Mechanisms of Immunity BSC 9/12 Flashcards
(36 cards)
1
Q
Patterns of Pathology: Extracellular Bacteria
A
- Local Toxicity: bacteria cause diseases due to the release of a single toxin or because of their ability to attach to epithelial surfaces (immunity may require humoral Ab production to neutralize the function of endo and exo-toxins)
- Local Invasiveness: Bactera that are not toxic can cause disease by invasion of tissues and cells- damage results from the bulk or organisms (immunity may require cell-mediated immunity to resolve)
- Most organisms however fall between the two extremes, with some local invasiveness assisted by local toxicity and enzymes that degrade the ECM (humoral and cell-mediated responses are both involved in resistance)
2
Q
Neisseria Gonorrhoeae
A
* the perfect Extracellular pathogen
N. gonorrhoeae is an example of a bacterium that uses several strategies to avoid the damaging effects of antibody.
- First, it fails to evoke a large antibody response, and the antibody that does form tends to block the function of damaging antibodies.
- Second, the organism secretes an IgA protease to destroy antibody. (it is found on the mucosal surfaces, thus IgA is the main Ab targetting it)
- Third, blebs of membrane are released, and these appear to adsorb and so deplete local antibody levels.
- Finally, the organism uses three strategies to alter its antigenic composition:
- the LPS may be sialylated, so that it more closely resembles mammalian oligosaccharides and promotes rapid removal of complement;
- the organism can undergo phase variation, so that it expresses an alternative set of surface molecules;
- the gene encoding pilin, the subunits of the pilus, undergoes homologous recombination to generate variants.
3
Q
Extracellular Bacteria: Innate Immunity mechanisms
A
- First challenge: Epithelia barrier, normal flora
- Second part: Alternative C’ cascade
- Phagocytic Cells: Mf, Neutrophils are first on site to Extracellular bacteria
- Pro-inflammatory cytokines/chemokines (principle mechanisms against extracellular bacteria)
Mechanisms:
- Bacterial PAMPs are recognized by molecules present in serum and by receptors on cells. (resident macrophages)
- Activation of the alternative complement pathway (factors C3, B, D, P), with consequent release of C3a and C5a
- Activation & migration of neutrophils, macrophages, and NK cells
- Triggers of cytokine/chemokine release; mast cell degranulation
- Increased blood flow in the local capillary network; increased adhesion of cells and fibrin to endothelial cells.
- These mechanisms, plus tissue injury caused by the bacteria, may activate the clotting system and fibrin formation, which limit bacterial spread.
4
Q
Extracellular Bacteria: Adaptive Immunity Mechanism
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Humoral: major effector branch!!!
- antibody production and activation of CD4+ helper T cells.
Antibodies:
- Antibodies neutralize and eliminate microbes and toxins by several mechanisms. (neutralization by binding, handed off to erythrocytes and cleared by kupfier cells in spleen, have opsonization and phagocytosis, and Ab dependent cellular cytoxocity, complement actiation and bacterial lysis)
- Helper T cells produce cytokines that stimulate B cell responses (IFNgamma, IL4/5/13), macrophage activation, and inflammation.
5
Q
Opsonization: Extracellular Bacteria
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- Bacteria that are coated with an Ab and C’ (C3b) increases adherence to phagocytes and results in more rapid opsonization. This allows for greater bacterial clearance
6
Q
Role of Abs in Extracellular Bacterial Elimination
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- Humoral (antibody mediated system) response is the major effector branch!
- Ags are soluble and the 3-D conformation is recognized by Abs
- Ab block attachment of the bacterium to the host cell membrane.
- Ab triggers complement-mediated damage to some bacteria.
- Ab directly blocks bacterial surface transport proteins.
- Ab opsonizes the bacteria via Fc and C3 receptors for phagocytosis.
- Abs block bacterial factors that interfere with normal chemotaxis or phagocytosis.
- Ab neutralize bacterial toxins, as well as bacterial spreading factors that facilitate invasion (e.g. by the destruction of connective tissue or fibrin).
7
Q
Consequences of Host Responses: Extracellular Bacteria
A
- Excessive release of cytokines can lead to diffuse intravascular coagulation with consequent defective clotting, changes in vascular permeability, loss of fluid into the tissues, a fall in blood pressure, circulatory collapse, and hemorrhagic necrosis, particularly in the gut.
- LPS= Endotoxic shock
- TNF (secreted first) and IL-1 cause endothelial cells to express cell adhesion molecules and tissue thromboplastin.
