Lecture 3 - Immunology & Autoimmune disorders Flashcards
different autoimmune disorders, their incidence, treatment, pathogenesis, symptoms
How many autoimmune diseases are there that can affect humans?
100 autoimmune diseases
How many Americans may suffer from an autoimmune disease?
25-50 million
How does autoimmune disease affect females?
It is one of the top 10 causes of female death in any age group.
What is the downside of using immunosuppressants to treat autoimmune disease?
They work by suppressing the entire immune system and can bring lots of long-term side effects.
Briefly explain what causes autoimmune disease in humans?
When the body’s immune system mistakenly recognizes the body’s self antigens as foreign, it causes immune cells to release cytokines that can destroy cells, causing inflammation.
What are the two classifications of autoimmune diseases?
Autoimmune diseases can be organ-specific or systemic.
What are some examples of organ-specific autoimmune diseases?
Type 1 diabetes, Multiple sclerosis, Crohn’s disease, Psoriasis, Grave’s disease.
What are some examples of systemic autoimmune diseases?
Rheumatoid arthritis, Systemic lupus erythematosus.
What is Rheumatoid arthritis?
This is an autoimmune disease where the immune system produces antibodies that mistakenly target the body’s joints and bones, bringing about inflammation.
Briefly explain the pathology of Rheumatoid arthritis.
Two antibodies:
Rheumatoid factor - which targets the Fc portion of the IgG antibody
Anti-citrullinated protein antibodies (ACPA) - which targets citrullinated proteins in joints.
The antibody-antigen binding creates immune complexes (clumps) that travel to the macrophages and bind onto their receptor triggering them. Macrophages release cytokines: TNFA, IL1, IL6 they then stimulate TH1 and TH17 cells that release further cytokines to stimulate macropghes further causing inflammation in the joints and cartilage destruction as well as bone erosion.
What are the cytokines released by macrophages to further amplify inflammation and damage to the joints in RA?
TNFA, IL-1, IL-6, IL-15, IL-17.
What damage is done to the joints in Rheumatoid arthritis?
The cartilage is destroyed, the joints fuse into one, and the fused joint becomes non-functional and damaged.
What is the incidence of Rheumatoid arthritis in the adult population and how does it differ between genders?
The incidence is 0.4-1.3% of the adult population, with women being 3x more affected than men.
List some symptoms of rheumatoid arthritis.
Numbness and tingling in hands and feet, warm and swollen joints, disrupted sleep, low-grade fever, fatigue, mood changes, weight loss.
What are some conventional treatments used by doctors to treat Rheumatoid arthritis?
- Disease Modifying Antirheumatic Drugs (DMARDs) - slow disease progression
* Methotrexate (first-line treatment)
* Sulfasalazine - Steroids - helps with joint inflammation
* Prednisolone
* Prednisone - NSAIDs - reduce pain, does not stop disease progression
* Ibuprofen
* Naproxen
What are some biological treatments for Rheumatoid arthritis?
Anti-TNFa Inhibitors (taken parenterally)
* Infliximab
* Etanercept
Anti-IL1R antagonist
* Anakinra
Targeted Molecular Interventions
* Rituximab (B-cell surface receptor antagonist)
* Tofacitnib (Janus kinase inhibitor - they help control white blood cell proliferation and differentiation)
What is systemic lupus erythematosus?
This is an autoimmune disease where the bodies B cells produce the wrong antibodies that can attack the endothelium of Bv in any part of the body
Briefly explain the pathology of systemic lupus erythematosus.
The body mistakenly produces lots of autoantibodies that target nuclear antigens (proteins inside the nucleus of cells). Once these autoantibodies arrive at the nuclear antigen they bind onto them forming immune complexes (antibody-antigen clumps). The immune complexes then travel through the bloodstream and attach onto the endothelial cells of the Blood vessel, immune cells come along and recognise these complexes as “foreign” targeting them, bringing about inflammation - endothelial damage & Cellular debris. Depending on which blood vessel the immune complexes are deposited in inflammation will occur there. The inflammation can end up occurring in multiple organs: joint, skin, lungs, heart, kidneys etc bringing about symptoms throughout the body.
