7 autoimmunity 2

Question 1

What is the role of Notch signalling in T cell development?

Answer 1

Notch signalling commits precursors to the T-cell lineage and initiates T-cell receptor gene rearrangement.

Question 2

What happens to immature T cells that recognize self-MHC?

Answer 2

They receive survival signals; those strongly recognizing self-antigen are removed.

Question 3

Where do mature T cells migrate?

Answer 3

They travel to peripheral lymphoid organs to encounter foreign antigens.

Question 4

What happens when T cells encounter foreign antigens in lymphoid organs?

Answer 4

They become activated, proliferate, and eliminate infections.

Question 5

What is central tolerance?

Answer 5

A mechanism that deletes or edits autoreactive T and B cells during development in the thymus and bone marrow.

Question 6

What is antigen segregation?

Answer 6

A physical barrier preventing self-antigen access to lymphoid organs (e.g., in the thyroid, pancreas).

Question 7

What is peripheral anergy?

Answer 7

Inactivation of autoreactive cells due to weak signalling without co-stimulation.

Question 8

How do regulatory T cells contribute to tolerance?

Answer 8

They suppress immune responses via cytokines and intercellular signals.

Question 9

What is functional deviation in immune tolerance?

Answer 9

It involves regulatory T cell differentiation to limit inflammatory cytokine secretion.

Question 10

What is activation-induced cell death?Apoptosis of autoreactive immune cells in secondary lymphoid tissues.

Answer 10

Apoptosis of autoreactive immune cells in secondary lymphoid tissues.

Question 11

What two signals are required for naive T cell activation?

Answer 11

TCR/pMHC interaction; 2) CD28/B7 interaction from an activated APC.

Question 12

What two signals are required for T-dependent B cell activation?

Answer 12

BCR/antigen interaction; 2) CD40/CD40-L interaction from an activated T cell.

Question 13

What are natural autoantibodies?

Answer 13

IgM autoantibodies produced by B1 B cells, usually low-affinity and rarely pathogenic.

Question 14

Why do some autoreactive B2 B cells require CD4+ T cell help?

Answer 14

To produce autoantibodies, as many are anergic upon leaving the bone marrow

Question 15

What is the nature of disease-associated autoantibodies?

Answer 15

They are often high-affinity IgG with extensive somatic mutations, indicating T cell involvement.

Question 16

What makes some individuals prone to autoimmune diseases?

Answer 16

A combination of genetic susceptibility and environmental triggers.

Question 17

What role do genetic factors play in autoimmune disease?

Answer 17

They significantly contribute but are not the sole cause (<100% twin concordance).

Question 18

What does polygenic mean in the context of autoimmune disease?

Answer 18

Multiple genes contribute to disease susceptibility.

Question 19

Why are many autoimmune diseases more common in females?

Answer 19

Possible hormonal effects.

Question 20

What is the association between MHC alleles and autoimmune diseases?

Answer 20

Different MHC class II alleles are linked to various autoimmune diseases.

Question 21

What is the significance of HLA-B27 in ankylosing spondylitis (AS)?

Answer 21

People with HLA-B27 are 87.4 times more likely to develop AS, but most do not.

Question 22

How do MHC molecules influence autoimmune disease?

Answer 22

They determine the peptides presented to T cells, influencing immune responses.

Question 23

What are the major genetic susceptibility loci for Type 1 diabetes (T1D)?

Answer 23

HLA-DQ2/DQ8, CTLA-4, and PTPN22

Question 24

What is the role of AIRE in immune tolerance?

Answer 24

It promotes negative selection of self-reactive T cells; mutations cause APECED.

Question 25

What does Fas do in immune regulation?

Answer 25

It induces apoptosis of autoreactive cells; defects cause ALPS.

Question 26

What is FoxP3's role in immune function?

Answer 26

It regulates Tregs; mutations cause severe autoimmunity.

Question 27

How does CTLA-4 regulate T cell activity?

Answer 27

It competes with CD28 for ligands to inhibit T cell activation

Question 28

How can environmental factors contribute to autoimmunity?

Answer 28

Smoking, vitamin D levels, infections, and microbiome composition may play roles.

Question 29

What is molecular mimicry?

Answer 29

A mechanism where microbial antigens resemble self-antigens, triggering autoimmunity.

Question 30

Give an example of molecular mimicry.

Answer 30

Rheumatic fever: Streptococcal M protein cross-reacts with heart tissue.

Question 31

How do PAMPs contribute to autoimmunity?

Answer 31

They activate APCs, increasing the chance of autoreactive T cell activation.

Question 32

How can self-antigens trigger autoimmune responses?

Answer 32

Unmethylated CpG DNA (SLE) and ECM fragments (RA) can activate TLRs

Question 33

What is the role of immune privilege in autoimmunity?

Answer 33

Damage to immune-privileged sites can expose hidden antigens, triggering autoimmune reactions.

Question 34

How is multiple sclerosis (MS) initiated?

Answer 34

An unknown trigger causes inflammation, allowing immune cells to attack CNS myelin.

Question 35

What are post-translational modifications, and how do they contribute to autoimmunity?

Answer 35

Alterations in proteins (e.g., citrullination in RA) make them immunogenic.

Question 36

How can smoking increase RA risk?

Answer 36

It induces citrullination of proteins, potentially leading to autoimmunity.

