Inflammation and Immunity

  1. Distinguish between affinity, affinity maturation, avidity, multispecificity, and cross-reactivity
    • Affinity: how specific or tight a binding site is; reversible reaction that can be quantified
    • Affinity maturation: average Ab affinities increase with time
    • Avidity: overall strength of the combined binding site; IgM will always win
    • Multispecificity: a binding site in an Ab can bind several different Ags (helps diversity of Abs)
    • Cross-reactivity: Abs are said to be cross-reactive if they bind more than one Ag; can be a godo thing (cross-protection seen in flu vaccines); polyclonal Abs are more cross-reactive than monoclonal Abs; Ab, BCR, and TCR can all be cross-reactive
  2. What are 2 consequences of the conformational change Abs undergo when they bind their antigens?
    • steric conformational changes reveal cryptic sites that allows for binding between Fc region of Igs and Fcgamma receptors or C1q
    • Conformational change results in transmembrane signaling to the B cell
  3. How can Ag-Ab reactions be measured in the lab?
    • soluble Ags are precipitated by Ab
    • Particulate Ags are agglutinated by Ab
    • Abs are conjugated to other molecules (Radioimmunoassays and ELISA;enzyme linked)
    • Abs are conjugated to fluorescent labels (tissue immunofluorescence and flow cytometry on cell suspensions; can count and separate cells based on miniscule differences)
    • Nephelometry (light scatter test that occurs when Ag-Ab precipitates; very insensitive (takes a high concentration to get a good test); quantitation of Igs and complement)
  4. Define hemagglutination and distinguish it from isohemagglutination
    • Take a suspension of RBCs in test tube, add Ab, mix, analyze precipitate (agglutination) that forms
    • Iso: carbohydrate antigens; ABO types; these are IgM related (low affinity, high avidity); one Ab to one ABO antigen can activate the whole complement system
  5. Define Coombs test
    • Coombs reagent is anti-IgG
    • Abs are not normally present on RBCs and platelets; they are present on mast cells, B cells, and phagocytosing cells; if you see Abs on erythrocytes, positive Coombs test
    • Tells you autoimmune hemolytic anemia, thrombocytopenia purpura due to intravascular lysis and clearance
    • The indirect Coombs test is used in prenatal blood testing of pregnant women and typing for blood transfusions; it detects Abs against RBCs that are currently unbound in the patient's serum
  6. Define titer
    extent to which a serum Ab can be diluted and still have an effect
  7. Define immunoprecipitation
    • test for presence of Ab within the serum
    • Place serum on one side of a plate and place Ag on other side; allow to diffuse across plate; equivalence is point where Ag and serum meet (line of precipitation)
    • Partial identity occurs when there is cross-reactivity (ags share some antigenic determinants)
    • Can either have a pattern of identity, nonidentity, or partial identity (depends on how similar they look)
  8. What is the difference between immunoelectrophoresis and immunofixation?
    • Immunoelectrophoresis: detects specific Ags in complex biological samples; patient serum separated by electrophoresis, Abs and serum allowed to diffuse toward each other; lines of Ag-Ab precipitation form; gel is washed and drained; analyze Ags based on reactivity with Abs
    • Immunfixation: used to determine whether hypergammaglobulinemia is monoclonal or polyclonal; samples are electrophoresed and then precipitated with Abs to IgH or L chains; Ag-Abs are stained; if you run lambda tests and they are negative, you have a monoclonal situation (myeloma or MGUS)
  9. Define Radioimmunoassay
    • RIA
    • Detects very small quantities of Ag in body fluids
    • Procedure: sample is incubated in a microtiter plate with Ab bound to the wells; rinse well and add rdaioactive ag in excess to the unbound Ab; measure bound radioactivity; if Ag was present in the sample, then it would bind to the Ab, blocking binding of the radioactive Ag
    • Used clinically to measure IgE Abs to allergens (radioallergosorbant)
  10. Define ELISA
    • detects very small quantities of Ag in body fluids
    • Procedure: bind sample (Ag) to a well; add a second Ab that is conjugated to an enzyme; after washing, add substrate and a colorimetric change is measured and compared to a standard curve of pure Ag
    • Used clinically for pregnancy tests (HCG), measuring serum complement levels, and detecting many different types of infectious disease (HIV)
