Immunology Flashcards

Question

What is the function of thromboxane/Prostaglandins?

Answer 1

chemotactic for PMNs and eosinophils

Answer 2

• TCR Complex: o TCR: heterodimer Ag-specific receptor (first signal necessary to activate T cells) o CD3: pan T cell marker; signal transduction, transports TCR to cytoplasmic membrane; invariant o Zeta chains (2): signal transduction; invariant • CD2: pan T cell marker; lymphocyte adherence and signaling • Integrins (LFA-1 and VLA-4): adherence to APC and endothelial cell • CD62L/L-Selectin: homing molecule that binds addressins on the endothelium; facilitates migration of T cell into LN • ICOS: interacts with ICOSL on B cell; facilitates germinal center formation in LNs and other lymphoid tissue • CD4: on Th cells; stabilizes binding and involved in signaling • CD8: on Tc cells; stabilizes binding and involved in signaling • CD28: binds B7 on APC (required for activation of T cell) • CTLA4/CD154: upregulated in activated T cells; interaction with B7 on APC shuts down T cell • Class I MHC: on all nucleated cells • FasL: on CD8+ T cells; allows for killing of Fas+ cells • CCL2 (MCP-1): allows for migration of TH1 cells to site of infection

Answer 3

pan T cell marker; signal transduction, transports TCR to cytoplasmic membrane; invariant

Answer 4

• BCR: Ig + Igα and Igβ (signal transduction molecules associated with the Ig H chain) • B-Cell Co-Receptor: - CD21: binds C3dg (cleavage product of C3b) on bacteria to increase Ag signaling 100x; also a receptor for the Epstein Barr Virus - CD19 - CD81 • CD22: downregulate B cell activity • CD32: downregulate B cell activity (bind Ag-Ab complexes) • CD5: on the surface of B-1 cells • B7: interacts with CD280 (stimulation) or CTLA4 (inhibition) on T cells • CD40: interacts with CD40L on T cells to allow for Ab class switching • FcR: receptor for Fc portion of Igs (one for each class); delivers signal to B cell - MHC molecules

Answer 5

• Class I MHC: on all nucleated cells - 3 loci (A,B,C) encode alpha chain only - Alpha chain combines with invariant beta-2 microglobulin - Alpha3 domain interacts with CD8 on T cells - Alpha1 and 2 domains form CLOSED peptide binding groove (8-9 aa) •Class II MHC: on APCs - 3 loci (DP, DQ, DR) encode both alpha and beta chains - Beta2 domain interacts with CD4 on T cells - Alpha1 and Beta1 domains form OPEN peptide binding groove (12-20 aa)

Answer 6

* Mannose-Binding Lectin Receptor: binds MBL bound to mannose on bacterial surface (increases binding affinity) * Mannose Receptor: binds mannose on surface of bacteria * Surfactant Protein A and D Receptors: binds SPA/SPD bound to bacteria (increases binding affinity) * Scavenger Receptors: react with lipoproteins * fMet-Leu-Phe (N-formylated peptides) Receptor: receptor for these peptides, which are chemotactic factors for phagocytes * Toll-Like Receptors:

Answer 7

found on phagocytes; o TLR-4: binds bacterial LPS and triggers activation of NFkB (genes transcribed to fight bacteria) o TLR-3: binds viral dsRNA triggering synthesis of IFN alpha and beta o TLR-5: bacterial flagellin o TLR-9: unmethylated CpG DNA o TLR1:TLR2 heterodimer: peptidoglycan and zymosan

Answer 8

Integrins (ie: LFA-1?) : bind ICAMs on endothelium and APC (strong binding)

Answer 9

- Systemic anaphylaxis - Allergic rhinitis - Asthma - Food allergies

Answer 10

- ABO/Rh incompatability reaction - Myastenia gravis - Grave’s Disease - Penicillin drug allergy (can also be IgE mediated-type I)

Answer 11

- Serum sickness - Arthus reaction - SLE - Rhematoid arthritis

Answer 12

- Posion ivy (contact dermatitis) - Tuberculin rejection - Graft rejection - Hashimoto’s Thyroiditis - Multiple Sclerosis - IDDM

Answer 13

1. Allograft: self (from a different part of the body) 2. Synergic: from a genetically identical twin 3. Allogenic: w/in the same species, but not genetically identical (ie: any other human but a twin) 4. Xenogenic: from a different species

Answer 14

1. First Set Rejection: 1st time you see something: 7-10 days post transplant rejection occurs 2. Second Set Rejection: the second time you are grafted with the same source: 2-3 days layer; much faster "memory" type response Rejection occurs by: 1. Foreign alloantigen is recognized 2. memory cells (adaptive immunity) generate and remember the alloAg **GRAFT REJECTION CAN BE ADOPTIVELY TRANSFERRED** if you transfer the lymphocytes (serum) of the first mouse that rejected the graft into a new mouse that hasn't been exposed to the graft yet, the second mouse will respond like a second set rejection (fast)

Answer 15

MHC I: HLA -A, B, C to CD 8+ T cells MHC II: HLA- DR, DP, DQ to CD4+ Tcells the genes are codominantly (both mom and dad) expressed; and they are the most polymorphic genes in the human genome **MHC I peptide is SHORTER than MHC II peptide binding site

Answer 16

Direct Presentation = the donor's APC presents the UNPROCESSED allogenic MHC to the Host T-Cell (Self MHC recognizes struture of an intact MHC molecule of the graft); involves BOTH CD 8+ and CD4+ Indirect: HOST APC presents a PROCESSED peptide of the allogenic MHC to the host T-cell; (host sees MHC as foreign Ag and handles it like any other foreign Ag--it presents it on the host APC); ONLY INVOLVES CD4+ (presented by MHC II of the host APC)

Answer 17

1. Presentation of donor MHC as 'foreign Ag' (direct/indirect) 2. Stimulation: APC MHC --> TCR 3. Costimulation via: (**APC MOLECULES WRITTEN FIRST): B7/CD28 CD40/CD40L LFA-3/CD2 ICAM/LFA-1 4. Release of cytokines from APC to simulate Tcell: IL-12, IL-18 **** If no costimulation occurs then CTLA4 is expressed and induces clonal anergy

Answer 18

Both: Measure of how compatible two people are for transplant by seeing how reactive their T-Cells are -- "In vitro test of T-Cell Regulation of allogenic MHC" MLR: Simulators = donor irradiated mononuclear cells (treated with mitomycin C to make the cells mitotically inactive) Responders = recipient mononuclear cell Measure: proliferative response of responders Mix inactive donor cells with blood mononuclear cells of recipient to see if normal T-cell function occurs; if so the recipient views the donor cells as "foreign", and donor/recipient are of different MHC II Class; donor acts as the Ag and Recipient as the normal functioning immune system; You add Radioactive Thymidine and see if there is any cell proliferation and DNA Synthesis; If there is this indicates that CD4+ proliferated ... MEASURE OF MITOGENESIS (suggest that MHC's are incompatible) CML: Basically the same thing, except you measure cell lysis instead of mitogenesis; a measure of CTL mediated response (and that MHC I are incompatible)

Answer 19

1. Hyper-acute Rejection 2. Acute Rejection 3. Chronic Rejection

Answer 20

DOESN"T EXIST IN BONE MARROW TRANSPLANTS! For solid organ transplants: its the fastest mediated response-- within minutes/hours ** Due to PRE-EXISTING IgG (due to a history of blood transfusions, transplantations, or multiple pregnancies); activates the complements system, inflammation, thrombosis, and epithelial damage

Answer 21

Response occurs within a few days Solid organ: due to CD4+ and CD8+, Ab response; causes parenchymal damage and inflammation (endothelitis) Bone Marrow: due to Host NK causing lysis of donor stem cells

Answer 22

Response occurs up to 6 mo (BM) or 1 year (SO) post transplant Solid Organ: due to CD4+ (TH2), CD8+, MACROPHAGES; causes chronic fibrosis + atherosclerosis and chronic DTH reaction in vessel wall and SMC Bone Marrow: due to autologous CD4+ and CD8+ lysing donor stem cells

Answer 23

IL -2: promote T-cell proliferation and generation of TH1 IFN-G: Increase MHC I and II expression and promote delayed hypersensitive response TNF B: cytotoxicity to graft IFN A, B, G, TNF A, B = all upregulate MHC I expression IFN G also upregulates MHC II

Answer 24

Kidney > Heart > Pancreas > liver > lung Skin can also be grafted Need to be immunosuppressed because a lot of time they aren't MHC matched

Answer 25

Fetus; Fetal trophoblasts DO NOT express MHC I or MHC II Only express HLA-G (Class Ib) which is actually used as a ligand for KIR to prevent maternal NK from killing the fetus

Answer 26

NF-kB, NFAT, AP-1

Answer 27

1. MHC allele close matching 2. ABO Compatibility: to prevent hyper acute rejection in solid tumors and transfusions in BM/PBSC 3. Calnineurin Inhibitor: causes inhibition of NFAT and thus inhibition of IL-2 transcription so T-Cells aren't proliferating and inducing an immune response; aka cyclosporine immunosuppressant 4. IMPDH inhibitor (inosine monophosphate dehydrogenase): inhibits guanosine nucleotide synthesis

Answer 28

bacterial infections with high grade extracellular encapsulated pathogens; Ex: otitis media, pneumonia

Answer 29

low grade oppotunistic fungus, virus, protozoa; Ex: pneumocystic carni infection

Answer 30

virus, fungus, protozoa, braceria

Answer 31

systemic infection of bacteria of LOW VIRULANCE, superficial skin infections, infection w/pyogenic organisms, impaired pus formation and wound healing

Answer 32

viral infections; associated with several T-Cell disorders and X-lymphoproliferative diseases

Answer 33

pyogenic micro-organisms, bacterial infections, autoimmunity **difficult to differentiate between B-Cell deficiencies; thus look at B-cells def first (more prevalent) and if not then test for complement component

Answer 34

Chromosome 22q11 deletion leads to no thymus formation; Extreme immuno-suppressed because NO T-CELLS; Have certain facial characteristics (fish lips, low ears) and heart defects (great vessels) which leads to surgery and thats how they first realize there isnt a thymus; then they do flow cytometry on the cells using ANTI-CD3 ANTIBODY to check for T-Cells (CD3 = pan marker of all T-Cells)

Answer 35

Normal T-Cell function EXCEPT for candida albincans (a fungus) thus frequent infections by it

Answer 36

No transcription factor for the Gamma-Chain of IL-2, 4, 7, 9, 15; NO T -CELLS present which leads to decreased (to no) B-cells functioning

Answer 37

JAK3 Tyr Kinase mutation results in no activation of Gamma-Chain of IL-2, 4, 7, 9, 15; Presents just like X-SCID except it isn't linked to the X-chromo NO T -CELLS present which leads to decreased (to no) B-cells functioning

Answer 38

No Adenosine deaminase, resulting in toxic amounts of ATP and dATP in B and T cells so then they can't form properly.. results in NO B or T cells (aka bubble boy until they get a bone marrow transplant)

Answer 39

Autosomal recessive; no PNP enzyme so it presents just like ADA deficiency (NO B OR T CELLS)

Answer 40

Mutation in RAG-1 and RAG-2 leads to no gene rearrangement of B or T cells and thus these cells stay in the pre-B/pre-T cell state

