Download Classification of Immunodeficiency states

Primary Immunodeficiency
Conleth Feighery
Dept. of Immunology
MSc in Molecular Medicine 2009
Primary Immunodeficiency
• Great advances in genetic identification in late
1980s, early 1990s
• Over 150 genetic disorders now recognised
• Selection of disorders presented here
Learning objectives
 Primary immuno-deficiency – rare genetic disorders
 Secondary immuno-deficiency – common quantitative,
disorders
 How to suspect its presence, importance of early
diagnosis
 Tests employed in diagnosis
 Implications of immuno-deficiency: infection,
malignancy, auto-immunity
 Specific treatment of immuno-deficiency states.
Secondary immunodeficiency
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Multiple factors can affect immune function
Age - reduced function in young, old
Nutrition - dietary defects eg. iron deficient
Developing world - malnutrition
Other disease - eg. cancer
Therapy - drugs, radiation
Viruses - HIV, others
Primary Immunodeficiency - examples
• Failure of antibody production – cause: btk
defect
• Failure of T cell:APC interaction – cause: CD40
ligand defect
• Failure of T cell development – cause: IL-7
receptor gamma chain defect
• Failure of neutrophil killing – cause: NADPH
oxidase defect
Primary Immunodeficiency
• Issues
• Delayed diagnosis
• Rare genetic defect - diagnosis requires
detailed molecular investigation
• Patients may have features of rare syndrome
Type of infection helps predict the
type of immunodeficency
• B lymphocyte - pyogenic bacteria lungs
• T lymphocyte - viruses, fungi,
mycobacteria
• Complement - meningococcus CNS
• Phagocyte - staphylococcus - skin
Primary immuno-deficiency
Case histories
Immunodeficiency
- case history.
• BB - 25 year old male – unwell as child
• Lobar pneumonia x 3
• Family history - 2 brothers died
following recurrent lung infections
• Investigations - absence of antibodies IgG, IgA, IgM
• DIAGNOSIS - X-linked
agammaglobulinaemia
BB - patient with XLA
Essential role of BTK
XLA - BTK defect
• Defect in B cell
maturation
• Genetic disorder gene on Xchromosome
• codes for Bruton’s
tyrosine kinase - BTK
essential for B cell
development
Common variable
immunodeficiency - case
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AB - 29 year old male
Recurrent ear and sinus infections
Strep. pneumoniae lung infection
Malabsorbtion - Giardiasis lamblia
infection
• DIAGNOSIS - Common Variable
Immunodeficiency - CVID
Antibody deficiency – infection sites
Pneumonia - affecting right lower lobe
Otitis media
CT scan of lung - bronchiectasis
Antibody deficiency 2.
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Common variable immunodeficiency - CVID
Incidence - 1:20,000
Heterogeneous - group of disorders
Males and females affected
Some genes now identified* – but account for
only 10% of patients
• * ICOS, CD19, TACI, BAFF-R
Antibody deficiency
• Easy to make the diagnosis
• Critical issue – THINK of possibility
Case history 3 .
• PO, aged 20 years
• Recurrent bacterial infections,
early childhood
• Tuberculosis, disseminated aged 6
years
• Brother with similar history died
from brain inflammatory disorder
Antibody deficiency 3.
Diagnosis • Hyper IgM syndrome
• Absent IgG, IgA
• Fail to switch IgM to other Ig classes
CD40 ligand
B
Th
CD40 ligand
Cytokines - IL-4, 5, 6
Hyper-IgM - HIGM
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Patients may have elevated IgM levels
Low levels of IgG, IgA
Cause - CD40 ligand deficiency
Incidence < 1: million
CD40 ligand
Th
Macroph
APC
CD40 ligand
Cytokine – IFN-gamma
HIGM - infections
Major cause of morbidity and mortality
• Pyogenic bacteria
Also - “Opportunistic” infections • Pneumocystis carinii
• Cryptosporidium parvum - in drinking water
• Toxoplasma gondii
Hyper-IgM - infections
RISKS • Cryptosporidiosis protozoa - in farm
animals, milk, water;
toxin released
• Can cause chronic
biliary inflammation
• Boiled/filtered
drinking water
Case history 4
• 1 year old boy
• Recurrent chest infections - viral, fungal,
bacterial
• Constantly in hospital
• Severe “failure to thrive”
• Blood tests - low lymphocyte count
T cell immunodeficiency
• Severe combined immunodeficiency - SCID
• 9 different molecular causes
T cell immunodeficiency
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Rare - 1: 100 000
X-linked - commonest - 60% of SCID
Males
Rapidly fatal
Emergency bone marrow transplantation
Early diagnosis important
SYMPTOMS • Present early - by 3 months
• Oral candidiasis
• Lung inflammation “pneumonitis”
• Diarrhoea
• Failure to thrive !!!
