7 autoimmunity 2 Flashcards
What happens when developing autoreactive B cells bind self-antigen in the bone marrow?
They undergo deletion (death) or inactivation to prevent autoimmunity.
What happens when developing autoreactive T cells bind self-antigen in the thymus?
They are deleted or inactivated to maintain immune tolerance.
What is the role of Notch signalling in T cell development?
Notch signalling commits precursors to the T-cell lineage and initiates T-cell receptor gene rearrangement.
What happens to immature T cells that recognize self-MHC?
They receive survival signals; those strongly recognizing self-antigen are removed.
Where do mature T cells migrate?
They travel to peripheral lymphoid organs to encounter foreign antigens.
What happens when T cells encounter foreign antigens in lymphoid organs?
They become activated, proliferate, and eliminate infections.
What is central tolerance?
A mechanism that deletes or edits autoreactive T and B cells during development in the thymus and bone marrow.
What is antigen segregation?
A physical barrier preventing self-antigen access to lymphoid organs (e.g., in the thyroid, pancreas).
What is peripheral anergy?
Inactivation of autoreactive cells due to weak signalling without co-stimulation.
How do regulatory T cells contribute to tolerance?
They suppress immune responses via cytokines and intercellular signals.
What is functional deviation in immune tolerance?
It involves regulatory T cell differentiation to limit inflammatory cytokine secretion.
What is activation-induced cell death?Apoptosis of autoreactive immune cells in secondary lymphoid tissues.
Apoptosis of autoreactive immune cells in secondary lymphoid tissues.
What two signals are required for naive T cell activation?
TCR/pMHC interaction; 2) CD28/B7 interaction from an activated APC.
What two signals are required for T-dependent B cell activation?
BCR/antigen interaction; 2) CD40/CD40-L interaction from an activated T cell.
What are natural autoantibodies?
IgM autoantibodies produced by B1 B cells, usually low-affinity and rarely pathogenic.
Why do some autoreactive B2 B cells require CD4+ T cell help?
To produce autoantibodies, as many are anergic upon leaving the bone marrow
What is the nature of disease-associated autoantibodies?
They are often high-affinity IgG with extensive somatic mutations, indicating T cell involvement.
What makes some individuals prone to autoimmune diseases?
A combination of genetic susceptibility and environmental triggers.
What role do genetic factors play in autoimmune disease?
They significantly contribute but are not the sole cause (<100% twin concordance).
What does polygenic mean in the context of autoimmune disease?
Multiple genes contribute to disease susceptibility.
Why are many autoimmune diseases more common in females?
Possible hormonal effects.
What is the association between MHC alleles and autoimmune diseases?
Different MHC class II alleles are linked to various autoimmune diseases.
What is the significance of HLA-B27 in ankylosing spondylitis (AS)?
People with HLA-B27 are 87.4 times more likely to develop AS, but most do not.
How do MHC molecules influence autoimmune disease?
They determine the peptides presented to T cells, influencing immune responses.
What are the major genetic susceptibility loci for Type 1 diabetes (T1D)?
HLA-DQ2/DQ8, CTLA-4, and PTPN22
What is the role of AIRE in immune tolerance?
It promotes negative selection of self-reactive T cells; mutations cause APECED.
What does Fas do in immune regulation?
It induces apoptosis of autoreactive cells; defects cause ALPS.
What is FoxP3’s role in immune function?
It regulates Tregs; mutations cause severe autoimmunity.
How does CTLA-4 regulate T cell activity?
It competes with CD28 for ligands to inhibit T cell activation
How can environmental factors contribute to autoimmunity?
Smoking, vitamin D levels, infections, and microbiome composition may play roles.
What is molecular mimicry?
A mechanism where microbial antigens resemble self-antigens, triggering autoimmunity.
Give an example of molecular mimicry.
Rheumatic fever: Streptococcal M protein cross-reacts with heart tissue.
How do PAMPs contribute to autoimmunity?
They activate APCs, increasing the chance of autoreactive T cell activation.
How can self-antigens trigger autoimmune responses?