- Promote adhesion of circulating cells and deposition of fibrin, respectively. Platelet activating factor (PAF) enhances these effects.
“Cytokine Storm”: Gram+ bacteria can induce shock by massive release of cytokines mediated by superantigens.
SIRS = Systemic Inflammatory Response Syndrome: local inflammatory response starts to have a systemic effect
8
Q
Extracellular Bacterial Evasion of C’
A
- An outer capsule or coat prevents complement activation.
- An outer surface can be configured so that complement receptors on phagocytes cannot obtain access to fixed C3b.
- Surface structures can be expressed that divert attachment of the lytic complex (MAC) from the cell membrane.
- Membrane-bound enzyme can degrade fixed complement or cause it to be shed.
- The outer membrane can resist the insertion of the lytic complex.
- Secrete decoy proteins that cause complement to be deposited on them and not on the bacterium itself.
9
Q
Evasion of Phagocyte Killing: Intracellular Bacteria and Fungi
A
- Secrete repellents or toxins that inhibit chemotaxis
- Others have capsules or outer coats that inhibit attachment by the phagocyte (S. pneumoniae or C. neoformans)
- Phagocytosed, but release factors that block subsequent killing mechanisms. Once ingested, inhibit lysosome fusion with the phagosome. May also inhibit the proton pump that acidifies the phagosome, so the pH does not fall.
- Some secrete catalase (staphylococci), which breaks down hydrogen peroxide.
- Organisms such as M. leprae have highly resistant outer coats. M. leprae surrounds itself with a phenolic glycolipid, which scavenges free radicals.
- Mycobacteria also release a lipoarabinomannan, which blocks the ability of macrophages to respond to the activating effects of IFNγ.
- Cells infected with Salmonella enterica, M. tuberculosis, or Chlamydia trachomatis have impaired antigen-presenting function.
- Several organisms (Listeria and Shigella spp.) can escape from the phagosome to multiply in the cytoplasm.
- Finally, the organism may kill the phagocyte via either necrosis (staphylococci) or induction of apoptosis (Yersinia spp.)
10
Q
Types of Intracellular Bacteria:
A
- Rickettsia
- Mycobacterium
11
Q
Immune Response to Intracellular Bacteria:
A
- Innate immune response to intracellular bacteria: phagocytes, NK cells, IL-12 and IFN-γ
- Limits growth, spread
- IFNgamma is most important to inhibit bacterial growth, followed by IL-12
- Adaptive immune response is cell-mediated immunity
- T cells activate phagocytes to eliminate the microbes.
- T-cell dependent Ags
- Linear protein peptides
- HLA recognition
12
Q
Cell- Mediated Immunity: Intracellular Bacteria
A
*** This is the major effector branch
- Intracellular bacteria are phagocytosed by macrophages and may survive in phagosomes and escape into the cytoplasm.
- CD4+ T cells respond to class II MHC-associated peptide antigens derived from the intravesicular bacteria.
- Produce IFN-γ activating Mfs to destroy the microbes in phagosomes.
- CD8+ T cells respond to class I–associated peptides derived from cytosolic antigens and kill the infected cells.
Innate immunity may control bacterial growth, spread. But elimination of the bacteria requires adaptive immunity: CD4+ & CD8+ T cells
13
Q
Cross-presentation
A
- important for intracellular bacterial infection control
- DC’s ingest virall infected cells and can display Ag to CTL’s using both CLass I and Class II HLA at the same time to simultaneously stimulate CD4+ and CD8+ cells
14
Q
Consequences of Host Responses: Intracellular Bacteria
A
Granuloma formation: collection of Mfs: trying to wall off the spreading in the area
- Activated Mfs fuse to form multinucleated giant cells
- May or may not contain necrotic center
Individual genetics influence outcomes: this is influenced through production of Th1/Th2- Th1 would be the most protective cell type
15
Q
Mechanisms of Immune Evasion by Bacteria
A
Extracellular Bacteria:
- Antigenic Variation: N. gonnorrhoeae, E. Coli, Salmonella Typhimurium
- Inhibition of C’ Activation: many bacteria
- Resistance to phagocytosis: Pneumococcus
- Scavenging of reactive oxygen intermediates: Staph
Intracellular Bacteria:
- Inhibition of phagolysosome formation: M. tuberculosis, L. pneumophilia
- Inactivation of ROS/NOS: M. leprae
- Disruption of phagosome membrane, escape into cytoplasm: L. Monocytogenes
16
Q
Risk of being asplenic
A
Can put you at most risk for SEPSIS from encapsulated bacteria because spleen normally functions in filtering the Ags from the blood when bound by Abs and C’
- At risk for fulminate sepsis
- Encapsulated bacteria
- Recommended vaccination schedule
- Antibiotic Prophylaxis
Spleen is located in upper left
Liver is located in upper right
17
Q
Acute Mononucleosis: EBV
A
*** viral infection***
- Emma was a healthy 15 y/o female when she suddenly developed a very sore throat accompanied by fever & malaise. Her throat was so swollen she had trouble swallowing. Over the next few days her fever waxed & waned, her sore throat became worse and she became progressively more tired and anorectic.
