New Immuno Slides - Clinical Immunology Does It Matter

8/17/2019 New Immuno Slides - Clinical Immunology Does It Matter

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Clinical Immunology:

does it matter?

Conleth Feighery

Department of Immunology


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Medical disordersBroad classification -

1. Caused by infection - bacterial, viral etc

2. Malignant disorders

3. Inflammatory disorders

4. Genetic

5. Vascular 6. Metabolic


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Immune response in ….

1. Infection - bacterial, viral etc

2. Malignant disorders

3. Inflammatory disorders

4. Genetic disorders - some

5. Vascular disease?Immune system frequently plays a key role in

disease pathogenesis


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Infection Elimination dependent on immune

response

Disease manifestations frequently

caused by the response - inflammation

All features caused by response eg

hepatitis B infection


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Malignancy Symptoms due to physical presence of

tumour

Tumour control now considered to

involve the immune response

Releasing immunity to tumour antigens

- now one of big hopes for therapyRelease the Hounds! Activating the T-Cell Response to Cancer; Mario Sznol, M.D., and Dan L. Longo; NEJM,

Dec 6, 2015


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Inflammation Chronic inflammation responsible for

many conditions

Cause of inflammation commonly

unknown

Disease often labeled (loosely) as

“auto-immune”


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Allergy – acute inflammation Very common ~ 10% of population

Specific type of immune response

IgE, mast cells, allergen

Called - Type 1 hypersensitivity

Sometimes fatal


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Can you name an auto-

immune disease; why? Crohn’s disease

Rheumatoid arthritis

Sarcoidosis

Coeliac disease

Type I diabetes mellitus Graves’ disease

Multiple sclerosis


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Auto-immunity Overused term?

Any unexplained inflammatory

diseases?

“Immune mediated” better term

Certain features typical in “classical”

auto-immune disease


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Classic auto-immune

disordersTypical features -

Female preponderance

Auto-antibodies associated

MHC genes linked; other genes also

Respond to immunosuppressives No known aetiology


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Systemic lupus erythematosus Classic ‘prototype’ auto-immune disease

Female:male 9:1

Lots of auto-antibodies !

MHC association - HLA-DR3

Responds to immunosuppressives

No known aetiology


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SLE


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Systemic lupus erythematosus So-called “connective tissue disease” - CTD

Many other CTDs

May have features of SLE

Examples

Sjogren’s syndrome

Scleroderma Anti-phospholipid syndrome



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Some illustrative cases


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Case 1 24 year old female chef

Multiple purpuric lesions on trunk,

pelvis, legs

Hobby - sky diving

Previously well but

DVT diagnosed - 2 years previously


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Case 1 What diagnoses come to mind?

What further questions?

What tests would like initially?


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Case 1 FBC

Hgb - 10g/dl

WCC - 3 x 109/l

Platelets - 10 x 109/l

Comment! Additional tests?


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Case 1 PTT - 14, normal 12 seconds

APTT - 47, normal 28 seconds

What range of diagnoses?

What tests should be performed


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Case 1 Idiopathic thrombocytopaenic purpura

Anti-phospholipid syndrome - APS

APS - thrombosis, thrombocytopaenia,

miscarriages

Prolonged APTT


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Case 1 APS - thrombosis, thrombocytopaenia,

miscarriages

Prolonged APTT

Case 1 has many suggestive features

Get more confirmatory evidence?


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Case 1 Does this patient have auto-immunity?

Is it a connective tissue disease?

Would auto-antibody tests help?

Anti-nuclear antibodies – present in

most CTDs


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Antinuclear antibody test


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ANA test Helpful, but not specific for SLE, CTD

Titre useful – can ignore low titres eg

1/40, 1/80 ……

Pattern of staining – limited value

except “centromere” pattern – found in

CREST


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Case 1 – more results Anti-nuclear antibody +

If diagnosis is anti-phospholipid syndrome,

test for anti-phospholipid antibodies -

Cardiolipin antibodies ++ (IgG)**

Beta-2 glycoprotein antibodies ++ **

Lupus anticoagulant ++

**reproducible when retested!


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Case 1Treatment?

Immunosuppression

Corticosteroids - prednisolone

Azathioprine

Intravenous immunoglobulin Anti-coagulation ??


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Case 2 29 year old male

Dyspepsia, heartburn

Certain foods exacerbate - fatty foods

Investigated elsewhere - barium meal

diagnosis of IBS = irritable bowelsyndrome


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Case 2 Additional history ?

