Primary

Immunodeficiency
Conleth Feighery
Dept. 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 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 immunodeficiency 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 immunodeficiency
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 Xchromosome
codes for
Brutons 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

Th
CD40 ligand

CytokinesIL4,5,6

Hyper-IgM - HIGM
Patients may have elevated IgM
levels
Low levels of IgG, IgA
Cause - CD40 ligand deficiency
Incidence < 1: million

CD40 ligand

Th

Macroph
APC
CD40 ligand

CytokineIFNgamma

HIGM - infections
Major cause of morbidity and mortality
Pyogenic bacteria
Also - 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, IL15, IL-21 receptors.

X-linked SCID

chain gene - for

cytokine 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 .
lymphocytes

neutrophil
T cell

APCs

Complementproteins
B cell

Multiple cells of the

IS

Case617yearoldmale
History
Normal health until 1 month ago
Acute episode of headache, neck stiffness
Hospital admission meningococcal
meningitis
Treated with antibiotics full recovery

Case417yearoldmale
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, Xlinked
Ataxia-telangiectasia

Classification of
Immunodeficiency
states

Primary - intrinsic defect

in immune system - many
genes now identified.
Secondary - known
causative agent
eg. HIV virus, drug