Answer 41

Problem with MHC due to TAP (transporter protein) gene mutation Type I: No MHC I-- ASYMPTOMATIC; just a decrease in CD8+ Type II: No MHC II: No presentation of Ag to T or B cells so effectively NO B OR T FUNCTIONING "T + B+"

Answer 42

No signal cascade that TCR is bound to a peptide; thus NO CD8+ T-Cell! All CD4+ T-cells in circulation, but they are unresponsive and thus B-Cell functioning is also decreased NO B OR T CELLS basically; "T + B+"

Answer 43

Neurodisease due to INABILITY TO REPAIR DNA/CHROMOSOMAL BREAKS IN IG CELLS; Result = decreased functioning in T cells; decreased concentration of IgA, IgE, and some IgG

Answer 44

X-linked; 3 hallmark features: 1. Thrombocytopenia 2. eczema 3. recurrent pyogenic bacterial infections causing otitis media, meningitis, pneumonia, from normally low virulent organisms; T Cell response = ineffective (signaling pathway screwed up) and decreased IgM

Answer 45

due to X-linked BTK Brutun Tyrosine Kinase mutation resulting in so signal that the pre-B cell is mature (and has H chain bound) and so the cell can start making L chain; thus all B-cells are stuck in the pre-B state realize at 6 mo that baby has no IgG (because at this point it used up all of moms IgG passed down)

Answer 46

NOT X LINKED; usually in pre-mature babies until age 2 and then resolves serum IgM, IgA and B-cells = normal IgG = lost (and thus T-cell function also decreases)

Answer 47

Unknown causes of B-cells not maturing into Ab secreting cells (@ 15-35 y/o)

Answer 48

MOST COMMON B-CELL DEFICIENCY! unknown cause NO MAJOR Sx; but its important for individuals to know that they have the disease because if they get a blood transfusion they could react with an immune response to the transfused IgA

Answer 49

recurrent infection by POLYSACCHARIDE ENCAPSULATED ORGANISMS like pneumococci and the flu

