The cellular basis of autoimmunity 1

• Learning objectives


  • To review evidence for the role of CD4+ T cells in the pathogenesis of organ specific autoimmunity
  • To understand current hypotheses for the initiation of autoimmunity at the level of immune recognition
  • To learn about cellular mechanisms underlying common patterns of disease
• Overview of autoimmunity


  1. Initiation

  2. Reactivation

  3. Expansion, Trafficking

  4. Target organ localisation, activation and damage

  5. Amplification, Regulation, Memory generation

  6. Remission
• Organ specific autoimmune disease and its models


  • Spontaneous models: Type 1 diabetes - NOD mouse, TCR transgenic animals
  • Induced models: Multiple sclerosis - Experimental Autoimmune Encephalomyelitis (EAE), Uveitis - Experimental Autoimmune Uveoretinitis (EAU), TCR transgenic animals
• Attenuation to make a rabies vaccine


  • 1885: Rabid rabbit spinal cords dried in air and used to treat patients
  • Approximately 0.1% of vaccine recipients developed an acute paralytic illness; most recovered
  • The immune system is confusing the rabbit brain and the human brain
• Graves' Disease


  • Autoantibodies stimulate the TSHR
  • Predominantly IgG1 - T helper dependent
  • Thyroid grows and secretes thyroid hormones
  • Symptoms and signs of increased metabolic rate
  • Associated eye and skin diseases
• CD4+ T cells as mediators of specificity


  • 1960 Mixed lymphocyte populations can transfer EAE
  • 1969 Thoracic duct cells can Tx EAE
  • 1981 Antigen specific T cell lines can Tx EAE
  • 1984 TCRs cloned
  • 1985 Antigen specific, MHC II restricted T cell clones can Tx EAE
  • Transgenic CD4+ cells are sufficient to cause spontaneous EAE
• Identifying autoantigens


  1. Choose a candidate protein

  2. Analyse immune response to whole protein

  3. Screen overlapping peptides to find epitopes

  4. Induce disease in a model

  5. Identify and characterise the inciting cells

  6. Correlate with responses in humans

  7. Caution – the presence of autoreactive cells does not equal disease
• In the absence of additional triggers, the MHC II of all professional antigen presenting cells are loaded with self-derived antigens and T cells are interacting with these in secondary lymphoid organs, and nothing happens!
• T cells get activated by

  • Molecular Mimicry
  • Bystander Activation
• What the TCR looks at


  • H S L G K W L G H P D K F (Autoantigen)
  • E Q L V K W L G L P A P I (Bacterial antigen - Mimic)
  • Mimics modulate autoimmune responses
  • Can enhance or reduce risk of autoimmunity
• Mimics modulate autoimmune responses; they can enhance OR reduce risk of autoimmunity
• Reactivity with self


  • Single specificity against Foreign Antigen, Low Avidity for Self
  • Single specificity against Self Antigen, High Avidity for Self
  • Multiple specificities, Response to cross-reactive autoantigen, Response to pathogen
• Bystander Activation


  Innate immune activation can precipitate autoimmune keratitis
• Progression in autoimmune disease

  Why relapses and remissions?

  • Eliminating autoantigens may be very difficult
  • 'New' immune responses to previously untargeted antigens
  • Changes in activation threshold of the environment (infection)
  • Changes in the target tissue make reactivation more likely
• Epitope Spreading


  • Can drive progression of disease
  • Intramolecular
  • Intermolecular
• At this point there is a narrow view that T cells are necessary and sufficient for the development of autoimmune disease.
• What drives specificity?

  • Genetics demonstrate MHC (class II > class I) association with susceptibility
  • Pathogenic immunoglobulins in thyroid autoimmunity are high affinity IgGs, implicating T cell help
  • Class II expression is upregulated in inflamed tissues
  • CD4 cells?
• MHC restriction established using blocking antibodies

  
• Transgenic CD4+ cells are sufficient to cause spontaneous EAE
• Molecular architecture of T cell recognition: TCR binds to MHC class II molecules on the surface of the target cell

  
• Candidate autoantigens in different diseases

  
• Several autoantigens in one protein

  • Epitopes that bind MHC
  • Naturally processed
  • Induce disease

  
• What amino acid substitution studies tell us

  • TCRs can be exquisitely sensitive to single amino acid changes • TCRs can accept multiple substitutions without cells losing the ability to respond
  • TCRs can be activated by two peptides of completely different sequence
  • A single TCR in a mouse has the potential to be stimulated by about 13 self-peptides
• The consequences of a cross-reactive T cell repertoire

  
• Experimental evidence for molecular mimicry


  HSV keratitis in mice

  • Scratch and infect eye Virus undetectable after 5 days, but disease continues to increase in susceptible strains
• Molecular mimicry can precipitate autoimmune keratitis


  HSV keratitis in mice

  • Defined virus (KOS) and a replication competent mutant with single amino acid change in TCR epitope (S309L)
  • Transgenic low affinity TCR (C1-6) recognises wild type epitope

  
• Normal Activation

  • dendritic cell activating T cell w/ foreign antigen
  • leads to normal immune response

  
• Bystander Activation


  • dendritic activated by trauma

  • no foreign antigen on its surface

  • can still lead to activation of autoreactive t cells

  • traffic to tissue & cause damage

  
• Bystander activation can also precipitate autoimmune keratitis


  HSV keratitis in mice

  • Transgenic low affinity TCR (C1-6)

  
• Intramolecular Epitope spreading

  
• What drives organ specific autoimmunity?

  Tissue antigens
• What initiates autoimmunity?


  Infection, danger and chance
• Why is it a relapsing remitting process?


  Reactivity can spread; activation thresholds can vary
• Why can’t autopathogenic T cells be eliminated from the repertoire?

  Because the only thing worse than autoimmunity is no immunity