week 3 Autoimmune disease and diagnosis Flashcards
what is the definition of sensitivity?
measure of how good is the test in identifying people with the disease
what is the definition of specificity?
measure of how good is the test at correctly defining people without the disease
what is the definition of Positive predictive value ?
The proportion of people with a positive test who have the target disorder
what is the definition of negative predictive value ?
The proportion of people with a negative test who do not have the target disorder.
Give a example of a non specific diagnostic test?
Inflammatory markers
Give a examples of a disease specific diagnostic test?
Autoantibody testing
HLA typing
what is erythrocyte sedimentation rate (ESR)?
old way of measure the inflammation in the serum
how does ESR work?
Put blood in a narrow capillary tube
Viscosity of the plasma increase if you have an ongoing autoimmune response of inflammation –> thicker it is the higher grade of inflammatory response
Takes a while for ESR to dissolve fully
What is C reactive protein when is it produced?
liver produces after acute phases of systemic inflammation of the liver
how is CRP used ?
Rapidly produced and rapidly used up –> use the marker in space of 12 to 24 hrs –> use it to see how the treatment is working
give example of Non-specific markers of systemic inflammation?
Erythrocyte sedimentation rate (ESR CRP Ferritin Fibrinogen Haptoglobin Albumin Complement
what does low albumin in the blood mean?
liver disease/damage
What happens to levels of ferritin and fibrinogen in inflammation?
Increase in acute inflammatory response
What are Antinuclear Ab? (ANA)
Auto-Ab which recognise structures or substances found in the nucleus of cells - involved in alot of autoimmune diseases
What is meant by Extractable nuclear antigens (ENAs)?
Structures found in the nucleus which are the specific targets of different types of Anti-nuclear Ab
how do you detect ANA?
Use large fibrocyte type cells - they have a large nucleus Spread them along the microscope slide and incubate with patients serum If ANA is present in the serum it will bind to the cells You can visualise these bound ANAs using a second Ab with a fluorescent marker which binds to the constant Fc region Thus by visualising the fluoresence you can detect the presence of ANAs in the serum
Anti-DNA ANAs are likely to give what kind of fluorescent pattern?
Peripheral or homogenous
Anti-histone and anti-DNP ANAs are likely to give what kind of fluorescent pattern?
Homogenous
what are the techniques to detect ENA’s?
Immunoblots
Individual ELISA’s
Combination of antigens
what are antibodies to ENA’s are assoicated to what?
To particular connective tissue disorders
Including Systemic lupus erythematosus SLE
How does a microbead-based immunoassay to identify non-organ specific autoantibodies work?
1) Have beads with a unique internal colour which can be recognised by a machine and gives them a unique identity 2) To each bead you can attach a certain Ag you want to measure 3) Incubate these beads with patient serum 4) If auto-Ab are present they will attach to the bead with their specific target Ag 5) Use a second fluorescently labelled Ab which binds to any bound auto-Ab 6) Put beads through a machine, tells you which bead it is (ie. which specific Ag) and whether anything is attached
what antibody is assoicated with dsDNA (antigen)? What des this cause?
Anti-ds DNA
High specificity for SLE –> often correlates with high active severe disease
what is RF?
It is a antibody directed against the Fc portion of IgG
When is RF found?
Commonly found in rheumatoid arthritis
Why is Rf not used for diagnostic of the disease?
Not used because it has sensitivity and specificity around 70%
Can be seen with other diseases in which polyclonal stimulation of B cells is seen (chronic infections such as Hep B)
How does the RF cause a immune response?
RF and IgG join to form immune complexes which contribute to the immune process
What can high concentation of RF cause?
Vasculitis
What is VAsculitis?
is a group of disorders that destroy blood vessels by inflammation
What biomark is used to detect Rheumatoid arthritis? How specific is it?
Anti-CCP (ACPA) more specific (95%) for RA then RF
what does a positive ACPA indicate?
