Autoimmunity

Question 1

Describe and explain the nature of the body’s response to self-antigen

Answer 1

The body’s response to self-antigen, self-tolerance, prevents harmful autoimmune responses, categorised into 2 broad phrases

Central Tolerance:

1) Negative Selection of T cells:

• Within the thymus, the TCR expressed on T cells is tested for its affinity against self-antigens
• Cells with TCR that binds too strongly to self-antigens presented by MHC molecules are eliminated through apoptosis - negative selection
• Cytokines like IL-7 play a crucial role in thymocyte survival during this selection process

2) Negative Selection of B cells:

• B cells undergo a similar process in the bone marrow
• Those with BCRs that bind to self-antigens with high affinity are deleted or undergo receptor edition to change their specificity
• The cytokine BAFF (B cell-activating factor) is involved in survival signals for B cells

Peripheral Tolerance:

1) Anergy:

• Anergy is a state of unresponsiveness
• If a T cell encounters its antigen in the absence of appropriate co-stimulatory signals (typically CD28 on T cells with B7 on APCs), it becomes anergic
• In this state, it won’t respond to its specific antigen in the future, effectively sidelining any potential auto-reactive T cells
• IL-2 is also required for full T-cell activation, their absence can contribute to anergy

2) Regulatory T cells (Tregs):

• Tregs are a subtype of T cells that suppress the immune response
• Tregs can secrete anti-inflammatory cytokines like IL-10 and TGF-β, which inhibit the activation of self-reactive T cells and help maintain peripheral tolerance

3) Activation-induced cell death (AICD):

• Auto-reactive cells in the periphery can be induced to undergo apoptosis upon repeated exposure to self-antigen
• This process often involves Fas-Fas ligand interaction

Immunological Ignorance:

• When self-antigens are hidden from the immune system in immune-privileged sites (like the brain and testes) or simply at low levels that don’t trigger an immune response

Question 2

Describe characteristics of autoimmune disease (genetics, environmental factors, endocrine factors) and some of the mechanisms involved in the pathology

Answer 2

Genetic Factors:

1) Human leukocyte antigens (HLA):

• Part of the MHC which are crucial for antigen presentation
• Certain HLA alleles have been strongly associated with autoimmune diseases
• HLA-DR2 and HLA-DR3 are linked with systemic lupus erythematosus (SLE) and HLA-DR4 is linked with rheumatoid arthritis

2) Non-HLA genes:

• These include genes involved in immune regulation, such as PTPN22 (for T-cell activation) and CTLA-4 (T cell regulation)

3) Cytokine genes:

• Certain polymorphisms in genes encoding cytokines (interleukin-1, interleukin-10, TNF-ɑ) may influence the severity and course of autoimmune diseases

Environmental Factors:

1) Infections:

• Certain viral and bacterial infections can trigger autoimmune diseases through molecular mimicry
• where microbial antigens resemble self-antigens, or by activating immune cells nonspecifically

2) Diet:

• High intake of salt, sugar and fat can influence inflammation and auto-immunity

3) Stress and Trauma:

• Psychological stress and physical trauma can also trigger an immune response that, in genetically predisposed individuals, may lead to autoimmunity

Hormonal Factors:

• Oestrogen: stimulates the immune response, which might explain why autoimmune diseases are more prevalent in women, especially during reproductive years
• Pregnancy: Changes in hormone levels during pregnancy and postpartum period can trigger or exacerbate autoimmune diseases

Mechanisms Involved in Pathology:

1) Failure of T-cell anergy:

• Under normal circumstances, self-reactive T cells become anergic (non-reactive) in the absence of co-stimulation
• However, if these T cells receive the second activation signal, they can trigger an autoimmune response

2) Tregs Dysfunction:

• Dysfunction or a decrease in the number of these cells can lead to autoimmunity
• secreting anti-inflammatory cytokines like IL-10 and TGF-β, which inhibit the activation of self-reactive T cell

3) Molecular Mimicry and Epitope Spreading:

• Infections can lead to an immune response against antigens that resemble self-antigens, leading to an autoimmune response
• the initial immune response can ‘spread’ to different epitopes on the same

Question 3

Describe potential therapies for autoimmunity

Answer 3

Immunosuppressive Therapies:

1) Glucocorticoid:

• Prednisone and other corticosteroids have powerful anti-inflammatory and immunosuppressive properties by suppressing activity of T cells, macrophages and the production of pro-inflammatory cytokines
• Often used in autoimmune diseases like lupus and rheumatoid arthritis

2) Cytotoxic Agents:

• Drugs like Cyclophosphamide and Azathioprine inhibits the replication of cells, including immune cells, thereby suppressing the immune response

3) Calcineurin Inhibitors:

• Cyclosporin A and Tacrolimus inhibit T-cell activation by blocking the function of calcineurin (essential for T cell activation)

Biologic Therapies:

1) Tumour Necrosis Factor (TNF) Inhibitors:

• Etanercept, infliximab, and adalimumab block the action of TNF, a cytokine that promotes inflammation

2) Interleukin Inhibitors:

• anakinra (IL-1 inhibitor), tocilizumab (IL-6 inhibitor), and ustekinumab (IL-12 and IL-23 inhibitor)

3) B-cell Depleting Agents:

• Rituximab is a monoclonal antibody that depletes B cells

Immune Modulating Therapies:

• DMARDs (Disease-Modifying Antirheumatic Drugs)
• JAK inhibitors: inhibit Janus Kinases, enzymes involved in the signalling pathway

Cell-based Therapies:

• Stem Cell Transplantation: hematopoietic stem cell transplantation (HSCT) can be used to essentially “reboot” the immune system