Answer 50

``` NO CD40L (CD154) on T-Cells so there is no isotype switching of B-cells resulting in high IgM but low IgG, IgA, IgE; Sx = recurrent resp infection ***Sx present like a B-Cell deficiency (low Igs) but really it caused by a T-Cell deficiency!! ```

Answer 51

due to T-cell failure to regulate B-cell Growth | Result = Bcell lymphoma (usually occurs after EBV-infection) ie: Burkitts lymphoma

Answer 52

Normal: ***ALL MEDIATED BY IL-8 1. E-selectin on epi binds to PMN = weak, slow "roll" down epi cells 2. ICAM on epi binds to integrin on PMN = strong; PMN stops 3. diapedesis 4. Migration to infection 1. LAD I: mutation for CD 18 INTEGRIN: results in NO ICAM (stopping) bonding and WBC doesn't adhere or migrate into tissue 2. LAD II: mutation in SELECTIN on WBC (which thus can't bind to E-Selectin on epi) so WBC doesn't slow down or migrate

Answer 53

monocytes do not respond to IFN gamma with TNF-Alpha secretion thus increase in myobacterial infection

Answer 54

Autosommal recessive; | Microtubiles and lysosomal defect in which they can't release enzyme and lyse bacteria after phagocytosis

Answer 55

= NADPH Oxidase Deficiency Peroxidase not generated and thus no oxygen free radial to digest catalase + phagocyted bacteria; thus the bacteria just stays inside the phagocyte (alive and able to multiply) ``` Nitoblue Tetrazolium (NBT) Test: if - (purple) = can oxidize; thus don't have the disease if blue = +; cannot oxidize; thus have the disease ```

Answer 56

1. Early components (C1, C4, C2) = problem with capsulated organelle ingestion 2. Middle component (C3) = rhuematic disaese (esp SLE) 3. Late components (C5-C9, MAC) Neisseria infections

Answer 57

Lack of C1 esterase inhibitor (C1INH) causing uncontrolled production of vasoactive peptides and local edema

Answer 58

Deficiency in Decay Accelerating Factor (DAF) results in increased sensitivity to complement mediated lysis of RBC (occurs at night mainly)

Answer 59

TREC assay to see if they have T-Cells (confirm with flow cytometry) and make treatment decision (ie: BM transplant)

Answer 60

tumor cells are formed in normal individuals and then destroyed by the normal immune cells; the immune system can recognize and destroy nascent transformed cells

Answer 61

Immune system kills and induces changes in the tumor that can result in tumor escape and reoccurance

Answer 62

1. mutation 2. gene amplification 3. clonal mutation

Answer 63

Because they are: 1. foreign 2. Hig molecular weight 3. Complex chemically 4. Degradable and so can be presented by MHC

Answer 64

We have a repertoire of T-cells with low affinity agains self proteins (due to positive/negative selection) in the thymus; thus expression of altered self proteins by tumors increases the affinity of T-Cells for the tumor Ag

Answer 65

1. Spontaneous Regression (melanoma, lymphoma) 2. Regression of metastases after removal of 1' tumor (pulmonary metastases from RCC) 3. Inflitration of tumor by macrophages/lymphocytes (breast cancer, melanoma) 4. Lymphocyte proliferation in the draining lymph node 5. Increased incidence of cancer following immunosuppression, immunodeficiency, aging, etc.

Answer 66

A tumor Ag that was present on fetal cells, but disappears with normal adult cells, then reappears (ie: prostate cancer, colo-rectal cancer)

Answer 67

Tumor Ag on normal cells, but overexpressed

Answer 68

virus that transforms normal cells into cancerous (HPV --> cervical cancer)

Answer 69

- Substance that activates normal genes into a tumor - lacks cross reactivity in physically or chemically induced tumors - responsible for clonal amplificiation

Answer 70

damages/mutates DNA; Melanoma = metastatic, highly immunogenic, spontaneous rejection Nonmelanoma = BCC (rarely spreads), Squamous CC(can spread)

Answer 71

Free radicals + other oxidants 'steal' electrons from DNA leading to cancer; Anti-oxidants (vit A/C)

Answer 72

highly immunogenic because of viral antigen; DNA viruses = papova (papilloma, Hepatitis, EBV) RNA viruses: retrovirus (Human T-Lymphotropic disease causes T-Cell leukemia)

Answer 73

1. Act as an antigen - self Ag gets mutated to act as a foreign Ag - viral Ag act as molecular mimcry of a self Ag - can express a 'hidden' epitope 2. Expression of costimulatory molecule in tumors (or cross presentation of tumor Ag by APC ---- exogenous Ag causes CD 8+ effector)

Answer 74

1. NK cells: when MHC I is low, they bind and lyse the tumor; secreted TNF Alpha (+ hemorrhage and tumor necrosis) 2. gamma-delta T cells 3. NKT Cells 4. Macrophages/Neutrophils: Ag specific Tcell becomes activated by the tumor Ag, and causes release of cytokinds including IFN gamma to activate macrophages and make them highly toxic; macrophages damage/kill the tumor by releasing lysosomal enzymes and TNF-alpha * *increased tumor resistance accompanies increased number of activated macrophages

Answer 75

1. Ab-mediated: leads to opsonization and Ab dependent cell-mediated cytotoxicity 2. B-Cell blocking: Anti-IL2R ab displaces IL-2 at the IL-2 receptor and causes decreased T-Cell production (in T-Cell leukemia) 3. T-Cells: CD8+ release IFN-Alpha and TNF for virally induced tumors; CD4+ induces/regulates CD8+

Answer 76

1. TGF - B = + tumor growth due to angiogenic and immunosuppressive properties 2. TNF-A = + inflammation 3. IFN-G = upregulated MHC I and MHC II on tumors

Answer 77

1. Tumor fails to provide Ag Target (due to no tumor Ag, No MHC I, antigenic masking of tumor, poor Ag processing, OR resistance of tumor to tumoricdal pathway) 2. Tumor fails to induce effective immune response (No antigenic epitopes, decreased MHC or tumor Ag expression, no costimulatory signal, tumor produces negative response, shedding of tumor Ag, tolerance induction, t-cell signaling defects by tumor ) 3. Host fails to respond

Answer 78

= pathologic condition resulting from failure of tolernace mechanism to self antigens (damage of self tissues): 1. self reactive and foreign reactive cells arise from the SAME POOL of lymphocytes (no specific that is more/less prone to autoimmunity) 2. autoimmune pathogenesis resembles that of invading pathogen 3. Both T cells and Ab mediate the response (although some lean more towards one mediator than another)

Answer 79

according to their immune mechanism or via target of attack Organ-specific = targeting Ag expressed within a particular organ; usually Cell mediated immune response Systemic = pathology not limited to a single organ; generally associated with humoral response **note some AI diseases can involve both cellular and Ab

Answer 80

MHC genes = best indications of genetic contribution/susceptibility for disease Other non-MHC genes that affect: - genes related to Ag clearance and presentation (ie: AIRE.. expressed in the thymus activated negative selection and deletion of autoreactive cells) - genes associated with cell signaling - genes associated with co-stim molecules (CTLA-4) - genes associated apoptosis (Fas/FasL.. if not expressed, then no apoptosis and then increased AI response) - genes related to Treg development (Foxp3)

Answer 81

1. Geographic: incidence in the northern hemisphere = higher in north than south (*MS if you move from north to south before age 12, then you assume risk of south) 2. Infection: inflammation and expression of co-stim molecules break tolerance to self-antigens (some viral infections exacerbate/stimulate AI response) 3. Anatomical injury: release of immune privileged site Ag 4. Hormonal: incidence of AI is higher in women (perhaps estrogen plays a role?) 5. Exposure to radiation, drugs, and toxins (sometimes transient sx that go away after drug removed; UV light stimulates SLE flares)

Answer 82

General: - Autoantibodies agains Ach Receptor of NMJ blocks the transmission of nerve impulses = sever muscle weakness - Affects at any age, predominantly FEMALES AGE 20s (3:2 F:M) or males age 50s Genetics: HLA-DR3 Diagnostic Features: - FATIGUE - abnormal chewing, talking, swallowing, breathing, eye movement (muscle movements that may present) Pathogenesis: Auto-Ab agains Ach Receptor, so Ach can't bind; also can destroy the ACh receptor by complement fixation (formation of immune complex) PURELY Ab DEPENDENT DISEASE (Auto Ab can transfer the disease) Treatments: Acetylcholinesterase inhibitors, immunosuppressants Animal Model Animals immunized with ACh receptors purified from torpedo fish or electric eel to generate symptoms

Answer 83

General: -Women 20-40 y/o (10F:1M) Genetics: - increased risk among family members - HLA-DR2, DR3 associated Diagnostic Feature: - skin rash (malar) - joint pain - kideny lesions = primary cause of mortality Pathogenesis: - IgG autoAb agains constituents of cell surfaces, cytoplasm, nucleus (since IgG of high affinity, implies involvement of T Cells); - usually anti-nuclear antibodies (ANA) such as anti-dsDNA that form immune complexes - location of immune complex dictates the location of disease presentation: skin = sensitive to UV light (rash), joints = non erosive arthritis, kidney = glomerularnephritis Treatment: - Too many Ag so you can't remove the Ag or target it - Mainly just immunosuppression of B and T cells

Answer 84

General: - Thyroid gland produces thryoid hormones thyroglobulin which is the precursor of T3 (triiodthyronine) and T4 (thyroxine) for regulation of cellular metabolism - 6F:1M Genetics: DR3, DR5 Diagnostic features: LOW thyroid hormones (T3, T4) High TSH due to feedback regulation High anti-thyroglobulin and anti-thyroid peroxidase Ab Sx = dry skin, brittle hair and nails, weight GAIN, depression, extreme depression Pathogenesis: AutoAb to thyroid peroxidase and thyroglobulin cause Ab-mediated destruction of thyroid gland; T-Cells also contribute via + macrophages, CD8 cells destroy follicular cells Treatments: Thyroid hormone for life

Answer 85

General: primarily affects North American and European whites 2.5F: 1 M Genetics: - Familial aggregation - HLA-DR2 Diagnostic features: Muscle weakness including: paralysis, urinary incontinence, vision functions, difficulties with coordination and balance, problems in speech/swallowing -can take on a slow progressive course, or a relapse/remission course Pathogenesis: Demyelination of the myelin sheath around neurons which forms plaques on MRI (white matter); Mediated by CD4+ TH1 cells that secrete IFN-G and TH17 that secrete IL-17; oligoclonal IgG is present in CSF but unclear function of B-Cells; AutoAg = components of the myelin sheath: Myelin Basic Protein (MBP), Proteolipid Protein (PLP), Myelin Oligodendrocyte glycoprotein (MOG) Treatments: 1. INF-B = non-specific anti-inflammatory molecule that inhibits the T-Cells from being activated, so they can't enter the CNS 2. Copaxone = resembles MBP and has neuroprotective properties 3. Tysabri = Anti-integrin monoclonal Ab that prevents Tcell migration to brain and spinal cord Animal model = Experimental autoimmune encephomyelitis (EAE)

Answer 86

General: AI of pancreas NO GENDER BIAS Genetics: HLA-DR3/4 heterzygous Diagnostic Features: - Hyperglycemia, increased hunger, frequent urination, and excessive thirst; - weight loss, nausea, fatigue Pathogenesis: AutoAb against cytoplasmic islet cell Ag generated; Chronitc inflammatory destruction of the Insulin producing B-cells in the islet of Langerhans causing little/no insulin production - CD8+ cause B-cell destruction -Cytokines include: IL-1, IL-6, IFN-A ``` Treatment Lifelong insulin (2+ injections a day) ``` Animal Models Nonobese diabetic mouse (NOD)

Answer 87

General: Most common rhuematic disease in US 3F:1M Genetic HLA-DR1 HLA-DR4 Diagnostic feature Sx = pain, swelling, and stiffness of joints Pathogenesis: - Affects primarily peripheral synovial joints - Previous theory: RF = IgM that binds to IgG forming immune complexes that deposit in the joints; but 30% of pt dont have detectable levels of RF - Synovium is densely packed with dendritic cells, macrophages, T/B cells, NK, and plasma cells; - some autoAg stimulates a CD4+ cell which produces IFN-G and IL-17 to induce activation of synovial macrophages and fibroblasts; macrophages secrete IL-1 and TNF-alpha causing tissue damage and destroy the integrity of the catilage - Suspected Ag = type II collage, proteoglycan, heat shock proteins Treatments - NSAIDs - anti-TNF-A (infliximab) - anti-CD20 (rituximab) on B-cells - nonbiologic and biologic disease modifying antirheumatic drugs - immunosuppressants - corticosteroids

Answer 88

1. Sequestered Ag not exposed to selection during tolerance induction-- absence of low concentrations of self Ag escaping negative selection 2. Pathogens as trigger of autoimmune disease via molecular mimcry, heat shock proteins (homology between some HSP and self proteins is so similar, that immune system thinks self are HSP!) 3. Superantigen as a polyclonal activator of autoreactive T cells (superAg are unprocessed and stimulate all T-cells that have a certain TCR V-B gene segment; thus some of these T-cells activated could be self-Tcells)

Answer 89

1. Replacement Therapies (ie: insulin for TIDM, thyroid hormone for HT) 2. Immunosuppressant drugs (corticosteroids, cyclosporine for Tcell signaling/IL-2, NSAIDs, cytokine inhibitors) 3. Monoclonal Ab to block accessory molecules/signal molecules 4. Altered Peptide Ligands-- to interact with TCR instead of peptide (induces clonal anergy) 5. Oral tolerance 6. Bone Marrow/tissue transplant

Answer 90

Genetics: HLA DR3 Diagnostic Feature: Hyperthyroidism, Goiter Pathogenesis: AutoAb to TSH receptor (acts as a TSH agonist without any feedback control) Thyroid produces thyroid hormones with TSH binds to receptors on epithelial cells; AutoAb to TSH receptors also induce production of T3 and T4, thus bypassing normal Feedback inhibition mechanisms resulting in excess thyroid homorne

Answer 91

State of indifference/non-reactivity towards a substance that would normally be expected to excite an immunological response - Tolerance is immunologically specific - Immature or developing lymphocytes are more susceptible to tolerance induction than are mature or functionally competent cells - Tolerance to foreign antigen is induced even in mature lymphocytes when these cells are exposed to Ag under particular conditions

Answer 92

1. Self Ag 2. suppresion of Allergic rx 3. allowing chronic infectin instead of rejection and elimination 4. preventing attack of fetuses by maternal immune system * *TOLERANCE INDUCTION THRESHOLD FOR TCELLS IS MUCH MORE STRINGENT FOR T CELLS THAN B CELLS becuase if you block the T cells (more upstream of Bcells) then you don't need to worry about B cells!)

Answer 93

Central: immature cells in primary lymphoid organs; during the development of the immune system AKA negative selection by clonal deletion, clonal anergy, receptor editing, and clonal ignorance Peripheral: post-thymic and bone marrow; mature cells in secondary lymphoid organs mediated by: - deletion: activation induced cell death, superantigens, due to high concentration of self-Ag - clonal anergy - functional deviation - regulatory/suppressory T cells - FAS/FASL interactions (and immune privelege sites) - oral tolerance

Answer 94

Anergy = functional inactivation of lymphocyte resulting in unresponsiveness upon contact with self Ag -occurs as a central mechanism mainly when a B-cell expressing Ab agains self Ag doesn't cause appropriate response; B-Cell is arrested in IMMATURE STATE **usually for B-cells of moderate affinity to self

Answer 95

ONLY OCCURS ON B-CELL LIGHT CHAINS! = ongoing receptor gene rearrangement to alter/edit Ag receptor specificity -RAG-1 RAG-2 expression leads to rearrangement of the already rearraranged L-chain to be replaced by upstream V and downstream J genes in order to lead to a BCR that has a new specificity (not for self)... continues until a non-self Ab is produced; if non then DELETION **usually for B-Cells of high affinity to self

Answer 96

= autoreactive B and T cells eliminated by APOPTOSIS -if B/T encounter a self Ag, then extensive cross-linking results and there is delivery of a STRONG signal which induces deletion (if encounter involves just MODERATE cross-linking then ANERGY results) -occurs in: double negative T-cells, double + T cells with high self affinity (negative selection) to prevent mature autoreactive Tcells from exiting the thymus

Answer 97

= expressed by THYMPIC EPITHELIAL and DENDRITIC CELLS; facilitates the expression of peripheral self Ag on thymic MEDULLARY CELLS in order to assist in NEGATIVE SELECTION of self reactive T cells ** PRevents the escape of thymic deletion (and autoreactive cells from leaving thymus into periphery)

Answer 98

= autoreactive lymphocytes (mainly B cells) that have escaped tolerance mechanisms because they have a "weak" affinity for self-Ag or becasue the self Ag is present in such a low concentration, can mature and move out into periphery although they persist in the host in an UNACTIVATED **usually for B-cells of weak aviditiy

Answer 99

= AVIDITY (strength) of BCR/TCR interaction with AutoAg ``` BCELLS: depends on: - [autoAg] - density of surface BCR - BCR affinity ``` High avidity = receptor editing (if that fails = deletion) Moderate = anergy Low = clonally ignorant TCELLS: depends on: affinity for TCR for peptide/MHC, level of TCR on surface, level of MHC molecule expressed High Avidity for peptide/MHC = Negative selection or Deletion **anergy and receptor editing not present in Tcells

Answer 100

BCells: Autoreactive T-cells are usually deleted in the thymus and not available in the periphery to provide costimulatory signal (ie: CD40L) needed to activate autoreactive B-Cell, thus the B-Cell becomes anergized; Anergic Bcells cannot compete successfully for entry into B-Cell follicles in the spleen/lymph nodes so they are arrested in development at the T/B border in follicular exclusion and die by apoptosis TCells: if MHC/peptide-TCR is not accompanies by B7/CD28 interaction, then IL-2 mRNA is rapidly degraded, and no IL-2 = no TCell proliferation; APC must be activated before they present costimulatory molecules, such that even if a macrophage preset the Ag to the T-Cell its not activated becasue its a self Ag and doesn't express costim molecules and so T-Cell anergy happens.

Answer 101

BOTH ARE ON LYMPHOCYTES; the interaction of the two induces apoptosis via stimulation of a caspsase (cysteine protease) cascade; Fas/FasL causes Fas to trimerize and thus stimulate FADD formation which goes on to simulate a caspase cascade that terminates in DNA Fragmentation leading to CELL APOPTOSIS MUTATED FAS = autoimmune lymphoproliferative syndrome (no apoptosis, therefore tons of lymphocytes)

Answer 102

Treg = a CD4+ that downregulates Tcell function - express CD25, the IL-2 receptor (so do ALL T-cells) - express Fox3p = TF for suppressive activity unique to Treg * *Treg requires specific TCR engagenemnt to be activated, but once they are activated, their suppressive activity is Ag NONSPECIFIC-- they can suppress autoreactive effector CD4+ CD8+ cells that are specific for an Ag DIFFERENT then the one the Treg recognized - also can suppress B cells, dendritic cells, NK cells, and via TGF-B they inhibit tTH1, TH2, TH17 Two classes: 1. Natural T-reg: involved in + selection in thymus - secrete IL 10 (prevents IL-12 secretion) and TGF B - Express CTLA 4 at high affinity (competes with B7 on APC) - Express FoxP3 = interferes with AP-1/NFAT thus prevents IL-2 2. induced Tregs (iTreg) = arise from naive CD4+ T-cells in the tissues A). FOXP3 Tregs: induced by TGF-B on CD4+ naive Tcells and secrete TGF B B). TH3 = NO FOXp3; found in mucosal immune system; produce IL-4, IL-10, TGF-B (which distinguishes them from TH2) C). TR1: differentiate invitro: produce IL-10 and TGF-B but not IL-4 MECHANISM: inhibit IL-2 production through IL-10 and TGF-B Downregulate B7 (CD80/CD86) on APC through CTLA-4

Answer 103

= where lymphocytes are generally excluded - in Testes, stromal cells constitutively express FasL which induces apoptosis in any immune cells entering the tissue - In the placenta maternal/fetal tissues are tolerant to eachother due to absence of HLA Ag

Answer 104

Normal immune responses involve: 1. TH1-- produce IFN-G (inhibits TH2), and TNF-A 2. TH2-- produce IL-4 (inhibits TH1), IL-5, IL-10, IL-13 3. TH17 Altered peptide ligands (changes one or two amino acids in the peptide) may switch a TH1 cell to perform TH2 functions

Answer 105

= lack of humoral or cellular immune response to ingested food antigens Low doses induce TH3 suppressor cells High doses induce Tcell anergy/deletion

Answer 106

Naive T-Cells (matuer) migrate to and enter the peripheral lymphoid tissue to encounter their specific antigens; Immature dendritic cells from infection sites pick up pathogen peptides by phagocytosis and migrate to the peripheral lymphoid tissue (lymph node, spleen, MALT) where they present MHC/peptides to naitve T-cells for activation

Answer 107

Naive T-Cells circulate between blood and the lymphoid tissues in search of specific antigens necessary for development into effector T-cells; To enter the lymphoid tissues, naive T-Cells bind to HIGH ENDOTHELIAL VENULES (HEV) through cell-cell mediated interactions by ADHESION moleculess: -selectins -integrins -ICAM (intracellular adhesion molecules)

Answer 108

1. L-Selectin on T-cells bind to Addressins on the vascular or mucosal endothelium = "slow roll" along surface 2. CCL21 (chemokine) activates LFA-1 (an INTEGRIN ON ALL T-CELLS) as the TCell comes into contact with HEV 3. LFA-1 (T-cell) binds ICAM-2 and ICAM-1 on endothelial surface = FIRM ADHESION that stops the T-cell so it can enter lymphoid tissue 4. Transmigration along the endothelial layer into the paracortical areas of the T-Cell Zone

Answer 109

- Naive TCell migrates into T-Cell zone of peripheral lymphoid tissue, and CCR7 (on its surface) bind to CCL21/CCL19 stromal ligands, which makes the T-Cell stay in this area - Dendritic Cells in the T-Zone produce CCL19/CCL18 and which attracts T-Cells to bind its CCR7 to - Naive T-Cell scans the surface of the dendritic cell for specific peptide/MHC complexes and if they find it then they are trapped in the lymph node.. PRIMING (if not activated, then the Naive T-cell leave node back into circulation)

Answer 110

**Only 3 APC present the costimulatory molecule necessary for activation of T-Cell (No co-stim = no infection = no T-cell response) 1. Dendritic Cell: Ag = any source Present to T-Cells located in = all areas of lymphoid organ **drive INITIAL cloning expansion and differentiation of naive T-cells into effector T-Cells; note: as immature, they are better at phagocytosis than presentation (flips once matured) 2. Macrophages Ag = intracellular pathogen Present to T-Cells already primed as effector CD4 Tcells (CANT PRESENT TO NAIVE T-CELLS!!!!) 3. BCells Ag = soluble Ag Present to T-Cells already primed as effector CD4 Tcells (CANT PRESENT TO NAIVE T-CELLS!!!!)

Answer 111

1. Using complementary receptors 2. Fc Receptors (Ag/Ab uptake) 3. C-Type lectins (mannose receptor etc)

Answer 112

1. Receptor Mediated Phagocytosis Pathogen = extracellular bacteria MHC pathogen loaded onto = MCH II Naive T-Cell activated = CD4+ 2. Macropinocytosis Pathogen = NONSPECIFIC Extracellular Ag/bacteria/virus MHC pathogen loaded onto = MHC II Naive T-Cell activated = CD4+ 3. Viral Infection Pathogen = Virus MHC pathogen loaded onto = MHC I Naive T-Cell activated = CD8+ 4. Cross-Presented phagocytic macropinocytosis Pathogen = Extracellular virus/pathogen MHC pathogen loaded onto = MHC I Naive T-Cell activated = CD 8+ **Dendritic cells are able to detect pathogens using TLR signaling receptors

Answer 113

TLR signaling facilitates entry of the dendritic cell into the peripheral tissues (LICENSING) by: 1. TLR picks up pathogen and induces CCR7 and pathogen processesing 2. CCR7 directs migration into lymphoid tissues and augments co-stim molecules and MHC 3. Mature dendritic cell in T-CEll zone primes naive T-Cell (program of differentiation = activation of naive T Cells)

Answer 114

- cause dendritic cell to no longer engulf antigens by phagocytosis or macropinocytosis - have high level of co-stim and adhesion molecules - secrete chemockine CCL 18 to attract naive T-Cells

Answer 115

binding of Tcell and APC is initally through LFA-1/ICAM-1 interaction; after TCR binds MHC, there is a conformational changes in LFA-1 that causes it to have an increased affinity for ICAM-1/ICAM-2; this causes a stable association between the Tcell and APC (prolongs cell-cell contact)

Answer 116

1. Activation = Interaction of specific peptideMHC/TCR 2. Survival = co-stimulatory signal that promotes survival and expansion of the T-Cell 3. Differentiation = co-stimulatory signal that directs the differentiation of four effector Tcell subsets ** antigen recognition in the absence of co-stim leads to clonal anergy or clonal deletion of peripheral cells

Answer 117

1. Re-enters cell cycle (G1 phase) and divides rapidly 2. Production of IL-2 * *CD28 signaling activates PI3-kinase which increased the production of AP-1 and NFkB (not NFAT) which prolongs the lifetime of mRNA IL-2 and promotes cell growth and survival

Answer 118

1. TH1 secretes IFN-G = killing of intracellular bacteria inside macrophage 2. TH2 secretes IL-4, IL-5, IL-13 = promotes eosinophil and mast cells to the site; production of IgE 3. TH17 secretes IL-17 which acts on fibroblasts and epithelial cells to cause them to secrete chemokines which attract neutrophils towards the infection 4. THF (follicular) = bind to B-Cells in the follicule and promote class swithcihng, affinity maturation (somatic maturation) 5. TReg = inhibit immature dendritic cells resulting in inhibition of CD4+ and TCell inactivton

Answer 119

Function: control BACTERIAL INTRAVESICULAR infection in MACROPHAGES by stimulating microcidal actiity of macrophage (and its lysosomes) to kill the resident bacterial; Secrete: IL-2 (promote more T-Cells) and IFN-G (promote macrophage acidic killing) Induced by: IFN -G (from activated NK of innate system) and IL-12, which go on to stimulate STAT1 transcription factor which induces T-bet Transcription Factors which codes for IL-2 and IFN-G expression; STAT4 also promotes expansion and differentiation of the committed TH1 cells

Answer 120

