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Foundations 2 > 9/26 > Flashcards

9/26 Flashcards

1
Q

Phases of B Cell Development

A
  1. Repertoire Assembly: generate diverse B cells in bone marrow
  2. Negative Selection: alteration, elimination, or inactivation of B cell receptors that bind components of the human body
  3. Positive Selection: promotion of a fraction of immature B cells to become mature in the secondary lymphoid tissues
  4. Searching for infection: recirculation of mature B cells between lymph, blood, and secondary lymphoid tissues
  5. Found Infection: activation and clonal expansion of B cells by pathogenic antigens in secondary lymphoid tissues
  6. Attacking infection: differentiation to antibody secreting plasma cells and memory B cells in secondary lymphoid tissue
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2
Q

Recombination-Activating Genes

A

RAG1 and RAG2, cut and paste DNA back together for B and T cell recombination

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3
Q

Severe Combined Immunodeficiency

A

No B or T cells develop so no adaptive immunity

Due to several different mutations, Adenosine deaminase deficiency is second most common

Can have mutation in IL-7 or its receptor, prevents differentiation of lymphoid progenitor cells into Immature B cells

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4
Q

B Cell Development

A

Dependent on interaction with stromal cells in bone marrow, bind to receptors like CAMs and get secreted IL-7 when late Pro-B cell

Stem cell (lymphoid progenitor cell): germline H and L chains

Early Pro-B Cell: D-J Rearrangement of H chain, germline L chain

Late Pro-B Cell: V-DJ rearrangement, germline L chain

Large Pre-B cell: VDJ Rearranged for H chain genes, mu H chain is made

Small Pre-B cell: V-J rearrangement for L chain genes, mu chain is in ER

Immature B cell: VJ rearranged for L chain genes, mu H chain and lambda/kappa L chain, IgM on surface

Checkpoints where apoptosis if no functional heavy/light chain

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5
Q

Burkitt’s Lymphoma

A

Myc proto-oncogene on chromosome 8 is joined to a immunoglobulin heavy chain gene on chromosome 14, kappa light chain gene on chromosome 2, or lambda light chain gene on chromosome 22

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6
Q

B Cell Negative Selection

A

If no reaction with self antigen on bone marrow cell with B cell receptor (IgM and CD79 or Igalpha/beta) then move to blood and expresses IgD/IgM

React with self antigen: immature B Cell retained in bone marrow with IgM ligated, can do a few more rounds of light chain (VJ) rearrangement known as receptor editing

Can leave if rearrangement made not self reactive, apoptosis after some rounds if still self reactive

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7
Q

Central vs. Peripheral Tolerance

A

Central: testing self reactivity in bone marrow for B cells

Peripheral: encounter soluble antigens from tissues while circulating in the blood

If bind then downregulate IgM while keeping normal levels of IgD to make the B cell anergic (functionally unresponsive), enters peripheral circulation but doesn’t survive for long

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8
Q

Immature B Cell going to a Lymph Node

A
  1. Chemokine CCL21 attracts immature an Cell to HEV (high Endothelial venule)
  2. Chemokines CCL21 and CCL19 attract B cells into lymph node (the T Cell area)
  3. Chemokine CXCL13 attracts B Cell into the primary follicle
  4. Interaction with follicular dendritic cells and cytokines drive the maturation of immature B cells
  5. Mature B cells recirculate between lymph, blood, and secondary lymphoid tissues

Immature B cells become mature B cells in primary follicles

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9
Q

B Cell Positive Selection

A

Some mature B cells that encounter an antigen that binds their BCR will differentiate into plasma cells, in the lymph node

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10
Q

B Cell Life Overview

A
  1. Immature B cell with IgM but no IgD leaves bone marrow and enters peripheral circulation
  2. Immature B cell with high IgM/low IgD does alternative splicing to both delta and mu chains, gains access to primary lymphoid follicle and matures
  3. Mature naive B cell with low IgM/high IgD enters circulation and binds specific antigen in lymphoid tissue draining infection
  4. Antigen activated B lymphoblast does alternative splicing to secrete Ig, isotope switching, somatic hypermutation
  5. Plasma cells secrete antibodies to fight infections, antibodies are replicas of the BCR
  6. Memory cells can prepare for future infections
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11
Q

B Cell Activation

A
  1. First Signal: BCR receptors become cross-linked when their receptors bind to a pathogen, happens in lymph node by site of infection

Require CD19, CR2, and CD81 (deficient antibodies if mutated CD19 or CD81), CR2 binds to C3d Complement protein on pathogens

Set Up: naive CD4 T cells activated when dendritic cells in lymph node present antigens and get trapped in T cell zone, antigen activated B cells meet up with helper at cells

