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Primary Immunodeficiency Conleth Feighery Dept. 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 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.
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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 h Macroph Cytokine – IFN-gamma CD40 ligand APC
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HIGM - infections Major cause of morbidity and mortality Pyogenic bacteria Also - “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 - for cytokine 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 neutrophil APCs 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
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