Immune Deficiency Diseases Flashcards
How are immunodeficiencies classified?
Primary Immunodeficiency diseases (PID)
• Inborn errors of immunity
• Caused by mutations in genes important for immune function
• familial (inherited) or sporadic (de novo)
• Variable presentation and severity
Secondary immunodeficiency • HIV/AIDS • Immunosuppressive therapy, drugs, chemotherapy • Malignancy • Other conditions
Problems with which cells can cause susceptibility to which infections?
Macrophage- mycobacteria
Neutrophil- bacteria and fungi
T cell- viruses, mycobacteria and fungi
B cell- bacteria
How is primary immunodeficiency classified?
- Humoural immune defects (most common- antibody defects)
- T cell defects
- Combined immune defects- combination of cellular and humoural
- Neutrophil defects
- Other innate immune defects
Outline humoural immune defects
- Common Variable immunodeficiency- lower levels of Ig
- X-linked agammaglobulinaemia (XLA)- few B cells- no antibodies
- Selective IgA deficiency- common, often asymptomatic
- Specific antibody deficiency- normal Ig levels, poor function
- Transient hypogammaglobulinaemia of infancy- delay in production of Ig
- HyperIgM syndromes- defects in class switch recombination result in high IgM levels and low/absent IgG/A
Outline T cell defects
- Di George syndrome (22q deletion syndrome)- cardiac problems, intellectual disability, low/absent T cell production
- Idiopathic T cell lymphopaenia- unexplained T cell defects
Outline combined immune defects
• Severe combined immunodeficiency (SCID)
• Combined immunodeficiency syndromes:
- Wiskott Aldrich syndrome- deficiency of WASP protein- interactions between B and T cells- eczema, thrombocytopenia
- CD40/CD40L deficiency- important costimulator- X-linked, leads to hyperIgM syndrome
- DOCK8 deficiency- recurrent viral, fungal infections
• Late onset combined immunodeficiency disorder (LOCID)
Outline neutrophil defects
- Autoimmune neutropaenia
- Severe congenital neutropaenia
- Chronic granulomatous disease
- Leukocyte adhesion defect
Outline other primary immune defects
- Complement defects- Autoimmune/kidney disease/recurrent meningitis
- IRAK-4 deficiency- Toll-like receptor defect
How can we measure immune function?
• Assessing cell number- flow cytometry:
- basic tests- FBC, immunophenotyping (WBC subsets)
- more complex- T/B naïve/memory
• Assessing cell function- T cells:
- plate PBMCs in culture medium
- stimulate with T cell antagonists and add PHA and Anti-CD3/CD28
- normal-> proliferation measured using CFSE dye
• Assessing cell function- B cells:
- basic tests- levels of IgG/A/M/E, post vaccine responses
• Extended tests to facilitate diagnosis:
- western blotting to measure protein expression (WASp deficiency)
- functional studies (phosphorylation of (STAT1)
- genetics- single bp changes
Outline X-linked agammaglobulinaemia (XLA)
- Defects in BTK gene- no mature B cells/antibodies
- Can be antigen-independent (Pro/Pre-B cells affected)- defects in BTK, BLNK, λ5, Igβ, LRRC8
- Can be antigen-dependent (mature and memory B cells affected)- CSR defects, CVID, Specific antibody deficiencies
Outline common variable immunodeficiency (CVID)
- Antibody deficiency disorder- marked decrease in IgG and IgM or IgA
- Poor vaccine responses, age of onset >2
Outline sever combined immunodeficiency (SCID)
• Present in infancy- immunological emergency
• Due yo mutation in genes important in T cell development and function
-> defective: cytokine signalling, antigen presentation, VDJ recombination, TCR signalling
-> low/absent T cells
What are TRECs?
TCR excision circles- excluded during VDJ recombination in T cells
KRECs in B cells
Outline chronic granulomatous disease (CGD)
• Impaired oxidative burst due to mutations in phox proteins
• Normally, activation of neutrophil phagocytosis-> assembly of NADPH oxidase components-> electron pump which generates reactive oxygen species and superoxides which catalyse change of H2O2 to HOCl
• Mutations in any Involved proteins causes CGD
- phox component gp91 most common (X-linked)
- others are autosomal recessive- p22, p47, p67, p40
• Assessment of neutrophil function:
- NBT assay, blue NBT formazan deposits in normal stimulated cells
- Protein expression assay- checking for phox (eg, gp91phox)
Outline secondary immunodeficiencies
• Malnutrition
• Loss of Cellular/humoural components
- lymphocytes passively lost into intestine in intestinal lymphangiectasia
- proteins (especially antibodies) lost into urine in nephrotic syndrome
• Other systemic diseases
- diabetes
• Tumours, malignancies
- direct effect on immune system
- Cytotoxic therapies- chemotherapy and radiotherapy
• Immunosuppressive therapy
• Infectious diseases:
- Malaria- inhibits development of immune responses
- HIV/AIDS-> CD4 T cell lymphopaenia