ACPA positive patients tend to have more severe and erosive disease
what is the advantage of ACPA ?
Much more specific and can pick up the disease before the symptoms are present so much more effective treatment?
Anti-neutrophilic cytoplasmic Ab (ANCA) were first described as an auto Ab specific for what?
Wegeners granulomatosis
what is Wegeners granulomatosis?
t is a form of vasculitis (inflammation of blood vessels) that affects small- and medium-size vessels in many organs.
what does Cytoplasmic (c)ANCA show?
Granular fluorescence of neutrophil cytoplasm with nuclear sparing
what does Perinuclear (p)ANCA show?
Apparent fluorescence of the nucleus only
but sparing the cytoplasm
what are the target antigens of Cytoplasmic (c)ANCA show?
PR3 (90%)
Azurocidin
Lysozyme (1%)
MPO
what are the target antigens of Perinuclear (p)ANCA?
MPO (70%) Azurocidin B-glucuronidase Cathepsin G (5%)* PR3
Name 3 ANCA associated systemic vasculitidies (AAV)?
1) Granulomatosis with polyangitis (Wegener’s granulomatosis) 2) Microscopic polyangitis 3) Churg-Strauss syndrome
In Wegener’s granulomatosis which Ag is more common, PR3 or MPO?
PR3 much more common than MPO
In microscopic polyangitis which Ag is more common PR3 or MPO?
MPO is more common than PR3
In Churg-Strauss syndrome which Ag is more common, MPO or PR3?
MPO is more common than PR3
what is PR3?protein used by neutrophil to destroy antibacterial
protein used by neutrophil to destroy antibacterial
why is Positive ANCA extremely useful ?
useful in suggesting the diagnosis in the proper clinical setting
what does negative ANCA does not exclude?
AASV since 10%-50% of patients may be ANCA neg
what does Reemergence of ANCA pos in a patient who was ANCA neg whilst in remission suggest?
risk of disease flare
what is Anti-mitochondrial Ab specific for?
primary biliary sclerosis
what is ANCA assoicated to waht condition?
ANCA-associated vasculitis
ANCA positivity is highest in which ANCA associated vasculitis?
Wegener’s granulomatosis followed by microscopic polyangitis followed by Churg-Strauss syndrome
what is the gold standard for testing AASV?
Histopathology
what is histopathology?
refers to the microscopic examination of tissue in order to study the manifestations of disease
what antibodies are found in found in autoimmune hepatitis?
Anti-smooth muscle and anti-liver/kidney/microsomal (LKS) Abs,
what antibodies are found in autoantibodies in type 1 diabetes?
islet cell antibodies
anti-GAD65 anti-GAD67
anti-insulinoma antigen 2 (IA-2)
insulin autoantibodies (IAAs)
what happen to the antibodies are the type 1 diabetes progress?
Disappear with progression of disease and total destruction of β islet cells
what is the Role of autoantibodies in diagnosis of type I DM?
Disease conformation
to identify relatives and patients at risk of developing autoimmune diabetes
Negative predictive value of ICA and IAA is almost 99%
Increased risk of disease development with greater number of different autoantibodies present and younger age of patient
what are the main characterstics of autoinflammation?
seemingly spontaneous attacks of systemic inflammation
no demonstrable source of infection as precipitating cause
absence of high-concetration of autoantibodies and
antigen specific autoreactive T cells
No evidence of auto-antigenic exposure
what are the 3 factors that are involved in autoimmunity?
genes, immune regulation and environment
what are the two types of HLA and where are they found?
HLA 1 found on all cells
HLA 2 –> found on antigen presenting cells
what does mutation in FoxP3 cause?
mutation of FoxP3 causes failure to develop regulatory T cells – severe autoimmunity from birth
For example X linked syndrome
what does mutation in PTPN22 cause?
mutations in PTPN22 cause T cells to be activated more easily – stronger immune response in general
Example Type 1 diabetes and RA
where do B cells and T cells grow?