- Day 3: doc noted severe pharyngitis. Culture for streptococci was negative. The symptoms persisted and she was unable to eat as she could barely swallow. She reported no SOB but that her ULQ felt slightly uncomfortable.
- Her temp was 38.2°C, RR:18, BP: 85/55 Pulse: 84 PE: tonsils red & enlarged, met midline leaving a passage of approximately 2X2 cm. Palatal petechiae were seen with lymphadenopathy of anterior & posterior cervical nodes. Palpable moderate hepatosplenomegaly.
WBC with Diff: WBC 18,590 (high); 39% PMNs, 27% Lymphs, 22% atypical lymphs (very high), 11% Mono (high)
Presumptive Dx: Acute infectious mononucleosis with complications including partial pharyngeal obstruction
Titers: IgM & IgG to EBV capsid antigen
- EBV (HHV4)
- One of the most common
- ~95% 35- 40 y/o have titer
- Infects B cells and some epithelials
- Adolescence present with infectious mononucleosis (“mono”)
- Supportive care only
- Symptoms resolve 1 -2 months
- viral latency for life in B cells (BM)
- Associated with some cancers, autoimmune diseases
18
Q
Viruses
A
- Obligate intracellular pathogen
- Use host cellular machinery to replicate
- Latent infections: viral DNA persists in host cells: requires control not eradication (i.e. herpes virus)
- Lytic infections: Infected cell is lysed (Budding –>Virion spreading)
- Block further infection and eliminate infected cells
19
Q
Viral Immunity: Innate and Adaptive
A
Innate immunity:
- IFNs: prevent infection
- NK cells: eliminate infected cells
Adaptive immunity:
- Antibodies: block infection during extracellular stage
- Must have had previous infection
- CTLs : kill infected cells
- CD8+: Class I HLA
- Phagocytosis of infected cells and presentation by APCs
20
Q
IFN’s: “Antiviral State”
A
IFNs: protect against viral infections and promote cell-mediated immunity
- Inhibits viral replication in both Infected and uninfected cells
- Increases Class I HLA
- Promotes Th1 development
- Promotes lymphocytes migration and sequestering in lymph nodes: increases opportunit for lymphocyte specific to the epitope to be where it needs to be to be activated
21
Q
Typical Acute Viral Response:
A
- NK cells and interferon are detected in the blood stream and locally in infected tissues.: day 0-6
- CTLs activated in lymph nodes or spleen, followed by the appearance of neutralizing antibodies in serum- starting at day 2-14
- Activated T cells are absent by the second to third week
- T & B cell memory is established and may last for many years.
- Antibody present from day 4-18+
22
Q
Cell-Mediated Immunity: Viruses
A
*** Major Effector Branch!!!!
CTLs: major effector cell
IFNs
Abs:
- Block attachment
- Neutralize extracellular stage
- Must have had previous exposure
23
Q
Consequences of Host Response: Viral Immunity
A
Persistent viral infections (HCV) can lead to circulating immune complexes (Type III Hypersensitivity)
Viral Infections may provoke autoimmunity
- Cytolytic mechanism may expose “hidden” self-Ags: Epitope spreading
- Molecular Mimicry: Mumps
CTLs can cause tissue damage
- Noncytopathic viruses
- CTLs infiltrate tissue
- Chronic damage
24
Q
Evasion: Viruses
A
Latency
- Months to years (HHV3)
Antigenic variation: Mutation of regions normally targeted by Abs and T cells.
