Lec 9-Failures of the defence Flashcards
3 types of failure
1) Pathogens evade or manipulate immune response
2) The immune system has a primary genetic defect
3) Pathogens can lead to acquired immune deficiency syndrome
1) Pathogens evade or manipulation immune response- Ag variation
- Protect immunity to extracellular pathogens relies on neutralising Ab
- Changing surface Ag will reduce or prevent Ab binding
- 3 main strategies for Ag variation
1) Variable serotypes
2) Antigenic drift and antigenic shift
3) Gene conversion
1) Pathogens evade or manipulate immune response- Variable serotypes
- Streptococcus Pneumoniae
- There are many serotypes of S.pneumoniae, which differ in their capsular polysaccharides
- Person infected with one serotype of S.pneumoniae
- Ab response clears infection (Ab can act as opsonins)
- Subsequent infection with a second serotype of S.pneumoniae is unaffected by response to first serotype
- New Ab response clears second infection
1) Pathogens evade or manipulate immune response- Antigenic drift
- Neutralizing Ab against hemaggultinin block binding to cells
- Mutations alter hem agglutinin epitopes so that neutralising Ab no longer binds
- Minor changes as a result of random mutations
- Point mutations alter Ab binding
- Mild disease- continued recognition by T cells and other Ab
1) Pathogens evade or manipulate immune response- - Antigenic Shift
- This is a major change as it refers to the appearance of an entirely novel virus
- S secondary host is infected with a human and an avian strain of virus
- Recombination of viral RNA in the secondary host produces virus with a different hemagglutinin
- No cross-protective immunity in humans to virus expressing a novel hemagglutinin
- Recombination produces large changes- new virus not recognised by T cells
- Severe and widespread infection
- Because there is a cross of 2 specie type of infective agent and Ag there will be no one with the correct response as it has never been seen before
1) Pathogens evade or manipulate immune response– Gene Conversion
- Trypanosomes have 1000 genes for variable surface glycoprotein (VSG) but express one at a time
- During infection- most parasite express the same VSG
- Ab’s will be produced to the dominant form of VSG will clear this population
- Gene conversion allows expression of a different VSG and the population expands
- Eventually these will stimulate the immune response, produce Abs, clear infection
- Gene conversion, minority population starts to expand
1) Pathogens evade or manipulate immune response- - Latency
- Effective viral defence requires destruction of infected cells by CD8 T cell
- Recognition of infected cells requires production and presentation of virall peptides in MHC class I
- Viruses that enter a dormant (non-dividing) state in cells are difficult to clear (no peptides on MHC because no peptide is being produced)
- Viruses can later reactivate and cause further disease
- Viruses can change there state rapidly this is a problem because they can bring about there effect leading to a immune response and then switch back to being dormant in which case the immune system cannot find it leading to increased production of virus and no way of clearing them
Herpes virus use latency as their strategy for persistence
- Herpes simplex virus infects epithelial cells and spreads to sensory neurones
- Virus is cleared from epithelium but remains in neurones in a latent state
- Various factors can reactivate the virus which travels down the axon to re-infect epithelium (Cold sores)
- Repeated cycles of infection
- Herpes zoster- same strategy but just one activation
1) Pathogens evade or manipulate immune response- - Exploitation- the immune system provides a favourable environment
- Avoid destruction- Mycobacterium tuberculosis (TB) prevents fusion of the phagosome with the lysosome- No digestion and is protected
- Escape destruction- Listeria monocytogenes moves from the phagosome into the cytoplasm- no digestion and is protected
- Prevent destruction- treponema palladium coats itself with human protein- avoids recognition and detections
1) Pathogens evade or manipulate immune response- Subversion inhibiting our immune response
- Inhibit humoral immunity- use virally encoded receptors which block effector pathways e.g. Herpes simplex (FcR), Vaccinia (C)
- Inhibit inflammatory response- Virally encoded receptors; Block cytokine/chemokine effects e.g. Vaccinia (IL1R), cytomegalovirus (betaCR)
- Block Ag processing and presentation- Inhibit MHCI or peptide transport which leads to impaired Tc cell recognition (Herpes simplex inhibit TAP)
- Immunosuppression- virally encoded homologue of IL-10 which inhibits Th1 cells (Epstein-Barr virus)
1) Pathogens evade or manipulate immune response- - Sabotage
-Cytomegalovirus has various mechanisms to alter synthesis and expression of MHC class I
Stratergy 1
-Prevent synthesis or loading of MHC class I- no viral Ag presentation- no detection (however if all of the MHC was not there the cell would get killed anyway because when we detect self peptide there is a inhibitory signal stopping killing)
Strategy 2 -Alter NK-cell receptor expression- no detection -Overall strategy- prevents anti-viral response of NK and CD8 cells
-Overall strategy- prevents anti-viral response of NK and CD8 cells
Nk look for MHC class I, so CMV produces it
A) self: if self peptide is produced then no lysis
B) Missing self peptide = lysis
C) Non-Self= lysis -CMV will make our human peptide to present it on MHC so immune system will leave it alone
2) The immune system has a primary genetic defect