Which parts of the body do autoantibodies affect in systemic lupus erythematosus?
Kidneys, skin, joints, cardiovascular system.
What are the two main causes of death in patients with systemic lupus erythematosus?
Glomerulonephritis and Accelerated Atherosclerosis.
What is glomerulonephritis and how can it lead to death?
Inflammation of the glomeruli of the kidney (part that has blood flow, and filters out waste). this region if destroyed cannot have blood flow, and cannot get rid of waste which means the waste builds up and we get kidney failure.
What is accelerated atherosclerosis and how can it lead to death?
Accelerated atherosclerosis is the rapid growth of fat plaque in blood vessels, restricting blood flow and potentially causing heart failure or brain damage.
What is the incidence of systemic lupus erythematosus in the adult population?
0.1 – 0.5% of the adult population, with 90% of cases in women and more common in ethnic minorities.
List some common symptoms of systemic lupus erythematosus.
Mouth and nose ulcers, butterfly rash on the face, atherosclerosis, severe abdominal pain, hair loss, high fever, swollen joints.
What are some conventional treatments used by doctors to treat systemic lupus erythematosus?
- DMARDs - slow down disease progression
* Methotrexate
* Hydroxychloroquine - Corticosteroids - reduces inflammation
* Prednisolone - Cytotoxic Drugs - treats glomerulonephritis
* Cyclophosphamide
* Azathioprine - Intravenous Immunoglobulin - treats inflammation in BVs.
What are some biological treatments for systemic lupus erythematosus?
B-Cell Targeted Therapies (this is used to help reduce the B cell activation, if B cells activated is reduced then autoantibodies cannot be produced, reduces chances of immune complexes formed and inflammation in endothelial cells)
Mainly used in SLE when DMARDs and steroids, NSAIDs fail to manage symptoms & reduce disease progression.
Rituximab (CD20 monoclonal antibody)
Epratuzumab (CD22 monoclonal antibody)
Belimumab (BAFF monoclonal antibody)
What is multiple sclerosis?
This is an autoimmune disorder where the immune system attacks the myelin sheath of neurons, disrupting signaling and impacting movement.
Briefly describe the pathology of multiple sclerosis.
TH1 travel to the BBB and release cytokines stimulating macropghes to release more cytokines that target the myelin of neurons.
CD8+ cells also attack the myelin sheath, causing inflammation and further damage.
What is the incidence of multiple sclerosis in the adult population?
0.1 – 0.2% of the adult population, more prevalent in females and northern regions.
List some symptoms of multiple sclerosis.
Vision problems, speech impairment, movement impairment, loss of senses.
What are some conventional treatments used by doctors to treat multiple sclerosis?
- Disease modifying antirheumatic drugs - slows down disease progression/ reduces chances of flares, by blocking immune cell activity.
- Interferon-β
- Glatiramer acetate - Intravenous Corticosteroids - is used to manage symptoms
- Methylprednisolone
Which DMT is FDA approved for multiple sclerosis?
Glatiramer acetate.
How does glatiramer acetate work?
It mimics myelin as they both have 4 of the same amini acids in their structure, causing immune cells to attack it instead of the real myelin sheath.
Explain why glatiramer acetate is described as a MH2 and CD8+ T cell antagonist.
It prevents APCs from presenting myelin to TH1 cells, reducing CD8+ T cell activation.
What are some biological treatments for multiple sclerosis?
Natalizumab.
Explain how natalizumab works.
There is a protein found on the surface of T-cells called alpha-4 integrin. This protein helps T-cells stick to blood vessels, allowing them to cross the blood-brain barrier (BBB) in multiple sclerosis (MS) and cause more inflammation. When Natalizumab, a lab-made monoclonal antibody, is taken, it blocks alpha-4 integrin from attaching to blood vessels. As a result, T-cells can’t cross into the brain, leading to less inflammation and fewer MS relapses.