- HIV
- Foot and mouth
- Influenza
Cytokine Analogs:
- vIL-10 – immune suppression
- vIL-6
- vCCL3 – complement binding analogues
Complement binding protein analogs
Inhibition of Ag processing by Viruses:
- Class I:
- Block peptide uptake into the ER
- Prevent assembly and migration of peptide:HLA
- Encode their own homolog
- Class II:
- Block transcription
- Premature targeting for degradation
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Mechanisms of Immune Evasion by Virus
1. Antigenic Variation: Influenza, HIV, Rhinovirus
2. Inhibition of Ag processing (blockade of TAP transporter - Herpes, REmoval of Class I molecules from the ER - cytomegalovirus)
3. Production of cytokine receptor homologs: Vaccina/Poxvirus (IL1, IFNgamma) and cytomegalovirus (chemokines)
4. production of immunosuppressive cytokine: Epstein-Barr Virus (IL-10) "mono"
5. infection of immunocompetent cells: HIV
26
Fungi
* Rigid cell wall made of complex polysaccharides
* No approved vaccines
* Antifungal drugs often have severe side effects
* Can exist as Yeasts: single cells, Hyphae: long, slender branching
* Highly immunogenic: Bs & Ts
* Very few are pathogenic
* Immunocompromised at greatest risk
27
Immune responses to Fungi
\*\*\* Cell-mediated immunity (Tcells) is the major effector branch!!
Innate:
* Neurophils, Mfs and defensins
Adaptive:
* Th1 activation of Mfs – want macrophages to take up the fungus, phagocytose it, and kill it
* IFNg & IL-12 production
Candidiasis = thrush = usually happens when people are immunosuppressed, long term steroids, chemotherapy, how resistant you are, periods of stress. This is kept under control by the bacteria living in your mouth. Candida is normal flora in your mouth. It doesn’ t hurt, but need to get an anti-fungal mouthwash, need to do this longterm to restabilish the normal bacteria of the mouth. It becomes a problem if people are on chemotherapy, and it grows down the esophagus and towards the gastric tract
- if have no thymus/problem with thymus would increase susceptibility to viral, fungal and intracellular bacterial infections
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Immunity to Parasites: both Protazoan and Helminthes
**Protozoan: **
Innate Immunity: Protozoan
* Phagocytosis (Neutrophils, Mfs, DCs)
Adaptive Immunity: Protozoan
* Th1 activation of Mfs
* Specific Ab protection
**Helmithes: **
Innate Immunity: Helminthes
* Phagocytes secrete microbial substances to kill organisms to large to be internalized
* Alternative C’ pathway
Adaptive Immunity: Helminthes
* Th2 class switch to IgE (IL-4, IL-5)
* IgE binds to outer cuticle, mast cell degranulation
* IL-5: recruit Eosinophils to area for degranulation (more toxic than Mast)
* ADCC
29
Immunity to Parasites: Humoral vs. Cell-mediated
- Antibody is the most important immune response against parasites that live in the blood stream, such as African trypanosomes and malarial parasites,
* Antibody can damage parasites directly
* Enhance their clearance by phagocytosis (opsonize)
* Activate complement
* Block entry into host cells and limit the spread of infection
- Cell-mediated immunity is active against parasites that live in the tissues.
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Consequences of Host Response: Parasitic Infections
* Chronic infections:
* Immunosuppression
* Granulomas (body trying to block worms off), fibrosis
* Physically block circulation, lymph, portals to organs, obstruct GI
* Formation of circulating immune complexes if can’t be cleared
* Cytokine overload
* Mast cell & Eo mediators
* Molecular Mimicry
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Parasitic mechanisms of Evasion: Phagocytic Mechanism
- Parasites actively enter the cell into a membrane-bound vacuole. Lysosomes do not fuse with this vacuole. Dead parasites, however, are taken up by normal phagocytosis into a phagosome and are destroyed by the enzymes of the lysosomes that fuse with it. T. gondii
- Survival parasite depends upon stage of development
* T cruzi: trypomastigotes escape from the phagosome and divide in the cytoplasm whereas epimastigotes do not escape and are killed.
- Parasites multiply within the phagosome and resist digestion by the presence of a surface protease. Activated macrophages, the number of parasites entering the cell and the number that replicate diminish. Leishmania spp.
32
Parasitic Mechanism of Evasion: Antigenic Variation
Parasites change their surface Ags during their life cycle in the host.
Two forms:
* Stage specific: mature vs. infective
* Continuous Ag variation (Programmed expression of genes encoding major surface AGs)
Every seven days the parasites shed their surface Ags and express a different Ag. Just when immune system is starting to recognize them, it has to start all over again
33
Mechanisms of Immune Evasion by Parasites:
1. Antigenic Variation: Trypanosomes, Plasmodium
2. Aquired resistance to C' and CTL's: Schistosomes
3. Inhibition of host immune responses: filaria, trypanosomes
4. Antigen shedding: entamoeba
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Hygeine Hypothesis
We’re too clean!
