Lecture 16: Autoimmune Disorders Flashcards
What causes autoimmunity?
Lymphocytes that recognise self antigens
What is a self antigen?
molecules or proteins that are naturally present in the body’s cells and tissues. These antigens are recognized by the immune system as “self,” which means that they are not foreign or harmful to the body.
What usually prevents autoimmune diseases from developing?
Self tolerance mechanisms
What are the two classes of autoimmunity?
- Organ specific
- Systemic
What are the organ specific autoimmune diseases?
- Type 1 diabetes
- Goodpastures syndrome
- Multiple sclerosis
- Crohns disease
- Psoriasis
- Graves disease
- Hashimotos throiditis
- Autoimmune hemolytic anemia
- Autoimmune addisons disease
- Vitiligo
- Myasthenia gravis
What are the systemic autoimmune diseases?
- Rheuamatoid arthiritis
- Scleroderma
- Systemic lupus erythematosus
- Primary sjogrens syndrome
- Polymyositis
What is rheumatoid arthiritis?
Chronic inflammation and joint damage
What cytokines play a role in rheumatoid arthiritis?
TNF-a
IL-1
IL-6
IL-15
IL-17
What causes rheumatoid arthiritis?
Immune system mistakenly attacks the synovium, which is the lining of the joints, leading to inflammation and damage to the cartilage and bone.
What is the mechanism of tissue damage in rheumatoid arthritis?
antibodies to IgG Fc (“rheumatoid factor”) and citrullinated peptides activate macrophages and promote inflammatory response in the joint
What is the mechanism of tissue damage in rheumatoid arthritis?
antibodies to IgG Fc (“rheumatoid factor”) and citrullinated peptides activate macrophages and promote inflammatory response in the joint
What is the conventional treatment for rheumatoid arthritis?
- Disease modifying antirheumatic drugs (methotrexate; hydroxychloroquine, sulfasalazine)
- Methotrexate
- Anti-inflammatory agents (NSAIDs)
What do DMADs do in rheumatoid arthritis?
Improve symptoms and decrease joint damage
What do NSAIDs do in rheumatoid arthritis?
Reduce pain and stiffness but dont affect long term disease course
What are the biological treatments for rheumatoid arthritis?
- Anti TNF alpha inhibitors e.g., infliximab; etanercept
- Other cytokines e.g., anakinra (IL-1R antagonist)
- Reagents against cell surface molecules: e.g., rituximab (mab against CD20 on B cells); abatacept (CTLA4-Ig fusion protein – binds to CD80/CD86 on antigen presenting cells)
- Targeting signal transduction: e.g. Janus kinases (tofacitnib)
What is Systemic Lupus Erythematosus (SLE)?
Chronic autoimmune disease that can affect multiple organs and tissues in the body, including the skin, joints, kidneys, heart, lungs, and brain.
What are the symptoms of systemic lupus erythematosus?
May include joint pain, rash, fatigue, fever, and sensitivity to sunlight.
What are the mechanisms of tissue damage in systemic lupus erythematosus?
Characterised by high titres of autoantibodies, particularly against nuclear antigens, which generate immune complex-mediated inflammation in the kidneys, skin, joints and cardiovascular system
What are major contributers to mortality caused by systemic lupus erthematosus?
Glomerulonephritis and accelerated atherosclerosis are major contributors
What causes renal failure in systemic lupus erthematosus?
Deposition of immune complexes in the renal glomeruli. Causes thickening of the glomerular basement membrane
What are the conventional treatment for systemic lupus erythematosus?
- DMARDs: methotexate and hydroxycgloroquine
- Corticosteroids
- Cytotoxic drugs
- Intravenous immunoglobulin
What are DMARDs used for in systemic lupus erythematosus?
Reduce incidence of flairs
What are corticosteroids used for in systemic lupus erythematosus?
Treatment of flares
What are cytotoxic drugs used for in systemic lupus erythematosus?
Treatment of glomerulonephritis
What are intravenous immunoglobulins used for in systemic lupus erythematosus?
Vasculitis
What is vasculitis?
A group of diseases that involve inflammation of the blood vessels, which can lead to damage and dysfunction of the affected organs or tissues. The inflammation can cause the walls of the blood vessels to become thickened, narrowed, or weakened, affecting the flow of blood to and from the affected organs.
What are the biological treatments for systemic lupus erythamatosus?
Reagents against B cell molecules:
- Rituximab
- Epratuzumab
- Belimumab
What is rituximab against?
CD20
What is epratuzumab against?
CD22
What is belimumab against?
against BAFF (first FDA-approved SLE treatment for 50 years)
What is multiple sclerosis?
Chronic autoimmune disease that affects the central nervous system, including the brain, spinal cord, and optic nerves.
What causes multiple sclerosis?
Occurs when the immune system mistakenly attacks the myelin, which is the protective covering that surrounds nerve fibers and allows them to conduct electrical impulses efficiently. promoted by myelin-specific T cells, which are able to cross the blood-brain barrier
What is given during symptomatic attacks of MS?
Intravenous corticosteroids, e.g., methylprednisolone
What are disease modifying treatments for relapsing remitting MS?
IFNb - considered to reduce disease progression if started early and also reduce rate of relapses
What reduces rates of MS relapse?
Glatiramer acetate: FDA-approved random polymer of 4 amino acids from myelin basic protein
What are the biological treatments for MS?
- Natalizumab
What is natalizumab?
Humanised mab against the cell adhesion molecule a4-integrin
How does natalizumab prevent relapse and cognitive decline in MS?
Prevents immune system cells from exiting the bloodstream to cross the blood-brain barrier thereby preventing relapse and cognitive decline
What is a risk of the use of natalizumab?
Progressive multifocal leukoencephalopathy
How do biological agents work?
Block cell migration to sites of inflammation and reduce immune responses
What is type 1 diabtes?
Associated with loss of insulin production due to destruction of beta cells in the pancreas
What is the mechanism of tissue damage in type 1 diabates?
Participating immune system components include auto-reactive CD4+ T helper cells and CD8+ T cytotoxic cells and also auto-antibody producing B cells
What do alpha cells secrete?
Glucagon
What do beta cells secrete?
Insulin
What do s cells secrete?
Somatostatin
How are beta cells destructed in type 1 diabetes?
An effector T cell recognizes peptides from a B cell specific protein and kills the B cell so no insulin can be made
What is the mechanism of tissue damage in inflammatory bowel disease?
there is a role for genetic and environmental factors in disease development but symptoms caused by imbalance between pro- and anti-inflammatory cytokines. Roles for macrophage, e.g., source of TNF-a and Th 17 cell, e.g., source of IL-17
What surgical procedure is used in IBD?
proctocolectomy used to cure
What are the treatment options fro IBD?
- Immunosuppression
- Mabs: Anti-TNF-a mabs, e,g., infliximab very effective (but not etanercept); anti - IL-12 mabs have shown mixed results
- Microbiome: feacal microbiota transplant being investigated
