1
IMMUNOLOGY EXAM 4
CH.13 FAILURES OF THE BODY’S DEFENSES
EVASION & SUBVERSION OF THE IMMUNE SYSTEM BY PATHOGENS
13-1 Genetic variation within some species of pathogens prevents effective long-term
immunity
Ab = most imp. long-term protective immunity against pathogens
Serotypes = strains of a bacterial species that can be distinguish antigenically (differ from each other
on Ag on their surfaces) → this genetic variation prevents effective immunological memory of host
13-2 Mutation and recombination allow influenza virus to escape from immunity
- Long-term survival of the influenza virus is only possible by the generation of new viral strains that
evade the protective immunity acquired by human hosts during past outbreaks and epidemics.
- Error prone genome replication → selection for viral strains lacking Ag targeted by human immunity
- → Antigenic drift: random mutations cause alteration in the surface Ag and thus creates new strains
yearly which causes mild epidemics
- Every 10-50 years a very different strain may emerge that’s able to cause pandemic (worldwide
epidemic) → recombinant strains derived from avian and human influenza viruses replicate in pigs
(RNA molecules of avian origin encode for Ag completely different to what humans have protective
immunity towards)
- Arise in areas where people live close to animals
- → Antigenic shift: virus reassorts their segmented genomes (recombination) with other viruses and
change their surface Ag radically (cause pandemics)
13-3 Trypanosomes use gene conversion to change their surface antigens
- → Antigenic variation: change of surface Ag by gene rearrangement
- Variable surface glycoproteins (VSGs): family of glycoproteins on African trypanosomes surface.
Can be repeatedly changed by gene conversion (part of a gene is replaced by a different version or
part of a gene)
- VSG gene has to be rearranged into a ‘site of expression’ (one in each genome only)
- In infections: 1ary immune response gets rid of majority of pathogen with dominant VSG but pathogen
with minority VSG keeps growing until it dominates population and process might repeat → chronic
cycle of Ab production = constant inflammation = neurological damage = sleeping sickness
- Protozoan parasites that do this: Trypanosome, Malaria, …
- Bacteria (“): Salmonella enterica (flagella protein variation), Neisseria gonorrhoeae (pilin protein
variation)
13-4 Herpesviruses persist in human hosts by hiding from the immune response
- large double-stranded DNA viruses with mild effects on humans
- some provide = benefits that harm (improvement of immune responses) → part of the human virome
- 1st infection → initial lytic phase (virus replication, hosts cells die) → host immune response →
latency (virus remains in cell in dormant cell, creating no disease or provoking immune response)
→viral genome becomes circular → host subjected to stress → disease episode
- Ex) Human cytomegalovirus (CMV): survives without hurting healthy human host (only dangerous to
compromised immune systems) → benefits: improved anti-influenza response in people vaccinated
against influenza that also infected with CMV
→ CMV proteins limit activation of NK & CD8 cells (through MHC I degradation and interfering
of recognition of MHC I by NK cells)
, 2
13-5 Human herpesviruses cause a variety of diseases
- Herpes simplex virus (cold sores) infects epithelial cells 1st & then spread to sensory neurons (stays
there in latency) → stresses that can activate: sunlight, bacteria or hormones
- Killing of infected epithelium by CD8 T cells creates cold sore
- Neurons good latency site bc they express little MHC I (low chance of presenting Ag to CD8)
- Herpesvirus varicella-zoster (chickenpox) → latent in ganglia → reactivated by stress or
immunosuppression → reinfection only in area served by infected ganglia (called shingles) (happens
only once in life)
- Epstein-Barr virus (EBV) (mononucleosis/glandular fever) → memory B cells infection ( binds to CR2
of co-receptor and produce virus = high EBV-specific T cell proliferation in blood) → CD8 T cells kill
infected B cells (latent in minority of B cells → EB nuclear Ag1 (EBNA-1) maintains viral genome
circular (not integrated into host genome) in B cells → this Ag can’t be degraded into peptides so CD8
won't be activated by MHC I presentation so latent virus B cells aren’t killed → reactivation unusually
causes disease but sometime can cause Burkitt’s lymphoma (B cell lymphoproliferative disease)
13-7 Bacterial superantigens stimulate a massive but ineffective CD4 T-cell response
- Species of gram + bacteria secrete toxins that disrupt immune system activating many CD4
T cell clones
- → Superantigens: molecule that binds nonspecifically to MHC II & CD4 TCRs (crosslinks
them), stimulating polyclonal activation of CD4 T cells → excessive IL-2, INFg, TNF-a.
