Immunodeficiencies Flashcards
1
Q
What is immunodeficiency
A
- Caused by defects in one or Primary immunodeficiencies more components of the immune system
- May lead to serious and often fatal syndromes or diseases
- Collectively called immunodeficiency diseases
- Classified as primary and secondary immunodeficiencies
- Data difficult to estimate as no current screening program at birth exists
2
Q
What are the 2 classifications of immunodefiencies
A
- Primary (congenital) immunodeficiencies
- Secondary immunodeficiencies
3
Q
Describe primary immunodeficiencies
A
- A condition resulting from a genetic or developmental defect. * The defect is present from birth and is mostly inherited
- May not be clinically observed until
- Abbreviated as PID Classification Primary (congenital) immunodeficiencies later in life.
4
Q
Describe secondary immunodeficiencies
A
- Originate as a result of malnutrition, cancer, drug treatment or infection
- By far the most well known and commonly occurring is AIDS
5
Q
What are the clinical features of PID
A
- Recurrent infections (normal: <6-8 URI/year for the 1st 10 years; 6 otitis media and 2 gastroenteritis/year for the 1st 2-3 years)
- Severe infections, unusual pathogens (Aspergillus, Pneumocystis), unusual sites (liver abscess, osteomyelitis)
6
Q
What are the 10 warning signs that are used in diagnosis of PID
A
- Failure of child to gain weight
- Need for IV antibiotics
- Family history of PID
- 4 or more ear infections within a year
- 2 or more sinus infections within a year
- 2 or more months on 2 antibiotics with little effect
- 2 or more pneumonias within 3 years
- Frequent deep skin or organ abscesses
- Persistent thrush or fungal infections
- 2 or more deep-seated infections within 3 years
Having 2 or more of these signs could mean PID
7
Q
What are the causes of PID
A
- These deficiencies may affect either the innate or adaptive immune function
- Defects in innate immunity are generally caused by a defect in phagocytic or complement function * Lymphoid cell disorders may affect T cells or B cells or both (combined immunodeficiency.
- Antibody disorders
8
Q
How does PID affect haematopoiesis
A
- The consequences of the defect depend upon the number and type of immune system components involved
- Defects in the earlier stem cells affect the entire immune system
- Defects in later stage haematopoietic cells show a more restricted pathology
9
Q
What are the subclassifications of PID
A
What primary component is affected:
- B cells, T cells or both
- Often T cell defects impair antibody production
- Defects in lymphocyte development activation
10
Q
List some Major B cell disorders in PID
A
- X-linked agammaglobulinaemia (Bruton’s disease)
- Common variable immunodeficiency (CVID)
- Selective IgA deficiency
- IgG2 subclass deficiency
- Specific Ig deficiency with normal Igs
11
Q
Describe X-linked agammaglobulinaemia (Bruton’s disease)
A
- Defect in BTK gene (X chromosome)
- Encodes Bruton’s tyrosine kinase
- Block in B-cell development (stop at pre-B cells)
- Recurrent severe bacterial infections
- 2nd half of first year (lung, ears, GI)
- Autoimmune diseases (35% of patients)
- X-linked inheritance pattern
12
Q
How is X-linked agammaglobulinemia diagnosed
A
- B cells absent / low; plasma cells absent
- All immunoglobulins absent / very low
- T cells and T cell mediated responses normal
- Diagnosis of missing Igs by immunoelectrophoresis
13
Q
How is X-linked agammaglobulinemia treated
A
- IVIg: 200-600mg/kg/month at 2-3 wk intervals
- or subcutaneous Ig weekly
- prompt antibiotic therapy (URI /LRI)
- Do not give live-attenuated vaccines
14
Q
How does selective IgA deficiency present in patients
A
- Most common: 1:400-1:800
- Most cases asymptomatic; some => infections of respiratory,
urogenital or gastrointestinal tract - Low levels serum & secretory IgA
- Sometimes: increased incidence allergic disease
15
Q
What are the causes of Severe Combined Immunodeficiency
A
- Common cytokine receptor γ-chain defect (signal transducing component
of receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, IL-21) - IL-7 needed for survival T cell precursors resulting in defective T cell development and concomitant lack in B cell help (low antibodies)
- RAG-1/RAG-2 defect => no T and B cells
- ADA (adenosine deaminase deficiency); => accumulation of
deoxyadenosine & deoxy-ATP which is toxic for rapidly dividing thymocytes
16
Q
What are the key characteristics of Severe Combined Immunodeficiency
A
- Lymphocyte subsets: T, B, NK (% and numbers) result
low total lymphocyte count meaning SCID sign - Pattern: very low/absent T; normal/absent B,
production
sometimes also absent NK (γ-chain defect affecting IL- 15 receptor) - Immunoglobulins are low
- T cell function reduced proliferation and cytokine
17
Q
How is SCID diagnosed
A
Analysis with a flow cytometer
18
Q
How is SCID treated
A
- Isolation to prevent further infections
- Do not give live vaccines
- Blood products from CMV-negative donors
- IV Ig replacement
- Infection prophylaxis
- Bone marrow/haematopoietic stem cell transplant
- Gene therapy (for ADA and γ-chain genes)
19
Q
What are the outcomes of SCID
A
- Dependent on promptness of diagnosis
- Survival >80% (early diagnosis, good donor match, no infections pre-transplant)
- Survival <40% (late diagnosis, chronic infections, poorly matched donors)
- Regular monitoring post BMT => engraftment
20
Q
What is DiGeorge syndrome
A
- Thymic hypoplasia due to 22q11 deletion
- Results in failure
development 3+4th pharyngeal pouches
21
Q
What are the symptoms of DiGeoreg syndrome
A
- Complex array of developmental defects
- Dysmorphic face: cleft palate, low-set ears, fish-
shaped mouth - Hypocalcaemia, cardiac abnormalities
- Variable immunodeficiency ( Complete DiGeorge-
absent thymus Incomplete DiGeorge - reduced
thymus. - These result in absent or partial T cell
development
22
Q
How can we treat DiGeorge syndrome
A
Treated with Thymus transplantation
23
Q
What is Wiskott-Aldrich syndrome
A
- X-linked
- Defect in WASP (protein involved in actin
polymerization. T cells remodel cytoskeleton for
correct signalling) - Thrombocytopenia, eczema, infections
- Progressive immunodeficiency (T cell loss)
- Progressive ↓ T cells; ↓ T cell proliferation
- Antibody production (↓ IgM, IgG; high IgE, IgA)
24
Q
What are associated with Innate immunity effects in PID and haematopoesis
A
- Phagocyte defects
- Quantitative. Low phagocyte numbers
- Qualitative. Altered function
- Recruitment defects
- Transmigration defects
- Complement defects
25
Q
What is Chronic granulomatous disease
A
- Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidase (NADPH) components
- Presence of formation of granulomas
26
Q
How is CGD diagnosed
A
- Nitro blue tetrazolium reduction test
- Dihyrorhodamine assay
27
Q
What is Chediak-Higashi syndrome
A
- Rare genetic disease
- Defect in LYST gene (regulates lysosome
traffic) - Neutrophils have defective phagocytosis
- Repetitive, severe infections
28
Q
How is Chediak-Higashi syndrome diagnosed
A
- Decreased number neutrophils
- Neutrophils have giant granules
29
Q
What is Leukocyte adhesion deficiency
A
- Defect in β2-chain integrins (LFA-1, Mac-1)
- Defect in sialyl-Lewis X (selectin ligand)
- Delayed umbilical cord separation => diagnosis defect in β2-chain
integrins (LFA-1, Mac-1)
30
Q
How does LAD present in patients
A
Skin, GIT infections and perianal ulcers
31
Q
How is LAD diagnosed
A
- Low Neutrophil chemotaxis
- Low Integrins expression on phagocytes (flow cytometry)
32
Q
What are the main aims in treating PID
A
- Minimise/control infection
- Prompt treatment of infection
- Prevention of infection: isolation, antibiotic prophylaxis, vaccination
(not live vaccines) - Nutrition
- Replace defective/absent component of the immune system
33
Q
How can gene therapy be used to treat PID
A
- Bone marrow cell removed
- Separate immune cell progenitors
- Infected with virus to introduce a correct copy of mutated gene
- Cells take up normal gene
- Cell retired to patient
34
Q
What are secondary immunodeficiencies
A
- Much more common
- May be caused bye other conditions:
- HIV
- Protein-calorie malnutrition
- Irradiation and chemotherapy
- Spleen removal
