Clinical Immunology:

does it matter?
Conleth Feighery
Department of Immunology

Medical disorders
Broad classification 1.
Caused by infection - bacterial, viral etc
2.
Malignant disorders
3.
Inflammatory disorders
4.
Genetic
5.
Vascular
6.
Metabolic

Immune response in .
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
1.

Infection
Elimination dependent on immune
response
Disease manifestations frequently
caused by the response - inflammation
All features caused by response eg
hepatitis B infection

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 therapy
Release the Hounds! Activating the T-Cell Response to Cancer; Mario Sznol, M.D., and Dan L. Longo; NEJM,
Dec 6, 2015

Inflammation
Chronic inflammation responsible for
many conditions
Cause of inflammation commonly
unknown
Disease often labeled (loosely) as
auto-immune

Allergy acute inflammation

Very common ~ 10% of population
Specific type of immune response
IgE, mast cells, allergen
Called - Type 1 hypersensitivity
Sometimes fatal

Can you name an autoimmune disease; why?

Crohns disease
Rheumatoid arthritis
Sarcoidosis
Coeliac disease
Type I diabetes mellitus
Graves disease
Multiple sclerosis

Auto-immunity
Overused term?
Any unexplained inflammatory
diseases?
Immune mediated better term
Certain features typical in classical
auto-immune disease

Classic auto-immune
disorders
Typical features Female preponderance
Auto-antibodies associated
MHC genes linked; other genes also
Respond to immunosuppressives
No known aetiology

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

SLE

Systemic lupus erythematosus

So-called connective tissue disease - CTD
Many other CTDs
May have features of SLE
Examples
Sjogrens syndrome
Scleroderma
Anti-phospholipid syndrome
Rheumatoid arthritis

Some illustrative cases

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

Case 1
What diagnoses come to mind?
What further questions?
What tests would like initially?

Case 1
FBC
Hgb - 10g/dl
WCC - 3 x 109/l
Platelets - 10 x 109/l
Comment!
Additional tests?

Case 1
PTT - 14, normal 12 seconds
APTT - 47, normal 28 seconds
What range of diagnoses?
What tests should be performed

Case 1
Idiopathic thrombocytopaenic purpura
Anti-phospholipid syndrome - APS
APS - thrombosis, thrombocytopaenia,
miscarriages
Prolonged APTT

Case 1
APS - thrombosis, thrombocytopaenia,
miscarriages
Prolonged APTT
Case 1 has many suggestive features
Get more confirmatory evidence?

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

Antinuclear antibody test

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

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!

Case 1
Treatment?
Immunosuppression
Corticosteroids - prednisolone
Azathioprine
Intravenous immunoglobulin
Anti-coagulation ??

Case 2
29 year old male
Dyspepsia, heartburn
Certain foods exacerbate - fatty foods
Investigated elsewhere - barium meal
diagnosis of IBS = irritable bowel
syndrome

Case 2
Additional history ?
What tests would you like to perform ?

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 ?

Case 2
Iron deficiency anaemia
Blood loss - peptic ulcer disease,
inflammatory bowel disease
Malabsorbtion - coeliac disease,
bacterial overgrowth etc.
Auto-antibodies?

Endomysial antibody test

> 99% specific for coeliac disease

Case 2
Diagnosis - coeliac disease
Antibody tests - tissue
transglutaminase, endomysial aby
Biopsy of small intestine - findings can
be subtle!
Mistaken diagnosis of IBS common

Coeliac disease

Coeliac disease

Destruction of villi - atrophy

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!

Coeliac disease - genes

Very strong association with HLA-DQ2
and DQ8
Possession of DQ2 or DQ8 essential for
disease to develop
Gluten fractions bind to these
molecules, initiate T cell response

Auto-immune diseases - types

ORGAN SPECIFIC
Endocrine diseases thyroid, adrenal
Intestinal disease coeliac disease
Liver disease primary biliary cirrhosis
CNS disease multiple sclerosis
Blood components platelets ITP
Kidney anti-GBM disease

Auto-immune diseases - types

NOT ORGAN SPECIFIC
Multiple structures targeted
Systemic lupus erythematosus
Rheumatoid arthritis
Vasculitic diseases - GPA

Auto-immunity - causes
Normally immune tolerance prevails
Thymus deletion of auto-reactive cells
Periphery regulation of immune
response

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

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

19 year old female

Systemically unwell hospital admiss.
DIAGNOSIS?
Immune deficiency?
Connective tissue disease? Lupus?
Vasculitis?
Auto-antibody tests?

