Autoimmunity Lecture Notes

Mid-Semester Exam Information

  • The exam is computer-based and in-person on Highfield campus.
  • Date: Next Tuesday, March 18th.
  • There will be no lectures next week for this immunology module (Tuesday and Wednesday).
  • Content: Only innate and adaptive immunity lectures from the first four weeks (lectures by the instructor and Emily Findlay).
  • Format: 40 questions, 45 minutes (unless extra time has been arranged).
  • Check Blackboard for more information.

Autoimmune Diseases: Basic Principles

  • Today's focus: Basic principles of autoimmunity and why the immune system attacks self cells.
  • Tomorrow's focus: Specific examples of autoimmune diseases, their features, symptoms, and immunological basis.
  • Learning Objectives:
    • Describe how the normal functioning of the immune system breaks down in autoimmunity.
    • Explain why the plasticity of the immune system leads to autoimmunity.
  • Topics:
    • Effector cells of the acquired immune system.
    • Antigen-presenting cells and antigen presentation.
    • Mechanisms of tolerance, especially tolerance to self.

Prevalence of Autoimmune Diseases

  • Significant prevalence: Approximately 4 million people in the UK are affected.
  • Recent studies suggest up to 10% of the UK population may have an autoimmune disease.
  • Around 80 different autoimmune diseases have been identified.
  • Common autoimmune diseases include:
    • Multiple sclerosis
    • Rheumatoid arthritis
    • Inflammatory bowel disease
    • Type 1 diabetes
  • Disproportionately affects women (75% of cases), potentially related to differences in immune response between sexes.
  • Fourth largest cause of disability in women.
  • Often affects individuals in their prime, impacting quality of life.
  • Rheumatoid arthritis affects approximately 1 in 100 people.

T-Cell Activation and Autoimmunity

  • Review of normal T-cell responses to pathogens highlighting the importance of:
    • MHC molecule.
    • Antigen.
    • Co-stimulation.
  • Antigen-presenting cells (e.g., dendritic cells) recognize, internalize, and process antigens.
  • Peptides are presented on the cell surface via MHC class II molecules.
  • T cells with specific T-cell receptors (TCRs) recognize the antigen presented by MHC II.
  • Co-stimulatory signals (e.g., CD28 on T cells interacting with B7 on APCs) are required for T-cell activation.
  • The T-cell receives two signals:
    • Signal 1: Antigen recognition via TCR-MHC interaction.
    • Signal 2: Co-stimulatory signal (CD28-B7 interaction).
  • These signals initiate T-cell proliferation and cytokine responses.
  • T helper cells then signal B cells and CD8+ cytotoxic T cells to contribute to the downstream immune response.
  • In autoimmunity, the immune system fails to distinguish between self and non-self antigens.
  • Loss of recognition leads to the destruction of the body's own cells.
  • Normal regulatory processes are disrupted, leading to the activation of self-reactive T cells.
  • Mechanisms of tolerance fail, or cells escape these mechanisms.
  • Environmental triggers (bacteria, viruses, toxins, drugs) can initiate autoimmune responses, particularly in individuals with a genetic predisposition (MHC alleles).
  • There's a genetic component and a strong environmental component to autoimmunity.

Tolerance and MHC Molecules

  • Tolerance: T and B cells are educated during development to recognize self-antigens as “safe”.
  • Autoimmunity arises when tolerance to self-antigens is broken.
  • MHC molecules are crucial for T-cell activation and antigen presentation and act as a structure to present the antigen.
  • MHC class I and class II molecules present antigens (self or foreign).
  • Certain MHC alleles are linked to an increased risk of autoimmune diseases.
  • MHC molecules provide a sense of self, playing a vital role in determining responses to self vs. non-self.

Peter Doherty and Rolf Zinkernagel

  • Won the Nobel Prize in 1996 for discovering the specificity of cell-mediated immune defense (T cells).
  • Peter Doherty (Australian) worked on T cells.
  • Rolf Zinkernagel (Swiss) worked on MHC molecules.
  • Their work explained how T cells are educated to interact with infected cells.
  • T cells specifically interact with virus-infected cells but not with free virus.
  • They discovered that T cells must recognize both self-MHC and foreign antigen to be activated.
Experiment
  • Using mice with genes from mother A and father B (F1 offspring), which carry MHC alleles H2 a b.
  • Mice underwent thymectomy (removal of the stimulus) and radiation to remove bone marrow.
  • The thymus was replaced with as strain B thymus graft (expressing only H2b MHC alleles).
  • Bone marrow was from the mouse own bone marrow, expressing MHC alleles with the haplotype of H2 a b.
  • The mouse was infected with LCM virus.
  • Spleen cells were tested for their ability to kill B cells from strains A and B.
  • Results:
    • The mouse could kill strain B cells, but not strain A cells.
    • T cells have to be educated in the thymus to recognize self MHC, a self, and foreign antigens without changing the thymus.
  • Conclusion: T cells are educated to recognize self-MHC molecules in the thymus and will only respond to foreign antigens presented on those MHC molecules.