``` Function: Control infections by PARASITES (esp helminths), but promoting responses mediated by EOSINOPHILS, MAST CELLS AND IgE Ab ISOTYPE **TH2 cytokines are required for class switching to IgE ``` Secrete: IL-4 and IL-5 Induced by: IL-4 induces TH2 development from naive CD4 Tcells which activates STAT6 which promotes expression of GATA3 which switches on genes for TH2

Answer 121

Function: Induced early in adpative immune responses agains EXTRACELLULAR BACTERIA AND FUNGI; stimulate neutrophil responses to clear the pathgens Secrete: IL-17: acts on local tissue to produce IL-8 IL22: Acts on the gut, skin, and lungs to promote local innate defense to pathogens Induced by: IL-6 and TBG-B, which in the abscence of IL-4 and IL-12 induce development of TH17, which produces IL-21 and activates STAT3 to turn on ROR-G-t TF that drives IL-17 expression

Answer 122

=Follicular Helper Cells = (unlike Th1/TH2), they provide B-Cell help for production of Ab production Secrete: cytokines characteristic for either TH1 or TH2 Induced by: IL-6; also Bcl6 is required for expression of CXCR5 which is produced by stromal cells of C-cell follicle

Answer 123

Classified by killing mechanism: 1. Release of cytotoxic granules upon contact with target cell - perforin = causes a pore to form in the target cell plasma membrane for granzymes to pass through -granzymes = trigger apoptosis in the target cells by activating CASPASE 3 (a protease that Cuts after ASPartic acid residues) and a cascade that acivates CAD (caspase-activated deoxyribonuclease) which degrades DNA - granulysin (only in human) = has antimicrobial activities that induce apoptosis at high concentrations * ** NOTE: cytotoxic proteins are replenished each time ligation of a TCR occurs so a SINGLE CTL can kill a SERIES of targets 2. Fas-FasL interaction induced apoptosis = mainly for regulating lymphocyte numbers (not for killing infected cells); activated lymphocytes have both Fas/FasL and when they bind they induce a trimeric Fas = FADD which activates caspases leading to apoptosis and degradation of DNA

Answer 124

1. Neutralization = binding to pathogen presents the pathogen from entering target cells 2. Opsonization = promotion of phagocytosis 3. Activation of of the complement system = promotes opsonization and lysis of pathogen

Answer 125

Common allergens: drugs, venom, peanuts Route of entry: IV, food, oral ``` Response: Vascular permeability (leads to rapid decrease in BP), laryngeal edema (leads to constriction), and shock ```

Answer 126

= inflammation of upper resp tract Common allergens pollen, dust mite feces Route of entry = inhalation Response = nasal edema, sneezing

Answer 127

Common allergens = dander, dust mite, pollen Route of entry = inhalation Response = bronchial constriction, mucus production

Answer 128

common allergen = peanuts, shelfish, eggs route of entry = oral response = vomiting, hives, anaphylaxis

Answer 129

1. Sensitization Period = first exposure to the allergen induces B cells to produce IgE; IgE production requires TH2 cells which produce IL-4, IL-5, IL-13; IgE is short lived in blood, but persists for months bound to mast cells in tissues and basophils in blood via a receptor for the Fc portion of IgE (FcERI)

Answer 130

Environment: - early exposure to infectious agents - pollution (diesel exhaust increases IgE 20x) Genetic: - Chromosome 5: IL-4, IL-13, GM-CSF associated with elevated IgE - some MHC Class II are associated with a SPECIFIC allergen - if both parents have allergy risk for the child increases from 10% to 40-60%

Answer 131

DERp1 = enzyme in dust mite feces that breaks down the tight junctions in mucosal epi cells and allows allergens to enter into the tissue more easily

Answer 132

IgE (already present on mast cells) is crosslinked by a reexposure to allergen (**ALLERGEN MUST BE AT LEAST BIVALENT*) which causes activation and rapid release of granules -activated mast cells also secrete more IL-4 and express CD40L so more B-cels will produce IgE

Answer 133

= allergic symptoms due to substances produces/released by mast cells Preformed substances = histamine, heparin, proteolytic enzymes and chemotactic facotrs (IL8 for PMN, Eosinophil chemotactic factor for eosinophils), other cytokines (IL13, 4, 5, GMCSF = attract and activate INFLAMMATORY cells) Synthesized substances = leukotrienes, thromboxanes, prostaglandins, platelet activating factor

Answer 134

(a) binds H1 receptors on smooth muscle (bronchial constriction) and on endothelial cells (vascular permeability); lead to systemic anaphylaxis (b) binds H2 receptors involved in mucus secretion, vascular permeability, and secretion of stomach acid

Answer 135

play major roles in antihistamine release-resistance asthma (1) leukotrienes: cause prolonged constriction of smooth muscle (2) thromboxanes, prostaglandins: constrict bronchi, also chemotactic for PMNs and eosinophils (3) platelet activating factor (PAF): cause release of histamine and thromboxanes

Answer 136

Eosinophils and PMNs come to site and prolong symptoms (occurs 7-8 hours after exposure) (1) eosinophils release: leukotrienes, PAF, toxins for helminths (eosinophilic cationic protein), enzymes and chemotactic factors (2) PMNs release: leukotrienes, PAF, lysosomal enzymes

Answer 137

prevents blood vessel leakage AND relaxes bronchial/tracheal smooth muscle

Answer 138

inject patient with small amount of allergen and increase the does weekly for several months (1) mechanism: elevates IgG antibody which binds allergen and prevents it from reacting with IgE on mast cells; also induces a switch from TH2 to TH1 cells; may induce Treg cells (2) useful for: allergic rhinitis, bee stings, asthma, and peanut allergies

