Primary Immunodeficiency

Conleth FeigheryDept. 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 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 – 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 populationDiagnosis 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 X-chromosome

• 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

T h B

Cytokines - IL-4, 5, 6

CD40 ligand

Essential for “class switching – to IgA, IgG synthesis

CD40 ligand

T hMacroph

Cytokine – IFN-gamma

CD40 ligand

APC

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 mortalitySusceptible to -• Pyogenic bacteriaAlso - “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

chain gene - forcytokine 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 ….

T cell

B cell

lymphocytes

neutrophilAPCs

Complement proteins

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 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

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 analysisof 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.