Ontogeny of the immune system Flashcards
Are hematopoietic stem cells (HSC) totipotent or multipotent?
To what cells do HSC give rise to?
Stem cells are undifferentiated cells which, when they divide, give rise on average to another stem cell and a daughter committed to differentiation. That way you never run out of stem cells.
They vary in their potential; the fertilized ovum is the totipotential stem cell, eventually giving rise to all other differentiated cells.
The hematopoietic stem cell, HSC, is more restricted, as it gives rise to red and white cells and their derivatives, including the microglia of the brain, but not other cells — it is multipotential.
Where do B cells develop in mammal? What is the process of B cell development and the different characteristics of each cell stage?
What Igs do fully mature B cells have?
What about an immature B cell?
- In the bone marrow.
- B cell progenitors can be identified as such when they begin to synthesize immunoglobulin components.
► The first to be detectable is mu chain in the cytoplasm; then complete cytoplasmic IgM (cIgM). What does this indicate?
This indicates that B cells rearrange their heavy chain genes before their light chains. Since it may be useful, the pro-B cell divides a few times, so you won’t have just one of a good thing.
- Next, one of the light chain genes rearranges, making a complete IgM. A cell with cytoplasmic IgM but no surface IgM is called a pre-B cell.
- Next to appear is surface IgM (sIgM), which is an IgM monomer with an extra membrane-embedded extension at the end of its Fc.
- Finally, when the cell is fully mature, both IgM and IgD (of the same specificity, of course) are found on the cell surface.
- All of this results from alternative splicing of the VDJ- mu -delta primary RNA transcripts, which you might like to review now.
► A functionally and diagnostically important point: an immature B cell has sIgM only; a mature B cell has sIgM and sIgD:
What is clonal deletion?
What does clonal deletions attempts to prevent?
If inmature B cell does not encouter self-antigen, what will happen next?
When a mature B cell is exposed to its correct antigen it gathers its receptors (IgD and IgM) at one spot on the surface and then takes them inside by endocytosis. The antigen is partially digested (processed), and if other conditions (that we’ll learn a bout later) are right, the cell will go on to differentiate into an antibody secretor.
►If an immature B cell (sIgM but no sIgD) is similarly exposed to antigen, this signal causes the cell to try receptor editing; if that fails it activates a suicide program (apoptosis), and dies. This is called clonal deletion, and it partially explains why we do not make antibody to self. In the bone marrow pre- B cells are differentiating into immature B cells; you can imagine that any cell whose receptors happen to be anti-self will be likely to encounter self in the environment of the bone marrow, and it will either make a new receptor, or be deleted. If it does not encounter antigen (because its receptors are not against self) then it will mature further so that it expresses both sIgM and sIgD. Then, when it meets antigen, it will be stimulated, not deleted.
Please note, though, that many anti-self B cells (usually to scarce antigens, not seen in the marrow; or with low affinity to more common antigens) escape clonal deletion and other measures are necessary to keep them from becoming activated ; we’ll consider some of these when we discuss T cells, and autoimmunity .
-Antibody production and response is greater in the second exposure to antigen because?
The helper T cells in the gut and lung preferably dirve what switch in antibody isotype?
If the IgM response is the same for secondary exposures to antigen, what change makes the acquired immune system more efficient?
During primary (initial exposure) B cell responses to antigen► IgM is secreted first, then for most antigens, helper T cells get involved and there is a switch to IgG, or possibly to IgA or IgE.
–>The helper T cells in the gut and lung preferentially drive an M to A (IgA, found in mucosal secretions) switch. The ‘switch helper’ mechanism indicates that B cells in general do what helper T cells tell them to. We discuss all this more in a little while.
► In response to secondary (booster) immunizations the IgM response is about the same as in a primary, what changes then?
The **IgG response, efficiently helped by memory T cells, is sooner, faster, higher and more prolonged.
When does babys start making IgG?
What is the half-life of IgG? What does this means for the baby who acquired it from the mother?
What other antibody does the baby starts making around the same time as IgG?
Where are complement system precursors made?
In what circumstances are babies low in complement proteins?
COMPLEMENT DEVELOPMENT. Not much is known here. Newborn Complement levels are usually around those of adults;** preemies are often low.
Complement components are mostly made in the liver, though white blood cells also contribute.
T-cell development (just read it, since it is not very detailed):
If T cells stay in the bone marrow, what do they become?
In the thymus, what induces T cell differentiation?
T cells are very interesting. They carry out their development in three different locations: the bone marrow, then the Thymus, and finally the peripheral lymphoid organs. Lymphoid precursors in the bone marrow have not yet decided what to become; the default, if they stay there, is to become a B cell.
- Others go to the thymus, where a very high concentration of Notch ligands induce T cell differentiation. They rearrange receptor genes (V(D)J, but a completely different set of genes from the H and L families) and then are selected for their responsiveness to “self-plus antigen .”
- T cells only see antigen on the surface of another cell, which could thus be called an antigen- presenting cel (APCs) .
- Developing lymphocytes in the thymus display a variety of differentiation antigens which allow us to understand their maturation. Newly-arrived pre-T cells divide energetically at the thymus periphery, while they are trying to make T cell receptors (TCR); at this stage they express neither of the markers, CD4 and CD8, but soon those that successfully made TCR become CD4+/CD8+ “double positives .” As these filter through the thymus from cortex to medulla, they undergo selection, the topic of upcoming discussions. The result is a few mature T cells that get exported as CD4+ (only) helper T cells, or CD8+ (only) cytotoxic T ce lls. About 99% of thymocytes don’t survive selection, and die within the thymus.
How does age affects immunological memory?
B and T cells age as well, but do their numbers decline with age?
After what age does increasign the diversity of T cells becomes limited?
What type of cells do old people have in fewer amounts that young people?
Older people are more susceptible to most infectious diseases and usually get sicker and take longer to recover. The explanations are probably spread around just about all body systems; for example, the cilia in lungs beat less efficiently so bacteria aren’t as easily cleared. But T cells and B cells age, too, though the numbers in the blood do not decline. We know that the thymus gradually becomes replaced with fat, though there are islands of healthy-looking lymphoid tissue in it up to a great age.
► People can completely reconstitute their T cell numbers and diversity up to about 40 years of age, then diversity becomes increasingly limited, and more and more cells show a ‘memory’ phenotype while fewer are naïve; old people have fewer but larger clones than do the young.
A similar change takes place in B cells, too, possibly a decade or two later. ► So older folks generally make good responses to antigens they saw in the past, but fail to respond well to completely new antigens. This may help explain why the recent SARS epidemic — featuring a brand new pathogen — was disproportionately fatal in the elderly, as is West Nile Fever, brand new in America since 1999. It may also suggest that flu shots in the elderly (unless they are cross-reactive with an earlier strain of virus) are not as useful as we would like to think. And if H5N1 avian flu becomes widespread in humans? Fuhgeddaboudit! However, for the H1N1 virus formerly known as Swine, older folks had cross-reactive immunologic memory of a relate d virus, and generally did better than the young.
