(FE) Week 12 Immunodeficiency Flashcards
What are the causes of primary immunodeficiency?
1) Deficiency in lymphocyte GENERATION and MATURATION
- Early (generatn)
~ Severe combined immunodeficiency (SCID)
~ Affects mostly T cells but may lose some B and NK cells (entire adaptive immunity)
- Late (maturatn)
~ Affects either B or T cells
~ Ig heavy chain deficiency, DiGeorge syndrome and ATM
2) Deficiency in lymphocyte ACTIVATION
~ Cross-linked hyper-IgM syndrome
~ Bare lymphocyte syndrome
3) Deficiency in INNATE immunity
~ Leukocyte adhesion deficiency-1, 2
~ Complement C3 deficiency
~ HSV1 encephalitis
What are the causes of secondary immunodeficiency?
1) Cytotoxic drug treatments
2) Malnutrition
3) Burns
4) AIDS
What are the cytokines/receptors/proteins needed during lymphocyte generation and maturation?
- Hematopoetic stem cells -> CLP
- CLP -> Pro-B/T (IL-7 for pro B + gamma-c, ADA, PNP for T cells)
- Pro-B/T -> Pre-B/T (RAG1,2 for VDJ recombination)
What are the deficiencies that cause SCID?
1) Cross-linked SCID
- gamma-y (cytokine receptor) mutation
~ gamma-y disrupts many IL signals (2,4,7,9,15,21)
- Lack of IL-7 signals
- dec T cells and normal/increased B cells
2) Autosomal recessive SCID (1)
- ADA or PNP enzyme deficiency
~ Accumulation of toxic metabolites
- Dec in mostly T cells
3) Autosomal recessive SCID (2)
- RAG gene mutation
- Lack of IL-7R signaling
- Dec T and B cells, and serum Ig
What are the implications of SCID?
- Increased susceptibility to infection in childhood with fungus
- Vaccination with live-attenuated vaccines can be fatal (eg polio, mmr, chickenpox, bcg, typhoid)
- Treatment must be through bone marrow transplantation
What are the 3 deficiencies that causes impaired lymphocyte maturation/late generation?
1) Ig heavy chain deficiencies
- Deletion of chromosome 14q32 (heavy chain formation from Pre-B to immature B)
- Deficiency in IgG, sometimes IgA or IgE
2) DiGeorge syndrome
- Deletion of chromosome 22q11.2 (from CLP to Pro-T)
- Complete/partial lack of CD4 and CD8 cells
- Affects multiple organs
- Anatomical abnormalities (small jaw/mouth, slanted eyes, low set ears, short stature, cardiac malfunctions and little/no thymus)
- Recurrent infections
3) Deletion in ATM protein (Ataxia Telangiectasia Mutated)
- Impairs non-homologous end joining in DNA repair
What are the implications of ATM deletion?
- In lymphocytes:
~ Defective VDJ recombination
~ T cell, IgA and IgG deficiency
~ Poor response to vaccination
~ Severe RTI - In blood vessels:
~ Telangiectasia (spider veins on surface of eyes, cheeks) - In nervous system:
~ Ataxia (wobbly gait)
How does cross-linked hyper Ig-M syndrome impair B cell activation?
- Mutations in CD40L (in CD4 T cells) affect T-cell dependent macrophage activation
- May only produce IgM
~ Cannot isotype switch to IGA, IgG and IgE
How does Bare lymphocyte syndrome impair T cell activation?
- Mutations in genes encoding for transcription of MHC II expression
- Lack of MHC II impairs CD4+ T cell activation
~ Affects CTL and humoral immunity - MHC I deficiency is rare and causes unstable binding of Ag (failure to process)
What are the mechanisms of defect for the 4 diseases that impair innate immunity?
1) Leukocyte adhesion deficiency 1
- Gene mutations in beta chain of B2 integrins -> defective adhesion dependent functions
2) Leukocyte adhesion deficiency 2
- Mutation in proteins for E and P-selectin ligands
~ Failure of leukocyte migration into tissues
3) Complement C3 deficiency
- Mutation in C3 gene for complement cascade activation
4) HSV-1 encephalitis
- Mutation in TLR3
~ Poor antiviral immunity
What is the immunological hierarchy/disease severity for diseases caused by primary immunodeficiency?
1 (Mildest): IgG deficiency
2: IgA deficiency
3: B cell deficiency
- lack and mutations in CD40L
4: CD4 deficiency
- HIV/AIDS
5: CD4 and CD8 deficiency
- DiGeorge syndrome
6: Severe lack of T and B cells
- SCID
What immunosuppressive drug can cause secondary immunodeficiency?
- Corticosteroids
~ Prednisolone
~ Dexamethasone - Tacrolimus, Cyclosporin
How does nutrition cause secondary immunodeficiency?
Malnutrition associated with impairment of:
~ Cell-mediated immunity
~ Phagocyte function
~ Complement system
~ Secretory IgA production
~ Cytokine production
How do burns cause secondary immunodeficiency?
- Significant thermal injuries induce immunosuppression
~ Predisposes px to infectious complications - Deaths often due to burn wound sepsis or complications due to inhalation injury
What is the HIV infection cycle?
1) HIV virion binds to CD4 using gp41+120 and CCR5
2) HIV membrane fuses with CD4+ cell, allowing entry of viral genome into cytoplasm
3) Proviral DNA synthesis
4) Integration of provirus into cell genome
5) Transcription of HIV genome to produce HIV proteins
6) Expresses gp41+120 on cell surface and budding of mature virion
