Exam 3 Flashcards

Question

What can lead to phagocytic disorders in PID

Answer 1

Defects in any steps in Destroying microbes by neutrophilic granulocytes: Adhesion, chemotaxis, Phagocytosis (opsonisation: coating with Ig and/or complement), killing: oxygen radicals can lead to Chronic Granulomatous Disease (CGD): A defect in the NADPH oxidase subunit prevents ROS production = neutrophils unable to kill ingested pathogens, resulting in recurrent infections. > Frustrated immune cells form granulomas

Answer 2

Neutrophils engulf and kill the microbes to which they bind > Bacteria are taken up into phagosomes > Phagosomes fuse with granules, assembly of a functional NADPH oxidase in the phagolysosome membrane, leading to generation of O2- Acidification as a result of ion influx releases granule proteases from granule matrix

Answer 3

Antibiotic profylaxis, Interferon gamma, Stemcell transplantation, (Gene therapy: Not in NL)

Answer 4

. Removal of waste products * Mineral housekeeping * Regulation body fluids * Regulation acid & base balance * Activation of vitamin D and production of strong bones * Production of EPO

Answer 5

Millions more develop kidney failure and require KRT but lack access to therapy and die prematurely (mainly people from LICs or LMICs)

Answer 6

* To feel more fit * To live longer (better survival) * To gain more freedom * To improve chances to work * To live a “normal life”, to have a family * Better QoL *Cheaper medical lifestyle

Answer 7

risk of death decreases as more days pass after transplantation

Answer 8

Via HLA matching

Answer 9

They are proteins found on the surface of most cells in the body. They are encoded by genes in the HLA complex, located on chromosome 6 Help the immune system distinguish between the body's own cells and foreign substances Essentially human MHC Important there is HLA matching when donating so immune cells dont start to attack self cells

Answer 10

HLA Class I (A, B) and HLA Class II (DR) A person inherits one set of HLA genes from each parent, giving two alleles per gene (e.g., HLA-A, HLA-B, HLA-DR). Siblings have a 1 in 4 chance of being an exact match since they can inherit the same combination. Best fit: HLA mismatch 0-0-0 Worst fit: HLA mismatch 2-2-2 * Better survival * Less immunization * Not necessary

Answer 11

Highly polymorfic (there is an extensive variety of alleles (genetic variants)) Present peptides derived from pathogens or “altered self” to the immune system Differences in HLA elicit an immune response, both cellular and humoral Big barrier in transplantation medicine

Answer 12

Immunization - recipients immune system becomes sensitized to foreign HLA markers (can be due to exposure from foreign HLAs in previous transplants, blood transfusions, or pregnancies) Sensitization - immune system has developed antibodies against certain HLA types = more difficult to find compatible donor kidney = hyper acute rejection

Answer 13

Direct (recipient's T cells directly interact w/ donor's HLA molecules on the surface of the transplanted organ) Semidirect (donor cells transfer their HLA molecules directly to recipients APCs which present donors HLA molecules on their surface + recipients T cells recognize foreign HLA molecules) Indirect (recipient’s APCs take up donor tissue, process donor’s HLA molecules + present them as peptides on their own MHC molecules. Recipient’s T cells recognize these as "foreign," activating an immune response) Interaction of APC + T cell is regulated by 'uppers' and 'downers'

Answer 14

Homozygous twin brother

Answer 15

Signs: Kidney color not pink, Flabby tissue, No urine production Cause: preformed HLA (or anti-blood type) antibodies Prevention: a crossmatch test is performed to prevent hyperacute rejection

Answer 16

CDC-based assay Patient serum (contains their antibodies) > Donor lymphocytes (T cells usually) are isolated (express donor HLA molecules) > mix serum + donor cells > addition of complement > if antibodies against donor HLA = antibodies bind to lymphocytes > complement system activated = lysis of donor lymphocytes

Answer 17

Cell-based assays (e.g CDC cross-match), Solid-phase assays (e.g ELISA), Flowcytometry cross-match, Luminex

Answer 18

1. Complement dependent cytotoxity detects preformed antibodies 2. Flow cytometer tests antibodies attached to lymphocytes 3. Solid-phase assays: * Antigens bound to microtiter plates * Single antigen beads (Luminex)

Answer 19

Hyperacute rejection is an immediate and irreversible response to pre-existing antibodies. Acute antibody-mediated rejection happens later and is a result of new antibody production after the transplant, which can often be managed if caught early.

