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What are the (3) important antigen-presenting cells?
- 1. Dendritic cells
- 2. Macrophage/monocytes
- 3. B-lymphocytes
What is the function of Functions of IL-1 and TNF?
- they increase the sticky-ness of (activate) endothelial cells by putting adhesion molecules on them to get polymorphonuclear leukocytes
- endothelial cells THEMSELVES once activated by cytokines makes IL-8, a chemokine that attracts WBCs
C-reactive protein (CRP)
- an acute phase protein released by the liver in response to cytokines IL-1 and TNF
- acts as a marker of how active the innate immune system is
OVERALL, what are 3 things IL-1 and TNF do?
- 1. increased adhesiveness of endothelial cells
- 2. activation of the liver to release acute phase proteins such as C-reactive protein (CRP)
- 3. signal the hypothalamus to produce fever, depression, anorexia (sometimes they're called “sickness" cytokines)
the general term for the messenger protein molecules that moderate the body’s natural defenses
- a unique type of cytokines that focus on white blood cell migration TO damaged or infected body parts
- both cytokines and chemokines use chemical signals to induce changes in other cells, but chemokines are specialized to cause cell movement
IFN-α & IFN-β
antiviral cytokines - they kill viruses (innate immune system)
cytokine that activates the bone marrow causing an increased WBC count
- cytokine that activates TH1 cells and NK (natural killer) cells
- key inducer of cell mediated immunity
- also promotes interferon-gamma production BY NK & T cells
- a SUPPRESSOR cytokine that inhibits the entire immune response
- it's important in inhibiting activated macrophages & therefore controlling innate & cell mediated responses
Were do APCs (antigen presenting cells) go after they've been activated?
when toll like receptors on APCs bind to antigen and become activated they move to the DRAINING LYMPH NODES to interact with T-cells
What is the only way T cells will recognize antigens?
- when they are presented inside a Major Histocompatibility Complex (MHC) Class II molecule
Major Histocompatibility Complex (MHC)
- cell surface molecules that mediate interactions between T cells and antigens
- also called human leukocyte antigens (HLA) & determine whether a donated organ is compatible for transplant
- genes for the molecule found on the short arm of chromosome 6, Class II (DP, DQ, DR) & Class I (B, C, A)
What is the most polymorphic system in biology?
the MHC system - there are thousands of different alleles @ each locus
Where does every individual inherit his or her MLA haplotypes from?
- two are inherited, one from each parent
- a couple could have 4 children each of whom could have different haplotypes
- a 5th child would ALWAYS be MHC identical to one of the other children
An identical twin will have _______ HLA genes/molecules
if you have an identical twin, they'll have the SAME HLA molecules as you do
MHC class l molecule
- Major Histocompatibility Complex Class I Molecules are found in ALL cells of the body EXCEPT RBCs
- made up of:
- α chain: 3 polymorphic units
- β2-microglobulin: identical in all MHC Class I molecules
What is β2-microglobulin in a blood sample indicative of?
- tissue destruction, eg. cancer
- dying cells release Class I MHC (b/c they're found on all cells), and inherent in MHC class I is β-microglobulin
MHC class lI molecule
- ONLY found on antigen presenting cells (eg. Dendritic cells, Macrophage/monocytes, B-lymphocytes)
- has a groove in which antigen binds and can be presented to a T cell
- composed of two peptide chains: α & β
Which HLA molecule is Ankylosing Spondylitis associated with?
- HLA B27
- Ankylosing Spondylitis is an inflammatory disease that can cause spinal vertebrae to fuse, making the spine less flexible & resulting in a hunched posture
Which HLA molecule is Narcolepsy associated with?
- DR2 & DQ1
- [MHC Class II molecules]
Which HLA molecule is Type 1 Diabetes Mellitus associated with?
- DR3 & DR4 [class II MHC]
- *DR2 seems to be PROTECTIVE of Diabetes Type I
Which HLA molecule is Rheumatoid Arthritis associated with?