Bone marrow and Thymus
how does central tolerance in bone marrow and thymus work.
The B cell or T cell have specific receptors that bind to the peptide antigen MHC –> the B cell or T cell reacts to the self antigens then it will get destroyed –> negative selection and the ones that are released are through positive selection.
It is also at this point where all the different types of receptors are produced.
what is Peripheral tolerance?
Peripheral tolerance is immunological tolerance developed after autoreactive T and B cells mature and enter the periphery.
what are the other causative associations of autoimmune disease ?
Sex (hormonal influence): women»_space; men
Age–> autoimmunity more common in elderly + due accumulation of environmental factors
Sequestered Antigents
May be recognised as foreign by the immune system
Environmental triggers
Infection
Trauma-tissue damage
smoking
how does autoreactive B cells and autoantibodies cause clinical disease?
directly cytotoxic
activation of complement
Interfere with normal physiological function
General inflammation and end organ damage
how does autoreactive T cells cause clinical disease?
Directly cytotoxic
Inflammatory cytokine production
General inflammation and end organ damage
when is the usual onset of autoimmune disease and does it affect males or females more?
Onset in middle age, old age
More common common in the elderly and women
what are the characteristics of autoimmune disease?
Can affect any organ of body Leads to loss of organ function Lifelong-chronic condition Characteristic exacerbation and remission Common for diseases to overlap
what are autoimmune disease classified into?
More than 100 different diseases
Traditionally divided into organ specific or systemic
what are characteristics of autoimmune Organ specific disease?
Affect a single organ
Autoimmunity restricted to autoantigens of that organ
Overlap with other organ specific diseases
Autoimmune thyroid disease is typical
what are characteristics of autoimmune systemic disease?
Affect several organs simultaneously
Autoimmunity associated with autoantigens found in most cells of body
Overlap with other non-organ specific diseases
Connective tissue diseases are typical
what symptoms can be seen with over reactive thyroid?
anxiety, weight loss, diarrhea and palpitations.
Although it is winter she hardly notices cold weather. She finds it almost impossible to sleep
Abudance of energy
Examination:
rapid pulse
sweaty hands.
has rapid reflexes
what symtpoms can be seen with under reactive thyroid?
recent tiredness and difficulty concentrating had experienced a decline in memory
decreased frequency of bowel movements
increased tendency to gain weight
chille with slight sweat even when warm
examination –> pulse rate low and high BP
Delayed relaxation
what is Hashimotos thyroiditis?
Destruction of thyroid follicles by autoimmune process
Associated with autoantibodies to thyroglobulin and to thyroid peroxidase
Leads to hypothyrodism
what is hypothyrodism?
Abnormal low activity of thyroid gland
in retardation of growth and mental development in children and adults.
what is Graves Disease?
Inappropriate stimulation of thyroid gland by anti-TSH-autoantibody
Leads to hyperthyroidism
The antibody is not attacking the thyroid but over stimulating the thyroid organ
what is the result of hyperthyrodism?
Causes rapid heartbeat and an increased rate of metabolism.
what are symptoms of Myasthenia gravis?
Difficulty keeping his eyes open, speaking and swallowin
Does not smile any more
His symptoms get worse as the day goes on
Pathologically what happens in Mysathenia gravis?
anti ACH receptors bind to the ACH receptors preventing the ACH from binding to them –> so you get no stimulation of muscles
what is the cause of Pernicious anaemia?
lack of B12
What are possible symptoms of Pernicious anaemia?
Fatigue, tingling in the feet and vitiligo
what is vitiligo?
a condition in which the pigment is lost from areas of the skin, causing whitish patches, often with no clear cause.
why is there a failure for the uptake of B12 in Pernicious anaemia? What is the treatment?
The B12 does not attach to RF in the stomach so it can be absorbed
Treat it by injecting B12 every 3 months
Give me 4 examples of connective tissue disease?