  1. Second Signal: CD4 T Cell will bind to MHC Class II receptor on B Cell that broke down antigen

CD40L on T Cells binds to receptor on B cell also, B cell divides and proliferates, cytokines made by type of CDT cell determines antibody isotype

T-Independent Antigens: few antigens bind to the BCR with such high affinity that they can induce B cell differentiation into plasma cells without T Cell help, makes IgM antibodies

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12
Q

Primary vs. Secondary focus for expansion of antigen-activated B cells

A

Primary: medullary cords

Secondary: germinal center, in B Cell area

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13
Q

Somatic Hypermutation

A

B cells bind to their antigen via interaction with follicular dendritic cells, generates antibodies that have higher affinity for the antigen and help them be more effective at clearing an infection

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14
Q

Affinity Maturation

A

Process of increasing the affinity of the antigen binding sites of antibodies for antigens that occur during the course of adaptive Immunity

Due to somatic hypermutation d the consequent selection of mature B cells

Compete and low affinity ones die

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15
Q

Five Isotypes of Antibodies

A

IgG: most abundant, 4 subtypes, high affinity

IgM: first isotype made by plasma cell, low affinity, pentameric structure

IgA: monomeric in tissue, dimeric in mucosal surfaces

IgE: low abundance in circulation, binds to FceRI on mast cell surface, cross-linking IgE causes production of inflammatory mediators associated with allergies

IgD

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16
Q

Hyper IgM syndrome

A

Mutation in Activation-Induced Cytidine Deaminase, plays a role in somatic hypermutation and Class switch recombination

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17
Q

How Monomeric Antibodies Tissues Enter Tissues from the Blood

A

Fc (constant) region of antibody like IgG binds to FcRN on endothelial cell surface, does endocytosis

Acidic pH of endocytosis vesicle causes IgG to bind tight to FcRn and not get degraded, basic pH of basolateral surface causes dissociation into extracellular space

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18
Q

Distribution of Antibodies

A

IgM: blood

Monomeric IgG and IgA: blood and tissues

IgE: connective tissue below epithelial associated with mast cells

Dimeric IgA: mucosal surfaces and breast milk

Baby development: passively transferred maternal IgG in womb, have high IgM at birth and slowly develop IgG

19
Q

Antibody Neutralization

A

IgA coats a pathogen at mucosal surface and prevents the pathogen from entering the host’s cells

Pathogen can’t bind to cell receptors with bound antibodies blocking it

20
Q

Selective IgA Deficiency

A

Most common antibody deficiency

Person is relatively healthy but increased risk of infection at mucosal sites and increased risk of asthma

21
Q

Antibody Function

A

Neutralization so can’t enter cell, IgA on mucosal surface

Can recognize proteins, lipids, carbs, and DNA

C1q binds to two or more IgG molecules and initiates complement activation

Opsonization: most common method to kill bacteria

Antibody binds to bacteria and antibody-coated bacteria bind to Fc receptors on macrophage, endocytosis and kill in phagolysosome

Antibody-Dependent Cell-Mediated Cytotoxicity

Allergic response: IgE binds to FceRI on mast cells, mast cells degranulate and release histamine to promote clearance of parasite

22
Q

Antibody-Dependent Cell-Mediated Cytotoxicity

A

Antibodies bind to antigen s on cell surface of virally infected cells or cancer cells, allows NK cells to recognize and destroy the cells

NK cells use Fc receptors, target cell dies by apoptosis

23
Q

B cell Memory

A

First exposure: don’t make antibodies until a week later, peak at about 2 weeks, little left after 4 weeks

Second exposure: make right away, peak at a week later, make much more antibodies also, antibody conc. doesn’t die down to near zero after multiple weeks

24
Q

Retrovirus Basics

A

Single stranded positive sense RNS with 5’ cap and poly A tail, 2 identical strands in capsid structure inside lipid envelope

25
Q

Genes of Retrovirus

A

Simple has four genes-

  1. Gag: core protein like capsid
  2. Pol: reverse transcriptase and integrase
  3. Pro: protease
  4. Env: envelope

Complex: same as with simple but spliced regulatory genes controlling protein synthesis and replication

26
Q

Long terminal repeat sequences of Retro viruses

A

Identical structures found at both ends of the DNA provirus, transcription generates RNA with same terminal organization as the parental virus

Contains signals necessary for gene expression: enhancers, promoters, transcription initiation/termination signals, polyA signal

Host TFs bind to LTRs

Provirus: integrated retrovirus has 5’ LTR for RNA Pol II promoter, 3’ LTR for terminator sequence

27
Q

Retrovirus Envelope Gene

A

gp120 binds tonCD4 of lymphocyte

gp41 is the transmembrane glycoprotein, fusion of viral envelope and allows viral entry into cell