Unmethylated CpG DNA (SLE) and ECM fragments (RA) can activate TLRs
What is the role of immune privilege in autoimmunity?
Damage to immune-privileged sites can expose hidden antigens, triggering autoimmune reactions.
How is multiple sclerosis (MS) initiated?
An unknown trigger causes inflammation, allowing immune cells to attack CNS myelin.
What are post-translational modifications, and how do they contribute to autoimmunity?
Alterations in proteins (e.g., citrullination in RA) make them immunogenic.
How can smoking increase RA risk?
It induces citrullination of proteins, potentially leading to autoimmunity.
What is the role of microbes in autoimmunity?
They may induce or prevent autoimmune diseases by influencing immune responses.
What is the relationship between gut microbes and T1D?
Differences in gut microbiota may influence disease development.
How does the microbiome influence T1D in mice?
Male mice have protective gut microbes that reduce diabetes risk.
What are the key treatment approaches for autoimmune diseases?
Anti-inflammatory drugs, immunosuppressants, and biologic therapies.
Give an example of a cytokine-targeting therapy.
TNF-alpha blockade (e.g., infliximab) used in RA.
What is an example of a B cell depletion therapy?
Anti-CD20 monoclonal antibodies (e.g., rituximab) used in RA and MS.
How do inverse agonist peptides work in tolerance induction?
They modulate T cell responses to restore immune tolerance.
What does GWAS reveal about autoimmune diseases?
It identifies genetic variants linked to disease risk, though their functions are often unclear.
Why do identical twins not always develop the same autoimmune disease?
Environmental and stochastic factors influence disease onset.
What is the role of autoreactive CD4+ T cells in autoimmunity?
They must escape tolerance mechanisms for disease to develop.
What is the two-step process required for autoimmunity?
olerance breakdown + environmental trigger.
What are key questions in autoimmune disease research?
Why do tolerance mechanisms fail?
How do genetics and environment interact?
How can treatments restore immune balance?
Describe the full process of T cell development and selection.
- Bone Marrow: T cell precursors originate here.
- Thymus Entry: Precursors commit to the T-cell lineage via Notch signalling.
- β-Selection (DN stage): Cells rearrange TCR β-chain; successful rearrangement leads to proliferation.
- αβ TCR Formation (DP stage): CD4+CD8+ T cells rearrange their TCR α-chain.
- Positive Selection: T cells binding self-MHC receive survival signals.
- Negative Selection: Strong self-antigen recognition leads to apoptosis.
- Lineage Commitment: Surviving cells become CD4+ (MHC II) or CD8+ (MHC I) T cells.
- Exit to Periphery: Naïve T cells migrate to secondary lymphoid organs for activation.
Outline the full process of B cell development and central tolerance.
- Bone Marrow Development: Pro-B cells undergo heavy chain (VDJ) recombination.
- Pre-B Cell Stage: Successful μ heavy chain pairing with a surrogate light chain leads to light chain recombination.
- Immature B Cell Stage: Express IgM on the surface.
- Central Tolerance:
- Strong self-antigen binding → Receptor editing (light chain rearrangement) or deletion (apoptosis).
- Weak/no self-antigen binding → B cell survives. - Mature B Cell Stage: Express IgM & IgD, exit to peripheral lymphoid tissues.
Explain the process of naïve T cell activation and differentiation.
- Antigen Recognition: Naïve T cells scan APCs in lymph nodes.
- Signal 1: TCR binds peptide-MHC on APC.
- Signal 2 (Co-stimulation): CD28 binds B7 (CD80/86) on APC.
- Signal 3 (Cytokines): APC cytokines direct T cell differentiation.
- Proliferation & Differentiation: T cells undergo clonal expansion and become:
Th1 (IFN-γ, IL-12) → Activate macrophages.
Th2 (IL-4, IL-5, IL-13) → Activate B cells.
Th17 (IL-17, IL-22) → Recruit neutrophils.
Treg (TGF-β, IL-10) → Suppress immune response.