Systemic lupus erythematosus
Scleroderma
Polymyositis
Sjogrens syndrome
what are the symptoms of systemic lupus erythematosus ?
Photosensitive malar rash
Mouth ulcer
Arthralgia
Alopecia
fever
general tiredness
arthritis
In SLE what type of antibodies do you get?
Anti nucleus antibodies.
In SLE the immune system forms antibodies against proteins and DNA in the nuclei of cells
How do the antibodies get access to the nucleus of a cell?
There is failure of apoptosis which exposes the nuclei –> this is apparent particularly when sun damages cells but apoptosis does not properly happen
what does anti nuclear antibodies form in SLE?
Anti nuclear antibodies and their antigen form immune complexes
What do immune complexes do?
Immune complexes deposit in any organ – activate complement and cause inflammation
What happens in Lupus Nephritis?
Happens in 20% of people with lupus.
Immune complex deposition
Inflammation
Leakly glomerulus
Loss of renal function due to deposition of a lot of protein in the glomerular
Scarring
Irreversible renal failure
what is the name of glomerular inflammation?
glomerulonephritis
What are the internal organs invovled in SLE? What disease is associated with that organ?
Kidney –> Lupus nephritis
Lung —> Pleurisy/ Pleural Effusion
Brain –> Cerebrak lupus, seizures, strokes
how you test and treat SLE?
Test for Antinuclear Antibodies
Treat by using immunosuppression, B cell depletion and Glucocrticoids
What is pupura? What can it be a indicator of?
blocked blood vessels in the skin –> all that skin dies due to lack of blood supply.
Can be a indicator of meningitis or vasculitis
What causes Vasculitis?
Anti neutrophil Cytoplasmic Antibodies (ANCA)
What is Vasculitis and how is it formed?
Inflammation of the vessel wall caused by white blood cells that have been stimulated by ANCA
What are the 3 forms of ANCA vasculitis?
Microscopic Polyangiitis (MPA)
Granulomatosis with Polyangiitis (GPA)
Eosinophilic Granulomatosus with Polyangiitis (EGPA)
In Eosinophilic Granulomatosus with Polyangiitis (EGPA) what is the pathological affect?
Get granuloma –> mass of inflammed tissue
Polyangiitis –? inflammation of many vessels
Where does Granuloma and Polyangiitis occur in EGPA?
Granuloma –> destruction lesion in nose, sinuses, trachea, lung, orbits
Polyangiitis –> inflammation of small vessels causing inflammation adn damage to the skin, kidney, lung and gut
What is granulomata and do all forms of ANCA vasculitis have this?
Only some forms
Its destructive masses of chronic inflammatory tissue
Tend to affect upper airways and lungs
May cavitate
Does polyangiitis happen in all forms of ANCA vasculitis?
yes
How do you test and treat ANCA vasculitis?
test for ANCA
Treat by using immunosuppression, B cell depletion and Glucocrticoids
What are the characterstics of Raynaud’s Phenomenon?
Common in young women
Runs in families
ANA negative
Fairly Harmless
What are the characterstics of secondary Raynaud’s Phenomenon?
ANA positive
May be assoicated with Scleroderm and also SLE
What are the symptoms of Scleroderma?
Digital ulcers due to tighetening and ischaemia
Skin fibrosis and tighetening around the mouth
Lung fibrosis
What are the treatment of Scleroderma?
Vascodilating drugs, Cylcoposphamide, autologous stem cell transplant
List 4 organ specific autoimmune diseases
Hashimotos thyrioditis –> thyriod
Graves disease –> thyroid
Myaesthenia Gravis
Pernicious Anaemia
What is the clinical syndrome and treatments of Myaesthenia Gravis?
Weakness and fatigue is the clinical syndrome
The treatment is: ACH inhibitor, Plasmaphersis, Thymectomy
List 3 connective tissue disease
ANCA vasculitis
SLE
Scleroderma
what is the autoimmune process of Scleroderma?
ANA cause vasculopathy with marked secondary fibrosis