Answer 20

Cell based assays * Positive assay highly clinical relevant (80% rejection of the graft) * Often IgG enhanced * Dithiothreitol (DTT) to remove IgM * Flowcytometer: both complement as noncomplementbinding depending on the second antibody Solid-phase assay * Sensitive * Both complement and noncomplement binding antibodies, no IgM autoantibodies or nonHLA antibodies * Pathogenic treshhold remains unknown

Answer 21

- Hyperacute rejection - Memory B cell response leading to early ABMR - Chronic active ABMR

Answer 22

Occurs within days or weeks after transplantation Rapid graft dysfunction Main target of these antibodies is the MHC antigens on the peritubular endothelium and glomerular capillaries Sometimes can be triggered by non-HLA antibodies which target other molecules or proteins on the transplanted kidney Caused by an anamnestic response ( recipient’s immune system being "primed") by previous exposure to similar HLA antigens from prior transplants, blood transfusions, pregnancy etc = generates complement-fixing antibodies leading to rejection

Answer 23

the earlier the kidney transplant is performed after the onset of kidney failure the less harm + better the chances for long-term success

Answer 24

A: anti-B, A antigen B: anti-A, B antigen AB: none, A and B antigens O: anti-A + anti-B, no antigens

Answer 25

A can donate to A or AB B can donate to B or AB AB can donate to AB (because others will attack, e.g if donated to A person the B antigens on AB will = immune system attack) O can donate to A, B, AB, O (because it has no antigens = doesnt trigger anything)

Answer 26

Type II Hypersensitivity is an antibody-dependent process in which specific antibodies bind to antigens = tissue damage or destruction E.g A transfusion is a type II reaction Hyperacute rejection is a type II reaction

Answer 27

Blood type antigens resemble carbohydrates expressed on the cell wall of bacteria Blood type carbohydrate antigens are also expressed on vascular endothelial cells

Answer 28

Pretreatment of blood (washing, leukodepletion, irradiation) aim to reduce the risk of immune reactions but these techniques DO NOT prevent HLA sensitization (the decelopment of immune responses against HLA) if anything they could increase the risk of sensitization They can lead to dev of antibodies against a broader range of HLA's = increasing likelihood of transplant rejection Highest risk for (further) sensitization in pre-sensitisized patients (pregnancies, transfusions, prior transplants)

Answer 29

Postmortal vs living Transplantation over blood type barrier (i.e incompatible blood types) can yield better outcomes than postmortal donors

Answer 30

those who got diagnosed + then received dialysis treatment (their survival rates significantly decreased over time) = sooner you get transplanted the better (with either living donor or dead donor your chances of survival are still better)

Answer 31

Organ donation act (1998): - competent - > 18 years of age - clear informed consent - to the benefit of someone else Voluntarily, not paid and always revocable Socially feasible Good chance of success of donation and transplantation

Answer 32

First one in 1908 Using bovine serum to impair immune system ability to produce antibodies 9 of 25 renal transplants survived more then 2 years but….Toxic

Answer 33

Steroids inhibit… * IL-1/2 * TNF * Chemotaxis and adhesion of neutrophils Calcineurine inhibitors (tacrolimus or ciclosporin) * Inhibit IL-2 * Stimulate production of TGF-beta Proliferation inhibitors (mycophenolate mofetyl or azathioprine) Rejection treatments * MPNS pulses * ATG/plasmapheresis

Answer 34

Hyperacute rejection * Very rare, due to cross matching * <24hr * HLA antibodies already present Chronic rejection * Months to years after transplantation * Multifactorial * Difficult to treat Acute rejection * 20% * Mostly <6-12 months * Easy to treat

Answer 35

Aim: acceptance of transplant 1. Induction therapy: intense initial immunosuppression 2. Maintenance therapy: long-term immunosuppression 3. Anti-rejection treatment: treats episodes of acute rejection

Answer 36

- Required as long as transplant is in - Tolerance unpredictable (rejection remains a risk) - Inter-individual variability (diff doses etc) - Secondary malignancies (increases risk of certain cancers) - Opportunistic infections - Cardiovascular events - Specific side-effects - ADHERENCE/COMPLIANCE (missing doses can lead to rejection, overuse can increase toxicity)

Answer 37

* Increase in weight * Type II Diabetes * Hypertension * Psychological changes * Changes in appearance * Thinining of skin * Osteoporosis Immunosuppressant drug

Answer 38

Tacrolimus (Prograft®/Advagraf®/Envarsus®) * Hypertension * Diabetes mellitus * Tremor * Hairloss * Hyperlipidemia Ciclosporin (Neoral®) * Hypertension * Excessive hairiness * Gingivahyperplasia * Gout * Hyperlipidemia * Both: Nefrotoxic! * Short term: vasoconstriction * Long term: Structural damage

Answer 39

AZA and MMF (drugs) * Bone marrow disease: anemia, leucopenia, pancytopenia (AZA and MMF) * Skin malignancies (in particular AZA) * Gastro-intestinal complaints (MMF) * (Viral) infections (MMF)