What tests would you like to perform ?


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Case 2 FBC - Hgb 10.3g/dl; MCV - 78;

ESR, C-reactive protein normal

Biochemistry screen normal

What diagnoses should be considered ?

What further tests would you order ?


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Case 2 Iron deficiency anaemia

Blood loss - peptic ulcer disease,

inflammatory bowel disease

Malabsorbtion - coeliac disease,

bacterial overgrowth etc.

Auto-antibodies?


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Endomysial antibody test

! ##$ %&'()*)( *+, (+'-).( /)%'.%'


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Case 2 Diagnosis - coeliac disease

Antibody tests - tissue

transglutaminase, endomysial aby

Biopsy of small intestine - findings can

be subtle!

Mistaken diagnosis of IBS common


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Coeliac disease


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Coeliac disease

!"#$%&'$()* ), -(..( / “0$%)123”


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Coeliac disease Treatment – gluten free diet

Common disorder, 1% of population

Female > male 2:1

Specific auto-antibody

Is it an auto-immune disorder? Does it matter!


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Coeliac disease - genes Very strong association with HLA-DQ2

and DQ8

Possession of DQ2 or DQ8 essential fordisease to develop

Gluten fractions bind to these

molecules, initiate T cell response


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Auto-immune diseases - typesORGAN SPECIFIC

Endocrine diseases – thyroid, adrenal

Intestinal disease – coeliac disease

Liver disease – primary biliary cirrhosis

CNS disease – multiple sclerosisBlood components – platelets – ITP

Kidney – anti-GBM disease


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Auto-immune diseases - typesNOT ORGAN SPECIFIC

Multiple structures targeted –

Systemic lupus erythematosus


Vasculitic diseases - GPA


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Auto-immunity - causes Normally ‘immune tolerance’ prevails

Thymus – deletion of auto-reactive cells

Periphery – regulation of immune

response


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Auto-immunity - causes Thymus – deletion of auto-reactive cells

Periphery – regulation of immune response

BUT Potential of auto-reactivity constant

Release of ‘hidden’ self -antigens

Infectious agents with similar antigens –cross reactivity


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Case 3 -19 year old female Recurrent ear infection, multiple ENT

procedures

Chronic sinusitis

Became systemically unwell, raised

temp

Joint pain, skin rash

Haematuria noted


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19 year old female Systemically unwell – hospital admiss.

DIAGNOSIS?

Immune deficiency?

Connective tissue disease? Lupus?

Vasculitis?

Auto-antibody tests?


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19 year old female Vasculitis?

Finding of haematuria – suggests

systemic inflammatory disorder withrenal involvement

Potential diagnoses include SLE and

condition called GPA = granulomatosiswith polyangiitis


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Anti-neutrophil cytoplasmic

ab.

40#'&.($(# 5(#)%5"%

6"*#($(-"778 #1"'(,('777


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19 year old female GPA = granulomatosis with polyangiitis

Auto-immune disease

Highly specific autoantibody test

ANCA test – anti-neutrophil cytoplasmic

antibody; 95% specific

Very strong association with HLA-DP

Early diagnosis is critical


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GPA presenting features


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Auto-antibodies and auto-

immune disease

Classic finding in auto-immune disease

Often very helpful in diagnosis

In many diseases, clinical and other test

findings often variable, inconclusive

Antibodies pathogenic? Other immune

components eg T cells may be primarily

responsible


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Pathogenic auto-antibodies Graves’ disease

Myasthenia gravis

Skin disease – pemphigus vulgaris


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Graves’

disease

9&$)/(::&*" $23%)(5

5(#"0#"

#1"'(,(' 0&$)/0*$(;)53$)


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Myasthenia gravis

9*$(;)53 5"#$%)3# 0'"$3.'2).(*" %"'"'"1$)%


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Endocrine auto-immunity

>.$"%(*? ), 0&$)/(::&*" 5(#"0#"#


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Anti-nuclear antibodies Always found in SLE

patients

“high sensitivity

”

Also found in many

other disorders

“low specificity”


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Antinuclear antibody test

- many patterns


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ANA centromere pattern

Specific patterns may indicate likely diagnosis, as here in CREST


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CREST features


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Anti-nuclear antibodies

React with multiple antigens

Can extract specific antigens and test

auto-antibodies further

Called -

Extractable nuclear antigens – ENA

dsDNA antibodies


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Antibody to double stranded

DNA

Crithidia luciliae – kinetoplast contains dsDNA


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Anti-dsDNA antibodies

Found in 30% of

SLE patients

“low sensitivity

”

Never found in other

disorders

“v. high specificity”


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Auto-antibodies to ENA

Series of extractable antigens

Assist diagnosis of several CTDs

Classic example is Sjogren’s syndrome

“anti-Ro” antibody


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Sorting out CTD diseases

Many connective tissue diseases have

overlapping features

Attempting specific diagnosis is important inselecting therapy and assessing prognosis

Majority are antinuclear antibody positive

Distinguishing between scleroderma and

milder variant, CREST is an example


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Extractable nuclear antigens

Sorting out the ANA + disorders …..

