nm0237: so can we start now please [0.2] just past nine o'clock [0.4] can i 
remind you today before we start the official lecture that you've got video 
discussion sessions [0.4] er [0.3] the third grou-, the third er period here [0.
7] okay same rooms but different members of staff [0.5] we will be discussing 
the tests and so on i think you might have found this test perhaps more 
difficult than the previous one but er [0.3] after all you are beginning to 
learn more of the subject so er [0.4] please er make sure that you go through 
it [1.8] okay so let's start with er [0.3] the subject then [2.9] can i have 
hush please at the back [1.5] er [0.3] we're dealing with if you remember [1.2] 
the lymph nodes okay [0.4] and especially we were talking about stimulation [0.
5] of [0.9] B-cells [3.9] which occur in the lymph node [0.9] er [0.3] if you 
take a typical lymph node [0.6] whereabouts in the [0.2] lymph node do you 
normally find B-cell activity [4.2] cortex paracortex medulla [0.4] 
ss: 
nm0237: sorry [0.6] 
ss: 
nm0237: cortex okay [1.3] mainly [0.7] occurring in these follicles the 
secondary follicles here [0.6] which we've 
discussed before but also there's some B-cell activity [0.4] outside of the 
follicles [0.5] er [0.2] still in the cortex in the sort of [0.2] non-
follicular area if you like as well so there's [0.3] activity [0.3] in both 
zones but [0.3] predominantly [0.2] it's in the follicles [0.9] so this picture 
don't [0.3] bother to [3.1] don't bother to try to copy it down but this tries 
to show an enlarged picture [0.3] of the cortex area here and the paracortex 
area [0.5] showing a follicle here [0.6] with a germinal centre which is where 
you find the B-cells proliferating [1.0] and also the sort of [0.5] cortex 
outside of the follicle round here [0.3] and you'll notice in both that it 
pictures [0.3] er [0.4] macrophages which are in effect antigen presenting 
cells [0.3] and also [0.3] these follicular dendritic cells which again [0.3] 
are antigen presenting cells remember [0.4] A-P-Cs [2.9] antigen presenting 
cells [1.8] and er [1.4] there does appear to be B-cell stimulation in both 
areas but the B-cells [0.3] in the follicles are different to those [0.3] 
outside of the follicles [0.5] in fact [0.2] in the 
follicles [3.3] you have cells which are called [0.6] B-two cells [3.2] and [0.
2] outside [2.0] you have [0.5] B-one cells and they do [0.2] appear to respond 
to different types of antigen okay so there's [0.3] two sorts of B-cells in the 
follicles B-two cells [0.4] outside of the follicles B-one cells still in the 
cortex [0.4] but they do appear to respond to [0.5] er [0.2] different [0.2] 
sorts of [0.2] antigen [3.5] and [0.6] if you look [0.3] in these [0.6] 
especially in the follicles then [0.5] you will find B-cells proliferating you 
get mytosis and maturation and so on [0.7] and [0.2] the memory cells will stay 
there [0.4] but remember the plasma cells once they're produced the plasma 
cells secreting the antibodies [0.4] will go to the medulla area [0.2] and 
secrete the [0.2] antibody from there [0.5] okay there we can to go the medulla 
area [0.6] and also they may go off to other lymph nodes and so on [2.5] okay 
so [0.4] what we want to know now [0.4] is to [0.4] to [0.5] try to [0.2] 
answer the question [0.5] er [0.3] how does antigen stimulate a B-cell [0.3] 
how do the B-cells [0.2] become stimulated to produce antibodies so really 
today's 
lecture [0.3] is about this topic about how B-cells become stimulated [0.4] by 
antigen [0.6] ultimately to produce [0.4] er antibodies [0.7] and er [0.3] i 
would say right from the start that i don't think anyone knows the complete 
story [0.5] er but er one can make pointers [0.3] in that direction [2.2] so [0.
2] okay [1.1] you get lots of different forms of antigen there's no doubt 
Professor namex's told you [0.5] er [0.4] and [1.0] some of them [0.3] are [0.