Central Tolerance

  • T cells mature in the thymus and are checked for their ability to recognize self-MHC and avoid responding to self-antigens.
  • Positive and negative selection:
    • T cell precursors rearrange TCR genes and express both CD8 and CD4.
    • Positive selection: Immature T cells interact with self-MHC molecules on epithelial cells. Those that don't interact undergo apoptosis.
    • Negative selection: Cells that strongly respond to self-antigens presented by APCs (macrophages, dendritic cells) in the thymus are deleted via apoptosis because they might become self-reactive autoimmune reactive T-cells.
    • This results in mature CD4+ or CD8+ T cells that do not strongly respond to self-antigens.
Affinity for Self-Antigens
  • High affinity: T cells that recognize self-MHC presenting self-antigen with high affinity undergo apoptosis.
  • No or low affinity: T cells with no or low affinity survive and mature.
  • Intermediate affinity: T cells with intermediate affinity upregulate FoxP3 and become regulatory T cells (Tregs), which can suppress self-reactive T cells.

Peripheral Tolerance

  • A second layer of protection for central tolerance.
  • T cells released into circulation require two signals to become effector cells:
    1. Antigen recognition
    2. Co-stimulatory signal
  • If a T cell reacts to an antigen but doesn't receive a co-stimulatory signal:
    • It dies by apoptosis.
    • It becomes anergic (inactivated).
  • Mechanisms to avoid autoimmunity:
    • Lack of co-stimulatory signal leads to anergy.
    • Regulatory T cells suppress self-reactive T cells.
    • Ignorance: Some T cells have low affinity for self-antigens but don't respond.
  • Environmental triggers (viral infections, toxins) can cause self-reactive T cells to become active, leading to autoimmunity.
  • Example: Epstein-Barr virus as a potential trigger for multiple sclerosis.

Summary of Self vs. Non-Self Discrimination

  • Central and peripheral tolerance mechanisms are essential for distinguishing self from non-self.
  • Encounters with antigens as immature T cells can lead to deletion of self-reactivity.
  • High, constant antigen concentrations without changes may lead to T cell ignorance.
  • Absence of co-stimulation/danger signal prevents T cells from becoming self-reactive.

B Cells and Autoimmunity

  • B cells and auto-reactive antibodies are important.
  • B cells, like T cells, undergo tolerance mechanisms.
B Cell Development
  • Occurs in the bone marrow and peripheral lymphoid organs.
  • Hematopoietic stem cells undergo B cell receptor rearrangement.
  • Heavy chain rearrangement first, followed by addition of a light chain to form the B cell receptor.
  • Immature B cells with a fully functional B cell receptor are checked for self-reactivity.
Negative Selection in B Cells (Central Tolerance)
  • B cells that react strongly with self-antigen in the bone marrow are either deleted or change their B cell receptor expression.
Experiment
  • Experiment using transgenic mice expressing either the 2D or H2 DK haplotype.
  • Mice with both sets of alleles express MHC molecules on bone marrow stromal cells.
  • Immature B cells with receptors that bind strongly to these molecules are deleted.
  • Transgenic mice lack mature B cells expressing B cell receptors specific to the K allele.
  • Mice without the K allele do not get signals of autoimmunity, B cells mature normally.
  • Immature B cells without strong reactivity to self-antigens can mature.
  • B cells with strong interactions are deleted.
Receptor Editing
  • B cells with potential self-reactivity can be rescued.
  • Recombination activating gene (RAG) is expressed during development and allows for the exchange of the light chain.
  • This can change the specificity of the B cell receptor and rescue potentially self-reactive B cells.

Peripheral Tolerance in B Cells

  • Mechanisms to avoid autoimmunity when antigens are expressed in the periphery.
Experiment
  • Experiment by Goodenough and Besson using transgenic animals:
    • One expresses an antigen (HEL - hen egg lysozyme).
    • Another expresses the B cell receptor against that antigen.
    • Uses a metallothionein promoter to control/increase expression experimentally.
  • Individual transgenic mice have normal B cell development.
  • Crossed mice (double transgenic) expressing both antigen and B cell receptor against the antigen have different results:
    • Expression of B cell receptors is significantly reduced.
  • Flow cytometry analysis:
    • Analyzes expression of B cell receptors on cell surfaces.
    • Non-transgenic mice lack B cells against experimental antigen HEL.
    • Mice with B cell receptor (but not self-antigen) have high levels of B cells expressing the receptor.
    • Crossed mice still make B cells, but expression levels of B cell receptors are dramatically reduced.
Anergic Response Summary
  • Immature B cells develop in the bone marrow. Several scenarios can lead to tolerance; otherwise, ultra-reactivity is possible.
Tolerance scenarios include:
  • B cells that interact with antigens on stromal cells in the bone marrow:
    • Strong interaction leads to clonal deletion/receptor editing = apoptosis.
    • This is to avoid autoimmunity.
  • Soluble self-molecule (e.g., HEL) results in no cross-linking but some reactivity:
    • These migrate to the periphery, but B cell receptor expression is reduced.
    • Non-responsive to antigens.
  • Low-affinity, non-cross-linking self-molecule:
    • No changes induced.
    • Migrate to periphery becoming mature B cells.
    • Remain ignorant to self-antigens until environmental trigger alters.
  • No reaction to self-antigens; normal migration; become mature cells.
  • Cells in the fourth scenario are most likely to become ultra-reactive B cells.