Answer 40

1) The recipient's anti-A or anti-B antibody levels (titer) must be reduced to a safe level (< 1:256). This prevents antibody-mediated rejection of the transplanted organ. Plasma exchange process: Recipients blood separated into plasma + blood cells Plasma treated to remove: A/B-specific antibodies and non-specific antibodies (Ig) Treated plasma is returned to patient e.g Friend w/ blood type A can donate to recipient w/ blood type O

Answer 41

Yes, bloodtype matching is preferable though

Answer 42

More donation during life, more postmortal donors, xeno-transplantation, organ donation after euthanasia

Answer 43

* Immunological * Infectious * Fysiological * Ethical

Answer 44

1) Hyperacute rejection Cause: Preformed antibodies in the human target sugar molecule (Alpha-Gal) on pig cells Binding triggers complement activation + MAC formation = xenograft failure 2) Acute Vascular Rejection Cause: Activation of... Human anti-pig IgG antibodies. NK cells (complement activation, MAC formation) Macrophages (= platelet aggregation, clot formation) = xenograft failure. 3) Coagulation Activation Cause: Mismatch between pig endothelial cells and human clotting mechanisms = abnormal coagulation. Platelet activation and aggregation. Clot formation, leading to dysfunction of the transplanted organ. Solutions to 1, 2, + 3: Genetically modified pigs expressing human complement regulatory proteins 4) Acute Cellular Rejection Cause: Activation of B cells and T cells against the pig xenograft T cells (via CD40) and B cells (via CD20) coordinate immune attacks on the xenograft. Complement activation by T and B cells further damages the organ. (MAC) Solution: Use of immunosuppressive drugs: Rituximab: Targets CD20 on B cells to deplete them. Anti-CD40 therapy: Blocks T-cell activation pathways. Eculizumab: Inhibits C5 in the complement cascade, preventing MAC formation.

Answer 45

Zoonosis (transmission of infections from animals to humans through transplanted organs) Specifically retroviruses (PERV-A, B, and C)

Answer 46

Physiological differences in: Blood pressure Body temperature Renin-activity Cholesterol Solutions?: Could knock-in human genes and knock-out pig genes Thymokidney (specifically engineered/modified organ that combines thymic tissue (from donor pig) w/ a kidney to promote immune tolerance in recipient as it learns to recognize donors tissues as self)

Answer 47

Lentivirus

Answer 48

HIV infection > primary infection > a-symptomatic phase > symptomatic phase (AIDS) Gradual depletion of CD4 T cells

Answer 49

CD4 <200 cells/ul Opportunistic infections e.g Candida, Cytomegalovirus, PCPneumonia Cancers e.g Lymphoma, Kaposi Sarcoma AIDS dementia

Answer 50

Course speed (rapid, typical, or slow) determined by CD4+ T cell levels and Viral load HIV-1 diversity HIV-1 specific immunity Development of Cytotoxic T Lymphocyte escape variants

Answer 51

Caused by HIV reverse transcriptase which lacks proofreading acitvity = high mutation rate = millions of viral variants within any infected person in a single day - Positive selection: viral variants with increased fitness escape Cytotoxic T cells, neutralizing antibodies, anti viral drugs, etc

Answer 52

Adaptive immune response: Cytotoxic T cells (CD8+) kill HIV-1 infected cells by binding of TCR with MHC of infected APC (Presentation of viral peptides in context of HLA class I) Each HLA-allele presents distinct peptides)

Answer 53

HIV-1 has a high mutation rate giving high viral diversity Initially only 1 variant may have a mutation that allows HIV infected cells to escape from CTLs Selection pressure is placed by CTLs All cells containing a virus with the intact epitope are eliminated (easier to recognize + kill etc) Only cells infected with escape variant survive (+ thus multiply)

Answer 54

They prevent presentation by either... Mutations in anchor residues (anchor residues are parts of the peptide that secure its fit into the MHC molecule) = peptide can no longer bind to MHC molecule or Mutations in the peptide (even if the peptide is successfully presented by the MHC molecule, CTLs must "recognize" it via TCRs, mutations can change the peptides shape or the way it interacts with TCRs) = TCR doesnt recognize the peptide

Answer 55

Single nucleotide polymorphism = genetic variation in human Variation is called a SNP when present in ≥1% of the population Constitute ~ 90% of variation in human genome they can occur in coding and non-coding regions of the human genome

Answer 56

genetic differences (SNPs) between individuals correlate with their ability to control HIV HIV controllers: people who maintain low viral loads naturally = slow progression Progressors: people whose HIV progresses more quickly (lose CD4+ cells + show high viral loads) They have different SNP profiles, may explain why some people control HIV infection better than others

Answer 57

Genetic variation in HLA-B peptide binding pocket HLA-B57 and HLA-B27 are associated with better control of HIV (slow disease progression) HLA-B35 is associated with rapid disease progression. Genetic differences, particularly in the HLA region influence progression of HIV