1) SuperAg binds to MHC II
2) Binds to V-beta domain of TCR
3) Binds to co-stimulator CD28 (does not affect interaction w/ B7)
- food poisoning w/ S.aerous = CD4 activation by bacterial superAg = vomiting/diarrhea
flushes out bacteria & toxins from GI tract
- SuperAg activates way more T cells than during normal Ag activation = overproduction of inflammatory
cytokines, hypotension, shock, sepsis and dead possible
13-8 Subversion of IgA by bacterial IgA-binding proteins
- Staphylococcal superantigen-like proteins (SSLPs): supeAg proteins secreted by S.aureus subvert
immunity in various ways
→ SSLP7: prevents monomeric IgA delivering bacteria to phagocytes → Bind to Fc
region of bacteria bound-IgA and a C5 (in regular conditions IgA Fc region binds to Fc
receptor in phagocyte)
INHERITED IMMUNODEFICIENCY DISEASES
- 1ary immunodeficiency: (inherited?) defect in genes encoding components of immune system
causes failure in immune function
- 2ary immunodeficiency: use of immunosuppressive drug or infections (environmental factors) causes
failure of immune function
13-9 Rare primary immunodeficiency diseases reveal how the human immune system works
- most autosomal recessive alleles, very little X linked genes or autosomal dominant
- less severe immune deficiency are more frequent:
- defective MHC1 alleles,
- lack of C4 isotype: lack of = + risk of lupus / lack B = = vulnerable to infections
- usually have no drastic effect bc defective gene is part of a family and another member can
compensate for it
, 3
13-11 Recessive and dominant mutations in the IFN-γ receptor cause immunodeficiency
of differing severity
- IFNg receptor deficiency (lack or low levels) on macrophages (= inability to clear intracellular bacteria)
- IFNg & IFNg-R (INFgR1 & INFgR) are dimers
- Homozygous recessive mutation that prevent INFgR1 expression = severe disease (non produced)
- Dominant INFgR1 mutations = truncation of cytoplasmic tail = heterozygous make some functional
INFgR1 still = less severe disease
13-12 Antibody deficiency leads to poor clearing of extracellular bacteria
- Pyogenic (pus-forming) encapsulated bacteria frequently escape innate immune response and
usually cleared by opsonization by Ab and complements for phagocytosis → big problem for people
lacking Abs
- X-linked agammaglobulinemia (XLA): males unable to produce functional B cells (defective BTK,
necessary for B cell maturation), heterozygous women are carriers (inactivate chromosome)
- XLA patients can end up developing Bronchiectasis: chronic inflammation of bronchioles due to
successive infections → to avoid chronic infections patients recieve Ab intravenous monthly (passive
immunity)
13-13 Diminished production of antibodies can arise from inherited defects in T-cell help
- CD40 ligand from T cells bind to CD40 in B cells stimulating B cell & macrophage activation → CD40
L necessary to make specific Ab (IgG,IgA and IgE very low whale IgM high)& macrophage activation
by CD4 cells also impaired
- CD40 ligand encoded on X Chrom. → mostly males with deficiency → X linked hyper IgM
syndrome
- leukocytosis: increased numbers of leukocytes in blood (like during acute infection)
- neutropenia: abnormally low number of neutrophils in blood → leads sores and blisters
13-14 Complement defects impair antibody-mediated immunity and cause
immune-complex disease
- defects on C3 = susceptible to a lot of infections
- defects on C5-C9 = few effects (only susceptibility to Neisseria since complement-mediated lysis
required for elimination)
- C1-C4 deficiency = accumulation of immune complexes = immune-complex disease: abnormal
deposition in tissue of Ag:Ab complexes cause inflammation and tissue disruption
- deficiency in proteins that controls complement activation → (factor I = c3 deficiency, factor P = fix
insufficient C3b to assemble MAC, DAF or CD59 = activation of alternative pathway causes
erythrocytes lysis (autoimmune disease))
- Hereditary angioedema (HAE): deficiency of C1 inhibitor (C1INH) (inhibits C1r & C1s by covalently
to it) = overactive classical pathways = overproduction of C2a (vasoactive) & bradykinin = fluid
leakage from vessels to tissue = epiglottal swelling & suffocation
13-15 Defects in phagocytes cause
enhanced susceptibility to bacterial
infection
13-16 Defects in T-cell function underlie
severe combined immunodeficiencies
13-17 Some inherited
immunodeficiencies cause
IMMUNOLOGY EXAM 4
CH.13 FAILURES OF THE BODY’S DEFENSES
EVASION & SUBVERSION OF THE IMMUNE SYSTEM BY PATHOGENS
13-1 Genetic variation within some species of pathogens prevents effective long-term
immunity
Ab = most imp. long-term protective immunity against pathogens
Serotypes = strains of a bacterial species that can be distinguish antigenically (differ from each other
on Ag on their surfaces) → this genetic variation prevents effective immunological memory of host
13-2 Mutation and recombination allow influenza virus to escape from immunity
- Long-term survival of the influenza virus is only possible by the generation of new viral strains that
evade the protective immunity acquired by human hosts during past outbreaks and epidemics.
