Download Immunodeficiency-3rd-Med

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
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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 –
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
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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 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
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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
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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
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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’
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Severe combined immunodeficiency = SCID
Rare – 1 in 100 000
Treatment – urgent bone marrow transplant
IgG replacement
Negative pressure isolation
SCID - treatment
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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.
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Neutrophils present
Able to migrate to target organisms
Able to phagocytose
Unable to kill certain organisms
Case history 5.
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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
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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
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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
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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
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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.