Autoimmunity

Question 1

Autoimmune Diseases

Characteristics

Answer 1

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

Question 2

Factors Leading To

Autoimmunity

Answer 2

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

Question 3

Genetic Susceptibility

to

Autoimmunity

Answer 3

• 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

Question 4

Infection

&

Autoimmunity

Answer 4

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

Question 5

Changes in Anatomical Structures

&

Autoimmunity

Answer 5

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

Question 6

Gender Differences

Answer 6

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

Question 7

Self-Tolerance Failure

Answer 7

• 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 T_reg cell generation

Question 8

Autoimmunity Stages

Answer 8

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

Question 9

Organ-specific

vs

Systemic Disease

Answer 9

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

Question 10

T vs B

Mediated Damage

Answer 10

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.

Question 11

Multiple Sclerosis

(MS)

Answer 11

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

Question 12

Type I DM

Answer 12

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

Question 13

Graves’ Disease

Answer 13

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

Question 14

Pernicious Anemia

Answer 14

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

Question 15

Goodpasture Syndrome

Answer 15

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

Question 16

Systemic Lupus Erythematous

(SLE)

Answer 16

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

Question 17

Rheumatoid Arthritis

(RA)

Answer 17

Combined T and B cell activity.

• Inflammatory process in joints results in dysfunction and deformity
• T_h1 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

Question 18

Myastenia Gravis

Answer 18

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

Question 19

Therapeutic Approaches

for

Autoimmune Diseases

Answer 19

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