Answer 139

1. Beta agonists = epinephrine, causes antagonist of histamine, used in anaphylaxis 2. Xanthine derivatives = aminophylline, causes relaxation of smooth muscle, used in asthma 3. Mast cell membrane stabilizers = cromolyn sodium, causes prevention of degranulation, used in asthma 4. Leukotriene modifiers = binds leukotriene receptor or inhibit formation of leukotrienes, used in asthma 5. Antihistamines = benadryl, Block H1 receptors, used in rhinitis, dermatitis 6. Corticosteroids = anti-inflammatory, used in asthma, rhinitis

Answer 140

(1) patient history (2) skin tests: small amount of allergen injected; positive reaction is wheal and flare, swelling and redness (occurs in 10-15 minutes) (3) radioallergosorbent test (RAST): quantitates the amount of serum IgE for a specific allergen

Answer 141

protect against parasitic worms (1) worms stimulate IgE production (2) mast cells recruit eosinophils that bind IgE and IgG on the worm and release cytotoxins

Answer 142

(1) more allergies prevalent in rich versus poor countries (2) theory: in industrialized countries, improved hygiene exposes children to fewer bacterial and viral infections early in life; this directs maturing immune system away from TH1 type responses leading to unrestrained TH2 responses that allow for an increase in allergy (3) early exposure to infectious agent in poor countries induces a prolonged TH1 bias to subsequent exposure to foreign substances including potential allergens (4) this hypothesis was tested by comparing kids in rich countries exposed to many infectious agents (early day care; farm life; many siblings) versus children with fewer exposures (single child, stays at home). the early exposure group had fewer allergues

Answer 143

immune reactant = IgG (or IgM) Antigen = cell or matrix associated antigen Effector mechanism = 1. activate complement 2. attract FcR+ cells (phagocytes, NK cells) to bind IgG (NOT IgM) = Ab Dependent Ceullular Cytotoxicity (ADCC); these can damage self-cells Examples: some drug allergies (ie. penicillin-however can also stimulate IgE release), chronic urticaria, ABO or Rh incompatibility

Answer 144

Immune reactant = IgG Antigen = soluble antigen Effector mechanism: formation of immune complexes that activate complement and attract phagocytes resulting in localized tissue damage Examples: serum sickness (immune complexes deposit in vascular system), SLE (Ab to DNA)

Answer 145

= Delayed Type Hypersenstivity = MEDIATED BY CYTOKINES AND CHEMOKINES!! Two major pathways 1. Immune reactant TH1: antigen: soluble, stimulates TH1 cells to be produced effector mechanism: TH1 cells secrete 1. Chemokines (recruit macrophages to Ag site) 2. IFN-G (induces vascular adhesion molecule expression, macophages activated, increases release of inflammatory mediators) 3. TNF-A + TNF-B (local tissue destruction, increased expression of adhesion molecules of local blood vessels) 4. IL-3/GM-CSF (stimulate monocte production by bone marrow stem cells) examples: contact dermatitis, tuberculin reaction 2. immune reactant CD8+ T cell antigen: cell associated effector mechanism: cytotoxicity examples: contact dermatitis (poison ivy), graft rejection Basically: Types of Type IV: 1. Delayed-Type Hypersensitivity: Ag: proteins (insect venom, mycobacterial proteins like tuberculin and lepromin) Consequence: local skin swelling (erythema, induration, cellular infiltrate, dermatitis) 2. Contact Hypersensitivity: Ag: haptens (poison ivy, DNFB), small metal ions (nickel, chromate) Consequence: local epidermal reaction (erythema, cellular infiltrate, vesicles, intraepidermal abscess) 3. Gluten-Sensitive Enteropathy (Celiac Disease): Ag: gliadin Consequence: villous atrophy in small bowel, malabsorption **T cell mediated hypersensitivity takes many hours: need to recruit cells to the site

Answer 146

o 2 chains (alpha,beta/delta,gamma): bind Ag + self-MHC o CD3: made of gamma-epsilon and delta-epsilon chains; transduces signals when TCR combines with peptide + MHC; transports TCR to cytoplasmic membrane; invariant o 2 zeta chains: transduce signals when TCR combines with peptide + MHC; invariant

Answer 147

``` TCR = recognizes only linear peptides BCR = recognizes proteins that are linear or globular; also recognizes carbohydrates, lipids, and nucleic acids ```

Answer 148

Consist of VJ-C or VDJ-C o α and γ Loci: VJ-C o β and δ Loci: VDJ-C o Note: alpha and delta loci located together -Genes are rearranged during T cell development, requiring the use of RAG1 and RAG2 enzymes -Variability again due to: o Random utilization of 2 chains o Multiple V, D and J alleles o Junctional variability -Allelic exclusion: prevents simultaneous rearrangement of beta and gamma chains, but NOT all alpha; as a result, many T cells express 2 different alpha chains

Answer 149

• CD28: a costimulatory molecule that interacts with B7 on B cells (and other APCs); stimulates the T cell and also induces the production of IL-2 • CD152 (CTLA-4): interacts with B7; triggers a negative stimulus to the T cell (turns off T cell) -Clinical Correlation: recombinant CTLA-4 used in the treatment of rheumatoid arthritis patients ``` • Adhesion molecules: facilitate adherence to APC and endothelial cell o CD2 o Integrins (LFA-1 and VLA-4) ``` * Homing Molecules (CD62L or L-selectin): binds addressins on the endothelium * CD40L: binds CD40 on B cells and APCs; activation occurs both ways - CD40L on T cell binding CD40 on B cell stimulates B cell to class switch - CD40 on APCs binding CD40L on T cell stimulates activation of T cell • ICOS: interacts with ICOS ligand on B cell; facilitates germinal center formation in LNs and other lymphoid tissue

Answer 150

* Location: skin, lungs and intestines (much lower in number than alpha-beta T cells in the blood) * Structure: gamma and delta chains associated with CD3 and zeta, but no CD4 (some have CD8) * Function: may be important as first line of defense against pathogens; respond to a limited number of proteins (not necessarily to peptide + MHC; phospholipids and heat shock proteins)

Answer 151

1) Stem cells from bone marrow travel to thymus (beginning in utero until puberty, when thymus atrophies) - Clinical Correlation: DiGeorge Syndrome results from lack of a thymus, which prevents T cell development 2) Stem cells proliferate and mature in the thymus due to 2 factors: 1. Physical contact of dendritic and epithelial cells in the cortex 2. Cytokine influence (IL-7) 3) TCR beta, gamma and delta genes rearrange - Gamma-delta T cells leave the thymus - Cells with a beta chain express beta attached to an invariant chain (pre-T alpha); this forms the pre-T cell receptor 4) Formation of the pre-T cell receptor (and its appearance at the surface of the cell) prevents beta chain rearrangement, and stimulates rearrangement of the alpha chain gene 5) Rearrangement of the alpha chain stops expression of the delta chain (located on the same chromosome; therefore, beta chain can never bind delta chain) - Remember: allelic exclusion is not complete for the alpha chain, and therefore, both alpha chains may rearrange (results in 2 cell with 2 different alpha chains and 1 beta chain) 6) CD4 and CD8 markers appear on the surface, forming a double positive cell 7) THYMIC SELECTION

Answer 152

•T cells in thymus are selected for based on: - Recognition of their own MHC - Unresponsiveness to self-peptides (in order to prevent autoimmune disease) Steps: 1) Cells expressing both CD4 and CD8 interact with cortical epithelial cells expressing MHC class I and class II, promoting further maturation of the T cell. Cells with weak or no interaction with self MHC die by apoptosis (positive selection) 2) T cell interacts with dendritic cells at the corticomedullary junction and epithelial cells in the medulla. Both of these cells have MHC class I and II, and some have self-peptide present. If the T cell reacts strongly with self-peptide-MHC, they are killed by apoptosis (negative selection). 3) Finally, CD4+CD8+ double positive cells downregulate one or the other, and become single positive cells (mature T cells). Mature T cells leave the thymus and circulate. AIRE (Autoimmune Regulator Gene); - Expressed in the thymus; allows it to express various important self antigens from other organs, facilitating the killing of T cells specific for various “sequestered antigens” (ie. from the pancrease, thyroid etc.)

Answer 153

* NK Cells: no TCR or CD3; kill virus infected cells and tumors expressing low MHC * NKT Cells: have a TCR with limited variability and an NK marker; regulate other T cells * Treg Cells: subset of CD4+ cells that are CD25+ and Foxp3+ as well; inhibit the immune response

Answer 154

1. Highly motile 2. Express TLR that can recognize a reagent as 'infectious' 3. uptake of injection agents stimulates the production of proinflammatory cytokines IL-1, TNF-A, and IL-12 to produce TH1

Answer 155

1. Peptide/MHC - TCR 2. MHC II and CD4 = increases the activation 100x 3. Costimulator pairs: B7/CD28 or CD40/CD40L (which upregulates B7) 4. Adhesion molecules to increase binding affinity: ICAM-1/LFA-1, LFA-3/CD2

Answer 156

1. Peptide/MHC interacts with TCR to activate CD3 and Zeta chains 2. Tyrosine kinases are activated = Lck and Fyn, which phosphorylate ITAMS on CD3 and Zeta, respectively 3. Phosphorylated CD3 and Zeta attach to ZAP-70 and Lck activates ZAP-70 4. ZAP-70 activates adapter molecules LAT and SLP-76 which go to the membrane 5. Adapter proteins bind PLC-Gamma which is then phosphorylated by ZAP-70; Adapter proteins also activate MAP Kinases 6. Activated PLC breaks down PIP2 into DAG and IP3 7. DAG leads to activation of NFkB transcription factor 8. IP3 leads to increased Ca2+ which activates calcineurin which activates NFAT 9. MAP kinases activate Ap-1 10. NFkB, NFAT, and Ap-1 all activate IL-2 and IL-2alpha Receptor transcription

Answer 157

B7-CD28 = costimulation needed for T-Cell activation because it: 1. increases transcription of IL-2 mRNA 2. increases half-life of IL-2 mRNA 3. mobilizes lipid rafts which facilitate kinase pathways When B7-CTLA4 (which is upregulated on activated T cells and has a higher affinity for B7 than CD28), IL-2 production and cell proliferation is blocked.

Answer 158

Down regulation of CD62L (L-selectin) a receptor that facilitated migration INTO the lymph node Upregulation of integrins/chemokines out of the lymph node

Answer 159

1. Superantigen pinding to specific Vbeta chains of the TCR causing activation of 10% of T0Cells 2. Plant proteins like ConA (Concanavalan A) and PHA (Phytohemaggluntinin) adhere to TCR and cause mitogenesis 3. NKT Cells are activated by lipids

Answer 160

``` DO NOT induce class switching or generate memory B Cells; Poorly immunogenic in young children ``` but, if polycassharide is conjugated to a protein then TH2 cells will be activated by the protein and provide help to B-Cells that react to the polysaccharide

Answer 161

1. by MHC I, B7-CD28, and IL-12 (thus CD4+) 2. In abscence of CD4+, via cross priming in which viral derived peptide is presented by MHC class I on dendritic cells (which present B7 for co stim)

Answer 162

Thymic Independent antigens (TI) = large polymeric molecules with mulptiple REPEATING antigenic epitopes EX: LPS and bacterial polysaccharides. Type I TI antigens (LPS) but NOT Type II TI antigents (polysaccharides) also act as B Cell mitogens ONLY CAUSE IgM RESPONSE AND NO MEMORY B CELLS

