Skip to content

Topic 6 Auto immune disease

Crohn's disease

  • ==Symptoms==: bloody diarrhea, abdominal pain, weight loss, failure to thrive in young; effects beyond just gut
  • NOD2 功能缺失变异 → 无法识别 MDP → DC 失控（过度激活 Th1/Th17）+ 潘氏细胞失职（菌群失调 + 屏障漏洞）→ 免疫系统攻击肠道共生菌 → 慢性炎症 → 克罗恩病。
  • caused by Th1 / Th17 CD4+ cell intermediated response; can cause inflammation anywhere in whole GI tract
    • CD4+ T cells , IFNg, IL-12, IL-23 are all elevated in Crohn's disease
    • Could be caused by ==deficient regulatory activity== or ==excess effector function==
  • Immune response to commensal bacteria; Gut bacteria are the antigen in Crohn's disease

Multiple Sclerosis

  • defined as an autoimmune disease where the body's immune system mistakenly attacks its own tissues
  • Attacker: Autoreactive ==lymphocytes==, immune cells
  • Target: ==myelin sheath== of the central nervous system (CNS)
  • Consequence: destruction of myelin; progressive loss of neurons
    • vision problems and fatigue
  • ==Hallmark==
    • Oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF)
    • What they are: These are specific antibodies (immunoglobulins) found in the spinal fluid but not in the blood.
    • OCBs expansion --> local clonal expansion of B cells, in CNS
  • ==Trigger==
    • While MS is autoimmune, the slides present strong evidence that it is triggered by a viral infection, specifically Epstein-Barr Virus (EBV)
    • Molecular Mimicry: a viral protein looks similiar to a human brain protein, immune system confused
      • The immune system creates antibodies to fight the EBV protein EBNA1
      • Self-antigen: These same antibodies cross-react with a human protein called GlialCAM, which is found in the brain (glial cells).
      • B cell will be the key attacker; CD9+ T cell will mistakenly recognize GlialCAM as a threat

SLE: systemic Lupus Erythematosus

  • a kind of systemic autoimmune disease; which means, unlike MS that only effect CNS, SLE is a multi-system disease
  • Attacker: auto-reactive B cells
  • Target: the whole body; highlight skin, joints, kidney, heart, and brain

  • ==Hallmark==: production of high-affinity autoantibodies; particularly those that target components of the cell nucleus (anti-nuclear antibodies)

  • Primary mechanism:

    • SLE results from a breakdown in B cell tolerance
      • Central Tolerance: eliminates self-reactive B cells in the bone marrow. In SLE, this process is defective, allowing more autoreactive cells to escape into the body.
      • Peripheral Tolerance: In SLE, all of these are impaired
    • Immune complex deposition
      • SLE is not caused by the antibodies directly attacking the organs. Instead, it is a consequence of forming immune complexes.
      • Autoantibody production: defective B cell tolerance leads to the production of autoantibodies against nuclear antigens like DNA and RNA
      • normal cell death --> RNA/ DNA release in blood --> antibody binds to them (antigen) --> form large antibody-antigen complexes
      • Inflammation & Damage: The deposited complexes trigger a Type III hypersensitivity reaction. They activate the complement system and recruit inflammatory cells like neutrophils, leading to widespread tissue damage and vasculitis.

  • TLR & Interferon Loop

    • this could amplifies the autoimmune response
    • TLRs on B cells and DCs recognize pathogen-derived DNA and RNA.
      • in SLE, they mistakenly bind to the patient's own DNA/RNA that is part of the immune complexes
      • --> after self-antigen binds to B cell, which will further drive B cell to produce more antibody
      • --> after self-antigen binds to plasmacytoid dendritic cells bind to the complexes, they produce massive amounts of type I ==interferon==
      • The Interferon Signature: This chronic production of Type I IFN is a key feature of SLE. It promotes inflammation, activates more dendritic cells, and enhances the survival and activation of autoreactive T and B cells, further fueling the disease.

AGS: Aicardi-Goutieres Syndrome

  • Definition: A mimic of congenital viral infection; caused by aberrant innate immune activation
  • Mutation: cleaning up nucleic acids; when these enzymes fail, self DNA/RNA accumulates --> trigger the sensors via cGAS/STING pathway --> cause the release of IFN --> autoimmune disease

COPA Syndrome

  • Mutation: a defect in intracellular trafficking (Golgi-to-ER), The STING protein normally recycles, but now the transportation fails
    • Which will cause the STINg protein stuck in an activate state, leading to constitutive IFN production