  11. How is the Western Blot used in immunology?
    To diagnostically detect infectious agents (i.e. anti-HIV Abs)
  12. How is immunofluorescence used in immunology?
    • detects cell or tissue associated Ags (including IgG or complement components, autoAbs to tissue Ags (i.e. DNA in lupus), Ags of infectious agents, and tumor Ags)
    • Can be direct if the primary Ab is conjugated to a flurophore
    • Indirect if a labeled secondary Ab is used (can be used to amplify a weak signal)
  13. What is the difference between flow cytometry and FACS?
    • Flow cytometry: detects Ags on cells in suspension through the use of fluorescent Abs to cell surface Ags; can detect multiple Ags at one time if you use multiple colors; used to enumerate T and B cell markers, tumor markers, and intracellular proteins
    • FACS: fluorescence-activated cell sorting; separates different populations of cells; can be recorvered for further studies as pure populations; doesn't actually detect anything, just separates things; could never be diagnostic
  14. A 72 year old AA male reports feelin fatigued, but denies any changes in body weight over the past 6 months. A complete metabolic panel indicates total serum protein and slightly decreased albumin. SPE also indicates slightly decreased albumin and a spike in teh G region. What is the most likely diagnosis?
    Monoclonal gammopathy of undetermined significance
  15. What are the primary lymphoid structures?
    • Sites of lymphocyte development and tolerance
    • Bone marrow: source of erythroid, myeloid, and lymphoid stem cells (B cells: exit bone marrow, populate lymph nodes, spleen, MALT; ready to respond Ag; T cells: precursors travel from bone marrow to thymus; NK cells)
    • Thymus: bi-lobed; further sub-divided into lobules by trabeculae (connective tissue that invaginates from capsules); contains a cortex and a medulla; lacks nodules; cells present in thymus include thymocytes, epithelial cells that promote and direct T cell development, macrophages (positive and negative selection with MHC interactivity), and Hassall's corpuscles; fully functional at birth; location of T cell education (self and nonself discrimination; CD4/CD8 differentiation and release into periphery); involutes (gets smaller) at puberty, pregnancy, and with old age (adipose deposition, lymphocyte depletion, but still remains functional)
  16. What are the secondary lymphoid structures?
    • Sites of initiation of immune response and tolerance
    • Lymph nodes: lymph borne antigens; drain the tissues and filter lymph fluidl principal site of T and B cell Ag-dependent proliferation
    • Spleen: blood-borne antigens; get rid of agining/deformed red blood cells
    • MALT: GALT + BALT + NALT + CALT + DALT; gut, bronchial, salivary, and conjuctiva associated lymphoid tissue; includes tonsils, peyer's patches; can get transient isolate nodules as well; diffuse lymphoid tissue (lamina propria); it's just there, not an organized structure
  17. What is the structure of the lymph nodes?
    • Range from 1mm-2cm depending on immune response
    • Hilium: entry and exit of blood vessels; exit of efferent lymphatics
    • Connective tissue capsule: surrounds the lymph node; trabeculael entry of afferent lymphatics
    • Cortex: follicles and germinal centers (means immune response is occurring); B cell rich; follicular dendritic cells
    • Paracortex: deep cortex; T cell rich and APC rich
    • Medulla: Afferents and efferents pass through here; plasma cells live and secrete Abs into the lymph
  18. What is the structure of MALT?
    • Source of Ag-specific IgA in gut/secretions of mucosal linings; important protective barrier against viruses, bacteria, systemic infection
    • Germinal centers
    • Associated with nearby epithelium (no afferent lymphatics because sampling comes from tissue); does have efferent lymphatics
    • Cellular components: B and T cells; epithelium; intrepithelial lymphocytes (sample antigens)
  19. Which embryological structures contribute to the thymus?
    Thrid pharyngeal (branchial) pouch; endoderm
  20. How do lymphocytes circulate through the lymphoid structures?
    • Pre-T cells come into thymus from bone marrow to cortico-medullary junction
    • Migrate up to the outer region of the cortex where they undergo massive proliferation influenced by supcapsular epithelial cells and cortical epithelial cells; positive selection
    • Developed T cells migrate down to the medulla; have already determined CD4/CD8; negative selection; medullary epithelial cells involved