19 year old female

Vasculitis?
Finding of haematuria suggests
systemic inflammatory disorder with
renal involvement
Potential diagnoses include SLE and
condition called GPA = granulomatosis
with polyangiitis

Anti-neutrophil cytoplasmic
ab.

Vasculitis disorder
Sensitive++, specific+++

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

GPA presenting features

Auto-antibodies and autoimmune 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

Pathogenic auto-antibodies
Graves disease
Myasthenia gravis
Skin disease pemphigus vulgaris

Graves disease

Auto-immune thyroid
disease

specific auto-antibody
to TSH receptor causes
disease

Myasthenia gravis

Antibody destroys acetylcholine receceptor

Endocrine auto-immunity

Clustering of auto-immune diseases

Anti-nuclear antibodies
Always found in SLE
patients
high sensitivity
Also found in many
other disorders
low specificity

Antinuclear antibody test

- many patterns

ANA centromere pattern

Specific patterns may indicate likely diagnosis, as here in CREST

CREST features

Anti-nuclear antibodies
React with multiple antigens
Can extract specific antigens and test
auto-antibodies further
Called Extractable nuclear antigens ENA
dsDNA antibodies

Antibody to double stranded

DNA

Crithidia luciliae kinetoplast contains dsDNA

Anti-dsDNA antibodies
Found in 30% of
SLE patients
low sensitivity
Never found in other
disorders
v. high specificity

Auto-antibodies to ENA
Series of extractable antigens
Assist diagnosis of several CTDs
Classic example is Sjogrens syndrome
anti-Ro antibody

Sorting out CTD diseases

Many connective tissue diseases have
overlapping features
Attempting specific diagnosis is important in
selecting therapy and assessing prognosis
Majority are antinuclear antibody positive
Distinguishing between scleroderma and
milder variant, CREST is an example

Extractable nuclear antigens

Sorting out the ANA + disorders ..
Antibodies to specific nuclear
components
Helps distinguish different types of CTD
Diseases include
CREST and scleroderma
Sjogrens disease and SLE
When myositis is a feature

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 are complex

autoantigens
Different components may be target of
autoantibody eg the Ro antigen

Sjogrens syndrome
autoantigens

Patients typically have anti-Ro 60 antibodies

Sjogrens syndrome Ro+

Sjogrens syndrome
Inflammation of
exocrine glands
Decreased saliva,
oral secretions
Caries++
ANA category
antibody called
Ro helpful in dx

Patient with polymyositis Ro

pos

Antibody found to be anti Ro 52 positive

Also found in Ro 52 found in scleroderma, PBC

Other anti-Ro antibody disorders

Sub-acute cutaneous lupus

Other diagnostic antibodies

Anti-mitochondrial antibodies in primary
biliary cirrhosis
Antibody may be detected before the
clinical disease emerges

Mitochrondrial antibody
Kidney tubule tissue

Auto-antibody in tissue
Best diagnostic test finding antibody
deposits in tissue
Dermatitis herpetiformis, gluten
sensitive skin disease

Antibody deposits in tissue

IgA deposits in skin papillae dermatitis herpetiformis

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

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

Case 3
Female, age 30
Urticaria for past 2 years
Intermittent
Worse pre-menstrually
Itch associated
Thinks it is related to food

Urticaria

Case 3
Swelling of lips - recent
Periorbital oedema
Had taken antibiotics 2 weeks earlier
Anxious ++
Sister with asthma

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 ?

Case 3
Urticaria/angioedema
Common
Often unexplained - idiopathic
Chronic spontaneous urticaria
Disabling - significant quality of life
impact

Angioedema

Case 3
Drugs which might be implicated
ACE inhibitors
NSAIDs, salicylates
Antibiotics?

Case 3
THERAPY
Anti-histamines
Combinations of anti-histamines
Push doses
Corticosteroids?
Self-injectable adrenaline?

Food allergy
History facts that make it likely?
What foods?
What tests?

Food allergy - history

Usually short time lapse after eating
food eg. 1 min to 1 hour
Symptoms skin rash/swelling, oral
itch, wheeze, nasal stuffiness,
diarrhoea, vomiting
Atopic

Food allergy - foods

Classic nuts, shellfish
Fruits apple, organge, kiwi .
Wheat ?
Dairy products, eggs in children

Food allergy - tests

Skin prick with food 10 min reaction
observed*
Specific IgE to food*
Food challenge
* demonstrate sensitisation, not clinical
reaction

Angioedema - hereditary

Angioedema hands

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