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- "hormones of the immune system" - TNF, IL-1, IL-6
- small proteins that serve as a way to communicate between cells
- tell the bone marrow to pump out lots of neutrophils (WBCs)
- cytokines act on the endothelium of blood vessels near infection so they become sticky --> recruit WBCs to enter the site of infection & eat bugs
- also tell hypothalamus to increase body temperature to try to kill the infection
- -INNATE IMMUNITY-
What is a B cell's receptor for antigen?
the antibody it can make (Ab=antibody)
What two classes of antibody do NAIVE B cells have on their surface?
- IgM, IgD
- if a B cell has both of these it's NAIVE (like all the 1st year MD's…)
- has not been chosen by antigen to undergo clonal expansion --> differentiation
What is the first thing seen after about 4 days if the adaptive immune system has been activated? After two weeks?
- IgM pentamer in the serum
- @ about 4-7 days the 1st thing you see in expanding B cells are plasma cells producing IgM (in pentamer form)
plasma cells making IgG, IgE, & IgA
- in addition, MEMORY B cells making IgG, IgA, & IgE
- over the course of an infection, cells have changed their class, but maintained antigen specificity: class switching
- you don't have to start off with a B cell that makes IgG (always start with M & D) to GET an IgG response
IgE (pregnant lady pic)
- underneath skin/dermis & mucosal surfaces (outlining)
- binds to mast cells and triggers release of their contents
- MAST CELLS are found skin/dermis & mucosal surfaces
- the mechanism by which lymphocytes create unique antigen-specific receptors
- T/B cell antigen receptors genes actually move and rearrange themselves within the genome of developing lymphocytes
- adaptive immune system there's a process by which you mix and match gene pieces to create the diversity of of -can partially explain autoimmune diseases
Light Chain Construction
- essentially 2 choices to make: which J (joining) sequence and which V (variable) sequence will be chosen and combined with the set, inherited constant region
- one DNA rearrangement occurs
- an individual B cell will rearrange and express only one light chain using either the kappa locus or the lambda locus NEVER both
- (the variable region of an Ab's light chain is made of V & J segments)
Heavy Chain Construction
- essentially 3 choices to make: which V (variable) sequence, which D (diversity) sequence and which J (joining) sequence will be chosen and combined with the set, inherited constant region
- TWO DNA rearrangements occur: 1st a D & J segment come together, then a V joins the already formed D-J segment, completing the heavy chain VDJ gene unit
- also there are multiple genes coding for the constant region of the heavy chain
- C region genes closest to the V region are Cμ and Cδ (IgM and IgD heavy chain constant regions)
Number of gene possibilities in heavy & light chains:
- heavy chain:
- 50 V genes
- 20 D genes
- 6 J genes
- (don't forget there are also 9 C regions, technically 13 given IgG & IgA 'isomers')
- light chain: 40 V & 5 J genes
What are all the different ways antibody diversity can come about?
- 1. germline: there are multiple versions of V, (D), & J genes
- 2. combinatorial: these version can combine to form antigen specific Ab receptors (V+D+J & H+L)
- 3. junctional: imprecise joining of V, D & J regions & TdT - huge amount of diversity
- 4. SMH (somatic hypermutaiton)
TdT (Terminal Deoxyribonucleotidyl Transferase)
- randomly adds nucleotides to cut (exonucleased) DNA regions surrounding V, D, & J genes before they're ligated together
- increases diversity in the immune system
- a rearrangement UNIQUE to B/T cells antigen receptor genes
SMH (somatic hypermutation)
- "survival of the fittest"
- after a B cell has been activated by an antigen, it proliferates and its antibody receptor genes undergo mutations at a rate that's orders of magnitude higher than average
- rapidly mutating variable regions of the heavy and light chains
- those that bind antigen with a higher affinity (more tightly) will be selectively chosen - can compete for the antigen much better
RAG-1 and RAG-2 (recombination-activating genes-1 & 2)
- two genes expressed only in developing lymphocytes required for V(D)J recombination [initial cutting of the Ig (or TCR genes)]
- w.out these genes no B or T cells are made
- SCID (severe combined immune deficiency) can be caused by defective RAG-1 or RAG-2 genes
In addition to RAG-1 and RAG-2, what other proteins are required for V(D)J recombination?
proteins present in all cells and function in DNA repair mechanisms (incision, excision, ligation)
class switch recombination (CSR)
- cells produce antibodies with DIFFERENT heavy chain regions but MAINTAIN their variable regions
- going from IgM or IgD --> IgG, IgA, or IgE but VDJ is maintained
- cut the DNA at the switch regions (one btwn VDJ & Cμ/Cδ, the other in front of other heavy chain genes) and ligate the two together
CSR and SHM occur in ______ _______ of ___________ organs
CSR and SHM occur in germinal centers of secondary lymphoid organs (together with clonal expansion/differentiation)
If a B cell is expressing IgG, E or A, what type of cell is it?
- must be a MEMORY B cell
- must have gone through SMH, clonal expansion, CSR
ONLY B cells undergo ___ & ___, T cells do NOT.