Answer 58

CTL response is raised against viral peptides presented by HLA-B57: * Presentation of viral epitopes from conserved regions of the virus * High affinity recognition of HLA-B57 presented peptides by TCR = relatively low amounts of antigen result in strong CTL response * Viral escape occurs in immune dominant epitopes = virus mutates these epitopes to avoid immune detection BUT these mutations reduce virus's ability to replicate/cause disease (i.e viral attenuation) essentially Strong cytotoxic T cell response (CD8+ T cells) recognizing conserved epitopes in viral proteins Escape from cytotoxic T cells response occurs and is associated with viral attenuation

Answer 59

HIV-1 neutalizing antibodies = prevent virus from entering + infecting healthy cells by either blocking the virus from binding to the host or by interfering with its fusion to the cell membrane gp41 and gp120 are important glycoproteins on HIV-1 surface + are involved in binding to CD4 receptors on T cells 120: recognition + binding to CD4 receptor 41: facilitates fusion of HIV-1 envelope w/ host cell membrane

Answer 60

Native HIV is relatively immunogenic Majority of people are capable of eliciting neutralizing antibodies against assumed conserved and vulnerable epitope HIV is highly mutable and can escape the effects of autologous (from the same individual) NAb response = virus continues to replicate even in presence of the body's neutralizing antibodies Neutralizing Antibody response is not associated with disease progression

Answer 61

Cellular immune response: CTL + viral escape > viral evolution > sometimes viral attenuation Humoral immune response: Neutralizing antibodies + viral escape = NAb are ineffective > viral evolution

Answer 62

Antiretroviral therapy (does not eradicate HIV-1, suppress HIV-1 replication = undetectable viral load in blood, as soon as treatment is interrupted = viral rebound (no immune control), HIV persists in viral reservoir during ART) Entry inhibitors e.g CCR5/CXCR4 Inhibitors = prevent binding Fusion Inhibitors Reverse transcriptase inhibitors Integrase inhibitors = prevent integration of viral DNA into host DNA Protease inhibitors = prevents release + maturation of new virus infected cells

Answer 63

Prevention of resistance development: * Combination of drugs from different classes (since 1996) * High treatment adherence

Answer 64

Decline due to Improvements in hygiene, sanitation and health - Vaccines - Antibiotics

Answer 65

The observed rise in inflammatory diseases may be attributed to - improved living standards, - increased wealth - reduced exposure to infections (Hygiene hypothesis)

Answer 66

Larger family sizes = protective against the development of allergic diseases such as hay fever and eczema Having older siblings = more unhygienic contact in early childhood which seemed to protect against the development of allergic diseases (so e.g 5th born has lower prevalence of hay fever than 1st born)

Answer 67

Early childhood exposure to microorganisms may protect against allergic diseases by contributing to the development of the immune system

Answer 68

Microorganisms that were once abundant trained our immune system: They were tolerated at the expense of excessive tissue damage to eradicate them. Our immune system has evolved in their continuous presence.

Answer 69

Rural > urban Outdoor > Indoor (isolation, central heating) Physical labor > sitting professions High fibre food > fast food

Answer 70

Vaccines + drugs can act differently Urban environments are associated with accelerated inflammatory diseases Rural environments are associated with protection against inflammatory diseases

Answer 71

Children growing up in microbe-rich rural traditional farming environments = less likely to suffer from asthma & allergies compared to their urban counterparts eg exposure to farm stables + farm milk Diversity of microbial exposure (e.g due to living on a farm) was inversely associated with risk of asthma

Answer 72

Although they are genetically close they have different farm layouts Amish: small single-family farms, traditional farming, animal barns close to home = higher diverse microbial exposure Hutterites: large communal farms, modern farming, animal barns very far from homes = lower diverse microbial exposure Amish had a higher bacterial compoition in dust compared to Hutterites

Answer 73

Maternal farm exposures during pregnancy = increase in cord blood regulatory T cells that may protect against allergies

Answer 74

Within urban areas differences in allergy outcomes based on socioeconomic status Urban areas w/ high SES = high prevalence of asthma + allergic sensitization Urban areas w/ low SES = low prevalence of asthma + allergic sensitization

Answer 75

parasitic infection = protective effect against allergic sensitization (e.g to house dust mite allergy or asthma)

Answer 76

Flatworms (platyhelminths) > Trematodes (flukes) > Cestodes (tapeworms) Roundworms (nematodes) Helminth infections can persist for years in humans

Answer 77

Parasitic roundworm Eggs in feces of infected individual (diagnostic stage) > larva hatches > development into larger larva > larva penetrates skin (infective stage) > larva exit circulation in lungs (coughed up > swallowed) > enter small intestine > excreted

Answer 78

Parasitic roundworm In adult small intestine + excreted eggs in feces > ingestion of embryonated eggs > hatched larva enter circulation + migrate to lungs > coughed up + swallowed > re-enter GI tract > mature in small intestine