    • Exit thymus through venule within medulla
  21. How do lymphocytes travel through the vascular and lymphatic circulation?
    The lymphatic system brings excess interstitial fluid from the tissue to the lymph node through the afferent lymphatic vessels (efferent could be afferent if going to another lymph node); the thoracic duct or right lymphatic duct drains the left side of head, neck and left arm and the entire body below the heart; drains into the left subclavian vein; the right lymphatic duct drains the right arm and the right sides of the chest, neck, and head; drains into the right subclavian vein
  22. How do pathogens enter the secondary lymphoid structures (thereby causing an immune response)?
    • Through the blood stream; going through the spleen
    • Through the tissue (APCs); going to the draining lymph node
  23. What is the difference between a primary and secondary lymphoid follice?
    • Primary follicle: not involved in active immune response; recirculating B cells; follicular dendritic cells; may have immature or mature B cells
    • Secondary follicles: involved in active immune response; contain a germinal center (T cell dependent responses and clonal expansion of B cells and differentiating memory or plasma cells); also contain memory B cells responses (proliferate in response to Ag on surface of follicular dendritic cells; T cell dependent responses; these give rise to plasma cells without GC formation because Ab has already been selected for); and may contain T cell independent responses (B cell responses to TI Ags; GCs may form)
  24. What is the structure of a secondary lymphoid follicle?
    • Outside of GC: mantle zone; small lymphocytes; resting cells displaced to outer edge by proliferating cells
    • Dark zone of GC: B cells primed, B-blasts, predominantly centroblasts (dividing B cells), and centrocytes
    • Light zone of GC: Predominance of centrocytes (undergoing affinity maturation); cells may return to dark zone for more replication (i.e. if B cell shows good response to Ag)
  25. What is the structure of the spleen?
    • Fist-sized organ; upper left quadrant of the abdominal cavity; immunologic and filtering functions
    • Hilium: medial surface, site of passage of blood/lymphatic vessels, nerves
    • Connective tissue: carries blood vessels, lymphatics, trabeculae, myofibroblasts (contractile, secrete ECM)
    • Cellular components: B cells, T cells, dendritic cells, macrophages and other APCs
    • White Pulp: immunological component of spleen; GCs and follicles; B cell rich with macropahges and dendritic cells; central artery; periarterial lymphatic sheath (PALS; T cell rich area surrounding central artery)
    • Red Pulp: filtering blood; vessels (penicillar arterioles, macrophages on sheathed capillaries that help sample blood antigens and are involved in clearing of bacteria, and sinusoids whihc are loosely packed and allow RBCs to flow through); splenic cords (parenchyma; reticular cells)
  26. What is the molecular basis of Celiac disease?
    • Autoimmune
    • Lose tolerance to food (specifically gluten); abnormal presentation of self antigen; APCs have increased CD80, MHC class II (increased cell activation, Ab production, Th1 cytokine production due to HLA of individual); destroys the epithelium and atrophic villi
    • Treatment is simple: stop eating gluten
  27. What is the molecular basis of DiGeorge syndrome?
    • Congenital thymic aplasia
    • 22q11.2 deletion syndrome; involves migration defects of neural crest-derived tissues
    • Affects development of the third and fourth pharyngeal pouches which affects development of thymus gland
  28. When would an immune response not be protective?
    • When the immune response is activated but doesn't eliminate the pathogen.
    • The immune response to Tuberculosis PPD is an example; as the Abs do not eliminate the pathogen, there is no protective value in activitating the immune system
  29. What is the difference between clearance, killing, and resolution?
    • Clearance: clearing an organism from circulation
    • Killing: lysing or destroying the pathogen
    • Resolution: eliminating all of the pathogens from the tissue
  30. When a gram negative infection enters the body, what are the consequences?
    • LPS signals the following:
    • Coagulation pathway
    • Alternative complement pathway
    • Phagocytosis and danger signaling
    • Cytokines involved include the following: IL-1B (fever), TNFalpha (increased integrins and adhesions), IL-6 (hepatocytes and acute phase proteins LBP, C3, and fibrinogen), IFNgamma (activates macrophages)
  31. Protective immunity is tailored to what?
    The behavior or lifestyle of the microbial pathogen
  32. Define extracellular bacteria
    • Live outside of cells in the body
    • Gram positive (Staph, Strep, C. tetani, C. botulinum)
    • Gram negative (E. coli, Pseudomonas, H. influenza, N. meningitidis, B. pertussis, P. aeruginosa)
  33. Define intracellular bacteria
    • Mycobacterium
    • legionella
    • salmonella
    • listeria
  34. Define encapsulated bacteria
    • Strep and Haemophilus
    • These 2 live outside of cells as well; thick polysaccharide capsule surrounds them
