Lecture 3 - Autoimmune diseases Flashcards
what are organs specific autoimmune diseases vs systemic autoimmune diseases ?
organic specific autoimmune diseases include type 1 diabetes mellitus, good pastures syndrome, multiple sclerosis, graves diseases, hashimotos etc
systemic autoimmune diseases include rheumatoid arthritis, scleroderma, sle, primary sjogrens syndrome, polymyositis etc
describe the type I classification of autoimmune diseases dependant on pathogenic mechanism
Type I: IgE mediated diseases. there is no direct evidence that IgE antibodies are involved in the pathogenesis of autoimmune diseases. however, IgE specific self antigens have been identified in autoimmune diseases of skin, thyroid, pancreas, eye, connective tissue and joints
describe Type II classification of autoimmune diseases based on pathogenic mechanism
type II autoimmune diseases are IgG or IgM mediated diseases.
types of type II mediated diseases include autoimmune haemolytic anaemia, autoimmune thrombocytopenia purpura, good pastures syndrome, pemphigus vulgarisms and acute rheumatic fever
ind myasthesisa gravis, Autoantibodies against the α subunit of the acetylcholine receptor, the binding leads to reduced numbers of receptor on the muscle
in good pastures disease, utoantibodies in Goodpasture’s disease cause local activation of cells that have Fc receptors,This binding leads to a series of immune responses, including complement activation, which is part of the immune system designed to destroy pathogens, and the influx of neutrophils
Describe type III mediated autoimmune disease by the pathogenic mechanisms
type III autoimmune disease is mediated by immune complexes
mixed essential cryoglobulinemia, rheumatoid arthritis and sLE are types of type III mediated autoimmune disease
Immune complex deposition in tissues such as blood vessels, heart, joints, skin and kidneys, leading to activation of complement, stimulation of an inflammatory response, and recruitment and activation of neutrophils result in damage to tissues of these organs.
what are type IV mediated autoimmune diseases?
type IV mediated diseases include type 1 diabetes, rheumatoid arthritis and ,multiple sclerosis.
what is Polyautoimmunity and
multiple autoimmune syndrome (MAS)
About 25 percent of people with autoimmune diseases have atendency to develop additional autoimmune diseases
More than one diagnosed autoimmune disease, it’s called poly-autoimmunity. The combination of three or more diagnosed autoimmune disorders in one person is called MAS
what are some well described overlapping syndromes?
overlappign connective tissue disease features more than ien autoimmuen rheamtic disease
SLE, polymyositis, and scleroderma - mixed connective tissue disease (MCTD)
Limited cutaneous systemic sclerosis (CREST), primary biliary cirrhosis, Sjogren’s syndrome
Polymyositis and scleroderma
SLE and rheumatoid arthritis
SLE and scleroderma
what is the treatment for autoimmune diseases?
Reduce inflammation and pain – anti-inflammatory drugs
Reduce inflammation – Corticosteroids
Manage pain – e.g. paracetamol and codeine
Immunosuppressant drugs – to inhibit the active immune response and reduce inflammation
Treatment for deficiency – e.g. insulin for T1D
Surgery - treat bowel blockage in Crohn’s disease
Physical therapy – to encourage mobility
describe the basic of rheamotid arthritis.
An inflammatory joint disorder primarily characterised by symmetrical polyarticular synovitis. affects females 2-3 times more than males, more common 25 to 50 years of age, reduced life expectancy and increased disability ,
A systemic disease – but, in the early stages it is only an articular disease (early morning stiffness, fatigue, joint swelling and pain), the systemic extra-articular manifestations (lung, kidney, blood vessels, muscles or neurological system) developing at the late stage of the disease.
in osteoarthritis bone ends rub together and there is thinned cartilage. in rhematoid arthritis there is bone erosion and swollen inflammed synovial membrane
what is the ethology of rheumatoid arthritis?
generally unknown, genetic predisposition is HLA-DR4 antigen increases risk by 5 times. Environmental, infection (suspected infectious organisms triggering RA include mycoplasma, rebella, parvovirus or EBV), diet, trauma or psychological factors may play a role in initiating immune response.
what are clinical features of rheumatoid arthritis?
the onset insidious in 70%. often begins with ache and morning stiffness lasting >30 minutes and gets better with motion. most common presentation of polyarticular
and symmetric especially of small joint of feet and hands.
forefoot symptoms may appear in up to 20% of patients initially and may be more common than reported but tolerated by patients until other symptoms develop eg fingers develop
what are systemic autoimmune disease with extra-articular manifestations (symptoms outside joints)
weightless, skin, eye, respiratory, cardiac, renal, haematological, gastrointestinal, Hand deformities, cervical spine involvement
what do lab results show in rheumatoid arthritis?
Blood – increased ESR in 90%;
rheumatoid factor - if you have RA and you have rheumatoid factor or other certain auto-antibodies in your blood, it could mean that your RA is more serious and may affect more than just your joints.
synovial fluid and increased white blood cells
what changes does an x-ray show in synovial joints in someone with rheumatoid arthritis?
- initially soft tissue swelling, widening of joint space with some osteoporosis.