DR4 [class II]
T cell receptor (TCR)
- made up of 2 glycoprotein chains: one α & one β chain (as opposed to 4 in B cell antibody)
- TCRs are monovalent (only bind to ONE antigen molecule) and stay the SAME (doesn't somatically hypermutate) throughout its lifetime on a cell surface
- some TCRs in the mucosa use γ and δ chains (instead of α & β)
TCR α (and γ) chains are constructed from _ and _ gene segments, like Ig _____ chains, whereas TCR β (and δ) chains are constructed from _, _, and _ gene segments, like Ig _____ chains.
TCR α (and γ) chains are constructed from V and J gene segments, like Ig LIGHT chains, whereas TCR β (and δ) chains are constructed from V, D, and J gene segments, like Ig HEAVY chains
differences between T cells receptors (TCRs) & B cell receptors (antibodies)
What molecules are always found complexed with TCRs?
- CD3 & ζ (zeta)
- responsible for signal transduction into the cell AFTER an antigen binds to the TCR
- b/c CD3 is expressed on all T cells in the body, it's used as a marker to separate all T cells from every other cell type
Why do we have T cells?
- because they respond to pathogens that have entered host cells
- B cells & antibodies interact with antigens in body fluids, however once this pathogen has infiltrated host cells, ANTIBODY IS USELESS
Cell Mediated Immunity (CMI)
- executed by T cells responding to pathogens/antigens that GET INTO host cells via infection or uptake processes
- b/c antigens are coming from inside the cells of the host, T cells use a completely different recognition mechanism than B cells
- T cells respond mainly to surface proteins on host cells
What specifically do T cells recognize?
a peptide molecule (usually derived from antigen) bound by an MHC molecule
MHC class I
- MHC class I is expressed on ALL nucleated cells (so not RBCs)
- INTERACTS WITH CD8 ON CD8+ T CELLS
MHC class II
- MHC class II is expressed constitutively ONLY on antigen presenting cells (APC) [dendritic cells, B cells, macrophages, & thymic non-lymphoid cells]
- INTERACTS WITH CD4 ON CD4+ T CELLS
- in T cells coreceptors (eg. CD4 & CD8) function as:
- 1. specific adhesion molecules (bind to INVARIANT region of respective MHC molecules)
- 2. signal transduction molecules: initiates & enhances a cascade signal & lower the threshold needed to activate a T cell immune response (like CD3 & ζ)
- they're only present on T cells whose receptors are made up of α & β chains (NOT γ & δ)
CD4+ T cells
- the predominant cytokine synthesizers
- (as a result of interacting with antigens in MHC class II's on APCs)
CD8+ T cells
- direct killers of infected host cells; also play a role in tumors and transplantation
- (as a result of interacting with MHC class I's on every potential cell in the body besides RBCs)
What is the ratio of CD4+ T cells to CD8+ T cells?
- there are double the number of CD4+ cells to CD8+ cells
- this is sometimes used as a marker of normality & the ratio changes in AIDS --> number decreases, fewer CD4+ T cells
What is the relationship between HIV & the coreceptor CD4?
- CD4 binds HIV & allows it to enter the cell --> causing infection
- because macrophages and dendritic cells have CD4 coreceptor molecules on their surface, HIV can infect CD4+ T cells, macrophages, & dendritic cells
Are CD4 & CD8 coreceptors ever both found on the same cell?
Nope. A mature cell NEVER has both.