- only B cells undergo SMH (Ab's w/ highest affinity are selected for) & CSR (class switch recombination, IgM & IgD --> IgG, A, E)
- both T & B cells use VDJ recombination though
AID (activation-induced cytidine deaminase)
protein that mediates BOTH class-switch recombination (CSR) & somatic hypermutation (SHM)
RAG proteins required for _________, and AID protein required for ________ & _________
- RAG: VDJ recombination
- AID: CSR & SHM
- a large amount of IgM is made in order to compensate for the inability of antibodies to switch to IgG, A or E
- can be caused by a deficiency in AID protein (required for CSR & SHM)
stages of B cell development:
- Pre-B: has only undergone HEAVY CHAIN VDJ recombination
- Immature B cell: after heavy chain recombination, proceeds with light chain recombination (V & J) and making the choice between kappa or lambda versions of light chains
- immature B cell: now has a complete IgM antibody (receptor) on its surface
- mature/naive B cell: IgD has a complete IgM antibody (receptor) on its surface
CD19 & CD20
- markers for B cells
- lineage associated CD molecules on the surface of B cells
- CD19: appears early in B cell development
- CD20: appears later in B cell development, specifically in immature/naive & memory cells
- if a patient has a B cell leukemia, 19 and 20 will stain in a sample; used to determine if a leukemia is from a B cell progenitor (as opposed to T cell)
What's the difference between passive & active immunity?
- passive: when you receive pre-formed antibodies
- active = a vaccination: the antiGEN is given to a person and an adaptive immune response naturally occurs to the antigen administered
What are examples of natural vs. artificial passive immunity?
- natural: maternal IgG present in newborn (from placental transfer via the neonatal FcR, Fcn)
- IgA in milk (secretory IgA)
- artificial: immunoglobulin injection of rabies immune globulin (RIG), IVIG (Intravenous immunoglobulin), or Monoclonal antibody (Mab)
What are examples of natural vs. artificial active immunity?
- a vaccination: the antiGEN is given to a person and an adaptive immune response naturally occurs to the antigen administered
- Natural: infection with pathogen
- Artificial: immunization (eg. “killed” or “attenuated” pathogen)
What is the half life of IgG?
Serum Immunoglobulin During Human Development
- prior to birth, IgG starts to be given to the baby from the placenta at about ~3 months gestations
- at birth, the baby has ADULT LEVEL of IgG
- after birth, newborn is not making it's own antibody right immediately b/c the immune system develops slowly
- the previously maternal supply lasts for a few months while the newborn starts making its OWN IgG
Which antibody is present in a baby at birth (prior to and after), and which develops much later?
- IgG is there in 1st year though & continues to climb
- IgA doesn't reach adult levels until much later (~6-8 y/o or so)
transient hypogammaglobulinemia of infancy (THI)
- occurs when a child's humoral immunity (usually IgG) is developmentally delayed
- present with infections at 3-6 months of age because mom's antibody has DISAPPEARED and they haven't made enough of their own
- (normal Ig levels are typically reached by 2-6 years of age in children with THI)
When someone has come in contact with a potentially rabid animal, what is the proceedure?
- arm #1: give  rabies vaccines (dead rabies ANTIGEN) [active]
- arm #2: give rabies immunoglobulin (ANTIBODIES from people who have been immunized against rabies) [passive]
Intravenous Immunoglobulin (Intravenous Immune Globulin) IVIG
- prepared from the pooled sera of thousands of donors 1000-10,000)
- is screened for viruses or pathogens
What can IVIG treat?
provides passive humoral immunity for 1) primary humoral immunodeficiency diseases & 2) children with HIV
What is the postulated mechanism by which IVIG treats certain autoimmune/inflammatory diseases?
- potentially if you dump a lot of immunoglobulins into individuals who are autoimmune to Igs, the person's plasma cells will decrease their production of Igs that are anti-self
- because there are already enough antibodies present, plasma cells slow their harmful production: feedback (mechanisms)
What are the two major ways antibodies are used?
- 1. for diagnostics: are specific for different antigens, or PROTEINS
- 2. therapeutically: putting antibodies in people
How to make an unending supply of monoclonal antibodies (Mab)
- 1. immunized mouse with AgX (antibody)
- 2. take antibody producing spleen cells
- 3. fuse with myeloma cells - plasma cell tumor cells (will grow forever in sterile environment)
- 4. pick out HYBRIDOMAS that make Mabs to AgX
Enzyme-linked Immunosorbent Assay (ELISA)
- test that uses antibodies and color change to identify a substance
- antigens from the sample are attached to a surface
- a more specific enzyme-linked antibody is applied over the surface --> binds the antigen
- a substance containing the enzyme's substrate is added
- the reaction between the enzyme & the substrate produces a detectable signal, most commonly a color change
- eg. pregnancy test uses ELISA
monoclonal antibodies (Mabs) are always specific for:
ONE antibody --> it will see one shape
Why aren't mouse monoclonal antibodies used often for therapeutic practices?
because humans will recognize the antibodies as foreign and produce human anti-mouse antibodies (HAMA)