Answer 163

1. Initial step is cross-linking of Ig receptor molecules which sends a signal via IgAlpha and IgBeta which causes activation of Src kinases (LYn, Fyn, Blk) 2. Src Kinases phosphorylate ITAMs on IgAlpha/beta and this recruits Syk which is activated 3. Activated Syk recruits and activates adapter proteins which go on to activate signalling pathways similar to T-Cell .. activating NFkB, NFAT, Ap-1 TF, which promotes transcription of Ig genes and cytokine RECEPTOR genes

Answer 164

Enhanced: When complement component C3d is deposited on bacteria, it binds to CD21 on a Bcell and provides a costimulatory signal that augments B-cell activation Dimininshed: When CD32 on the Bcell surface binds to Fc region of an Ig, it causes a phosphatase to bind which leads to inhibition of Ig synthesis

Answer 165

small, organic molecule that becomes part of an antigenic determinant when coupled to a carrier molecule (ie. small molecule that can only elicit an immune response when attached to a larger carrier) - Ab interactions with haptens are the most simplistic of interactions

Answer 166

number of sites reacting with Ag on an Ab molecule - IgG: 2 - IgA: 2 or 4 - IgM: 10 - IgD: 2

Answer 167

- Addition of a fixed amount of Ab to various amounts of protein in test tubes; incubate and spin to form precipitate and supernatant -The relative amounts of precipitate and supernatant can be plotted to form a QP curve o Weight of protein added on X axis o Weight of ppt on Y axis o Ab excess occurs on the left side of the curve (where ppt is increasing as protein is added) o Ag excess occurs on the right side of the curve (where ppt is decreasing even though protein is being added) o Equivalence point occurs slightly to the left of center, due to the fact that ppt actually briefly gets heavier as the lattices become stringier past the equivalence point

Answer 168

- Ag placed in 2 wells (can be the same or different); Ab placed in another opposite those - As Ag and Ab move towards eachother, a ppt line can be visualized representing equivalence zones - The pattern of the equivalence ppt line shows the relatedness or differences in the Ags being tested 3 Basic Precipitin Patterns Exist: 1. Both Ags are the same (Identity): a continuous, smooth ppt line will be present 2, Ags are completely different (Non-Identity): two crossing ppt lines will be present 3. Ags are have similarities but are not the same (Partial Identity): spur in the direction of the deficient Ag (ie. the one missing a piece that would react with Ab) Example: If Abs Ab1 and Ab2 are present, and Ag1/3 is also present, Ab1 will react with the Ag1 portion, but Ab2 will move past the ppt line to interact with Ag2 from the other Ag well, creating the spur in the direction of Ag1/3.

Answer 169

an adaptation of the precipitin reaction in gel - Method used to quantitate Ags - A series of known quantities of Ag are placed in wells in the gel, along with the unknown quantity of Ag you wish to determine - The diameter of the diffusion ring of the known quantities are used to create a standard plot of: o Log[Ag] vs. Ring Diameter - The diameter made by the unknown quantity of Ag can then be measured, and plotted on the graph to elicit the [Ag] in that sample

Answer 170

• Aggluntination: particulate Ags (RBCs, bacteria) - Major Blood Groups: ABO system is one of the major histocompability systems in humans A: polysaccharide backbone- N acetylgalactosamine • Isoantibodies: anti-B B: polysaccharide backbone- galactose • Isoantibodies: anti-A O: polysaccharide backbone • Isoantibodies: anti-A and anti-B AB: polysaccharide backbone- both N-acetylgalactosamine and galactose • Isoantibodies: none **Isoantibodies: do not appear until roughly the first year of life (unclear how they develop)

Answer 171

1. Immunize mouse with AgX; produce Anti-AgX Abs 2. Fuse Anti-AgX cells with immortal mouse myeloma cells 3. Creates a clone of Abs to AgX Applications: - Diagnostic: leukocyte identification, HLA antigen detection, typing of leukemias and lymphomas, detection of tumor-related Ags - Therapeutic: antitumortherapy, immunosuppression, fertility control, drug toxicity reversal (ie. digitalis)

Answer 172

good for measuring minute quantities of things** 1. Radioimmunoassay: - Particularly useful for measuring concentrations of drugs and hormones o Need Ab to drug/hormone o Need to couple drug/hormone to a radioisotope -Read out in a gamma counter 2. ELISA: - Enzyme linked immunosorbent assay - Good for measuring Ab levels to an Ag - Process: o Ag binds matrix (ie. plastic) o Add Ab (Ab1) to Ag; wash o Add Ab (linked to enzyme) to Ab1 (anti-Ig Ab); wash o Add substrate that changes color when reacting with enzme - Read out spectrophotometrically (ELISA plate reader) - Plotted on a [Ab] vs. Optical Density standard curve (unknown value should fall in linear region)

Answer 173

Use: primarily to detect Ags (ie. microbes like chlamydia inclusion bodies in vaginal smears, immune complexes in kidneys) Basic Process: o Cells fixed to glass slide (Ag) 1. Direct Test: • Fluorescent labeled Ab to Ag of interest added to slide; look for interaction ***MEAURES CELLS NOT Ab!! to test if there is protection post vaccination 2. Indirect Test: • Unlabelled Ab to Ag of interest added to slide • Followed by fluorescently labeled anti-Ag Ab to the Ab added 1st; look for interaction • Much more sensitive 3. Sandwich Test: • Example: you want to know if a plasma cell is making Ab to an Ag of interest -Add Ag of interest to coat the plasma cell • Add fluorescently labeled Ab to the same Ag; look for interaction

Answer 174

- Used to analyze and sort cell populations (measures kinds of cells you have in a mixture) o Example: quantitate lymphocyte subsets (CD4, CD8); sort lymphocyte subpopulations - Have fluorescently labeled Abs to cell markers; cells pass through small tube 1 by 1 and if they have fluorescently labeled Ab attached, that will be detected and they will be sorted accordingly - Uses: o Leukocyte/tumor cell phenotyping o DNA analysis (determine aneuploidy) o Leukocyte cross matching in transplant recipients

Answer 175

• Use: measures the presence of Abs to specific microbial Ags (ie. confirmatory test for Abs to HIV) •Process: - Disrupt virus particle and subject to electrophoresis - Transfer blotting to nitrocellulose sheet - Incubate patients serum (with Abs) with nitrocellulose; wash and add enzyme or radioactive anti-human Ig Ab o Enzyme linked- add chromogen to visualize; radioactive viewed on X-ray film

Answer 176

1. Apoptosis: occurs when cell responds to cell-bound self Ag 2. Anergy (Inactivation): occurs when cell responds to soluble self Ag 3. Receptor Editing (to produce different specificity): also response to soluble self Ag

Answer 177

1. Stem Cell: further development to B cells requires stromal cells and IL-7 2. Pro-B Cell: D-J rearrangement (H chain); no membrane Ig 3. Pre-B Cell: V-DJ rearrangement (H chain); μ + surrogate light chain at surface and with Igα and Igβ (signal transduction molecules). BtK signals for light chain rearrnagement 4. Immature B Cell: V L chain rearrangement (kappa or lambda); IgM expressed on surface, which combined with Igα and Igβ, is called the B CELL RECEPTOR 5. Mature B Cell: no gene rearrangement; IgM and IgD on surface (due to alternative splicing); can encounter infectious agents and proliferate to clones of cells (plasma or memory) 6. Memory B Cell: isotype switched to have IgG, IgA or IgE on surface after Ag exposure; long-lived and express IgA, IgG or IgE on their surface, along with adhesion molecule CD44;serves as protection for future infections with the same agent 7. Plasma Cell: no membrane Ig expression; secretes IgM, IgG, IgA, or IgE (switches from membrane bound form of IgM to secreted form via alternative splicing)

Answer 178

• Pre-B Cell Receptor = μ + surrogate light chain + Igα + Igβ Expression of the Receptor has 4 Effects: 1. Cell proliferation 2. Shuts off surrogate light chain production 3. Starts light chain rearragments 4. Stops H chain rearrangements Clinical Correlation: X-Linked Agammaglobulinemia -Defective BTK enzyme causes B cells to be arrested at the pre-B cell stage of development

Answer 179

In germinal centers of LNs, spleen and Peyer’s patches (secondary lymphoid organs) Cells: APC usually follicular dendritic cell = exposes BCell to Ag T helper cells = allow for isotype switching and memory cell formation Plasma cells = go back to bone marrow for proliferate

Answer 180

When B cells are activated by Ag and proliferate, the V regions are subject to high mutation rates Results in some cells producing Ab with higher affinity for Ag, and these cells are positively selected by Ag yielding more cells This results in the affinity of the Ab increasing with repeated/prolonged exposure to Ag, which is known as affinity maturation

Answer 181

T cells have CD40 ligands and release cytokines that augment B cell activation and Ig class switching Clinical Correlate: in the absence of CD40 ligand, only IgM is found in serum (Hyper IgM Syndrome)

Answer 182

- Igα and Igβ: part of the B cell receptor for Ag (BCR); associated with the IgH chain - B Cell Co-Receptor (CD21, CD19 and CD81): associated with the BCR Binding of C3d (a proteolytic cleavage product of C3b, along with C3dg, that remains bound to bacteria after complement activation) to CD21 increases Ag signaling 1000x; results in an enhanced signal through the BCR CD21 is also a receptor for the Epstein Barr virus Negative Signals: downregulate B cell activity = CD22 and CD32 (binds Ag-Ab complexes to downregulate B cell activity)

Answer 183

1. MHC Class II: binds peptide and interacts with TCR of CD4+ T cell; allows B cells to act as APCs for T cells 2. B7: interacts with CD28 and CTLA-4; allows B cells to act as APCs for T cells 3. CD40: receives signals from CD4+ T cells (CD40 ligand) that allow for Ab class switching

Answer 184

Location: subset of B cells found in peritoneal and pleural cavities Features: - CD5 on surface - Produce low affinity IgM in response to pathogens at mucosal surfaces - Do not require/receive T cell help, therefore generating an early response to pathogens - V region repertoire for these cells is limited - Little to no memory developed

Answer 185

- The MHC is on a single chromosome (6), and therefore you inherit the complex as a single unit called the MHC haplotype - Any of your siblings have a 25% chance of inheriting the same 2 chromosome 6’s, resulting in identical MHC - Note: you would still differ at minor histocompatability loci that are encoded for by other cs

Answer 186

Expression: constitutively on all nucleated cells, including APCs Encoding: Coded by 3 separate loci (A,B,C), with each locus coding for an α chain only (highly polymorphic) - Alpha chain combines with a nonpolymorphic/invariant chain, β2-microglobulin -Each cell will simultaneously express HLA-A, HLA-B and HLA-C Structure: - Alpha1 and Alpha2 domains interact with peptide (closed binding groove; 8-9 aa) - Alpha3 domain interacts with CD8 (on cytotoxic T cell) Function: to present foreign peptide antigens to CD8+ T cells (endogenous Ag) - Infectious agent (virus, bacteria, parasite) penetrates the cell in order to replicate - Undergoes protein synthesis, and some protein is degraded by proteosome - Peptides from proteosome transported to ER by TAP-1 and TAP-2 transporters - If peptide has sufficient binding affinity for the MHC molecule (immuodominant epitope), it becomes associated with MHC class I - MHC class I + foreign peptide move to the surface of the infected cell to present to CD8+ T cells

