The cellular basis of autoimmunity 2

• LO:

  • To review the function of different leukocytes in organ specific autoimmunity
  • To understand how knowledge of the cellular immunology relates to treatment strategies
• CD4+ T cell activation is not a complete or satisfactory description of organ specific autoimmunity
• Genetics


  • T1D association with an IRF7 dependent anti-viral expression network
  • Multiple sclerosis association with TNFSFR1
  • Rheumatoid arthritis association with IL6R
• Transgenic CD4+ cells do not always cause spontaneous EAE (Cell 78:399 (1994))
• T cell effector phenotypes correlate with disease phenotypes

  Human disease

  • Leprosy Lesions

  Murine disease

  • Transgenic T cells, differentiated to different phenotypes and transferred
• Homeostatic roles for Treg Cells


  • Homeostatic regulation of 'autoaggression' during normal immune responses
  • Resolution of subclinical autoimmunity
• Treg deficiency leading to autoimmunity


  Reduced Treg numbers or function

  • T regs have functional abnormalities in MS

  Inhibition or diversion of Treg function in inflammatory microenvironments

  • Limited IL-2; Loss of Foxp3 in inflammatory environments

  Hyper-functioning effector cells resistant to Treg

  • Effector cells from CNS/pancreas resist suppression in conventional assays
• Tumour Necrosis Factor (TNF)


  • Trimeric structure, important superfamily
  • Local and systemic effects
  • Signalling via two receptors TNFR1 and TNFR2
  • TNFR1 responsible for most proinflammatory activities
  • Therapeutic target in Rheumatoid arthritis, uveitis etc.
• TNFR1-/- phenotype in uveitis


  • Reduced clinical disease
  • Macrophages fail to release NO on stimulation with IFNγ
  • Defect in monocyte trafficking to target organ

  
• Sometimes antibodies can sustain disease

  • K/BxN model of arthritis (Benoist and Mathis)
  • T cell dependent development of high titre autoantibodies
  • Serum alone can induce chronic arthritis
  • Th17 T cells driven by gut resident segmented filamentous bacteria (Immunity 32:815 2010) also important
• B Cell:T cell interactions


  • Stimulate pathogenic autoantibodies
  • Expand pathogenic T cells
  • Convert Th to Treg
  • Produce IL-10 & IL-35
• CD8 Cells


  • Fundamental role in diabetes pathogenesis; timing in relation to CD4 cells is unclear
  • Three week old NOD mice have insulin (B:15-23) reactive CD8+ T cells in islets
  • CD8+T cells with other specificities (IGRP206-214) arrive later and are detectable in blood
  • These cells can kill islet beta cells
• Targeting inflammatory mediators


  • TNF knockout mouse, less EAE, EAU, IDD Blockade effective in arthritis, uveitis, Crohn’s disease Exacerbation of disease in MS
  • NOS2 knockout. Worse EAE, EAU
  • IFNγ knockout. Worse EAE, EAU
  • IL-17 blockade Blockade effective in psoriasis
• Anti-CD20 treatment in human disease

  • Rheumatoid arthritis – NICE approved, in combination with methotrexate for refractory disease
  • Relapsing remitting multiple sclerosis – reduced lesion burden,
  • Type 1 diabetes – improved beta cell survival
  • Uveitis (Behcet's disease) – trial ongoing
• Many signals inform activation

  
• Overview of autoimmunity

  
• Visualisation of disease (EAU)

  
• Cell populations in EAU

  
• Factors driving T cell differentiation

  
• Th effector cell phenotype signatures

  
• Macrophages amplify the inflammatory environment

  
• Infiltrating CCR2(+) Ly6C (hi) monocytes are licensed to damage tissue by GM-CSF

  • CCR2 expressing monocytes lack receptor for GMCSF (Csf2)
  • Animals resistant to EAE
  • Downstream defect in IL-1β release

  
• Antigen specific B cells are efficient APCs

  
• B cells can play a role in breaking tolerance

  
• B cells are not needed for the induction of EAE

  
• The autoimmunity ‘onion’

  
• Targeting trafficking

  • Entry into the target tissue
  • Exit of CD4 cells from lymph nodes
  • Non-specific adverse effects: Defects in immunosurveillance
• Targeting cell types

  • Macrophages reduce disease (mouse)
  • NK cells exacerbate disease (mouse EAE)
  • NK cells reduce disease (mouse EAU)
  • T cells effective in MS trials (human, mouse)
  • B cells effective in several different autoimmune conditions (human, mouse)
• Summary

  • The autoimmune process requires T cells but draws in many other types of leukocyte
  • The cellular infiltrate in disease changes with time
  • Treatment targeting single effector molecules or cell types can be effective but is complicated by rare serious adverse outcomes