1. IMMUNODEFICIENCY DISORDERS

2. Host Defense Mechanisms
Skin and mucosal barriers
Humoral immunity (B cells, plasma cells, Ab)
Cell-mediated immunity (T cells)
Phagocytosis
Complement

3. Classification of Immunodeficiency states
Primary - intrinsic defect in immune system - many genes now identified.
Secondary - known causative agent
eg. HIV virus, drug

4. 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
Organisms that respond poorly to therapy
Growth retardation
Family history

5. Suspecting Immunodeficiency
Humoral (antibody) deficiency associated with:
Recurrent infections with encapsulated bacteria
Chronic sinupulmonary infections
Cell-mediated deficiency characterized by:
Recurrent infections with
Viruses
Fungi
Opportunistic organisms (PCP)
Diarrhea, wasting, growth retardation
Combined immunodeficiency

6. Many of these disorders also include abnormalities in the cells responsible for generating or maintaining an antibody response.
The patients often improve with antibiotics but get sick again when these are discontinued.
The cornerstone of therapy for antibody deficiency disorders is immunoglobulin (Ig) replacement.

7. Primary Immunodeficiency
Version of lecture for Science students.

8. Primary Immunodeficiency
Great advances in genetic identification in late 1980s, early 1990s
Over 150 genetic disorders now recognised
Selection of disorders presented here

9. Humoral Immunodeficiency (B cells)
Transient hypogammaglobulinemia of infancy
Slow to develop normal levels of antibody
Asymptomatic, minor infections
Low levels of IgG, IgA (IgM usually normal)
Resolves by 3-6 yo
IgA deficiency
Most common humoral antibody deficiency
50-80% asymptomatic
Recurrent sinopulmonary infections most frequent manifestation
May have severe malabsorption (chronic diarrhea)
Isolated low IgA level
Increased risk of autoimmune disorders

10. Bruton’s X-linked Agammaglobulinemia
No B cells
Child clinically well for first 6 months of life
Recurrent upper/lower respiratory tract infections with encapsulated bacteria (S. pneumo, H.flu)
Bronchiectasis  chronic cough/increased sputum
Sepsis, meningitis, skin infections
Paucity of lymphoid tissue (tonsils, adenoids)
Markedly decreased IgG, IgA, IgM
Treatment: IVIG, antibiotic therapy

11. Bruton’s X-linked Agammaglobulinem- 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

12. Common Variable Immunodeficiency
B lymphs don’t differentiate into plasma cells
Recurrent sinopulmonary infections
Low IgG, IgA, IgM
Treatment: IV Ig
Associated with autoimmune disease, lymphoma

13. 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

14. Antibody deficiency – infection sites
Otitis media
Pneumonia - affecting right lower lobe

16. DiGeorge Syndrome No T cells secondary to thymic hypoplasia
Overwhelming infections with viruses, fungi, bacteria
Treatment: correct hypocalcemia, cardiac defects, fetal thymus transplant

17. SCID (severe combined immunodeficiency)
Defects in stem cell maturation
Manifestations seen in first 3 months of life
Recurrent, severe bacterial, viral, fungal, and protozoan infections (usually respiratory infections)
Failure to thrive, diarrhea, dermatitis, candidiasis
Most have lymphopenia, decreased IgG, IgA, and IgM
Diagnosis made by analysis of T, B, and NK cell subsets
Treatment: isolation, treat underlying infections, bone marrow transplant

18. 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

19. T cell immunodeficiency
Severe combined immunodeficiency - SCID
9 different molecular causes
children living in gnotobiotic isolation, ie bubbles! 'david' who lived in isolation until he was 12; he then received a bmt from his sister, but died about 4 months or so later from an overwhelming ebv infection

20. SCID - treatment SYMPTOMS - Present early - by 3 months
Oral candidiasis
Lung inflammation “pneumonitis”
Diarrhoea
Failure to thrive !!!
DIAGNOSIS
Absence of T cells
Some - absent B and/or NK cells
Low immunoglobulins
Medical Emergency
Isolation - negative pressure environment
Immunoglobulin replacement
Bone marrow transplant - curative 80%
Gene therapy - works but ……. leukaemia

21. Increased risk for hematologic malignancy
Treatment: manage bleeding/infections, BMT

25. Ataxia Telangiectasia
Autosomal recessive deficiency in DNA repair affecting T and B cells
Progressive ataxia, telangiectasia, variable immunodeficiency (recurrent sinopulmonary infections common)
Increased risk of malignancy (leukemia, lymphoma)

26. Hyper IgE (Job) syndrome
Autosomal recessive
Symptoms/signs
Coarse facial features/skeletal abnormalities
Recurrent staph infections
Impetigo (resistant)
Pneumonia with pneumatocele formation
3 E’s: Elevated IgE, Eosinophilia, Eczema

27. Hyper IgM Syndrome T cell abnormality preventing IgM  IgG
X-linked recessive (males 6 mo-1 year)
Frequent sinopulmonary infections, diarrhea, opportunistic infections (PCP)
Low levels of IgG/IgA, high levels of IgM
Treatment: Ig replacement

28. Case history 3-- Hyper IgM syndrome
PO, aged 20 years
Recurrent bacterial infections, early childhood
Tuberculosis, disseminated aged 6 years
Brother with similar history died from brain inflammatory disorder
Diagnosis -
Hyper IgM syndrome
Absent IgG, IgA
Fail to switch IgM to other Ig classes

29. 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

30. Antibody deficiency – infection sites
Otitis media
Pneumonia - affecting right lower lobe

31. CT scan of lung - bronchiectasis

34. 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

35. HIV Retrovirus infecting CD4 + cells
Vertical transmission, breastmilk, sex
Wide range of clinical manifestations
Failure to thrive, fevers, night sweats, malaise, recurrent thrush, recurrent bacterial infections
Decreased CD4 count, may have elevated Ig
AZT x 6 weeks, PCP prophylaxis

36. Complement System Disorders
Defects of early components (C1-C4) associated with infections with encapsulated bacteria
Present similarly to humoral immune deficiencies
Defects of late components (C5-C9) associated with Neisseria infections
Also associated with autoimmune-like conditions
CH50 functional assay assesses entire complement cascade
Also may use individual components
Treatment: treat infectious and autoimmune sequelae