5] able to stimulate some of these antigens are able to stimulate [0.2] B-cells 
directly [1.7] this picture [0.8] outlines how this [0.3] might be [0.6] here's 
a B-cell [0.3] remember it's got [0.2] I-G on its surface [0.7] immuno-globulin 
molecules on its surface [0.5] and one way [0.5] is for antigen [0.4] to [0.2] 
cross-link [0.3] these [0.5] I-G molecules directly cross-linking [0.4] so 
you've in fact [0.7] got a polymeric [0.3] form of antigen an antigen which 
contains lots of repeater units so that [0.9] all these groups on the outside 
remember [0.3] will have to be the same to attach to the I-G on any one B-cell 
because all these receptors are the same okay [0.4] so it's a polymeric 
molecule repeating molecule [0.5] er [0.3] 
which can stimulate B-cells directly [0.7] and [0.3] in fact [0.2] what happens 
is in all these cases [0.6] that [0.2] if you've got a B-cell [1.1] with its [0.
7] Y-chains on the surface like that i'm not going to draw them all but all 
round [1.0] what happens is [0.3] the antigen [0.9] has to cross-link [1.8] 
individual I-G molecules it has to link [0.6] at least two together and 
obviously you see in that first case [0.4] you've got [0.2] cross-linking 
between a lot [0.3] of [0.2] these molecules [1.2] and [0.8] all the once this 
happens [0.2] all the I-G is taken to one end of the cell [1.4] a process 
called capping [2.4] the I-G with the antigen on it goes to one end of the cell 
[0.4] and then it's taken into the cell [0.6] by endocytosis [1.7] so you get 
capping and endocytosis and that's what [0.3] appears to stimulate [0.5] the B-
cell [0.5] okay [0.6] material [0.3] has to cross-link the I-G [0.4] taken into 
the cell after it goes to one end [1.0] like that [2.6] so [0.5] one method is 
to use polymeric [0.3] molecules [0.9] the second method [0.4] is apparently 
you can get [0.4] equivalent stimulation by [0.4] antigen 
binding to a [0.5] a a an I-G chain [0.5] but also [0.7] a mitogenic effect 
that also appears to be able to stimulate a B-cell you get some cross-linking 
of Y-chains [0.3] but also [0.3] linkage to a mitogenic receptor [0.2] on the B-
cell [1.6] and the third sort of [0.3] response is where again you get cross-
linking but you get some complement binding as well remember B-cells have a 
complement receptor on you don't know what complement is yet except it's a 
polypeptide [0.7] but that can attach to the antigen so you get [0.4] multiple 
linking [0.4] I-G linking there [0.2] immuno-globulin linking there [0.3] and 
complement linking there [0.6] and that [0.2] also [0.3] will encourage this 
procedure [0.5] to start to occur so there's at least three sorts of bonding [0.
4] polymeric [0.6] mitogenic [0.5] complement [0.2] bonding [7.9] so [1.0] i'll 
give you [0.2] some examples of this [0.5] on a [0.5] an overhead [0.3] and you 
can [0.7] er [1.6] copy them down [1.9] so [0.7] antigen [0.6] can directly 
stimulate B-cells [0.5] you can have [0.5] polymeric [0.3] molecules long 
linear molecules [0.3] usually [0.3] relatively firm ones and examples of those 
[0.4] are pneumococcal [0.2] 
polysaccharides of [0.6] er bacteria [0.8] er diamino acid polymers [0.2] and 
also artificial [0.4] er compounds like polyvinyl pyrrolidone [1.1] pyrrolidine 
sorry [1.2] okay [0.2] and they cross-link [0.2] the antigen receptors to the B 
on the B-cell [0.2] just as the first example i gave you [0.8] an example of a 
mitogenic one of bacterial lipopolysaccharides [2.8] they bind to the antigen 
receptor on the B-cell possibly more than one Y-chain but they also seem to [0.
3] offer a mitogenic stimulus [1.0] and then thirdly [0.5] you can activate [0.
2] via complement binding [0.7] no specific example [50.7] now these [0.3] 
antigens they're probably [0.4] the exception rather than the rule they're [0.
4] perhaps somewhat strange [0.2] antigens in the sense that they can stimulate 
B-cells directly [0.6] and [0.4] it appears that predominantly the sort of B-
cell that is stimulated [0.5] are these ones that are [0.4] outside of the 
follicles [1.5] they seem to be the sort [0.2] that [0.4] can be stimulated 
directly [0.4] without any other assistance [0.3] probably macrophages present 
[0.2] this stuff [0.6] this antigen [0.4] to the B-cells [0.3] 
but they don't seem to need any further assistance to [0.3] produce [0.6] er [0.
