Immunodeficiencies Flashcards
What is primary and secondary immunodefiency?
- Primary (congenital): defect in immune system
* Secondary (acquired): caused by another disease
What are the clinical features of Immunodeficiencies?
- 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 (lives abscess, osteomyelitis)
What cells does a primary immunodeffiency effect?
- Adaptive immune system: affect T and B cells
* Innate immune system: affect phagocytes, complement
Describe the defects in adaptive immunity
Subclassification- primary component affected (B/T cell or combined).
Often T cell defect impair antibody production.
Defects in lymphocyte development or activation.
What are the major B lymphocyte disorders?
- X-linked agammaglobulinaemia (Bruton’s disease)
- Common variable immunodeficiency (CVID)
- Selective IgA deficiency
- IgG2 subclass deficiency
- Specific Ig deficiency with normal Igs
Describe X-linked agammaglobulinemia (Bruton’s disease):
- Also known as Bruton’s disease
- 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)
What causes DiGeorge syndrome?
- 22q11 deletion leading to failure to develop 3+4th pharyngeal pouches.
- Complex array of developmental defects.
- Dysmorphic face: cleft palate, low-set ears, fish-shaped mouth.
- Hypocalcaemia, cardiac abnormalities.
- Variable immunodeficiency (absent/reduced thymus => affects T cell development
Describe Wiskott-Aldrich syndrome
- X-linked
- Defect in WASP (protein involved in actin polymerisation => defect in signalling)
- Thrombocytopaenia, eczema, infections
- Progressive immunodeficiency (T cell loss)
- Progressive ↓ T cells; ↓ T cell proliferation
- Ab production (↓ IgM, IgG; high IgE, IgA)
What is SCID?
Severe Combined Immunodeficiency (SCID).
What causes SCID?
- Involves both T and B.
- 50-60% X-linked; rest - autosomal recessive
- Presentation- well at birth; problems > 1st month. diarrhoea; weight loss; persistent candidiasis. Severe bacterial/viral infections, failure to clear vaccines and unusual infections (Pneumocystis, CMV).
- 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 => defective T cell development => lack in B cell help (low Ab)
- RAG-1/RAG-2 defect => no T and B cells
- ADA (adenosine deaminase deficiency); => accumulation of deoxyadenosine & deoxy-ATP => toxic for rapidly dividing thymocytes
- Investigations- Lymphocyte subsets: T, B, NK (% and numbers) => low total lymphocyte count => SCID sign! Pattern: very low/absent T; normal/absent B, sometimes also absent NK (γ-chain defect affecting IL-15 receptor). Igs low
- T cell function ↓ (proliferation, cytokines).
- Treatment= isolation. No live vaccines, blood products from CMV-negative donors (cytomegalovirus). I.V. Ig replacement, treat infections, bone marrow/haematopoietic stem cell replacement, gene therapy (for ADA and y-chain).
- Outcome- dependent on prompt diagnosis. Survival >80% with early diagnosis, good donor match and no infections pre-transplant.
- <40% survival for late diagnosis, chronic infections and poorly matched donors.
- Regular monitoring post BMT.
Describe coimbined immunodeficiencies- Ataxia-Telangiectasia (AT):
- Autosomal recessive.
- Defect in cell cycle checkpoint gene (ATM) => sensor of DNA damage => activates p53 => apoptosis of cells with damaged DNA.
- ATM gene stabilises DNA double strand break complexes during V(D)J recombination => defect in generation of lymphocyte antigen receptors & lymphocyte development. B cell and antibody deficiency.
- Progressive cerebellar ataxia (abnormal gait).
- Typical telangiectasia (ear lobes, conjunctivae)- small dilated-blood vessels near the surface of the skin or mucous membranes.
- Immunodeficiency. Increased incidence of tumours later in life.
- Combined immunodeficiency (B & T).
- Defects in production of switched Abs (IgA/G2).
- T cell defects (less pronounced) <= thymic hypoplasia.
- Upper & lower respiratory tract infections.
- Autoimmune phenomena, cancer.
Phagocyte defects- chronic granulomatous disease:
What defects in phagocytes can occur?
- Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidase (NADPH) components
- Killing pathogens is oxygen dependent. Resting phagocyte becomes activated through assembly of NADPH oxidase generation of superoxide anion.
- Formation of granulomas.
- Diagnosis- tests measure oxidative burst e.g. NBT test (Nitroblue tetrazolium reduction- blue in normal red otherwise) and flow cytometry dihydrorhodamine (no change even when stimulates with PMA).
Describe Phagocyte defects- Chediak-Higashi syndrome
- Rare genetic disease.
- Defect in LYST gene (regulates lysosome traffic).
- Neutrophils have defective phagocytosis.
- Repetitive, severe infections.
- Defect phagosome-lysosome fusion => defective killing of phagocytosed microbes => recurrent infections.
- Decreased number neutrophils
- Neutrophils have giant granules
Describe Phagocyte defects- LAD (leucocyte adhesion deficiency):
- 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).
- Presentation- skin infections, intestinal + perianal ulcers
- Investigation- reduced neutrophil chemotaxis and reduced integrins on phagocytes (flow cytometry).
Describe complement deficiencies
• Can affect different complement factors severe/fatal pyogenic infections (C3 deficiency).
• Predisposition to infection with different pathogens.
• Symptoms differ depending on C factor affected.
• Recurrent infections (Neisseria) - deficiency terminal complex (MAC): C5, C6, C7, C8 & C9.
• Severe/fatal pyogenic infections (C3 deficiency)
• SLE-like syndrome (C1q, C2, C4 deficiency)
• Hereditary angioneurotic oedema: failure to inactivate complement (deficiency in C1 inhibitor); intermittent acute oedema skin/mucosa => vomiting, diarrhoea, airway obstruction.
• Investigations- complement function: CH50 (haemolysis). Measure individual components.
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