Question 37

What is the role of microbes in autoimmunity?

Answer 37

They may induce or prevent autoimmune diseases by influencing immune responses.

Question 38

What is the relationship between gut microbes and T1D?

Answer 38

Differences in gut microbiota may influence disease development.

Question 39

How does the microbiome influence T1D in mice?

Answer 39

Male mice have protective gut microbes that reduce diabetes risk.

Question 40

What are the key treatment approaches for autoimmune diseases?

Answer 40

Anti-inflammatory drugs, immunosuppressants, and biologic therapies.

Question 41

Give an example of a cytokine-targeting therapy.

Answer 41

TNF-alpha blockade (e.g., infliximab) used in RA.

Question 42

What is an example of a B cell depletion therapy?

Answer 42

Anti-CD20 monoclonal antibodies (e.g., rituximab) used in RA and MS.

Question 43

How do inverse agonist peptides work in tolerance induction?

Answer 43

They modulate T cell responses to restore immune tolerance.

Question 44

What does GWAS reveal about autoimmune diseases?

Answer 44

It identifies genetic variants linked to disease risk, though their functions are often unclear.

Question 45

Why do identical twins not always develop the same autoimmune disease?

Answer 45

Environmental and stochastic factors influence disease onset.

Question 46

What is the role of autoreactive CD4+ T cells in autoimmunity?

Answer 46

They must escape tolerance mechanisms for disease to develop.

Question 47

What is the two-step process required for autoimmunity?

Answer 47

olerance breakdown + environmental trigger.

Question 48

What are key questions in autoimmune disease research?

Answer 48

Why do tolerance mechanisms fail? How do genetics and environment interact? How can treatments restore immune balance?

Question 49

Describe the full process of T cell development and selection.

Answer 49

1. Bone Marrow: T cell precursors originate here. 2. Thymus Entry: Precursors commit to the T-cell lineage via Notch signalling. 3. β-Selection (DN stage): Cells rearrange TCR β-chain; successful rearrangement leads to proliferation. 4. αβ TCR Formation (DP stage): CD4+CD8+ T cells rearrange their TCR α-chain. 5. Positive Selection: T cells binding self-MHC receive survival signals. 6. Negative Selection: Strong self-antigen recognition leads to apoptosis. 7. Lineage Commitment: Surviving cells become CD4+ (MHC II) or CD8+ (MHC I) T cells. 8. Exit to Periphery: Naïve T cells migrate to secondary lymphoid organs for activation.

Question 50

Outline the full process of B cell development and central tolerance.

Answer 50

1. Bone Marrow Development: Pro-B cells undergo heavy chain (VDJ) recombination. 2. Pre-B Cell Stage: Successful μ heavy chain pairing with a surrogate light chain leads to light chain recombination. 3. Immature B Cell Stage: Express IgM on the surface. 4. Central Tolerance: - Strong self-antigen binding → Receptor editing (light chain rearrangement) or deletion (apoptosis). - Weak/no self-antigen binding → B cell survives. 5. Mature B Cell Stage: Express IgM & IgD, exit to peripheral lymphoid tissues.

Question 51

Explain the process of naïve T cell activation and differentiation.

Answer 51

1. Antigen Recognition: Naïve T cells scan APCs in lymph nodes. 2. Signal 1: TCR binds peptide-MHC on APC. 3. Signal 2 (Co-stimulation): CD28 binds B7 (CD80/86) on APC. 4. Signal 3 (Cytokines): APC cytokines direct T cell differentiation. 5. 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. 6. Effector Function: Activated T cells exit lymph nodes to target infection. 7. Contraction Phase: Most activated T cells undergo apoptosis, leaving memory cells.

Question 52

Describe the process of B cell activation and antibody production.

Answer 52

1. Antigen Binding: BCR binds antigen in lymphoid follicles. 2. Internalisation & Presentation: Antigen is processed and presented via MHC II. 3. T Cell Help (T-dependent Activation): CD4+ T cells provide CD40/CD40L interaction and cytokines. B cells proliferate in germinal centres. 4. 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. 5. Class Switching: B cells switch from IgM to IgG, IgA, or IgE, depending on cytokines. 6. Plasma Cell & Memory Formation: Some B cells become plasma cells (antibody secretion). Others become memory B cells for faster future responses.

Question 53

What are the full processes that prevent autoimmunity?

Answer 53

central tolerance and peripheral tolerance

Question 54

what is central tolerance?

Answer 54

T cells (thymus) → Negative selection (apoptosis) if strongly self-reactive. B cells (bone marrow) → Receptor editing, deletion, or anergy.

Question 55

what is peripheral tolerance?

Answer 55

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.

Question 56

Explain how autoimmune diseases develop.

Answer 56

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.

Question 57

What are key costimulatory and inhibitory signals in T cell activation?

Answer 57

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

Question 58

What are the main T cell subsets involved in autoimmunity?

Answer 58

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

Question 59

How are autoreactive B cells controlled in the periphery?

Answer 59

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

Question 60

What is epitope spreading and how does it contribute to autoimmunity?

Answer 60

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.

Question 61

How do cancer immunotherapies cause autoimmune side effects?

Answer 61

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.

Question 62

What is the hygiene hypothesis and how does the microbiome affect autoimmunity?

Answer 62

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.