SCID
• Various molecular causes
• X-linked form - absence of gamma chain in
cytokine receptor - commonest form
• Defect in IL-7 function
SCID - molecular defects
X-linked SCID
• commonest form X-linked - Xq
13.1-13.3 - 60% cases
• common  chain defective
• same  chain in IL-2, IL-4, IL-7, IL-9,
IL-15, IL-21 receptors.
X-linked SCID
 chain gene - for
cytokine receptors
SCID - diagnosis
• Absence of T cells
• Some - absent B and/or NK cells
• Low immunoglobulins
SCID - treatment
Medical Emergency
• Isolation - negative pressure environment
• Immunoglobulin replacement
• Bone marrow transplant - curative 80%
• Gene therapy - works but ……. leukaemia
Gamma chain deficient SCID
- gene therapy
• Gene therapy successful in > 10 patients.
Complete restoration of T cell populations,
restored Ig production • but 2 patients developed leukaemia
• Alain Fischer, Science 2000, NEJM 2002
Case history 5.
• JN - 25 year old male; female siblings
and one brother a/w.
• History of skin abscesses - Staph aureus
• Lung and liver abscesses Pseudomonas, Serratia marcesens
• Lung abscess, extending to spinal cord Aspergillus
Chronic granulomatous disease
• Note cervical nodal
abscess
• Gingivitis and
periodontitis
• Abscess indenting
the oesophagus
Chronic Granulomatous Disease
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Staph aureus
Burkholderia cepacia
Serratia marcescens
Nocardia
Aspergillus
Case history 5.
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Lung surgery - lobectomy
Spinal surgery
Paralysis on left side - temporary
4 month hospitalisation
Now well
Chronic Granulomatous Disease
Oxidative Burst Flow Cytometry
• Flow cytometric assay
• Neutrophils separated
• Stimulate with
Phorbol Myristate
Acetate
• Reduce DHR
• Shift in
immunoflourescence
Immunodeficiency - causes ….
lymphocytes
neutrophil
APCs
T cell
Complement proteins
B cell
Multiple cells of the IS
Case 6 – 17 year old male
History
• Normal health until 1 month ago
• Acute episode of headache, neck stiffness
• Hospital admission – meningococcal
meningitis
• Treated with antibiotics – full recovery
Case 4 – 17 year old male
History - continued
• 3 weeks later, second episode of headache,
diminished consciousness
• Hospital admission, CSF sample,
meningococcus identified
• Failed to respond to treatment, died
Fatal C7 deficiency
C1
C4, C2
C3
C5 C6
C7
LYSIS
17 year old boy with 2nd episode of Meningococcal meningitis
C8,9
Immunodeficiency - when to suspect?
Infections
• Recurrent – sinus, lungs
– abscesses; brain
• Atypical
– Atypical mycobacterium e.g. M. avium
– Opportunistic organisms eg. Pneumocystis carinii
– in T cell defects
Immunodeficiency - when to suspect?
Syndrome features • diGeorge – cardiac, facial, metabolic (calcium)
• Wiskott-Aldrich – eczema, bleeding (low
platelets, X-linked
• Ataxia-telangiectasia
Classification of
Immunodeficiency states
• Primary - intrinsic defect in
immune system - many genes now
identified.
• Secondary - known causative agent
eg. HIV virus, drug