Answer 79

Parasitic trematode (blood fluke) Eggs from feces or urine of infected human > eggs hatch + release larva > larva penetrate snail tissue > larva develop in snails > developed larva relesed from snail into water > penetrates skin > circulates blood > portal blood in liver + matures > adult worms migrate to bowel/rectum or bladder and lay eggs

Answer 80

Increase in mucus production, eosinophilia, bronchoconstriction, smooth-muscle contraction, airway remodelling = help expel helminths BUT chronic helminth infection can dampen the immune system e.g suppression/inhibition of lung eosinophilia + airway hyperresponsiveness But there are inconsistencies in population studies on the effect of helminth infection on allergy

Answer 81

* Different helminths have different effects (systemic versus local effects) * Mild versus chronic helminth infections * Different populations in different geographical locations * Varying age groups (children v adults) * Most studies are cross-sectional * Varying outcomes and exposure measures * Even variations in helminth detection methods

Answer 82

Randomization of sample: Intervention group Anthelminthic treatment > follow up Control group Placebo/no intervention > follow up Outcomes: allergic sensitization, eczema, asthme/wheeze, other inflammatory outcomes e.g : Does anthelminthic treatment during pregnancy increases the risk of allergy in infancy ?? outcome: doctor-diagnosed infantile eczema Conclusion: Exposure to maternal worm infections in utero may protect against eczema in infancy

Answer 83

Helminths are thought to induce an anti-inflammatory immune cell environment which is associated with insulin sensitivity (lowering risk of T2D) In helminth-infected subjects, treatment significantly increased insulin resistance (risk factor for T2D)

Answer 84

1) Th1 response: produce IFN-γ + TNF-α > activate macrophages (Mφ) Th1 activation peaks 2) Th2 response: produce cytokines IL-4/5, IL-9/13 Th2 response peaks 3) Regulatory response: Tregs > produce IL-10, TGF-beta Bregs > produce IL-10 Outcome: Survival or spill over tolerance > IBD, T2D, asthma etc

Answer 85

Tregs: B cell modulation, tissue remodelling, inhibition of cells from innate immunity, down-regulation of T effector cells, inhibition of antigen presentation Bregs: inhibition of Mφ, DC, NK, CTL, Th1 activation of Th2, Tregs

Answer 86

Treg induction by helminths Increase in Helminth excretory-secretory products (so increase in helminths) = increase in Foxp3 % = enhanced Treg response Treatment of helminth infection = sig reduction in Tregs

Answer 87

Colitis * Pre-cllinical Studies = Reduction in disease severity and mortality * Clinical = helminth therapy improved disease activity Type 1 Diabetes * Pre-cllinical Studies = Inhibition diabetes development in NOD mice * Clinical = no clinical studies / conflicting epidemiological data Multiple Sclerosis * Pre-cllinical Studies = Prevention of onset of experimental MS disease in animal models and delay in severity * Clinical = Decrease in relapses and numbers of disease lesions overall tho it is not clear, there are varying results + mainly a limited effect

Answer 88

Inconsistency in human studies: - Clinical outcome/severity - Age of the affected population - First infection v endemic population - Type of helminth/intensity - Pathology due to worm infection - Lack of standardized cultures

Answer 89

Chronic helminth infections = associated with immune regulation and protection against allergies Acute helminth infections are associated with induction of Th2-associated responses, increased IgE responses and induction of cross-reactive IgE = pro-inflammatory responses

Answer 90

Cons: reduced immune responses, increased susceptibility to other infections, reduced anti-tumor immunity, reduced efficacy of vaccines Pros: reduced incidence of allergy/autoimmunity/asthma/IBD

Answer 91

breast milk vs formula vs raw cow milk, antibiotic use, vaccination, close contact with animals, immune system dev, family size, daycare attendance, mode of delivery, maternal diet, maternal antibiotics

Answer 92

Immunological dysregulation Immunological Equilibrium: Healthy microbiota = a balanced composition of multiple classes of bacteria = intestinal homeostasis + immune tolerance − Symbionts: organisms with health-promoting functions − Pathobionts: Microbiota with the potential to induce pathology Immunological Disequilibrium: Dysbiosis = unnatural shift in the composition of the microbiota where #no. of symbionts are reduced and/or pathobionts are increased = immune dysregulation

Answer 93

Antibiotic treatment = changes in microbiota composition + dysregulation of host immune homeostasis Increased susceptibility to inflammatory disease

Answer 94

SCFA are produced by the gut microbiota from fermentation of dietary fibres. Most common: Acetate Butyrate Propionate Play an important role in immune regulation pathways = fortified barrier function, increased immunity, tolerogenic factors low fiber diets = more eosinophil influx = allergic airway inflammation high fiber diet = less eosinphil influx + more Treg activity = less eosinophil infiltration into airway tissues