    • Opportunistic infections seen in asplenic patients
  35. Candida, Aspergillus, and histoplasma are examples of what?
  36. Influenza, Herpes, Hepatitis, and HIV are examples of what?
  37. What are the 3 classes of bacteria?
    • Toxigenic: Staph, C. tetani, Pseudomonas
    • Extracellular: Haemophilus, Strep pneumo, N. meningitidis
    • Intracellular: Salmonella, Mycobacterium
  38. What are the 4 different classifications of viruses?
    • Acute, cytolytic: Influenza
    • Latent/chronic/persistent: Herpes simplex, Hepatitis C, HIV
    • Enveloped vs. noneveloped: enveloped is lipid bilayer and susceptible to lysis via complement proteins
  39. What are the 3 classes of fungi?
    • Superficial: tinea (athletes foot); minor/no immunological challenge
    • Subcutaneous/systemic: significant immunological challenge; blastomyces, histoplasma, coccidiomycosis
    • Opportunistic: only effect immunocompromised; Candida, aspergillus, cryptococcus
  40. What type of pathogen is most susceptible to toxin neutralization?
    • IgM, IgG, and IgA Abs are key components
    • Target exotoxins (most of these are proteins) and endotoxins
    • Excellent vaccine targets
  41. How does virus neutralization work?
    • Many viruses have protein coats; can either be in your serum or in your blood (viremia); mucosal immunity and microbial entry
    • Cyt T cells kill
  42. What types of pathogens are suscpetible to complement?
    • Opsonization: used against bacteria or fungi
    • Lysis: only rarely essential (exception of Neisseria)
    • Chemoattractant: C5a attracts neutrophils; large extracellular fungi and parasites
  43. What types of pathogens would be most susceptible to opsonophagocytosis and intracellular killing?
    • Extracellular pathogens (bacteria and fungi), pyogenic bacteria (Staph, strep, pseudomonas)
    • Requires chemotactic factors (microbe or host derived)
    • Phagocytic receptors (FcR, CR, MR, etc.)
    • Opsonins (IgG, iC3b, mannose, LPS, etc.)
  44. How does macrophage-mediated killing of intracellular pathogens work?
    • Antigen present cells take in intracellular pathogens and present their antigens; activates respiratory burst
    • Intracellular bacteria (M tuberculosis, L pneumophila, salmonella), fungi (candida)
    • Importance of Th1 cytokines (IFNgamma activates macrophages)
  45. How does phagocyte mediated extracellular killing work?
    Neutrophils act against large extracellular fungi and parasites; too large to engulf; they bind tightly to the microbe and reorient killing to the synapse between the neutrophil and the surface of the pathogen
  46. What type of pathogen is most susceptible to oxygen independent mechanisms?
    • Natural microbicidals; especially anaerobic bacteria
    • Use defensins and cathelicidins
  47. What type of pathogen is most susceptible to CTL-dependent killing?
    Nearly all viruses and intracellular bacteria that escape phagosome mechansisms (L monocytogenes and F tularensis)
  48. What type of pathogen is most susceptible to NK cell-mediated killing?
    • Latent viruses that inhibit MHC I expression (i.e. Herpes); virsuses that inactivate TAP (transporter associated with antigenic processing) protein
    • NK cells target cells not expressing MHC I proteins
    • Major source of IFNgamma(most viruses and intracellular bacteria)
    • Innate immunity in naive individuals
  49. What type of pathogen is most susceptible to eosinophil-mediated killing?
    • Parasites (especially intestinal helminths)
    • IgE-Fc receptor; binds IgE Ab; different from mast cells IgE receptor
    • ADCC (Ab dependent cellular cytotoxicity); Abs are bound to intestinal worm and then found by eosinophils
  50. What type of pathogen is most likely to activate cytokines?
    • Too many
    • Anything that results in chemotaxis, activation of phagocytes, CTL, or B cell activation
    • Apoptosis of infected cells (TNFalpha can damage epithelium of gut when lots of macrophages get activated)
    • Excess productino causes sepsis and toxic shock (superantigens)
