Download - Primary Immunodeficiency
Primary Immunodeficiency
Conleth FeigheryDept. 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 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.
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 - 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 X-chromosome
• codes for Bruton’s tyrosine kinase - BTK essential for B cell development
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
Antibody deficiency – infection sites
Pneumonia - affecting right lower lobe Otitis media
CT scan of lung - bronchiectasis
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
• 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
T h B
Cytokines - IL-4, 5, 6
CD40 ligand
Hyper-IgM - HIGM
• Patients may have elevated IgM levels• Low levels of IgG, IgA• Cause - CD40 ligand deficiency• Incidence < 1: million
CD40 ligand
T hMacroph
Cytokine – IFN-gamma
CD40 ligand
APC
HIGM - infections
Major cause of morbidity and mortality
• Pyogenic bacteriaAlso - “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
• 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 - forcytokine 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
• Staph aureus• Burkholderia cepacia• Serratia marcescens• Nocardia• Aspergillus
Case history 5.
• 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 ….
T cell
B cell
lymphocytes
neutrophilAPCs
Complement proteins
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 C8,9
LYSIS
17 year old boy with 2nd episode of Meningococcal meningitis
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