Failure of Host Defense Mechanisms Flashcards
what are primary immunodeficiencies
- inherited disorders with defects in one or more components of the immune system
- moderately common
- infections are hallmarks for PID
what are secondary immunodeficiencies
- non-inherited, acquired
- caused by environmental factors such as age, malnutrition, infection, irradiation, chemotherapy or exposure to toxins
- infections are hallmarks
what are combined immunodeficiencies
- impairments in both B-cells and T-cells due to inherited mutations
- e.g. SCID
types of inherited of SCID
autosomal recessive: caused by ADA
x-linked: mutation in IL-2RG gene - affects cytokine receptors
characteristics of primary immunedeficiencies
- inherited gene variants (caused by mutatuons
- recurrent infections early in life)
- often X-linked (affect mostly males)
- affect 1 in 1000 people
- fungal or viral infections cause a defect in T-cell function
- pyogenic bacteria cause a defect in antibody, complement or phagocyte function
what are the 9 categories of human immunodeficiency syndromes
- CID limited to the immune system
- CID with defects on tissues outside the immune system
- Antibody deficiencies
- immune dysregulation
- Phagocyte defects
- Innate immunity defects
- Autoinflammatory disorders
- complement deficiencies
- Phenocopies of inborn errors of immunity
what is the difference between the SCIDs ADA and Omenn syndrome
ADA: B and T cells affected
Omenn: T cells affected (autoreactive) + B cell development effected
what are the autosomal recessive SCIDs - (affect boys and girls + both B and T cells)
ADA and Omenn syndrome
characteristics of ADA (adenosine deaminase deficiency)
- disrupts the S-phase of the cell cycle
- improper lymphocyte development - lack of T and B cells
- causes SCID in infancy
- must be treated with bone marrow transplant
characteristics of Omenn syndrome
- partial loss of V(D)J recombinase activity through mutations in at least one of RAG-1 or RAG-2 alleles
- Peripheral T cells are autoreactive
- impaired helper-T cells also indirectly impacts B cells
x-linked SCID characteristics
- presents with lack of peripheral blood T cells and NK cells
- B cells are usually present but Ig production is decreased
- caused by mutation in IL-2RG (gene that encodes common gamma chain - yc - of cytokine receptors)
examples of immunodeficiencies that alter T-cell development and function
FOXN1 mutation
DiGeorge syndrome
Bare Lymphocyte syndrome (BLS)
FOXN1 mutation
- lack of thymic function
- abnormal T-cell development
DiGeorge syndrome
- small portion of chromosome 22 is deleted
- thymus is absent - abnormal T-cell development and function
- loss of T cells is very difficult to treat
Bare lymphocyte syndrome (BLS)
- MHC I or II deficiency
- mutations in TAP genes cause improper activation of CD8 T cells (MHC I)
- mutations in TFs responsible for MHC II expression cause improper activation of CD4 T cells (MHC II)
examples of immunodeficiencies that alter B-cell development
XLA
Hyper IgM syndrome
CVID
X-linked Agammaglobulinemia (XLA)
- defect in B cell development due to mutation in the BTK gene on X-chromosome
- low levels of all Ab isotypes
- reduced B cell numbers
- women not usually affected because they are XX and disease is recessive
- B-cell development is arrested in XLA male or carrier female if normal X is inactivated
Hyper IgM syndrome
- affects Igs and impacts only males
- caused by mutation in the CD40 ligand gene (on activated T-helper cells)
- low levels of IgG, IgA and IgE
- tightened susceptibility to infections that require high-affinity, class-switched antibodies for clearance
common variable immunodeficiency (CVID)
- most common form of primary ID
- variable deficiencies in 2 or more Ig isotypes
- low IgG and IgA, with or without low IgM
- mutates BAF receptor - needed for affinity maturation and to provide survival signal
Defects at different stages of the complement system
classical activation: immune-complex disease
lectin activation: bacterial infections (mainly in childhood)
alternative activation: infection with pyrogenic bacteria, but no immune complex disease
C3b deposition: pyogenic bacteria infection, sometimes immune-complex disease
MAC: infection with Neisseria spp.
what are some immunodeficiencies of the innate immune system
Chronic granulomatous Disorder (CGD)
Leukocyte Adhesion Deficiency (LAD) I
Chediak-Higashi Syndrome
chronic granulomatous disorder (CGD)
- causes defect in phagocytes
- phagocytic cells cannot kill certain pathogens - form gransulomas
- defective production of ROS
- patients vulnerable to severe recurrent bacterial and fungal infections
Leukocyte Adhesion Deficiency (LAD) I
- defect in migration of phagocytes (neutrophils)
reduced or absent expression of B2 integrins on leukocytes - patients deficient in expression of the 3 integrins containing CD18 (LFA-1, Mac-1, Gp 150/95)
- normal expression of selectin ligand PSGL-1
- if they can’t get into tissues then infection persists
Chediak-Higashi Syndrome
- defects in phagocytes
- impaired lysis of phagocytosed bacteria - recurrent bacterial respiratory infections
- mutation in CHS gene - affects synthesis of storage/secretory granules
- abnormal NK cell function
defective lysosomal function in macrophages, DCs abdominal neutrophils - hypopigmentation of skin eyes and hair - albinism
What are the mechanisms of immune evasion driven by genetic variation
antigenic variation
antigenic drift and shift
antigenic variation
- pathogen express different surface antigens without changing bacterial genus and species
- many species have multiple serotypes which differ on the surface, therefore not recognized by the same immunoglobulins
antigenic drift and shift
drift: viral genome replicated and slowly accumulates mutations
shift: complete and sudden reassortment of the viral genome, creates a variant
what is viral latency
- when a virus incorporates their viral genomes into target cells and undergo a dormant state
- in this dormant state the viral genome is present but host cells lower their production of viral particles
- reactivation of viral genome is pathogen specific
- e.g. HIV and the herpes simplex virus
- in primary infection of the trigeminal ganglion we get cold sores
Acquired Immune Deficiency syndrome (AIDS)
- major disease burden caused by HIV
- CD4 T-cell count drops and leads to opprotunistic infections
The virion of HIV
- primary targets = T-helper cells
- the protein gp120 on the vision surface recognizes CD4 (Th cell), CCR5 and CXCR4
The life cycle of HIV - pathway
- virus binds CD4 and co-receptor on helper T cell via gp120
- viral envelope fuses with cell membrane and viral genome enters cell
- reverse transcriptase copies viral RNA into double-stranded cDNA
- viral cDNA enters nucleus and is integrated in host DNA
- T-cell activation induces low-level transcription of provirus
- RNA transcripts are spliced allowing translation of tat and rev genes
- tat amplifies transcription of viral RNA, rev increases transport of viral RNA to cytoplasm
- the late proteins Gag, Pol and Env are translated and assembled into virus particles which bud from the cell
what is the typical course of an untreated HIV infection
- after initial infection with HIV, viral genome increases dramatically
- there’s an initial decrease in CD4 T cells until viral latency
- viral titer remains unchanged but CD4 T cells continue to decrease
- if untreated, CD4 T cell levels are so low that infection by opprotunistic pathogens occurs until the patient succumbs
Targets for therapeutic drugs to interfere with the HIV life cycle
- viral entry inhibitors
- reverse transcriptase inhibitors*
- viral integrase inhibitors
- protease inhibitors*
- viral assembly inhibitors
pathogenic bacteria target _____ to subvert immunity
the complement cascade
- at activation, convertase formation or MAC assembly