Answer 95

Intestinal microbiota contribute to the ability of helminths to modulate Allergic Inflammation Antibiotic treatment abolishes helminth protection against allergic inflammation Helminths releases excretory-secretory products + acetate Microbiota release SCFA All these lead to Foxp3 Treg cell activation = inactivates airway inflammation

Answer 96

old infections mostly lost diminished diversity + exposure of microbiota crowd infections are increased esp in inner cities

Answer 97

eukaryotes: prokaryotes: bacteria + archaea

Answer 98

true pathogen = primary pathogens potential pathogen = opportunistic pathogens (dont always cause disease, need an opportunity to do so) non-pathogenic

Answer 99

Have to prove all 4 of Koch's postulates 1) The microorganism is present in sick but not healthy individuals/animals 2) The microorganism must be grown to pure culture 3) The cultured microorganisms must cause the same disease in healthy individuals/animals 4) The same microorganisms must be culturable from sick individuals/animals but there are many exceptions to these

Answer 100

* Microorganisms cannot be cultured with available methods or require additional factors for in vitro growth (e.g. host cells - viruses) * Microorganism only causes disease in humans - No proof of disease from animal models * Long incubation period (time between infection and first symptom) - HIV-AIDS, prions (Creuzfeld-Jacob disease) * Microbes that can also asymptomatically colonize: commensals that turn into pathogens

Answer 101

Colonization resistance: protection against infiltration by new + harmful microorganisms Maturation + instruction of immune system Nutrition + metabolism of food

Answer 102

Disease association w/ disturbances in (intestinal) microbiome Source of infection (presence of opportunistic pathogens, immunocompromized host)

Answer 103

Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus, Group A Streptococcus

Answer 104

bacteria-associated molecules that are required for a bacterium to establish an infection and cause disease e.g toxins produced by some bacteria that kills the host cells by creating holes that lead to lysis Infection occurs when virulence factors outweigh the hosts immune defense

Answer 105

1. Colonization 2. Invasion (& dissemination) 3. Immune evasion 4. Nutrient acquisition

Answer 106

Mucosal membranes (airway, gut) and skin are common entry sites for bacteria Airway: droplets, aerosols Gut: infected food ingestion Skin: wounds, intravenous lines

Answer 107

Local and/or disseminated (widespread) symptoms - Local: skin redness, local pain, cough, diarrhea, vomiting… - (More) disseminated: fever, headache, confusion, petechiae, stiff neck (meningitis)… May vary depending on: - The route of infection - Type of bacteria causing the infection

Answer 108

1) Invading bacteria are detected by local tissue cells: * APCs: DCs, macrophages, mast cells - Pattern-recognition receptors (e.g. TLRs) * Non-immune cells: epithelial cells, keratinocytes, fibroblasts - Activated by bacteria but also in response to tissue damage - Produce AMPs + peptides for local non-specific killing 2) Local cells activate and coordinate downstream immune responses: - Attract phagocytes from the bloodstream (e.g. neutrophil-mediated killing) - In lymph nodes * Activated T- and B-cells, production of specific antibodies * Memory formation: prevent re-infection 3) Convergence of innate and adaptive immunity - antibodies bind to bacterium = phagocytosis - bacterial clearance

Answer 109

Direct killing of through complement activation (Gram-negative bacteria only) > MAC pore formation = cell lysis as extracellular fluids flood in Enhancing bacterial phagocytosis and killing: - For Gram-ve and Gram+ve bacteria Boost neutrophil recruitment and pathogen recognition > Complement activation (IgM, IgG) = pathogen opsonization + neutrophil recruitment (leading to more effector cells) > interaction with Ig receptors (IgG, IgA) = receptor-mediated phagoytosis

Answer 110

vaccines + antibiotics = kill or inhibit pathogen

Answer 111

Gram -ve has a much thinner peptidoglycan layer vs gram +ve has a much thicker peptidoglycan layer = MAC gets stuck in gram +ve and thus no lysis

Answer 112

Vaccination boosts host defense to increase long-lasting resistance against bacterial infections (inhibits virulence factors) Vaccination - Primary adaptive response (small lag time) Booster vaccination - activates immune system again Immunological memory > When you get primary infection there is no lag time and there is a secondary adaptive immune response

Answer 113

Edward Jenner, 1796 Observation: Milkmaids are protected from smallpox Infection with cowpox virus protects a person from smallpox virus

Answer 114

Made of certain components of the bacteria

Answer 115

Antibodies that neutralize bacterial toxins (that would otherwise cause lysis of host cells) - e.g: tetanus and diphtheria vaccines Induction of bactericidal antibodies that enhance bacterial phagocytosis and killing - e.g: meningococcal and pneumococcal vaccines - immunogenic surface antigens are good vaccine antigens to induce such antibodies

