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