(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
What is the pathogenesis of AIDS?
HIV infx acquired through infected mucus membranes, but AIDS develops over years as latent HIV becomes activated and destroys immune cells.
1) Infection of mucosal tissues
- Anti-HIV Ab and HIV-specific CTLs released
~ Partial control of viral replication + clinical equilibrium
- Other microbial infx or cytokines break equilibrium and increase viral replication again -> AIDS
2) Death of mucosal memory CD4+ T cells
3) Infection in lymphoid organs
- Due to infected dendritic cells
4) Spread of infection throughout body
What groups of people are HIV resistant?
- Mutation in CCR5 in humans
- Specific MHC I and II receptors
What are the clinical features of HIV/AIDS?
- Latent phase:
~ Few clinical problems but progressive loss of CD4+ and loss of tissue architiecture - Dementia (infection of microglial cells/macrophages in brain)
- Wasting syndrome of body mass
- Opportunistic infections (eg candidiasis and TB)
~ Years after AIDS onset - Cancers (eg Kaposi’s sarcoma, cervical cancer)