    • Often induced through TLR and NLR signaling
  51. What are the 11 protective immune mechanisms as presented in class?
    • Toxin neutralization
    • Virus neutralization
    • Complement cascade
    • Opsonophagocytosis and intracellular killing
    • Macrophage mediated killing of intracellular pathogens
    • Phagocyte mediated extracellular killing
    • Oxygen independent mechanism
    • CTL dependent killing
    • NK cell-mediated
    • Eosinophil-mediated
    • Cytokines
  52. Patients lacking antibody would be susceptible to what type of pathogens?
    • Extracellular (bacteria and cytolytic viruses (continue to infect cells and lyse contents))
    • Patients would not be able to prevent entry ofmicrobes into cells
    • Ab is important as an opsonin too and mediates clearane of pathogens, so they would have deposits in kidneys and joints
  53. Patients lacking neutrophils would be susceptible to what type of pathogen?
    • extracellular (bacteria and fungi)
    • Respond to chemotactic nuclei and have strong resp burst of oxides; very important phagocytosis cell
    • Neutropenia
  54. Patients lacking complement would be susceptible to what type of pathogen?
    • Gram-negative bacteria and enveloped viruses
    • Uses opsonins to clear pathogens, so there would also be Ag-Ab deposits in kidney and joints
    • C5a is chemotactic used to rbing neutrophils to site of infection, so neutrophils would likely remian in the blood stream and result in non-pyogenic infections
  55. Patient lacking macrophages would be susceptible to what type of pathogen?
    • Intracellular (bacteria that choose macrophage as replication site, those that are normally killed with resp burst (Staph and Aspergillus) and those normally killed with nitric oxide pathway (listeria and mycobacterium TB))
    • Also wouldn't be able to clear extracellular pathogens very well; more deposits
  56. Patient lacking Th1 cells would be susceptible to what type of pathogen?
    • Intracellular (viruses and bacteria) because of B cells
    • Th1 cells make IFNgamma to activate macrophages (so intracellular pathogens)
    • Th1 makes IL-2 (lymphocyte growth factor for Cyt T cells, so intracellular pathogens)
    • Lymphopenia because Th cells make up bulk of T cells
  57. Patients lacking CTLs would be most susceptible to what type of pathogen?
    • Intracellular (viruses and bacteria)
    • Pathogens must be cytosolic or replicate in the cytosol
  58. Patients lacking NK cells would be most susceptible to what type of pathogen?
    • Intracellular pathogens that morph APC cells (no MHC I)
    • Viruses, some bacteria, and tumors (hooray!); basically any disease that alters the cells to look non-human
    • Use IFNalpha/beta which is effective against viruses
    • Use IFNgamma which activates macrophages
  59. What are some common evasion mechanisms viruses use to avoid detection or clearance?
    • Antigenic variation: antigenic drift (point mutations) and antigenic shift (2 genomes of viruses rassort; i.e. influenza HA, NA)
    • Establish latent state
    • Inhibit expression of MHC (Herpes and CMV)
    • Mimic/inhibit cytokines (IFNalpha,beta,gamma, TNFalpha)
    • Mimic soluble receptors (FcR and CR; pox virsuses and EBV)
    • Induce apoptosis (selective destruction of an APC cell)
  60. What are some common mechanisms that bacteria use to avoid detection and clearance?
    • Produce capsules or highly charged O side chains of LPS to block complement activation and phagocytosis
    • Degrade and inactivate antibody (Staph protein A)
    • C5a peptidase (decrease neutrophil chemotaxis)
    • LPS, superantigens (dysregulate immune response)
    • Phagosome disruption and exit (escape intracellular killing)
    • Vary or disguise antigens (borrelia, relapsing fever; the fever gets cleared, but the pathogen rearranges its gene and cycling of disease begins again)
  61. What are the 3 main forms of vaccines?
    • Neutralizing antibodies (against microbial toxins and viruses tha cause acute disease, ie tetanus)
    • Opsonizing antibodies (against extracellular bacteria)
    • Cellular immunity (against intracellular bacteria and viruses, ie hepatitis)
  62. When shoudl vaccines be used?
    • When you can develop an immune response faster than the disease
    • When the lethal dose of a toxin<immunizing dose
    • When a quicker pace or longer duration of immunity is valuable
    • When higher titers or numbers of responding cells are desirable
    • When multiple Ab isotypes are advantageous
    • When preformed Abs might prevent disease or spread of infection
    • When immunization with a shared microbial antigenic determiannt provides cross-protection against multiple serotypes
  63. Subunit, inactivated microbe, live attenuated, live recombinant vector, polysaccharide, and conjugate are all types of what?