Answer 116

Capsular polysaccharides * Encapsulated bacteria have the ability to cause invasive disease e.g Streptococcus pneumoniae, Haemophilus influenzae b, Group B Streptococcus, Neisseria meningitidis * CPS composition varies between bacterial species but even within species * CPS is an important virulence factor: > Resistance to phagocytosis and killing by immune cells > Resistance to serum killing (Gram-ve bacteria) (complement killing, MAC pore)

Answer 117

Inverse correlation: bactericidal antibodies against capsular polysaccharide and IMD incidence % of serum w/ bactericidal activity increases = IMD incidence decreases (AS YOU GET OLDER)

Answer 118

Neisseria meningitidis

Answer 119

They are protected by maternal antibodies

Answer 120

Plain polysaccharide vaccines (isolated sugars from the coat + used in the vaccine) Insufficient for population-wide application: * Not immunogenic in young children (most ‘at risk’ group) * No immunological memory → repeated immunizations necessary to protect * Ineffective against carriage (commensal state, colonization) → only individual protection T cell-independent immune response: * Production of low affinity antibodies (T cells do not recognize these sugars) * No memory formation

Answer 121

Protein conjugation: CPS conjugated to a protein carrier T cell-dependent responses: T cell recognizes the protein = provides help to produce high affinity antibodies + polysaccharise-specific memory B cells

Answer 122

- Immunological memory - High affinity antibodies - Effective in infants - Herd immunity: protection of non-vaccinated individuals (as consequence of reducing carriage (transmission))

Answer 123

- Protection of non-vaccinated individuals - Consequence of reduction in carriage resulting in reduced circulation among population

Answer 124

Polysaccharide capsule structure determines serogroup: - 13 serogroups - groups A, B, C, X, Y, W most prevalent in disease

Answer 125

extracting CPS from different serogroups of Neisseria meningitidis, conjugate them to protein carriers (put all together in vaccine) > broader protection

Answer 126

Neisseria meningitidis + Streptococcus pneumoniae NOT for the other 2

Answer 127

*Limited vaccine coverage in case of wide range in CPS diversity > S. pneumoniae > 90 serotypes * Glycan antigen is not immunogenic * Glycan structures are similar to human structures (molecular mimicry) >Risk of inducing autoreactive antibodies >Group A Streptococcus, N. meningitidis serogroup B * Disease caused by low or non-encapsulated species/strains (often called nontypeable) >Examples: Group A Streptococcus (certain emm-types), non-typeable H. influenzae, Staphylococcus aureus

Answer 128

They stimulate their own growth, ignore growth-inhibiting signals, avoid death by apoptosis, angiogenesis, metastasis, replicate constantly to expand their numbers, evade + outrun the immune response

Answer 129

initiation: somatic cell experiences mutational event cancer progression: (proliferating cells) mutation + genome destabilization, dysregulation of growth control pathways evasion of cancer cell elimination: (precancerous cells) block apoptisis, block killing by T cells tumor growth + dispersal: (tumor) angiogenesis + metastasis

Answer 130

as time progresses survival decreases microevolution: the cells that can escape have an advantage cancer therapy does not cure only a gain of extra time

Answer 131

correlation between abundance of CD8+ in tumors with tumor progression fewer CD8 = worse prognosis more CD8 = better prognosis

Answer 132

Adaptive Access Memory

Answer 133

specific through their Antigen Receptor (TCR) allows them to see 'inside' cells viral peptides are cut and presented on APCs in MHC (binds to TCR = activated T cell) Activated T cells can kill infected cells and cancer cells with great precision (oncogenes > mutated proteins > neo-antigens) T cells expand by proliferation = well suited to fight cancer progression

Answer 134

Start from peptide antigens presented by MHC class I on normal cells which then undergo mutations and become cancerous Tumor-specific antigen - Presentation of mutant peptide from mutated cellular protein (neo-antigens) Tumor-associated antigens - reactivation of embryonic genes not normally expressed in the differentiated cell - overexpression of self protein by a tumor cell increases self-peptide presentation + recognition by T cells

Answer 135

Initiation of an immune response requires inflammation (danger!) 1) inflammatory inducers (e.g PAMPs) 2) Sensor cells (express PRRs) (e.g macrophages, DCs) 3) mediators (e.g cytokines, cytotoxicity) 4) target tissues

Answer 136

DAMPs: danger-associated molecular pattern released when cells are dying uncontrollably

Answer 137

- Recognition tumor antigen - Activation - Migration - Effector function

Answer 138

CD28 interacts with CD80/86 and produce cytokines

Answer 139

Tumor w/ DCs > DCs activate T cells in LNs > T cells migrate to tumor > T cells kill tumor cells