- Primary immunodeficiency disease (PID)- defects in genes for components of immune system
- PID first identified in the 1950s- before antibiotics, most children died without diagnosis
- Recurrent infections- nature of the infection provides clues about the genetic lesion
- PID identified for most components of the immune system
+Symptoms depend on genetic lesion
+Severity depends on the genetic lesion
2) The immune system has a primary genetic defect a) Ab deficiency B cell
-X-linked agammaglobulinaemia (IgG)
+Defective B cell development
+No Ab production
-People are susceptible to infection with extracellular bacteria
+Normally cleared by phagocytosis
-People are more susceptible to enterovirus infection
+No neutralising Abs
-People can be successfully treated with IVIG passive immunity
2) The immune system has a primary genetic defect a) Ab deficiency- B cell
- But you need more than B cells to make Ab
- Ag recognition induces expression of CD40 ligand and cytokines by the Th 2 cells which activate the B cell
- B cells proliferation and differentiation to antibody-secreting plasma cells
2) The immune system has a primary genetic defect c) complement deficiency
- Complement is a collection of soluble and membrane bound proteins
- Complement components are made by the liver constitutively (No stimulus required)
- Complement activates the acute inflammatory response
2) The immune system has a primary genetic defect d)Phagocyte defficiency
- Phagocytes detect, engulf and destroy pathogens
- Changes in phagocyte number or function can associate with severe immunodeficiency
- Defects in phagocyte recruitment or movement can associate with severe immunodeficiency
- Defects in phagocyte recruitment or movement can associate with severe immunodeficiency
2) The immune system has a primary genetic defect d) phagocyte deficiency
1) Leukocyte adhesion deficiency
- This is a defect CD18 (cell adhesion molecule); Defective migration of phagocytes into infected tissue;
Widespread infections with capsulated bacteria
2) Chronic granulomatous disease (CGD)-
Defective NADPH oxidase. phagocytes cannot produce O2; Impaired killing of phagocytosed bacteria; Chronic bacterial and fungal infection (granulomas)
3)Glucose-6-phosphate dehydrogenase (G6PD) deficiency-
Deficiency of G6PD defective respiratory burst; Impaired killing of phagocytosed bacteria; Chronic bacterial and fungal infection, anaemia is induced by certain agents
2) The immune system has a primary genetic defect e) T cell deficiency
- Defects in T cell function are severe and result in broad range of infections- role of T cells throughout adaptive immunity
- T cell defects mean limited humoral immunity, no cell- mediated immunity, no immunological memory
- The severe combined immunodeficiency or SCID phenotype can arise from defects in any one of several genes
2) The immune system has a primary genetic defect- Bone marrow transplantation can treat PID
1) irradiation and chemotherapy- to kill of the persons bone marrow- No production of bone marrow
2) Bone marrow infusion- If the wrong match for the patient the new immune system will recognise the patients peptide as foreign Ag so will kill all of the patients cells= death
3) Healthy patient
2) The immune system has a primary genetic defect Gene therapy can cure PID
- Bone marrow containing stem cells is removed from the hip bone
- The ‘vector’ is used to carry the gene into the stem cell (with the undesirable DNA)
- Stem cells with the new gene inside are given back to the patient 5 days later
- Gene therapy has be in trials for the past 20 years, some setback but now is looking promising
3) pathogens can lead to acquired immune deficiency syndrome
- The immune response controls but doesn’t eliminate HIV
- First 4-8 weeks there is a peak in virus numbers in blood, various Ab and immune response occurs
- The next 2-12 years there is a stalemate between immune system and virus
- After this time virus numbers increase, antibodies to HIV more protein reduce, HIV-specific Tc cells decrease
- In the last year, the number of T cells become so depleted that when another infection comes along the immune system can’t deal with it which is what kills you
3) pathogens can lead to acquired immune deficiency syndrome
- HIV keeps ahead of the immune response
- HIV is rarely eliminated
+High mutation rate- reverse transcriptases make mistake that get passes onto make new genomes
+Infection is with many viral variants
-Infected cells not recognised by virus specific Tc cells
3) pathogens can lead to acquired immune deficiency syndrome
- Anti-retrovirals (ARV) can increase the CD4 count
- Productive infection of CD4 T cells accounts for more than 99% of virus in plasma
- Infected cells are short-lived, so HIV must continually infected new cells -If virus production is blocked by a drug, the virus is rapidly cleared from the blood
- CD4 T cell numbers rapidly increase, replacing those lost by infection
3) pathogens can lead to acquired immune deficiency syndrome
- In combination Anti-retroviral therapies (ART) are favoured
- 6 classes of ARV, target different stages of viral life cycles
+Nucleoside reverse transcriptase inhibitors (NRTIs)
+Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
+Protease inhibitors (PIs)
+Integrase inhibitors (Iis)
+Fusion inhibitors (FIs)
+Chemokine receptor antagonist (CRAs)
-Use of these agents in clinical practise is largely dictated by their ease or complexity of use, side-effect profile, efficacy based on clinical evidence, practise guidelines and clinical preference