Why is natalizumab only approved as a monotherapy in the EU?
Due to the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection.
The FDA considers the clinical benefits more than the risks, but the EU restricts it to monotherapy to reduce the risk.
What is type 1 diabetes?
Type 1 diabetes is an autoimmune disorder where immune cells attack pancreatic beta cells, reducing insulin production.
Explain the pathogenesis of type 1 diabetes.
CD4+ T cells stimulate B cells to produce auto-antibodies and CD8+ T cells destroy beta cells (as they recognise islet cells as damaged or abnormal).
What is the incidence of type 1 diabetes and which populations are most affected?
Incidence is 0.01%, most common in children and people under 40 in northern industrialized countries.
What are the different cell types found in the Islet of Langerhans and their function?
- Alpha cells secrete glucagon
- beta cells secrete insulin
- delta cells secrete somatostatin.
In type 1 diabetes, what happens to the beta cells in the Islet of Langerhans?
Effector T cells recognise the beta cells of pancreas as foreign and destroy, leading to a lack of insulin production.
Which hormones can still be produced in type 1 diabetes despite the destruction of beta cells?
Glucagon and somatostatin can still be produced, but insulin cannot.
What does the destruction of beta cells in type 1 diabetes prevent?
It prevents the production of insulin, leading to blood sugar regulation issues.
Why has transferring promising treatments from models of type 1 diabetes to humans been challenging?
Treatments that work in models generally do not work in humans.
Why are monoclonal antibodies not effective enough for treating type 1 diabetes?
They are not powerful enough to help patients become insulin-independent.
Which treatment shows more promise for type 1 diabetes, and how does it work?
Autologous hematopoietic stem cell transplantation helps reset the immune system.
What is the main challenge with using monoclonal antibodies for type 1 diabetes treatment?
They are not strong enough to allow patients to stop needing insulin.
What is inflammatory bowel disease?
This is an autoimmune disorder where the immune cells attack the digestive tract, causing chronic inflammation.
What are the two conditions of inflammatory bowel disease?
Crohn’s disease and ulcerative colitis.
What is the incidence of inflammatory bowel disease, and which population is it most common?
- The incidence is around 0.02 - 0.2%, - More common in developed countries and urban areas.
Which body tissue gets damaged in inflammatory bowel disease?
The gut, stomach, intestines, and rectum.
How does gut tissue get damaged in inflammatory bowel disease?
Through genetics, environmental factors, microbiome imbalance, and problems with the immune system
- these all trigger an immune response
Can you explain how macrophages and TH17 contribute to tissue damage in inflammatory bowel disease?
Macrophages release TNF A.
TH17 release IL-17.
both cause more inflammation and enhanced immune response.
What else triggers the immune response in the gut?
The immune system loses tolerance of harmless substances and proceeds to attack the gut.
What happens to the innate immune system in IBD?
The innate epithelial lining of the gut becomes leaky, allowing more harmful toxins to enter, which leads to a stronger immune response.
What is the imbalance in the adaptive immune system in IBD?
There is an imbalance of TH1/TH2 cells, where one might be too activated, causing an overactive immune system.
What surgery can cure ulcerative colitis?
Proctocolectomy.
What can treat IBD?
Individualised medical treatments requiring immunosuppression.
Which monoclonal antibody is very effective for IBD?
Infliximab - anti TNFA
Which Monoclonal antibody is not effective for IBD?
Etanercept is not effective in treating IBD compared to other anti-TNF-α monoclonal antibodies.
What are the results of using anti-IL-12 monoclonal antibodies for IBD?
Anti-IL-12 monoclonal antibodies have mixed results in treating IBD.
What is being investigated as a potential treatment for IBD related to the microbiome?
Fecal microbiota transplant is being investigated to restore a healthy balance of gut bacteria in IBD.
What was the purpose of live helminth therapy in treating IBD?
Live helminth therapy was thought to change immune response from Th1 to Th2, but its effectiveness is now uncertain.