Antibodies to specific nuclear

components

Helps distinguish different types of CTD

Diseases include

CREST and scleroderma

Sjogren’s disease and SLE

When myositis is a feature


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CREST and scleroderma

Antibodies to ENA antigen, Scl 70, is

found in 30% of scleroderma patients

Not found in CREST patients

Scl 70 = enzyme called Topoisomerase

I

ENA l


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ENA are complex

autoantigens

Different components may be target of

autoantibody eg the Ro antigen

Sj ’ d


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autoantigens

Patients typically have anti-Ro 60 antibodies


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Sjogren’s syndrome – Ro+


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Inflammation of

exocrine glands

Decreased saliva,oral secretions

Caries++

ANA category

antibody called

“Ro” helpful in dx

P ti t ith l iti R


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Patient with polymyositis – Ro

pos

Antibody found to be anti Ro 52 positive Also found in Ro 52 found in scleroderma, PBC


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Other anti-Ro antibody disorders

Sub-acute cutaneous lupus


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Other diagnostic antibodies

Anti-mitochondrial antibodies in primary

biliary cirrhosis

Antibody may be detected before theclinical disease emerges


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Mitochrondrial antibody

Kidney tubule tissue


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Auto-antibody in tissue

Best diagnostic test – finding antibody

deposits in tissue

Dermatitis herpetiformis, glutensensitive skin disease


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Antibody deposits in tissue

@?9 5"1)#($# (* #A(* 101(..0" – 5"%:0$($(# 2"%1"$(,)%:(#


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Antibody deposits in skin disease

Indirect immunofluorescence

Pemphigus vulgaris – IgG, C deposits in

epidermis, intercellular Linear IgA disease

Bullous pemphigoid – IgG and C3 linear

deposition at dermal-epidermal junction


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Auto-antibodies of note

• Some are (almost) diagnostic

Anti-tTG; anti-dsDNA; ANCA; anti-GBM;

anti-PDH

Others are helpful, but not specific- ANA (anti-nuclear antibodies);

rheumatoid factor


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Case 3

Female, age 30

Urticaria for past 2 years

Intermittent

Worse pre-menstrually

Itch associated

Thinks it is related to food


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Urticaria


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Case 3

Swelling of lips - recent

Periorbital oedema

Had taken antibiotics 2 weeks earlier Anxious ++

Sister with asthma


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Case 3

QUESTIONS

What do you call this condition ?

What is it caused by ?

Is it due to food, drugs ?

How do you treat it ?


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Case 3

Urticaria/angioedema

Common

Often unexplained - “idiopathic”

“Chronic spontaneous urticaria”

Disabling - significant “quality of life”

impact


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Angioedema


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Case 3

Drugs which might be implicated

ACE inhibitors

NSAIDs, salicylates

Antibiotics?


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Case 3

THERAPY

Anti-histamines

Combinations of anti-histamines

Push doses

Corticosteroids?

Self-injectable adrenaline?


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Food allergy

History – facts that make it likely?

What foods?

What tests?


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Food allergy - history

Usually short time lapse after eating

food eg. 1 min to 1 hour

Symptoms – skin rash/swelling, oralitch, wheeze, nasal stuffiness,

diarrhoea, vomiting

Atopic


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Food allergy - foods

Classic – nuts, shellfish

Fruits – apple, organge, kiwi ….

Wheat ?

Dairy products, eggs in children


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Food allergy - tests

Skin prick with food – 10 min reaction

observed*

Specific IgE to food* Food challenge

* demonstrate sensitisation, not clinical

reaction


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Angioedema - hereditary


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Angioedema – hands


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Hereditary angioedema

C1-inhibitor defect – C1-inh

Genetic defect

Low, absence in majority of cases

Low levels of C4 at all times

Potentially life-threatening

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New Immuno Slides - Clinical Immunology Does It Matter