- Later: periarticular osteoporosis and uniform narrowing of joint space. marginal cortical bone erosions, subchondral bone erosions and cysts form, subluxations. In end stages may get bony ankylosis.
- Evidence of erosive damage to bone is seen in 45% patients on MRI within 4 months of symptom onset and 75% with 2 years
what s the rheumatoid arthritis criteria for diagnosis?
Four of the following criteria are required to diagnosis:
morning stiffness (> 1 hr for more than 6 weeks)
arthritis of three or more joints for greater than 6 weeks
arthritis of hand joints for more than 6 weeks
symmetrical arthritis for more than 6 weeks
rheumatoid nodules
serum rheumatoid factor
radiographic changes (including erosions or bony decalcification)
what is the pathogenesis of rheumatoid arthritis?
inciting agent activates the immune system causing immunological reactions, immune complexes in synovial fluid activate complement and there is an inflammatory resposne leading to joint destruction.
what are methods of rheumatoid arthritis management ?
patient education and motivation, physiotherapy, occupational therapy, good nutrition, exercise, complementary/ alternative therapies, surgical treatment
what is the treatment for rheumatoid arthritis?
There is no cure for RA, the goal of pharmacological management is to relieve symptoms, prevent joint damage and put the disease into remission.
NSAID’s are commonly used early, but disease-modifying agents are now being used earlier.
Biological agents, disease-modifying anti-rheumatic drugs (DMARDs).
More aggressive approaches – combination of drugs is common approach now as many of them are not as effective if used as monotherapy.
Delay of treatment often leads to poorer outcome
what is multiple sclerosis?
chronic inflammatory demyelination disease that affects the cns. most common neurological condition among young adults but MS is a diseases of all ages. higher in females than males
what is the ethology of multiple sclerosis?
MS is not a hereditary disease, genetic variation can increase the risk of developing MS. people who live further from equator more likely to have MS. ms is also more likely to strike those with Scottish genes
what are signs and symptoms of multiple sclerosis?
chances in sensation: muscle weakness and muscle spasm, or moving difficulty in moving,
coordination and balance; problems in speech, fatigue, acute or
chronic pain; bladder and bowel difficulties and cognitive impairment.
what are multiple sclerosis clinical subtypes ?
Progressive relapsing MS
–Steady decline since onset
Secondary progressive MS
–initial RRMS that suddenly begins to have decline without period of remission
Primary progressive MS
–steady increase in disability without attacks
Relapsing and remitting MS
–unpredictable attacks followed by periods of remission
describe the pathogenesis of multiple sclerosis
- Something initiates inflammation in the brain, making the blood-brain barrier permeable to lymphocytes and proteins.
- T cells that are specific to CNS antigens get activated in the periphery, then recognize and bind to these antigens presented by brain immune cells (microglia or dendritic cells).
- Inflammatory Reaction: The immune response escalates, with more immune cells activated, release of antibodies, and inflammatory molecules called cytokines.
- This demyelination impairs nerve signal transmission, causing the symptoms of MS
describe the role of T cells in autoimmune Encephalomyelitis.
EAE can be induced in mice by injecting them with myelin basic protein along with complete Freund’s adjuvant and causes mice to become paralysed
Th1 cells mediate the disease. These Th1 cells are specific for myelin basic protein and upon activation, they release pro-inflammatory cytokines, which contribute to the inflammatory response in the CNS and the subsequent damage to the myelin sheath.
EAE can be transmitted from one mouse to another through the transfer of T cells so they can induce the disease in another host, demonstrating the centrality of T cells in the pathogenesis of EAE
what is the treatment fro multiple sclerosis?
receive the pain and discomfort and prevent sight loss due to the disease or its complications. important to treat the cause of the disease where possible
Disease mdofyign treatments such as interferon beta1a, 1b, glatiramer acetate, mitoxantrone and natalizumab can be used
descried glatiramer acetate as a treatment drug for MS
Glatiramer acetate(GA, a synthetic amino acid copolymer, brand name is Copaxone) is an immunomodulatormedication used to treatMultiple sclerosis. GA is approved to treat Relapse remitting multiple sclerosis and clinically isolated syndrome (CIS), it reduce the frequency of relapses, but not for reducing the progression of disability.
It is a mixture of random-sized peptides that are composed of the four amino acids found inmyelin basic protein: glutamic acid, lysine, alanine and tyrosine.
describe the drug ocrelizumab
Ocrelizumab is used to treat ‘active’ relapsing MS. Its licence allows it to be used for early primary progressive MS too. It’s now recommended to be used on the NHS across the UK to treat both these types of MS.
It is ahumanizedanti-CD20monoclonal antibody.It targets CD20 marker onB lymphocytesand hence is animmunosuppressive drug. Ocrelizumab binds to anepitopethat overlaps with the epitope to whichrituximabbinds.
describe fingolimod as a treatment drug for Multiple sclerosis
Fingolimod is asphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction (stops immune cells leaving lymph nodes and getting into CNS).
Fingolimod is more effective and less side effects than GA but less potent than alemtizuman and natalizumba which have more serious side effects