- Error prone genome replication → selection for viral strains lacking Ag targeted by human immunity
- → Antigenic drift: random mutations cause alteration in the surface Ag and thus creates new strains
yearly which causes mild epidemics
- Every 10-50 years a very different strain may emerge that’s able to cause pandemic (worldwide
epidemic) → recombinant strains derived from avian and human influenza viruses replicate in pigs
(RNA molecules of avian origin encode for Ag completely different to what humans have protective
immunity towards)
- Arise in areas where people live close to animals
- → Antigenic shift: virus reassorts their segmented genomes (recombination) with other viruses and
change their surface Ag radically (cause pandemics)
13-3 Trypanosomes use gene conversion to change their surface antigens
- → Antigenic variation: change of surface Ag by gene rearrangement
- Variable surface glycoproteins (VSGs): family of glycoproteins on African trypanosomes surface.
Can be repeatedly changed by gene conversion (part of a gene is replaced by a different version or
part of a gene)
- VSG gene has to be rearranged into a ‘site of expression’ (one in each genome only)
- In infections: 1ary immune response gets rid of majority of pathogen with dominant VSG but pathogen
with minority VSG keeps growing until it dominates population and process might repeat → chronic
cycle of Ab production = constant inflammation = neurological damage = sleeping sickness
- Protozoan parasites that do this: Trypanosome, Malaria, …
- Bacteria (“): Salmonella enterica (flagella protein variation), Neisseria gonorrhoeae (pilin protein
variation)
13-4 Herpesviruses persist in human hosts by hiding from the immune response
- large double-stranded DNA viruses with mild effects on humans
- some provide = benefits that harm (improvement of immune responses) → part of the human virome
- 1st infection → initial lytic phase (virus replication, hosts cells die) → host immune response →
latency (virus remains in cell in dormant cell, creating no disease or provoking immune response)
→viral genome becomes circular → host subjected to stress → disease episode
- Ex) Human cytomegalovirus (CMV): survives without hurting healthy human host (only dangerous to
compromised immune systems) → benefits: improved anti-influenza response in people vaccinated
against influenza that also infected with CMV
→ CMV proteins limit activation of NK & CD8 cells (through MHC I degradation and interfering
of recognition of MHC I by NK cells)
, 2
13-5 Human herpesviruses cause a variety of diseases
- Herpes simplex virus (cold sores) infects epithelial cells 1st & then spread to sensory neurons (stays
there in latency) → stresses that can activate: sunlight, bacteria or hormones
- Killing of infected epithelium by CD8 T cells creates cold sore
- Neurons good latency site bc they express little MHC I (low chance of presenting Ag to CD8)
- Herpesvirus varicella-zoster (chickenpox) → latent in ganglia → reactivated by stress or
immunosuppression → reinfection only in area served by infected ganglia (called shingles) (happens
only once in life)
- Epstein-Barr virus (EBV) (mononucleosis/glandular fever) → memory B cells infection ( binds to CR2
of co-receptor and produce virus = high EBV-specific T cell proliferation in blood) → CD8 T cells kill
infected B cells (latent in minority of B cells → EB nuclear Ag1 (EBNA-1) maintains viral genome
circular (not integrated into host genome) in B cells → this Ag can’t be degraded into peptides so CD8
won't be activated by MHC I presentation so latent virus B cells aren’t killed → reactivation unusually
causes disease but sometime can cause Burkitt’s lymphoma (B cell lymphoproliferative disease)
13-7 Bacterial superantigens stimulate a massive but ineffective CD4 T-cell response
- Species of gram + bacteria secrete toxins that disrupt immune system activating many CD4
T cell clones
- → Superantigens: molecule that binds nonspecifically to MHC II & CD4 TCRs (crosslinks
them), stimulating polyclonal activation of CD4 T cells → excessive IL-2, INFg, TNF-a.
