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Primary Immunodeficiency Conleth Feighery Dept. of Immunology 3rd Med February 2010 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 • • • • • • • 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 – molecular causes • 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 - examples • Rare disorders c. 1: 20, 000 population Diagnosis depends on • Clinical awareness/experience • Unusual but characteristic presentation • History of unusual infections, symptoms • Family history + Primary immuno-deficiency Case histories Immunodeficiency - case history. • BB - 40 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 Antibody deficiency – infection sites Pneumonia - affecting right lower lobe Otitis media CT scan of lung - bronchiectasis 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 2 • • • • 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 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 Antibody deficiency • • • • • Encapsulated organisms “Pyogenic” Strep pneumonia, Haemophilus influenza ENT, lungs Immunoglobulin measurement – easy – if you think of it • Test IgG, IgA, IgM Antibody deficiency - treatment • Replace IgG – intravenous, sub-cutaneous • Antibiotics • Expectoration – frequent! Case history 3 . • PO, aged 25 years • Recurrent bacterial infections, early childhood • Tuberculosis, disseminated aged 6 years • Brother with similar history died from brain inflammatory disorder Case history 3 - diagnosis? • Low IgG, low IgA but IgM normal • B cells present • Tuberculosis – uncommon in pure Ig deficiency Case history 3 - diagnosis • Hyper-IgM syndrome • Significant T cell defect – absence of CD40 ligand Antibody deficiency 3. Diagnosis • Hyper IgM syndrome • Rare – 1 in million? CD40 ligand B Th CD40 ligand Cytokines - IL-4, 5, 6 Essential for “class switching – to IgA, IgG synthesis CD40 ligand Th Macroph APC CD40 ligand Cytokine – IFN-gamma Essential for killing of intra-cellular infections Hyper-IgM - HIGM • • • • Patients may have elevated IgM levels Low levels of IgG, IgA Cause - CD40 ligand deficiency Incidence < 1: million HIGM - infections Major cause of morbidity and mortality Susceptible to • Pyogenic bacteria Also - “Opportunistic” infections • Pneumocystis carinii • Cryptosporidium parvum - in drinking water • Toxoplasma gondii HIGM - treatment • • • • IgG replacement Prophylaxis – co-trimoxazole Boiled, filtred drinking water Bone marrow transplant 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 Case history 4 • Diagnosis ? Case history 4 • Diagnosis ? • Low IgG, IgA and IgM • T cells low David, the ‘boy in the bubble’ David, the ‘boy in the bubble’ • • • • • Severe combined immunodeficiency = SCID Rare – 1 in 100 000 Treatment – urgent bone marrow transplant IgG replacement Negative pressure isolation SCID - treatment • • • • Make the diagnosis - rapidly fatal Negative pressure isolation Urgent bone marrow transplant IgG replacement 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 X-linked SCID g chain gene - for cytokine receptors Case history 5. • Cells may be present – but not functioning • Neutrophil disorder Case history 5. • • • • Neutrophils present Able to migrate to target organisms Able to phagocytose Unable to kill certain organisms Case history 5. • • • • 30 year old male History of skin abscesses - Staph aureus Lung and liver abscesses Lung abscess, extending to spinal cord Aspergillus Case history 5. • Neutrophils – key role in protection against fungal infection • Killing involves “respiratory burst” – increased oxygen utilisation • NADPH oxidase defect Chronic Granulomatous Disease Chronic Granulomatous Disease • • • • • Staph aureus Burkholderia cepacia Serratia marcescens Nocardia Aspergillus Chronic Granulomatous Disease • Treatment • Bone marrow transplant • Prophylaxis – co-trimoxazole, itraconazole Immunodeficiency – defects in …. lymphocytes neutrophil APCs T cell Complement proteins B cell Immunodeficiency - diagnosis • • • • • Delay in diagnosis – significant issue Consider if … Chronic infection Atypical infection Atypical response to infection Immunodeficiency - tests • Many are simple, readily available • Tests and interpretation often requires specialist input • Some disorders are complex to investigate – become essentially research projects Immunodeficiency - tests • • • • White cell count and differential IgG, IgA, IgM levels Complement function (2 pathways) Lymphocyte subsets • If the above are normal, unless strong clinical suspicion, unlikely to be a significant defect Immunodeficiency tests • “Routine” tests initially performed • Complex tests - dependent on the likely defect • Guided by infectious agents, clinical scenario Take home messages • Well described human immune deficiency disorders • Diagnosis important - treatment, prognosis • Help in understanding the molecular basis of immune system Immunodeficiency slides • • • • Some additional slides Other examples of immunodeficiency Background literature Some repetition! 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 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 Immunodeficiency investigations Lymphocyte subsets • B cell count • T cell count • Helper T cell count - low in HIV disease • Cytotoxic T cell count • Natural killer cell count Flow cytometer - laser analysis of cell types Immunodeficiency Treatment options Treatment • Replacement - e.g. antibody infusions • Bone marrow transplantation - stem cell infusions, HLA matched family member • Gene therapy • Antibiotic, anti-fungal, anti-viral drugs Immunodeficiency - other causes • Leucocyte adhesion deficiency – LAD • White cells not able to ‘stick’ to endothelium • CD18 – the beta chain of an integrin – required for ‘sticking’ • Gene defect – chromosome 21 Leucocyte adhesion deficiency A. Normal aggregation to stimulus B. Failure of aggregation C. Periodontitis Leucocyte adhesion deficiency Leucocyte adhesion deficiency Immunodeficiency - other causes • Cytokine defects – e.g. interferon gamma – tuberculosis risk • Cell signalling defects e.g. STAT 3 – 2007 – severe boils, lung abscesses • Toll like receptor (TLR) 3 – herpes simplex encephalitis risk Primary Immunodeficiency • Rosen et al. N Engl J Med 333, 431, 1995. Excellent general review. • N Engl J Med. Last few years, series on Immunology including immunodeficiency - see Buckley RH. Nov 2000, lymphocyte defects • Fischer, A. Lancet, 357, 1863, 2001. Lists the many types of now identified immunodeficiency states Primary Immunodeficiency • Assari, TL. Review of CGD. Medical Immunology, 2006. Vol 5 • Cunningham-Rundles, C. and Ponda, PP. Molecular defects in T- and B-cell primary immunodeficiency disorders. Nature Reviews Immunology, 2005: 5, 883.