    Clincal vaccines
  64. What clinical risk factors would favor a diagnosis of immune deficiency?
    • Frequency, severity,or pace are increased; or complicated infections
    • Poor resolution after Ab therapy is applied
    • Early v. delayed age of onset (6 months with maternal Igs though)
    • Famiyl hx (some X linked)
    • Response to vaccines (negative)
    • Occupational exposures
  65. How would you diagnose and treat a B cell deficiency?
    • Blood B cell numbers are not really informative; measure the isohemagglutinin titers for an Ab response; Test Ab response based on DTP immunization; is small or insignificant there may be an Ab deficiency; Quantitative immunoglobulins test is better than serum electrophoresis
    • Need to consider possible defects in phagocytic or complement pathways because B cell deficiencies are so rare and these are involved in opsonophagocytosis; can all produce the same clinical picture
    • Treat with Abs prn and IVIG; stem cell reconstitution is rarely used
  66. Selective IgA deficiency, Transient hypogammaglobulinemia,, X-linked agammaglobulinemia (XLA), and IgH chain locus deletion are all examples of what?
    B cell deficiencies
  67. What are the key characteristics of T cell deficiency?
    • early onset of infection; progress rapidly and spread
    • Susceptible to intracellular pathogen (especially viral and fungal); avoid live viral vaccines; opportunistic flora; infrequently encountered pathogens (cryptosporidium, pneumocystis, and leishmania)
  68. What are the key characteristics of phagocytic cell deficiencies?
    • Decreased cell number
    • Abnormal cell adhesiona nd migration
    • defective intracellular granules
    • Impaired intracellular killing mechanism
  69. What are the 2 most common causes of acquired immune deficiency disorders?
    • HIV infection: 25-44; 2nd most common cause of death; started off primarily in rich, white males; risk for heterosexual partners is rising (<10% still); associated with hepatitis C and drug resistant TB infections
    • Iatrogenic (physician-induced) immunosuppression: Organ transplants and splenectomies
  70. Outline the HIV life cycle
    • Binding: gp120 to CD4 (receptor for HIV)
    • Internalization: via co-receptor CCR-5 (1% of caucasian have mutant genes; can't internalize; resistant to HIV)
    • DNA synthesis: reverse transcriptase
    • Viral integration: integrase puts provirus into hsot DNA
    • Viral replication: requires activation of T cell; remains latent until some kind of infection activates cytokine release
    • Viral dissemination: kiss of death with APC; virus is transferred from CD4 cell to macrophage
  71. How would you detect an HIV infection?
    • ELISA: but not until after 6 week latent period; develop anti-p24 Abs
    • PCR: detect viral RNA present at teh start of infection; can be done immediately
  72. What are the cellular targets of HIV?
    CD4 cells (Th) with CCR5 co-receptors
  73. Clinically, how does a patient with acute HIV syndrome present?
    • 2-3 weeks after exposure, mononucleosis-type illness; can detect with PCR, but not yet with ELISA
    • Persistent generalized lymphadenopathy (swollen/enlarged lymph nodes)
    • As CD4 levels continue to decrease, at greater risk for opportunistic infections
  74. What are the best strategies to prevent HIV transmission?
    • Education/behavior modification
    • Interruption of transmission from mother to child (antiviral tmnt of pregnant women)
    • Topical microbicides
    • Treatment of other STDs (may cause lesions for blood swapping and subsequent transmission)
    • Drug abuse treatment
    • Vaccination (only a theory at present; difficult because there are so many varieties of HIV)
  75. Name 5 ways that the immune system returns to homeostatsis
    • Clearance of Ag: removal of stimulus
    • Activation-induced cell death in lympocytes: TNF receptor leads to caspase 8 activation
    • Effectors are short-lived: Half-lives of B and T cells
    • Treg: T regulatory cells; express a TCR and the FoxP3 transcription factor; leads to production of IL-10 and TGFbeta; mediates self-tolerance
    • Ig half life decreases as Ig concentration increases: negative feedback
    • Immune complexes are also immunoregulatory: Fc receptors on B cells (cross-linking of BCR and Fcgamma turns off B cells); Fc receptors on macrophages
