Immunodeficiency diseases Flashcards
Difference between primary and secondary immunodeficiency diseases
Primary: inherited defects in different components of the immune system
Secondary: due to environmental factors such as immunosuppressive drugs
SCID
- RAG1 RAG2
- immune defect: no gene rearrangement in B and T cell
- suscepibility: all types of infection
Omenn syndrome
- RAG 1, RAG 2, artemis
- immune defect: impaired RAG function
- susceptibility: all types of infection
Bare lymphocyte syndrome
- TAP1, TAP2
- immune defect: low MHC class 1 expression
- susceptibility: respiratory viral functions
Complete DiGeroge’s syndrome
- no affected genes known
- immune defect: absence of the thymus and T cell
- susceptibility: all types
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy
- AIRE
- reduced T cell tolerance to self antigens
- autoimmune diseases
IPEX
- FOXP3
- lack of regulatory T cells and peripheral tolerance
- autoimmune disease
Rare primary immunodeficiency diseases
- caused by exceedingly rare mutant alleles of immune genes without selective benefit for the individuals who carry them
- found in small or culturally isolated populations
- help recognize novel forms of immunodeficiency syndrome
- other less dramatic effects in other immune genes are more frequent
Primary immunodeficiency diseases
- dominant
- recessive
- x linked
____ and ___ mutations in the INF-gamma receptor cause disease of different severity
Recessive; dominant
- INF- gamma: major cytokine that activates macrophages, make by NK, Th1 CD4 and CD8 T cells (important defense against intravesicular bacteria)
X linked agammaglobulinemia
B cells do not develop beyond pre-B cell stage
- Bruton’s tyrosine kinase protein that contributes to intracellular signaling form the BCR involved in growth and differentiation of pre-B cells
Antibody deficiency (B cells)
Leads to an inability to clear extracellular bacteria
Antibody deficiency (T cell help)
X linked hyper IGM syndrome - absence of CD40L, poor development of GC and isotype switching
- no specific antibody is made against T cell dependent antigens
- IgG, IgA, IgE are virtually absent, but IgM is extremely high
- treat with regular injections of gamma globulin
Defects in _____ result in enhanced susceptibility to bacterial infection
Phagocytes
SCID T cell function
Do not make T cell dependent antibody responses nor cell mediated immune responses
- T cell development and function depend on the action of many proteins, so SCID phenotype can arise from defects in any gene
- ADA OR PNP deficiences
X linked deficiency
Common gamma chain syndrome, cytokine signaling is affected
- severe: affected infants survive if kept isolated
Wiskott-Aldrich syndrome
Impairment of platelets and T cells
- WASP protein involved in cytoskeletal reorganization of T cells, T cell cannot deliver cytokines and signals to B cells, macrophages, etc
Bare lymphocyte syndrome
Lack of MHC class 1-2 - class 1 absence is less severe
HIV infects
CD4 T cells, macrophages, and DC
HIV life cycle in humans
Virion binds to CD4 and coreceptor on T cell –> viral envelope fuses with cell membrane and viral genome enters cell –> reverse transcriptase copies viral RNA genome into double stranded cDNA –> viral cDNA enters nucleus and integrates into host DNA –> T cell activation induces some transcription of provirus –> RNA transcripts are spliced to allow synthesis of early proteins Tat and Rev –> Tat amplifies transcription of viral RNA and Rev increases transport of RNA to cytoplasm
Depletion of CD4 T cells
Flu-like disease (infection) –> asymptomatic phase (seroconversion) –> symptomatic phase –> AIDS
Immune response to HIV
- HLA polymorphism: influences progression of AIDS
- KIR polymorphism: influences progression of AIDS suggesting that the type of NK cell response at the start of HIV infection affects the relative success of the subsequent adaptive response
- genetic deficiency of the CCR5 co receptor for HIV confers resistance to infection
High mutation rate
Seen in HIV and other retroviruses
- complicates vaccines and limits effectiveness of antiviral drugs
Potential targets for anti-HIV drugs
- viral reverse transcriptase that is responsible for the provirus synthesis
- viral protease that cleaves viral proteins
Highly active anti-retroviral therapy
Destroys the entire population of viruses before any one of the them has accumulated enough mutations to resist all the drugs
For protease inhibitors, resistance develops in ____
A few days
Mechanism of antiviral drugs (HAART)
Productive infection of CD4 T cells accounts for more than 99% of virus in plasma –> infected cells are short-lived, so HIV must continuously infect new cells –> if virus production is blocked by a drug, the virus is rapidly cleared –> CD4 T cell numbers rapidly increase, replacing those lost by infection
HIV infection leads to _____ and death from ______
Immunodeficiency; opportunistic infections
Inherited immunodeficiencies are caused by a defect in one of the genes necessary for
Development or function of the immune system
Immunodeficiencies can also be acquired as the result of ___
Infection