1) SuperAg binds to MHC II
2) Binds to V-beta domain of TCR
3) Binds to co-stimulator CD28 (does not affect interaction w/ B7)
- food poisoning w/ S.aerous = CD4 activation by bacterial superAg = vomiting/diarrhea
flushes out bacteria & toxins from GI tract
- SuperAg activates way more T cells than during normal Ag activation = overproduction of inflammatory
cytokines, hypotension, shock, sepsis and dead possible
13-8 Subversion of IgA by bacterial IgA-binding proteins
- Staphylococcal superantigen-like proteins (SSLPs): supeAg proteins secreted by S.aureus subvert
immunity in various ways
→ SSLP7: prevents monomeric IgA delivering bacteria to phagocytes → Bind to Fc
region of bacteria bound-IgA and a C5 (in regular conditions IgA Fc region binds to Fc
receptor in phagocyte)
INHERITED IMMUNODEFICIENCY DISEASES
- 1ary immunodeficiency: (inherited?) defect in genes encoding components of immune system
causes failure in immune function
- 2ary immunodeficiency: use of immunosuppressive drug or infections (environmental factors) causes
failure of immune function
13-9 Rare primary immunodeficiency diseases reveal how the human immune system works
- most autosomal recessive alleles, very little X linked genes or autosomal dominant
- less severe immune deficiency are more frequent:
- defective MHC1 alleles,
- lack of C4 isotype: lack of = + risk of lupus / lack B = = vulnerable to infections
- usually have no drastic effect bc defective gene is part of a family and another member can
compensate for it
, 3
13-11 Recessive and dominant mutations in the IFN-γ receptor cause immunodeficiency
of differing severity
- IFNg receptor deficiency (lack or low levels) on macrophages (= inability to clear intracellular bacteria)
- IFNg & IFNg-R (INFgR1 & INFgR) are dimers
- Homozygous recessive mutation that prevent INFgR1 expression = severe disease (non produced)
- Dominant INFgR1 mutations = truncation of cytoplasmic tail = heterozygous make some functional
INFgR1 still = less severe disease
13-12 Antibody deficiency leads to poor clearing of extracellular bacteria
- Pyogenic (pus-forming) encapsulated bacteria frequently escape innate immune response and
usually cleared by opsonization by Ab and complements for phagocytosis → big problem for people
lacking Abs
- X-linked agammaglobulinemia (XLA): males unable to produce functional B cells (defective BTK,
necessary for B cell maturation), heterozygous women are carriers (inactivate chromosome)
- XLA patients can end up developing Bronchiectasis: chronic inflammation of bronchioles due to
successive infections → to avoid chronic infections patients recieve Ab intravenous monthly (passive
immunity)
13-13 Diminished production of antibodies can arise from inherited defects in T-cell help
- CD40 ligand from T cells bind to CD40 in B cells stimulating B cell & macrophage activation → CD40
L necessary to make specific Ab (IgG,IgA and IgE very low whale IgM high)& macrophage activation
by CD4 cells also impaired
- CD40 ligand encoded on X Chrom. → mostly males with deficiency → X linked hyper IgM
syndrome
- leukocytosis: increased numbers of leukocytes in blood (like during acute infection)
- neutropenia: abnormally low number of neutrophils in blood → leads sores and blisters
13-14 Complement defects impair antibody-mediated immunity and cause
immune-complex disease
- defects on C3 = susceptible to a lot of infections
- defects on C5-C9 = few effects (only susceptibility to Neisseria since complement-mediated lysis
required for elimination)
- C1-C4 deficiency = accumulation of immune complexes = immune-complex disease: abnormal
deposition in tissue of Ag:Ab complexes cause inflammation and tissue disruption
- deficiency in proteins that controls complement activation → (factor I = c3 deficiency, factor P = fix
insufficient C3b to assemble MAC, DAF or CD59 = activation of alternative pathway causes
erythrocytes lysis (autoimmune disease))
- Hereditary angioedema (HAE): deficiency of C1 inhibitor (C1INH) (inhibits C1r & C1s by covalently
to it) = overactive classical pathways = overproduction of C2a (vasoactive) & bradykinin = fluid
leakage from vessels to tissue = epiglottal swelling & suffocation
13-15 Defects in phagocytes cause
enhanced susceptibility to bacterial
infection
13-16 Defects in T-cell function underlie
severe combined immunodeficiencies
13-17 Some inherited
immunodeficiencies cause