- the primary lymphoid organ for T cell development
- aka the site where during T cell development T cells acquire their TCR (receptor)
- congenital abnormality (missing chromosome) in which the thymus does not develop and therefore mature T cells aren't produced
- only a thymus independent immune response can result
a cell that travels from the bone marrow to the thymus, where it enters and starts differentiating
Double Negative Thymocyte
- T cell in which the TCR genes start to rearrange (RAG controlled V(D)J recombination)
- called double negative because neither CD4 nor CD8 are expressed
- develop from lymphoid progenitor cells before they are called double negative cell, therefore no TCR gene rearrangement has occurred
- NK Cells do not express T cell receptors
Double Negative --> γ & δ T cell
- if during gene rearrangement the γ & δ receptor genes rearrange properly, then γδTCR is put on the T cell surface & it leaves the thymus to go to mucosal surfaces
- this rearrangement happen early in life
Double Positive Thymocyte
- if during gene rearrangement the α & β receptor genes rearrange properly, then an αβTCR is put on the T cell surface AS ARE BOTH CD8 & CD4
- *major checkpoint of T cell development in the thymus
What form are the majority of the cells in the thymus found in?
- double positive thymocytes: αβTCR + CD8 & CD4 coreceptors
- these double positive cells are found predominantly in the cortex of the thymus
Selection in the Thymus
- Positive: only some cells survive --> Negative
- happens as cells cross from cortex to the medulla of the thymus
- double positive cells make CRITICAL interactions with thymic epithelial cells expressing MHC molecules & self peptides
- majority of precursor cells do not interact with MHC expressing epithelial cells --> die via apoptosis (some affinity for self-MHC is needed)
- about 10% of starting population interacts & survives
- these cells will forever be able to recognize antigen expressed by MHC molecules in the thymus and outside to aid immune respnse
What molecules define SELF for every person?
MHC class molecules (HLAs)
- weeds out αβTCR + CD8 & CD4 T cells that have TOO MUCH affinity for self
- prevents autoimmune responses
- cells that are have a reasonable affinity for self develop and down regulate either CD4 or CD8
autoimmune polyendocrine syndrome type 1 (APECED)
- autoimmune condition that develops when negative selection in the thymus does not take place
- multiple endocrine organs are damaged
- cells that pass through negative selection go on to down regulate either CD4 or CD8
- surviving cells become single positive cells, expressing either CD4 or CD8
- a subset of CD4+ T cells (~10% of peripheral CD4+ T cells) that inhibit the actions of other sets of T cells
- Treg cells that develop in the thymus are autoreactive: they recognize combinations of self-peptide & self-MHC, but have survived negative selection in the thymus
- Treg cells can develop outside the thymus
- play a role in inhibiting responses to both self and foreign antigens, maintain/regulate self-tolerance, & limit potentially damaging host responses to pathogens in tissues
Myocardial Infarction (MI)
- atherosclerosis that develops in coronary arteries results in decreased blood flow to the heart and can lead to an MI or other coronary heart diseases
- some studies suggest that atherosclerosis may in part be a response to a self-molecule (auto-antigen)
develops as the result of a response to self-molecules expressed in the pancreas.
- HIV binds to CD4, which in humans (but not every mammalian species) is expressed on macrophages and dendritic cells as well as CD4+ T cells --> all these cells can be infected with HIV
- in an HIV+ person a decrease in numbers of circulating CD4+ T cells below a threshold (200 cells per μL) characterizes AIDS
inflammatory condition results from the response to self-molecules in the joints
CD (“cluster of differentiation”) nomenclature
molecules expressed on the surface of lymphocytes (& other cell types are given a CD number)
Double Negative Cell
a thymocyte that does not express a TCR or either coreceptor CD4 or CD8
Double Positive Cell
thymocyte expressing αβ as its TCR plus both coreceptors, CD4 and CD8
T cells interact with a combination of MHC and peptide expressed on the surface of a cell
a mature T (or B) cell that has not been exposed to antigen
- T (and B) cells do not respond under normal circumstances to self-
- components (liver, kidney etc)
activation of an intracellular signaling pathway after a ligand binds to a cell-surface receptor
Single Positive T Cell
a thymocyte expressing αβ as its TCR and only one coreceptor molecule, either CD4 or CD8
T Cell Receptor (TCR)
- the two-chain molecule on T cells that interacts with antigen
- αβ is expressed on the major set of T cells
- gamma/delta on the minor set of T cells