28
Q

Gag Proteins

A

All cleaved from one long polypeptide by protease, 4 proteins

p24 forms capsid that surrounds RNA

Matrix protein as well

29
Q

Pol gene of retro virus

A

3 enzymes that are targets for drugs

RT: binds to RNA in viral capsid, creates RNA/DNA complex and ribonuclease digests RNA portion, duplicates ssDNA next

Protease: cleaves gag polyprotein

Integrase: integrates viral DNA into host cell

30
Q

Binding and Fusion of HIV

A

Binding: gp120 binds with high affinity to CD4

Conformational change to bind to coreceptor, CXCR4 in T cells and CCR5 for macrophages

Fusion: gp41 unfolds and pierces cell membrane, folds back on itself and pulls the virus towards the cell to initiate fusion

31
Q

HIV Nucleic Acid Synthesis

A

RNA genome becomes cDNA by RT and cleave RNA via ribonuclease, cDNA goes through RT again to make dsDNA that circularizes via LTRs

Preintegration complex: dsDNA and integrase enter nucleus

Integrate cleaves ends of dsDNA to make sticky and then can insert into host genome, proviral DNA

Cellular DNA Pol can make mRNA and proteins, viral protease cleaves polyproteins made, assemble new viruses and bud off cell membrane

32
Q

CD4 Count for AIDS

A

200, normal is 1,000

33
Q

RT Inhibitors

A

Nucleoside analogues: Zidovudine (AZT) resembles thymine but has azide group instead of OH so mess up transcription

Non-nucleoside analogues: interfere with binding of viral RNA to RT

34
Q

Entry Inhibitors

A

Attachment Inhibitors: receptor antagonist, Maraviroc interferes with gp120 binding to CCR5 coreceptor

Fusion Inhibitor:T-20 binds to gp41 to block its unfolding that allows viral envelope/cell membrane fusion

35
Q

Method for Treating HIV

A

Combination Therapy of three drugs, need to suppress replication so no new mutations arise

Monotherapy fails due to mutation and subsequent drug resistance

36
Q

Retrospective Cohort vs. Case-Control

A

Case-Control: always starts with diseased (case) and not diseased (control), design of choice for rare diseases (less than 10%), try to find exposure

Retrospective Cohort: need past records, helpful for rare exposures, try to find disease

37
Q

Strengths and Weaknesses of RCTs

A

Strengths:
Highest level of evidence
Can assess temporality
Minimize bias and confounding variables

Weaknesses:
Not always ethical to randomize
Costly
Inefficient for rare diseases or diseases with a delayed outcome
Might not generalize to larger pop.
38
Q

Cohort Studies Strengths and Weaknesses

A

Strengths:
Can measure multiple outcomes/exposures
Good for rare exposures
Can infer directionality

Weaknesses:
Not good for rare diseases
Costly and time consuming
Bias due to loss of follow up 
Being followed may alter participant's behavior
39
Q

Case-Control Strengths and Weaknesses

A

Strengths:
Cost-effective
Good for rare diseases
Good for diseases with long latency periods

Weaknesses:
Prone to selection/recall bias
Can only examine one outcome
Cannot estimate incidence
Poor for rare exposures
Often cannot determine temporality
40
Q

Cross-sectional Studies Strengths and Weaknesses

A

Strengths:
Cheap and quick
Can collect data on lots of exposures and outcomes
Good for Hypothesis generation

Weaknesses:
Cannot infer temporality
Prone to recall bias
Not good for rare diseases
Cannot estimate incidence
41
Q

Prevalence

A

HIV prevalence increases cut o transmission and also more effective anti-retroviral drug use

A proportion, number of infected / total number of people

Snapshot at a given time

Increases by: people acquire disease at a faster rate, live longer with the disease

Decreases by: people acquire the disease at a slower rate, get cured, die

42
Q

HIV Transmission

A

Spread by mucocutaneous contact: blood, semen, vaginal secretions

Routes of spread: vaginal/anal sex, contaminated blood products, perinatal transmission including breast feeding

Prevent transmission:treatment, pre-exposure prophylaxis, circumcision

Enhance Transmission: high viral load, disease stages like acute HIV and end-stage AIDS, lack of circumcision, co-infections with other STIs increase transmission/susceptibility

43
Q

HIV Risk Groups

A

MSM: big in western/Central Europe and North America, also Latin America and Caribbean, elsewhere MSM have higher risk than general pop.

Injection Drug Users: problem in Eastern Europe and Central Asia, most effective transmission mode, complex risk since overlap with sex work and jail

Sex Workers: higher number of partners and less protection, had highest prevalence early in, hidden pop. since marginalized/criminalizes but gov intervention can be effective, bridge to normal pop.

Foundations 2 (18 decks)

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