Decreasing incidence of infections leads to increasing incidence of autoimmune & atopic diseases.
Childhood exposures:
* Epidemiological & experimental evidence
* + correlation asthma, T1D & MS to GNP in Europe
* + correlation of atopic dermatitis to family income
Helminth candidates for anti-atopic & anti-inflammatory agents
- Took children and looked at their exposures to dirt, older siblings, farming, daycare, whether or not they had worm infections and microbial exposures and compared those to children who lived in the city in sterile, clean city urban upscale environments. Those that lived in sterile environments, had larger susceptibility to atopic diseases. They had greater Thype II balance than a type I. maybe we are seeing this switch to type II is because we are too clean. Got to give the eos and mast cells something to do – maybe we should give leminth candidates for anti-atopic and anti-inflammatory agents
35
How could Helminth infections result in less atopic/inflammatory diseases?
* Helminth infections are the most common cause of persistent eosinophilia
* Life cycles in tissues & blood cause profound change in cytokines
* IL-5, 3, GM-CSF
Evasion:
* Helminth-derived products lead to ↓ of eo & mast cell responses
* Modulate T cell responses
* Tregs increase in number in mucosa during a helminth infection
* IL-10
36
Summary Slide (super long)
* Innate immune responses to extracellular bacteria: Complement is activated via the alternative pathway, phagocytosis of the bacteria by neutrophils and Mfs with release of proinflammatory cytokines.
* • Antibody provides an antigen-specific protective mechanism. Opsonizing antibody responses are particularly important for resistance to extracellular bacterial pathogens.
* Complement can kill some bacteria, particularly those with an exposed outer lipid bilayer, such as Gram-negative bacteria.
* • Intracellular bacterially infected cells can be killed by CTLs. Other T cell populations and some tissue cells can contribute to antibacterial immunity (cytokines).
* • The response to bacteria can result in damage. Excessive release of cytokines caused by microorganisms can result in immunopathological syndromes, such as endotoxin shock.
* Ultimately most bacteria are killed by phagocytes. Macrophage killing can be enhanced on activation. Optimal activation of macrophages is dependent on Th1cells. Persistent macrophage recruitment and activation can result in granuloma formation.
* The virulence of bacteria can be linked to the number of mechanisms it uses to resist innate and adaptive immune responses.
* Innate immune mechanisms (interferon, NK cells, and macrophages) restrict the early stages of infection and delay spread of virus.
* Interferons exert antiviral activity by a variety of mechanisms.
* NK cells are cytotoxic for virally infected cells.
* • Antibodies and complement can limit viral spread or reinfection.
* T cells mediate viral immunity — CD8+ CTLs destroy virus-infected cells; CD4+ T cells are a major effector cell population in the response to many virus infections.
* • Responses to viral antigens can cause tissue damage from the formation of immune complexes and by causing immunosuppression, immunodeficiency, or autoimmunity.
* Viruses have evolved strategies to evade the immune response. Virus latency and antigenic variation are the most effective mechanisms.
* Many viruses deviate the immune response by the production of cytokine analogs and cytokine receptor analogs.
* Many DNA viruses have strategies to control the expression of MHC molecules.
* Fungi can cause life-threatening infections. Immunity to fungi is predominantly cell mediated and shares many similarities with immunity to bacteria.
* Parasites stimulate a variety of immune defense mechanisms.
* • Parasitic infections are often chronic.
* Many are spread by invertebrate vectors and have complicated life cycles.
* Their antigens are stage specific.
* • Innate immune responses are the first line of immune defense.
* • T and B cells are pivotal in the development of immunity. Both CD4 and CD8 T cells are needed for protection from some parasites, and cytokines, chemokines, and their receptors have important roles.
* • Effector cells such as macrophages, neutrophils, eosinophils, and platelets can kill both protozoa and worms. They secrete cytotoxic molecules such as reactive oxygen radicals and nitric oxide (NO•). All are more effective when activated by cytokines.
* Worm infections are usually associated with an increase in eosinophil number and circulating IgE, which are characteristic of Th2 responses. Th2 cells are necessary for the elimination of intestinal worms.
* • Parasitic infections have immunopathological consequences. Parasitic infections are associated with pathology, which can include autoimmunity, splenomegaly, and hepatomegaly. Much of this immunopathology may be mediated by the adaptive immune response.
* Parasites have many different mechanisms of evading host immune responses: antigenic variation, disruption of phagocyte functions.