Answer 140

1) release of cancer cell antigens 2) cancer antigen presentation 3) priming + activation in LN 4) trafficking of T cells to tumors 5) infiltration of T cells in to tumors 6) recognition of cancer cells by T cells 7) killing of cancer cells (more dead cells = release new antigens = cycle repeats

Answer 141

Hot tumors are inflammed, cold tumors = immune system doesnt get in e.g by suppression of chemokine production

Answer 142

Immune-excluded cancer (presence of T cells at invasive margin but abscent in tumor bed I.S cannot penetrate tumor) mechanism of immune evasion: stromal barriers, aberrant vasculature, lack of chemokines, ongogenic pathways, hypoxia

Answer 143

Elimination, Equilibrium, Escape Microevolution = cancer cells escape immune system by loss of tumor antigen expression

Answer 144

immune escape by HLA loss 1) antigen loss 2) decrease in subunits of proteosome 3) decrease in TAP 4) loss of MHC I heavy chain 5) loss of beta-2 microglobulin (by mutations for example) 6) diminished transport of MHC I-peptide complexes to cell surface Hard MHC-I lesions: genetic alterations leading to permanent loss Soft MHC-I lesions: are reversible BUT NK cells are activated when there is a loss of MHC

Answer 145

*Tregs: inhibit responses to self antigens, Treg abundance correlates w/ poor prognosis, low treg = better prognosis + anti-tumor response (but risk of autoimmune diseases) * Exhaustion > T cells get "exhausted" + lose their effector function/proliferation There are transcriptional factors that promote exhaustion Sustained expression of inhibitory receptors on exhausted CD8+ T cells * TAMs (e.g MR- macrophage associated w/ wound healing, cancers require constant repair) * MDSC (make factors that inhibit killing of cancer cells) > tumors shape their microenvironment: suppressive factors condition the skin + LN and sabotage immune protection against metastatic spread Subverted myeloid cells (MDSC, M2 macrophages) release pro-angiogenic + tumor invasion promoting factors = important cause of therapy resistance

Answer 146

by extra information e.g inflammation/costimulation

Answer 147

DCs can interact with naive T cells and lead to differentiation into Tregs = tolerance + immune suppression

Answer 148

tumoral hypoxia, increase in lactate, increase in acidification

Answer 149

*Many cancers are immunogenic * tumor antigens/neo-antigens * Adaptibility immune response asset * Immune editing > Loss of antigen/HLA * Tolerance mechanisms > Tregs, MDSC, TAM > T cell exhaustion * Inhospitable tumor environment

Answer 150

immunotherapy for cancer mobilizes T cell responses targets exhaustion make antibodies that target these inhibitory receptors

Answer 151

Inhibitory receptors: PD-1 and CTLA4 > turn off T cells Only happens when ligand is there, antibody blocks ligand (from checkpoint inhibition)

Answer 152

survival curve flattens out effects of anti-CTLA-4 (ipilimumab) and PD-1 blockade (nivolumab) are enhanced when used in conjunction

Answer 153

it is very very effective

Answer 154

There are many inhibitory receptors Responsiveness to Checkpoint Inhibition correlates with mutational load High mutation burden = increase in likelihood of generating neoantigens (which IS can target)

Answer 155

Loss of HLA = cancer cells can evade detection Tolerance mechanism by PD-L1: pathway suppresses T cell activity = cancer can evade IS but breaking tolerance w/ treatments can result in side effects

Answer 156

extract T cells, alter, inject back in effective disadvantage: Patient-specific (laborious + expensive)

Answer 157

BITEs: activate all T cells in tumors BITE antibody is composed of 2 single chains from diff antibodies (CD3 monoclonal Ab + target monoclonal Ab) leads to T-cell activation (by binding to T cells) + redirected lysis (by binding to tumor-associated antigens present on the target cells)

Answer 158

No need antigen-specific T cells No need antigen-presentation Relatively cheap Disadvantage: need T cells in the tumor already (i.e it does not work on cold tumors)

Answer 159

Chimeric Antigen Receptor Antibodies bind different types of antigen than TCR and can be generated against any protein fusion Antibody and TCR CAR T cells recognize and kill leukemic cells (their activation is independent of MHC presentation so they can bypass tumor cells evasive mechanisms)

Answer 160

Builds upon the 1st generation by adding one costimulatory signaling domain (e.g., CD28 or 4-1BB). (combines signal 1 (CD3ζ-mediated activation) with signal 2 (costimulation), enhancing T-cell proliferation, survival, and cytokine release) 3rd gen adds 2 costimulatory domains improves therapeutic efficacy

Answer 161

leukopheresis (blood removed from patient) > retroviral transduction w/ CAR > CAR T cell infusion

Answer 162

* Checkpoint inhibition > Revolutionary! > Role antigen > Neoadjuvant therapy * TIL therapy * BiTEs * CAR T cells

Exam 3 Flashcards

(186 cards)