  76. How do soluble immune complexes regulate Ab responses?
    • Soluble Abs released from B cell bind to Ags to form complexes; then bind a BCR
    • However, the IgG ab-Ag can then bind Fcgamma receptor on the B cell; this cross-linking causes the B cell to turn off
    • Soluble Ag-Ab complexes can also regulate macrophages; they bind to Fcgamma receptors on macrophages which then produce IL-10 (inhibits T cells), TGF beta (inhibits macrophage activation; negative feedback loop), and PGE2 (inhibits lymphocyte proliferation)
  77. How does administration of Rhogam inhibit immune responses to Rh Ags?
    • Eliminates and removes fetal Rh+ RBCs from maternal circulation
    • Turns off maternal B cells by crosslinking BCR and FCRIIB
  78. A fetus can be considered to be a semi-allograft (half of its tissue is foreign to the mother), yet the maternal immune system does not necessarily attack the fetus. EXPLAIN
    • Three main mechanisms contribute to fetal survival
    • 1. Trophoblastic cells that interact with maternal circulation are devoid of most HLA antigens
    • 2. B7 costimualtory molecules are also not expressed by trophoblast cells (anergy)
    • 3. Inhibitory factors are upregulated (IL-10, inhib B7 isoforms, FasL, and PGE2
  79. Define Treg
    • Express a TCR
    • Expresses the FoxP3 transcription factor (when this is activated, increase the expression of the following)
    • Produce IL-10 and TGF beta
    • Mediates self-tolerance
  80. What are the 4 disease that result from dysregulation of immunity?
    • Rheumatic fever (asthma)
    • Atopic allergies
    • Crohn's disease (Th17 cells found in the intestines; induceds inflammation)
    • Sepsis (systemic inflammatory response to infection; overactivation of immune system; therapy includes antimicrobials, IV fluids, and -pressors to maintain blood pressure)
  81. How do Th1 and Th2 interact with each other upon stimulation?
    • Th1: stimualted by IL-12 or IFNgamma; releases leukotrienes, IFNgamma (+ feedback) to activate macrophages and CD8 mediated response; IFNgamma inhibits Th2
    • Th2: stimualted by IL-4; releases IL-3 (activates mast cell growth); IL-4 and IL-5 which both activate B cell Ab responses; IL-4 inhibitsTh1
  82. Your patient is infected with an intracellular pathogen. The patient has and IFNgamma receptor deficiency. What happens?
    • IFNgamma would normally stimulate Th1 response (Cyt Tcell pathway). Since the patient is deficient, she/he cannot mount a proper response to eliminate the pathogen. In addition, IFNgamma normally inhibits the Th2 pathway, but it cannot do it in this patient.
    • Results in elevated IgG, IgA, and IgM antibodies. Potentially sepsis
  83. TNFalpha, IL1beat, IL-12, IFNalpha/beta, IFNgamma, and IL-17 have what in common?
    They are the pro-inflammatory cytokines
  84. What is the pro-inflammatory function of TNFalpha?
    • Adhesiona nd integrins
    • Neutrophil and macrophage activation
    • Acute pahse protein synthesis
    • Apoptosis
  85. What is the pro-inflammatory function of IL1beta?
    • Redundant with TNFalpha (adhesions, integrins, neutrophil and macrophage activation, acute phase protein synthesis, and apoptosis)
    • Also responsible for fever induction
  86. What is the pro-inflammatory function of IL-12?
    • Co-activates NK and NKT cells with IFNgamma
    • Induces Th1 cells
  87. What is the pro-inflammatory function of IFNalpha/beta?
    • Antiviral
    • Co-activate macrophages
    • Induces MHC class I
  88. What is the pro-inflammatory function of IFNgamma?
    • Activates macrophages
    • Induces TNFalpha and IL1beta
    • Induces CD4 Th1 cells
    • Increases MHC class II (?