CD8+ Cytotoxic T Cells → Kill infected cells. - Effector Function: Activated T cells exit lymph nodes to target infection.
- Contraction Phase: Most activated T cells undergo apoptosis, leaving memory cells.
Describe the process of B cell activation and antibody production.
- Antigen Binding: BCR binds antigen in lymphoid follicles.
- Internalisation & Presentation: Antigen is processed and presented via MHC II.
- T Cell Help (T-dependent Activation):
CD4+ T cells provide CD40/CD40L interaction and cytokines.
B cells proliferate in germinal centres. - Somatic Hypermutation & Affinity Maturation:
In dark zone, B cells mutate their BCR genes.
High-affinity B cells are selected for survival in the light zone. - Class Switching: B cells switch from IgM to IgG, IgA, or IgE, depending on cytokines.
- Plasma Cell & Memory Formation:
Some B cells become plasma cells (antibody secretion).
Others become memory B cells for faster future responses.
What are the full processes that prevent autoimmunity?
central tolerance and peripheral tolerance
what is central tolerance?
T cells (thymus) → Negative selection (apoptosis) if strongly self-reactive.
B cells (bone marrow) → Receptor editing, deletion, or anergy.
what is peripheral tolerance?
Anergy: T cells receive signal 1 without co-stimulation and become inactive.
Regulatory T cells (Tregs): Suppress self-reactive T cells via IL-10, TGF-β.
Antigen Segregation: Physical barriers prevent immune system access to certain self-antigens (e.g., eye, brain).
Activation-Induced Cell Death (AICD): Repeated activation triggers Fas/FasL apoptosis in autoreactive cells.
Explain how autoimmune diseases develop.
Genetic Susceptibility:
Certain HLA alleles increase risk (e.g., HLA-B27 in AS).
AIRE mutations lead to defective negative selection.
CTLA-4 polymorphisms reduce T cell regulation.
Environmental Triggers:
Molecular Mimicry: Pathogens express antigens resembling self-proteins (e.g., rheumatic fever).
Release of Sequestered Antigens: Trauma exposes immune-privileged self-antigens (e.g., sympathetic ophthalmia).
Microbial Activation of APCs: Infections upregulate B7/CD80, leading to bystander activation of autoreactive T cells.
Post-Translational Modifications: Smoking-induced citrullination triggers RA.
What are key costimulatory and inhibitory signals in T cell activation?
Costimulatory:
CD28/B7 → Essential for full T cell activation
ICOS/ICOS-L → Supports effector T cell function
Coinhibitory:
CTLA-4/B7 → Competes with CD28, dampens activation
PD-1/PD-L1 → Suppresses chronic immune responses
What are the main T cell subsets involved in autoimmunity?
Th1 → Produces IFN-γ, activates macrophages (e.g., RA, MS)
Th17 → Produces IL-17, recruits neutrophils (e.g., psoriasis, IBD)
Tregs → Suppress autoimmunity via IL-10, TGF-β
Th2 (less relevant) → Associated with allergies, not autoimmunity
How are autoreactive B cells controlled in the periphery?
Lack of T cell help → Leads to anergy (unresponsiveness)
Fas/FasL-mediated apoptosis → Removes B cells in germinal centres
Regulatory T cells (Tregs) → Suppress autoreactive B cells
What is epitope spreading and how does it contribute to autoimmunity?
Initial immune attack targets one antigen, but as tissue damage progresses, new self-antigens are exposed.
Example: In SLE, immune responses expand from DNA to histones and ribonucleoproteins.
How do cancer immunotherapies cause autoimmune side effects?
Anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab) remove immune “brakes,” allowing strong T cell responses.
This can break self-tolerance, leading to colitis, thyroiditis, myocarditis, etc.
What is the hygiene hypothesis and how does the microbiome affect autoimmunity?
Hygiene Hypothesis → Fewer infections in childhood shift the immune system towards autoimmunity & allergy.
Gut microbiome imbalances are linked to diseases like MS, RA, and type 1 diabetes.
Example: NOD mice (T1D model) show that gut microbes influence diabetes risk.