Answer 187

Expression: constitutively only on APCs (dendritic cells, macrophages, and B cells) and thymic epithelial cells; can also be induced on fibroblasts and endothelial cells Encoding: - Coded by 3 separate loci (DP, DQ, DR), with each locus having an A and B gene encoding for an α and β chain, respectively (chains are highly polymorphic) - An APC will simultaneously express HLA-DP, HLA-DQ and HLA-DR; this enhances the likelihood of binding to and presenting foreign peptide to T cells Structure: - Alpha1 and Beta1 domains interact with peptide (open binding groove; 12-20 aa) - Beta2 domain interacts with CD4 (on helper T cell) Function: to present foreign peptide antigens to CD4+ T cells (exogenous Ag) Mechanism - Extracellular Infectious agent is phagocytosed by an APC and enclosed in an intracellular vesicle - Vesicle fuses with an endosome or lysosome, and proteins are digested into peptides - Vesicle of degraded peptides fuses with vesicle containing newly formed MHC class II with CLIP attached - If peptide has sufficient binding affinity for the MHC molecule (immuodominant epitope), it binds MHC class II in exchange for CLIP, a process mediated by HLA-DM ``` CLIP: MHC class II is assembled in the ER/Golgi with CD74 attached • CD74 (invariant chain) acts as both a chaperone and an inhibitor of endogenous protein binding • When the Golgi releases the vesicle with the newly formed MHC, CD74 is degraded down to CLIP, which is eventually replaced with foreign Ag - MHC class II + foreign peptide move to the surface of the infected cell to present to CD4+ T cells ```

Answer 188

* Peptides can bind MHC at the cell surface * APCs can take up exogenous protein and process them both in the class I and class II pathway (will be presented by both); this is called cross-priming * Superantigens: proteins that binds both MHC class II and the germline configuration of the TCR Vβ simultaneously - These areas that it binds on MHC II and the TCR are highly conserved and therefore, they can interact with a large percentage of T cells (up to 10%) - Leads to overactivation of T cells

Answer 189

- Many self reactive T cells eliminated in thymus | - Self-peptides do not activate T cells in the absence of costimulatory signals

Answer 190

Basic Steps: 1. First rearrangement occurs, bringing D and J together 2. Second rearrangement occurs, bringing V and DJ together 3. This fragment is then joined to the C region to form a primary RNA transcript, which is spliced to form the mature mRNA that can be translated to a polypeptide chain Details: 1. Recombination begins on only one chromosome (maternal or paternal) in an immature B cell (Pro-B cell) 2. A primary RNA transcript is made with constant region μ (IgM) and δ (IgD); only IgM is expressed in the immature B cell 3. mRNA transcript is translated into protein, and this synthesis of IgM heavy chain prevents the rearrangement of the other chromosome (allelic exclusion) Note: if rearrangements on the first cs are non-productive, the other parental cs will undergo rearrangement

Answer 191

Basic Steps: Only one rearrangement occurs to bring V and J segments together - This fragment is then joined to the C region to form a primary RNA transcript, which is spliced to form the mature mRNA that can be translated to a polypeptide chain Details: • There are 2 light chain loci (one on each cs): κ and λ • Rearrangement begins once the heavy chain rearrangement has been successful and IgM μ chain is at the cell surface • Kappa rearranges first, and if successful, prevents lambda from rearranging (allelic exculsion- ensures Ab has one single specificity) • If the first kappa locus is unsuccessful, the other kappa locus will rearrange, followed by each of the lambda loci if necessary **Note: kappa:lambda ratio is roughly 2:1 in serum •Clinical Correlate: B cell tumor may result in all serum Ig being light chain homogenous (that is, all kappa or all lamba)

Answer 192

- V(DJ) Recombinase: found in all cells - RAG-1 and RAG-2: only in lymphocytes; directs V(DJ) recombinase Clinical Correlate: defects in RAG-1 or 2 will prevent T and B cell development -L Gene (Leader Peptide): helps direct protein to secretory pathway (cell surface) and is then cleaved

Answer 193

- Junctional Diversity: splicing between V, D and J is imprecise leading to changes in amino acid sequence at critical sites for Ab specificity - Insertional Diversity: small numbers of nucleotides can also be added at this site; mediated by terminal deoxynucleotidyltransferase (TdT) - Note: 2/3s of these amino acid changes are out of frame and non-productive, signaling the other chromosome to undergo rearrangement Occurs before exposure to Ag

Answer 194

- Occurs when a mature B cell is activated by Ag and produces a clone of cells - Recombined V regions very prone to mutations (especially in hypervariable region) - Mutated B cells with highest affinity are selected by Ag (proliferate) - Result: increased affinity for Ag with each exposure **Occurs after exposure to Ag

Answer 195

- Occurs when an immature B cell is expressing an Ab that is reactive to self Ag (autoantibody) - Additional rearrangement of the light chain gene occurs in an attempt to change the specificity of the cell (cannot occur in the heavy chain since D would be totally lost upon rearrangement) **occurs after exposure to Ag

Answer 196

- Cells initially only express IgM on the surface - Mature B cells express both IgM and IgD on the surface due to alternative splicing of mRNA - Mature B cells are induced to produce other classes of Ab upon second exposure to Ag and T cells Activated T cells secrete cytokines that result in further rearrangement of the H chain gene Constant region for IgM and IgD is spliced out, and VDJ region is put together with the constant region for IgG, IgA or IgE Result: cell produces Ab with the original specificity, but with a different isotype **occurs after Ag exposure

Answer 197

1. Nature and physical state of the antigen. - Degree of foreigness - Chemical features - Particulate (usually better Ags) vs. soluble (often leads to tolerance) - Adjuvants (non-specific potentiators; most are pretty toxic) 2. Route of Immunization: - Natural: infection (more potent route of immunization) - Deliberate: vaccination Normal vaccination route is through the tissue (epidermal, dermal or subcutaneous), Other routes include via the blood, tonsils and Peyer’s patches 3. Antigen Dosage: no generalizations (need to work out optimal dosages; dose/response curves) 4. Lymphocyte Traffic: - Homing receptors on lymphocytes react with vascular addressins on HEVs for transepithelial passage

Answer 198

Sites of Ab Synthesis = Plasma cells in spleen and LNs Appearance of Ab = Serum Predominant Ig = IgG Ig Structure = IgA can be monomer, dimer, or trimer + a J chain

Answer 199

Sites of Ab Synthesis = Plasma cells in glandular tissue and lamina propria of mucosal surfaces Appearance of Ab = Secretions 1. Internal: Aqueous humor, CSF, Synovial fluid, Pleural fluid, Peritoneal fluid 2. External: Saliva, Lacrimal fluid, Nasal fluid, Tracheobronchial fluid, Intestinal fluid, Bile, Cervical fluid Predominant Ig = IgG (internal secretion) sIgA (external secretion) Ig Structure = IgA is a dimer with a J chain and a secretory component (sIgA) ***IgM and IgG are the same in both systemic and mucosal immune systems; however, in patients that are IgA deficient, IgM can make it through the epithelial barrier and enter secretions (contains a SC)

Answer 200

- IgM (19S) - Low affinity Ab - Low Ab titer - Longer lag in response (longer response time) - IgG turns on late

Answer 201

- IgG (7s) - Higher affinity Ab - Higher Ab titer - Short lag in response (faster response time) - IgM may appear early

Answer 202

IgG > IgA, IgM > IgD, IgE

Answer 203

- Functions as a first line of defense - Produces Abs at sites of microbial replication - GI produces more Ig than spleen, bone marrow, and LNs - IgA accounts for 60% of the total Ig produced (much of it ends up in the feces, however) When an antigen enters: - Ag enters the small intestine and is transported to Peyer’s patches across M cells - Peyers patches are rich in IgA precursor cells, which encounter the Ag - IgA precursors travel to mesenteric node and then through thoracic duct to enter the blood stream - From the blood stream, they travel to several destinations, become plasma cells, and produce IgA: Small intestine (intestinal IgA); most cells end up going back here* • Note: released from plasma cell as dimer IgA; picks up SC in intestinal wall Mammillary gland (milk IgA), Salivary gland (salivary IgA), Bronchial tube (bronchial IgA), Urogenital tract (vaginal IgA), Lacrimal gland (tear IgA)

Answer 204

- Barrier defense - Antigen transport - Intracellular viral neutralization

Answer 205

- One single mRNA codes for H chains; a separate single mRNA codes for L chains - H and L chains made on separate polyribosomes - H and L chains are translated (including the leader sequence, which is eventually cleaved off) and then the chains associate Note: there are alternate pathways of association for different Ig classes - Disulfide Bond Formation: intrachain form first, interchain form last - Golgi complex adds carbohydrate to the molecule - Vesicle breaks off of the Golgi complex, travels to the cell membrane where it fuses and is secreted by reverse pinocytosis

Answer 206

IgM and IgA: L, H and J chains all produced in the plasma cell - J Chain = Limiting factor in polymerization , Catalyzes polymerization, which occurs shortly before secretion sIgA: L, H and J chains produced in plasma cell; SC produced in epithelial cell Steps for Producing sIgA: • pIgA released from plasma cell (dimer with J chain) • Binds poly Ig receptor on epithelial cell (SC component of receptor) •Taken into the cell, and released to the acinar lumen along with the SC to form sIgA • Membrane bound portion of poly Ig receptor remains behind

Answer 207

Polysaccharides | • Example: glucose/glucouronic acid (strep. pneumonia III)

Answer 208

Fetus: - 6-7 wks in utero = thymus develops - 10-12 weeks: surface Ig; lymphocytes; fetal contribution of IgM into circulation (IgG present, but comes from mother across placenta) •Human Neonate: - Limited capacity to mount a B-cell response at birth -Compensation via Natural Passive Immunity: Transplacental passage of maternal IgG: systemic protection - sIgA in mother’s colostrums/milk: provides local protection of infant’s GI tract

Answer 209

- Active: immunization directly carried out in the host; long-lived - Passive: immune components (Abs or cells) transferred into the host; transient protection - Adoptive: cells transferred into an irradiated host (ie. bone marrow transplants)

Answer 210

``` H Chain = gamma Subclass = 1-4 L chain = K or Lambda Size = smallest Serum conc = highest Main functions: passes through placenta, fixes the complement system, primary responder in the memory response, longest halflife, Fc portion binds for opsonization (does do bacterial lysis and antiviral, but not as good as IgM and IgA respectively) ```

Answer 211

H chain = mu Sublass = none L chain = K or Lambda Size = largest (900,000 kD); IgM>>>sIGA>>IgE>IgD>IgA>IgG Serum conc = middle; IgG>IgA>IgM>IgD>IgE Key Features: Best at complement fixation (due to size), made in fetus but does not cross the placenta, on all B-cell surfaces (first to respond in primary exposure to Ag, acts as evidence of recent infection) BACTERIAL LYSIS

Answer 212

H Chain = alpha sublass = 1,2 L Chain = K or lambda Size = monomeric = small, dimeric = middle sizes; IgM>>>sIGA>>IgE>IgD>IgA>IgG Serum conc= IgG>IgA>IgM>IgD>IgE Key Features: best for mucosal responses (secretory form), secreted from mammary gland, ANTIVIRAL dimeric form is secreted

Answer 213

