Primary Immunodeficiency Conleth Feighery Dept. of Immunology MSc in Molecular Medicine 2009.
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Transcript of Primary Immunodeficiency Conleth Feighery Dept. of Immunology MSc in Molecular Medicine 2009.
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Primary Immunodeficiency
Conleth FeigheryDept. of Immunology
MSc in Molecular Medicine 2009
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Primary Immunodeficiency
• Great advances in genetic identification in late 1980s, early 1990s
• Over 150 genetic disorders now recognised• Selection of disorders presented here
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Learning objectives
Primary immuno-deficiency – rare genetic disordersSecondary immuno-deficiency – common quantitative,
disordersHow to suspect its presence, importance of early
diagnosisTests employed in diagnosis Implications of immuno-deficiency: infection,
malignancy, auto-immunity Specific treatment of immuno-deficiency states.
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Secondary immunodeficiency
• 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
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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
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Primary Immunodeficiency
• Issues• Delayed diagnosis• Rare genetic defect - diagnosis requires
detailed molecular investigation• Patients may have features of rare syndrome
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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
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Primary immuno-deficiency
Case histories
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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
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BB - patient with XLA
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Essential role of BTK
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XLA - BTK defect
• Defect in B cell maturation
• Genetic disorder - gene on X-chromosome
• codes for Bruton’s tyrosine kinase - BTK essential for B cell development
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Common variable immunodeficiency - case
• AB - 29 year old male• Recurrent ear and sinus infections• Strep. pneumoniae lung infection • Malabsorbtion - Giardiasis lamblia
infection
• DIAGNOSIS - Common Variable Immunodeficiency - CVID
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Antibody deficiency – infection sites
Pneumonia - affecting right lower lobe Otitis media
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CT scan of lung - bronchiectasis
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Antibody deficiency 2.
• 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
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Antibody deficiency
• Easy to make the diagnosis• Critical issue – THINK of possibility
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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
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Antibody deficiency 3.
Diagnosis -• Hyper IgM syndrome• Absent IgG, IgA• Fail to switch IgM to other Ig classes
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CD40 ligand
T h B
Cytokines - IL-4, 5, 6
CD40 ligand
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Hyper-IgM - HIGM
• Patients may have elevated IgM levels• Low levels of IgG, IgA• Cause - CD40 ligand deficiency• Incidence < 1: million
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CD40 ligand
T hMacroph
Cytokine – IFN-gamma
CD40 ligand
APC
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HIGM - infections
Major cause of morbidity and mortality
• Pyogenic bacteriaAlso - “Opportunistic” infections - • Pneumocystis carinii• Cryptosporidium parvum - in drinking water• Toxoplasma gondii
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Hyper-IgM - infections
RISKS -• Cryptosporidiosis -
protozoa - in farm animals, milk, water; toxin released
• Can cause chronic biliary inflammation
• Boiled/filtered drinking water
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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
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T cell immunodeficiency
• Severe combined immunodeficiency - SCID• 9 different molecular causes
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T cell immunodeficiency
• Rare - 1: 100 000 • X-linked - commonest - 60% of SCID• Males• Rapidly fatal• Emergency bone marrow transplantation
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Early diagnosis important
SYMPTOMS -• Present early - by 3 months• Oral candidiasis• Lung inflammation “pneumonitis”• Diarrhoea• Failure to thrive !!!
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SCID
• Various molecular causes• X-linked form - absence of gamma chain in
cytokine receptor - commonest form• Defect in IL-7 function
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SCID - molecular defects
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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.
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X-linked SCID
chain gene - forcytokine receptors
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SCID - diagnosis
• Absence of T cells• Some - absent B and/or NK cells• Low immunoglobulins
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SCID - treatment
Medical Emergency• Isolation - negative pressure environment• Immunoglobulin replacement• Bone marrow transplant - curative 80%• Gene therapy - works but ……. leukaemia
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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
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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
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Chronic granulomatous disease
• Note cervical nodal abscess
• Gingivitis and periodontitis
• Abscess indenting the oesophagus
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Chronic Granulomatous Disease
• Staph aureus• Burkholderia cepacia• Serratia marcescens• Nocardia• Aspergillus
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Case history 5.
• Lung surgery - lobectomy• Spinal surgery • Paralysis on left side - temporary• 4 month hospitalisation• Now well
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Chronic Granulomatous Disease
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Oxidative Burst Flow Cytometry
• Flow cytometric assay• Neutrophils separated• Stimulate with
Phorbol Myristate Acetate
• Reduce DHR• Shift in
immunoflourescence
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Immunodeficiency - causes ….
T cell
B cell
lymphocytes
neutrophilAPCs
Complement proteins
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Multiple cells of the IS
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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
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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
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Fatal C7 deficiency
C1 C4, C2 C3 C5 C6 C7 C8,9
LYSIS
17 year old boy with 2nd episode of Meningococcal meningitis
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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
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Immunodeficiency - when to suspect?
Syndrome features -• diGeorge – cardiac, facial, metabolic (calcium)• Wiskott-Aldrich – eczema, bleeding (low
platelets, X-linked• Ataxia-telangiectasia
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Classification of Immunodeficiency states
• Primary - intrinsic defect in immune system - many genes now identified.
• Secondary - known causative agent eg. HIV virus, drug