  89. What is the pro-inflammatory function of IL-17?
    • Neutrophil infiltration and activation
    • Intestinal inflammation
  90. What is the function of IL-2, 4, 5, 6, 13, and TGFbeta in humoral adaptive immunity?
    • IL-2: B cell proliferation and J-chain synthesis
    • IL-4: Class switching to IgG1 and to IgE; Th2 induction
    • IL-5: class switching to IgA; inhibits switching to IgG3
    • IL-6: plasma cell differentiation
    • IL-13: Ig class switching to IgE
    • TGFbeta: class switching to IgA
  91. What is the function of IL-2, IFNgamma, and lymphotoxin (LT) in cell-mediated adaptive immunity?
    • IL-2: growth factor for CD4/CD8 T cells; promotes differentiation of Th, CTL, and NK cells; induces Treg cells; induces cell death
    • IFNgamma: activates macrophages, increases antigen presentation, Th1 cell polarization
    • Lymphotoxin: apoptosis
  92. Define CSFs, EPO, thrombopoietin, myelopoiesis, and lymphoiesis
    • CSF: colony stimulating factor; used in recombinant factors for therapy; stem cell factor and IL-3 are pluripotent
    • EPO: Erythropoiesis treatment
    • Thrombopoietin: Platelets therapy
    • Myelopoiesis: Use IL-5 to stimulate growth of eosinophils, G-CSF to stimulate growth of neutrophils, and M-CSF to stimulate the growth of monocytes
    • Lymphopoeisis: Use IL-7 to stimulate growth of B and T cells and IL-15 to stimulate growth of NK cells and memory CD8 T cells
  93. What are the major subsets of chemokines and to what receptor do they bind?
    • C-C chemokines: CCL4 is an example; attracts T cells, dendritic cells, NK cells, and monocytes
    • C-X-C chemokines; amino acid residue separates the 2 N-terminal cysteines; CXCL8 (IL-8) is an example; attracts neutrophils (think extravasation)
    • They bind to G coupled protein receptors; binding to these stimualtes cAMP and activates PLC (PLC-->IP3 and DAG); leads to chemotaxis
  94. How does chemotaxis occur?
    Actin polymerization, cytoskeletal rearrangement and adhesion
  95. How are cytokines similar to hormones?
    • Activate in a similar fashion
    • Autocrine, paracrine, and endocrine (circulation)
  96. What are the 4 pathways of intracellular signaling that cytokine (don't forget about chemokines) binding leads to?
    • Jak/STAT receptors: receptor dimerization, JAK recruitment and phosphorylation, STAT phosphorylation (STAT is a signal transducer and activator of transcription); and STAT dimerization; allows it to enter the nucleus and initiate transcription
    • Death domain receptors (TNFR): activation of caspase 8 and apoptosis
    • NFkappaB associated receptors: TLRs and IL-1R activated; activation of MyD88 (adaptor); IkappaK activated; NFkappaB transcription factor activated due to dephosphorylation; and increased inflammation response
    • Chemokine G-protein coupled receptors
  97. What are the Gell and Coombs hypersensitivity classes?
    • Type I: Immediate; systemic or localized; IgE mediated; mast cell activation; leads to vascular dilation, edema, smooth muscle contraction, mucus production, and inflammation; think asthma, hayfever, and atopic allergies
    • Type II: hours to days; think transfusion reactions; many forms of action; ADCC (Antibody dependent cellular cytotoxicity (monocytes, neutrophiles eosinophils, and NK cells; IgM and IgG mediated); Antibody opsonization of cell (pagocytes bind to Fc portions of IgG antibodies abound to cell; cell-tissue bound Ags); complement opsonization (classical; either make C3b and C4b which bind to cells and are recognized by phagocytes and/or kill by forming a MAC); anti-receptor antibodies formed
    • Type III: hours to weeks; think serum sickness and lupus; soluble antigens form immune complexes (~1 wk after Ag introduction); immune complexes deposit in the joints and kidneys (where blood is filtered to form transudates) resulting in tissue injury; so acute inflammation is responsible for the tissue damage; Ag-Ab complexes bind to Fc or C3b receptors on phagocytes which tiggers release of cytokines to attract more neutrophils and intiates mroe complement fixation (MAC); glomerulonephritis
    • Type IV: not Ab mediated!; think poison ivy and contact dermatitis; no antibodies produced; delayed type; T cell mediated; Macrophages present Ag to CD4 which release IL-2; CD8 cells kill tumor or virus infected cell using perforing and granzymes; treat with oral prednisone or topical calamine lotion
  98. What type of testing has the highest specificity for autoimmune disorders?
    • Tests that search for nuclear Ags (DNA, RNA, and proteins)
    • >90% specificity for most AI disorders while other tests (i.e. RNP and centromeric proteins have <10%)
Card Set
Inflammation and Immunity