``` H Chain = epsilon subclass = none L Chain = K or Lambda Size = IgM>>>sIGA>>IgE>IgD>IgA>IgG Serum conc = IgG>IgA>IgM>IgD>IgE Key Features = Mas cell/basophil degranulation (allergic reactions) and parasitic infection; least prevalant in serum ```

Answer 214

``` H Chain = delta subclass = none L Chain = K or Lambda Size = IgM>>>sIGA>>IgE>IgD>IgA>IgG Serum conc = IgG>IgA>IgM>IgD>IgE Key Features: found on B-cell surface along with IgM; no clear secretory function ```

Answer 215

located between the CH1 and CH2 on heavy chains; provides segmental flexibility (allows molecule to interact with antigens)

Answer 216

Fab: 2 per IgG; light chain + ½ heavy chain Fc: 1 per IgG; 2 x ½ heavy chain Fv: smallest fragment that retains site for reaction with Ag; 2 per IgG; made up of the variable regions of both light and heavy chains

Answer 217

1. Reduction/Alkylation of Disulfide Bonds: - Results in separation of the chains from one another - H chain has reduced (but not completely absent) binding capacity - L chain has NO binding capacity - Conclusion: both H and L chain needed for full Ag binding capacity 2. Papain Fragmentation: - Results in 2 Fab fragments and 1 Fc fragment - Monovalent Fab fragments retain full Ag binding capacity - Fc portion did not bind Ag 3. Pepsin Fragmentation: - Results in 1 F(ab')2 and peptides - Divalent F(ab')2 retained full Ag binding capacity - Fc function totally lost, resulting in: - Inability to fix complement - Inability to bind cells with FcR - Inability to cross placenta (IgG)

Answer 218

1. Plasma cell: produces L, H and J chains (MW 16,000) 2. Epithelial cell: produces secretory component (MW 70,000) Secretory Component: protects Abs from degradation

Answer 219

•Factors to Consider: - Ag-Ab interactions are noncovalent - Variation in capacity to bind Ag - Number of Ab combining sites - Gross architectural similarities •Parameters Defining Site: - Unique Amino Acid Sequence Defines Site: encoded by genome - Dimensions of the Site: varies from Ab to Ab, but very small (Angstroms) - Location of the Site: contacts residues within the variable regions of L and H chains (Fv) Affinity Labeling: made us aware of the presence of hypervariable regions/complimentarity determining regions (CDRs) on both heavy and light chains Variable Regions: • Hypervariable regions/CDRs: come together to form the antibody combining site, which binds Ag • Framework regions

Answer 220

1. Isotypic: heavy chains differ in either class or subclass (ie. IgM vs. IgG; IgG γ1 vs. IgG γ2) 2. Allotypic: variance among different individuals due to genetically determined amino acid insertions - Insertions usually in the constant regions of the heavy and light chains - Human allotype reagents come from patients receiving multiple transfusions 3. Idiotypic: amino acid inserts in the variable regions of both the light and heavy chains - Inserts can occur in both the hypervariable/CDR region and the framework residue - Have a shared antigen binding specificity - Important for: Immune regulatory network, vaccine development

Answer 221

Ag injected into 1 → Ab1 produced; injected into 2 → Ab2 produced; injected into 3 → Ab3 produced • Ab2: anti-idiotype (reacts with Ab1) • Ab3: anti-anti-idiotype (reacts with both Ab2 and Ag) Therefore, the injection of an anti-idiotype results in production of Abs against the Ag in question

Answer 222

- Barriers: epithelial surfaces, mucosa - Antimicrobial molecules: defensins, acidic pH - Phagocytic cells: macrophages, PMNs - TLRs: recognize pathogens - Inflammatory response - Cytokines/chemokines - NK cells - Complement system

Answer 223

- Penetration of epithelium (activates innate immunity) - Pathogen recognized by tissue macrophages and that macrophage is activated - Active macrophage produces chemotactic factors to recruit PMNs and cytokines (initiate inflammation) - Macrophage phagocytizes the pathogen and kills it -Inflammatory process allows cells to arrive from the blood (PMNs, monocytes, leukocytes) ... Monocytes entering tissue become either macrophages or dendritic cells, depending on cytokine environment - Complement and clotting proteins also arrive

Answer 224

- Tight junctions - Mucus/cilia - Low pH - Enzymes (lysozyme) - Anti-bacterial peptides (defensins) - Normal microbial flora (impede growth of pathogens via competition and production of antimicrobial compounds)

Answer 225

- Low pH in phagolysosome - Toxic oxygen products and NO * *Chromic Granulomatous Disease: patient unable to make superoxides; susceptible to bacterial and fungal infections - Defensins - Lysozyme (gram positive) - Lactoferrin (binds Fe)

Answer 226

- Mannose Binding Lectin (MBL) Receptor: MBL binds mannose on bacterial surface; MBL + pathogen then bind MBL receptor on phagocyte; increases binding affinity - Mannose Receptor: binds mannose on surface of pathogen - Surfactant Protein A and D Receptors: SPA and SPD both react with pathogen first and then bind these receptors; increases binding affinity - Scavenger Receptors: react with lipoproteins - fMet-Leu-Phe (N-formylated peptides) Receptor: chemotactic receptor (these peptides attract phagocytes) - Toll-Like Receptors (TLRs): signal inducers; 9-10 in humans; any one phagocyte has all receptors; trigger production of anti-fungal peptides. Some are on the outer cell membraine, others on intracellular endosomes

Answer 227

1. TLR-4: binds bacterial LPS; triggers activation of NFkB; genes encoding proteins involved in defense against bacterial infection activated 2. TLR-3: binds viral dsRNA; triggers synthesis of IFN α and β, which: • Protect uninfected cells: inhibit translation of viral mRNA • Activated NK cells: kill virus infected cells • Increase expression of MHC class I: promote cytotoxicity of infected cell by T cell ``` Other Targets: • Bacterial flagellin (TLR-5) • Unmethylated CpG DNA (TLR-9) • Peptidoglycan (TLR-1:TLR-2) • Zymosan (TLR-1:TLR-2 ```

Answer 228

1. IL1: proinflammatory - Local: activates endothelium and lymphocytes - Systemic: induces fever and stimulates IL6 production 2. IL6: proinflammatory - Local: activates lymphocytes, increases Ab production - Systemic: induces fever, induces liver to produce acute phase proteins 3. Acute Phase Proteins: produced in the liver in response to infectious agents ➢ C Reactive Protein (CRP)/MBL/SPA/SPB: all bind bacteria and act as an opsonin for phagocytes; also activate complement ➢ CRP is used as an indicator for inflammatory response (also elevated in cardiovascular disease) 4. TNFα: proinflammatory - Local: activates vascular endothelium (induces adhesion molecules); induces permeability 5. Adhesion Molecules on Endothelium: ➢ Selectins: on the endothelium; bind carbohydrates on leukocytes to initiate interaction/slow leukocytes; weak binding which slows leukocytes ➢ICAMs (intracellular adhesion molecules): ligands for integrins on leukocytes 6. Adhesion Molecules on Leukocytes: ➢ Integrins: bind to ICAMs on endothelium and dendritic cells; strong binding - Systemic: induces fever and shock 7. IL8: chemokine that attracts PMNs, basophils and T cells (local effects) 8. IL12: activates NK; induces CD4+ TH0 cells to become TH1 cells (local effects) 9. Natural Killer (NK) Cells: • Lymphoid precursor • Kill virus infected cells and tumor cells • Targets cells that are deficient in MHC class I • Also have inhibitory receptors that recognize MHC class I to protect normal cells

Answer 229

* Initiated by pathogen induced tissue damage and macrophage activation. * Dilation/increased permeability of capillaries= increased blood flow (swelling, heat, redness). * Expression of adhesion molecules on endothelial cells= leukocytes bind. * Secretion of vasoactive peptides increases vascular permeability. * Clot formation prevents spread of pathogen.

Answer 230

= a group of plasma proteins that function in both innate and adaptive immunity; plays a key role in host defense - Deficiencies in complement proteins lead to infection - Elevated activation of complement leads to several disease syndromes Activated by Ag-Ab complexes (adaptive immunity), microbial products, or acute-phase proteins (innate immunity) (Ie: classical, alternative, lectin pathways) • Activation results in a cascase effect where in each protein becomes enzymatically active and modifies multiple substrate molecules. C3 plays a major role in all 3 activation pathways. Functions: 1. Attracts phagocytes: C5a chemotactic for PMNs 2. Inflammation: C3a and C5a are vasoactive (smooth muscle contraction, activate mast cells) 3. Opsonization: macrophages and PMNs have receptors to bind C3b and C4b 4. Direct killing of pathogens: C5b-C9 disrupt cell membranes of pathogens

Answer 231

Activation: Ag-Ab complex (adaptive immunity); IgM or IgG Steps: 1. C1q binds the Fc portion of the Ab that is bound to the Ag 2. C1q undergoes conformational change to bind C1r and C1s (serine proteases); C1qrs complex can cleave both C4 and C2 3. C4 is cleaved into C4a (soluble) and C4b (remains attached) 4. C2 is cleaved into C2b (soluble) and C2a (remains attached) 5. Resultant molecule is C4b2a (C3 convertase) attached to the pathogen 6. C3 convertase cleaves C3 into C3a (soluble) and C3b (remains attached), forming C4b2a3b (C5 convertase) 7. C5 convertase cleaves C5 into C5a (soluble) and C5b (remains attached) 8. C5b initiates assembly of (and helps form) the membrane attack complex 9. C6-C9 forms a pore in the membrane, lysing the cell

Answer 232

Activation: MBL (acute phase protein) binds mannose on the pathogen (innate immunity) Steps: 1. MBL binds mannose on the pathogen and is then able to interact with MBL-activated serine protease (MASP), which cleaves C4 and C2 2. The C4b2a C3 convertase is formed 3. C3 convertase cleaves C3 into C3a (soluble) and C3b (remains attached), forming C4b2a3b (C5 convertase) 4. C5 convertase cleaves C5 into C5a (soluble) and C5b (remains attached) 5. C5b initiates assembly of (and helps form) the membrane attack complex 6. C6-C9 forms a pore in the membrane, lysing the cell

Answer 233

Activation: by microbial products (ie. LPS) Steps: 1. Spontaneous hydrolysis of C3 to C3a (soluble) and C3b (deposited on surface of pathogen) 2. C3b binds Factor B 3. Factor B is cleaved by Factor D to form Ba (soluble) and C3bBb (C3 convertase) The rest of the process is the same as above • C5 convertase will be C3bBb3b **Properdin (Factor P): binds to produced a stabilized C3 convertase (C3bBb is unstable

Answer 234

binds to produced a stabilized C3 convertase (C3bBb is unstable)

Answer 235

1. Regulatory proteins exist in plasma and on host cells o Prevent accidental activation o Not present on pathogens 2. C1 Inhibitor: dissociates C1r and C1s from C1q; prevents excessive activation of C4 and C2 3. Hereditary Angioneurotic Edema: lack C1 inhibitor; C2b buildup causes swelling o C1b also acts on bradykinin ``` 4. Other Regulators: o C4b binding protein o DAF o Factor I o Factor H ```

Answer 236

1. Cell Mediated Reactions: carried out by effector cells - Tissue rejection - Delayed hypersensitivity - Graft vs. host reactions 2. Humoral Antibody Synthesis: carried out by effector molecules - Agglutination - Toxin neutralization - Immediate hypersensitivity