious agents bind to self-Ag making them appear foreign
    • As immune response develops, epitope spreading could lead to autoimmunity
  4. Triggering a cross-reactive response due to molecular mimicry
    • Foreign-Ag induces T/B cells with cross-reactivity to self-Ag
    • Causes naive cells to expand to autoractive effector cells
  5. Overcoming anergy by the polyclonal activation of lymphocytes
    • T-cell activation by superantigen
    • B-cell activation by LPS or Epstein-Barr virus
    • Can activate previously tolerized or anergized autoreactive cells
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5
Q

Changes in Anatomical Structures

&

Autoimmunity

A

Inflammation, ischemia, or trauma can result in the release of self-Ag.

  • Post-traumatic uveitis and orchitis
    • Follows damage to an immunoprivileged site of the eye
  • Sympathetic ophthalmia
    • Rare bilateral granulomatous uveitis
    • Follows ocular trauma or surgery to one eye
    • Both eyes affected once tolerance or clonal ignorance lost
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6
Q

Gender Differences

A

Most autoimmune diseases have high incidence in women.

Thought to be secondary to hormonal changes.

Theories include:

  • women have more vigorous immune responses overall
  • women with more Th1 like responses
  • immunostimulatory role of estrogen and prolactin
  • fetal cells in maternal circulation
  • maternal cells in male circulation
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7
Q

Self-Tolerance Failure

A
  • defects in deletion
    • impacts central tolerance of T & B cells
  • defects in apoptosis
    • impacts central tolerance and AICD
  • defects in anergy
    • breakdown of T cell anergy
  • inadequate Treg cell generation
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8
Q

Autoimmunity Stages

A
  1. Predisposition of an individual to autoimmunity.
  2. Autoimmune event initiated by an environmental trigger or stochastic event.
    • loss of self tolerance
    • stimulation of autoreactive lymphocytes
  3. Autoimmune attack releases additional self-Ag which are not eliminated in an efficient manner
    • allows propagation of autoimmune response
    • often there is a response against an increasing number of self-Ag
    • epitope spread - recognition of additional epitopes within the recognized self-Ag
    • development of clinical features
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9
Q

Organ-specific

vs

Systemic Disease

A

Determined in part by distribution of auto-antigen.

  • Organ specific autoimmune diseases
    • often involve reactivity against a single antigen or target cell
    • can result in systemic symptoms
  • Systemic Disease
    • tend to be immune complex mediated
    • involves auto-reactivity against multiple self-antigens
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10
Q

T vs B

Mediated Damage

A

Various effector mechanisms responsible for tissue injury.

Most autoimmune diseases have varying roles for T-cells and B-cells in pathogenesis.

Most B-cell responses are T-cell dependent.

B-cells can act as important APC for T-cell activation.

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11
Q

Multiple Sclerosis

(MS)

A

Prominent T-cell activity.

Considered a type IV hypersensitivity.

  • Mediated by autoreactive CD4+ T-cells
  • Inflammatory process upregulates Fas on oligodendrocytes making them targets for FasL expressing T-cells
  • Results in demyelination or destruction of myelin sheaths in CNS
  • Relapsing-remitting course or chronic progressive form
  • Treatments include:
    • mAb for IL-2R α-subunit
    • mAb for VLA-4 on activated T-cells
    • blocking exit of WBC from LN
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12
Q

Type I DM

A

Prominent T-cell activity.

Considered a type IV hypersensitivity.

  • Pancreatic β-cells destroyed by CTL-mediated killing
  • Also involves CD4+ T-cells and macrophages
    • Secrete proinflammatory cytokines
  • Results in insulin deficiency or absence
  • Treatment includes:
    • insulin
    • immunosuppresion
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13
Q

Graves’ Disease

A

Prominent B-cell activity.

Considered a non-cytotoxic type II hypersensitivity.

  • Auto-Ab causes constitutive activation of TSH receptor
  • Can be transmitted from motehr to infant via placental igG
  • Results in overproduction of T3 and T4
  • See metabolic sx
  • Treatment includes:
    • anti-thyroid drugs to reduce production of thyroid hormones
    • surgery, radioiodine
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14
Q

Pernicious Anemia

A

Prominant B-cell activity.

Considered a type II hypersensitivity.

  • Auto-ab against intrinsic factor
    • IF needed for absorption of Vit B12
  • Erythropoiesis deficient leading to macrocytic anemia
  • Treatment with Vit B12 supplementation
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15
Q

Goodpasture Syndrome

A

Prominent B-cell activity.

Considered a type II hypersensitivity.

  • Auto-ab bind antigenic epitope in basement membranes
  • Results in recurrent alveolar hemorrhage
    • For Ab deposition, additional lung injury must occur which increases alveolar-capillary permeability
  • Rapidly progressive severe glomerulonephritis
  • Treatment includes:
    • Plasmapheresis
    • Prednisone
    • ACE inhibitors
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16
Q

Systemic Lupus Erythematous

(SLE)

Study These Flashcards
A

Combined T and B cell activity.

Considered a type III hypersensitivity.

  • High titers of antinuclear auto-Ab and nuclear debris form immune complexes
    • Often also auto-Ab against platelets, WBC, RBCs
  • Complexes activate complement components
    • Directs accumulation of granulocytes within glomeruli
    • Destruction of blood vessel wall and nephron
    • “lumpy bumpy” morphology with immunofluorescence
    • Glomerulonephritis most damaging
  • Butterfly rash on face
  • Auto-reactive T-cells play a critical role
    • Can activate auto B cells with more wide range of reactivities
  • Abnormalities in macrophage scavenger function results in poor clearance and increased pathogenesis
  • Treatment with immunosuppresive drugs
17
Q

Rheumatoid Arthritis

(RA)

Study These Flashcards
A

Combined T and B cell activity.

  • Inflammatory process in joints results in dysfunction and deformity
  • Th1 cells and macrophages play dominant role in RA development
  • Rheumatoid factor (RF) with role in inflammation and neutrophil recruitment but likely not causitive
  • Early stage:
    • Contain infiltrating neutrophils, lymphocytes, and plasma cells
  • Advanced stage:
    • highly vascular inflammatory tissue = pannus
    • mostly lymphocytes, plasma cells, macrophages, and fibroblasts
    • undergoes calcification
18
Q

Myastenia Gravis

Study These Flashcards
A

Combined T and B cell activity.

Type II Hypersensitivity

  • Auto-Ab bind Ach receptor at NMJ
    • Block interaction of Ach with receptor
    • interact with regions near the receptor and physically hinder Ach access
  • Bound Ab fix complement
    • Induces destruction of the folding membrane
  • IgG antibody can cross placenta
    • Cause transient disease in newborn
  • T-cells can transfer disease in animal models
  • Treatment includes:
    • plasmapheresis
    • exchanges with normal plasma
    • thymectomy
    • acetylcholinesterase inhibitors
19
Q

Therapeutic Approaches

for

Autoimmune Diseases

Study These Flashcards
A
  1. Corticosteroids
    • Reduce tissue injury
    • block inflammatory process
  2. Immunosuppressive drugs
    • Cyclosporine
      • Blocks T cell activity
    • Used to treat severe exacerbations
  3. Immune mediators
    • Antagonists of pro-inflammatory cytokines IL-1 and TNF-α
  4. Anti-integrins
    • inhibit pathologic immune reactions
  5. Costimulator antagonists
    • B7
    • CD40 ligand
    • Block T-cell activation
  6. Plasmapheresis
    1. reduce the amount of circulating Ab
  7. Induce tolerance
    • Oral administration of self proteins
    • administration of altered self proteins
IMS: Immunology
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