4] a an antibody response [2.3] but the vast majority [0.2] of [1.2] antigens 
are poor direct [0.2] B-cell stimulators most of them are poor [0.4] things [0.
3] like [0.6] a lot of parasites for example [0.4] like sheep red blood cells 
which are l-, [0.2] used in a lot of immune experiments and so on [0.4] these 
are relatively poor direct [0.4] B-cell stimulators they don't [0.2] do this 
sort of thing [0.5] and also [0.3] a lot of antigens [0.3] are [0.5] degradable 
[0.6] 
and so [0.2] are not present [0.2] and able to activate the B-cell [0.3] for 
fairly lengthy periods of time so [0.3] the predominant [0.4] B-cell's [0.6] er 
stimulation is not by the sort of antigen which i've already mentioned [1.3] so 
the majority [0.4] of [0.2] antigens [0.2] the majority of antigens [0.3] for 
instance sheep red blood cells as i say which is sort of thing that 
immunologists have tended to use [0.6] do not have the above molecular 
characteristics they're not linear they're not mitogenic [0.3] they might well 
not bind complements in any sort of way [0.8] but you still get immune 
responses against 
these other antigens okay they're not of this character up here but you still 
get [0.2] these responses [1.2] and [0.4] what you find is [0.6] that [1.0] the 
first three sorts these er [0.6] er polymeric mitogenic or complement binding 
ones [0.9] tend not to use [0.4] any cells that are derived from the thymus 
they don't depend upon T-cells [0.5] so [0.7] no T-cells required [0.3] okay [1.
1] but [0.6] for the majority of antigens like sheep blood cells if you're 
going to get an immune response against them [0.5] you need some T-helper cells 
[1.4] you need [1.6] T-helper cells [3.8] to get a significant immune response 
[0.6] and therefore [0.4] the majority of antigens like sheep red blood cells 
[0.2] are called thymus-dependent antigens [0.6] so the first three groups are 
thymus-independent antigens don't need T-cells to help the B-cells [0.5] the 
last group [0.3] are thymus-dependent antigens [0.5] needing [0.4] T-cells to 
help the B-cell [1.6] and these are [0.5] predominantly the ones that occur in 
the follicles [0.3] these B-two B-cell [3.8] okay [0.3] so [0.6] what we'll 
spend most of today really 
talking about [0.2] is the main re-, sort of response that you get with er [0.
5] as i say in the follicles [0.5] and [0.7] they'll be involving B-cells [0.9] 
they'll be involving T-helper cells [0.8] and [0.2] also [0.3] antigen 
presenting cells are important [0.4] in this story [3.0] okay so [0.9] this is 
all happening then [0.6] inside [1.0] the lymph node follicle or the equivalent 
area in the spleen or wherever in these follicles [0.3] in there [0.3] and 
you've got these [0.3] follicular dendritic cells [0.4] which are at least one 
form of antigen presenting cell [0.4] in there [4.2] so [0.2] how do we know 
that T-cells were involved [1.3] well there's some evidence right from the 
start remember i showed you [0.7] this last time [1.3] er [0.4] where we had 
chickens [0.8] they'd taken [0.3] out the thymus or the bursa at birth [0.2] or 
had left them intact [0.7] and remember [0.7] that when you measure the 
antibody production [1.3] taking out the bursa taking out the B-cells [0.7] 
antibodies taken out completely [1.4] if you take out the thymus you get a bit 
of antibody production but it's not as good as if you leave both systems in 
together so clearly 
the T-cells are playing a role [0.5] even [0.3] in that [0.2] experiment there 
[1.4] but you can go further than that [0.3] you can use [0.3] mice and do 
various nasty things to them [0.5] and you can show that T-cells and B-cells 
are important [2.7] okay [0.3] so [0.4] let's consider the situation of a 
lethally irradiated mouse [0.4] this is wa-, a mouse a mouse of an inbred 
strain so you can [0.5] have lots of different mice almost all the same [0.5] 
and they've been irradiated [0.6] and [0.5] er [0.3] they would die shortly 
afterwards but okay they'd probably die anyway of something or other [0.5] but 
what happens to them is that the irradiation [0.2] knocks out [0.5] lots of er 
[0.2] different cell types including the lymphocytes [0.4] okay so irradiation 
[0.3] knocks out the lymphocytes [0.6] and then you can take these mice and you 
can repopulate them with [0.3] lymphocytes [0.3] from the same inbred strain of 
mice [0.6] their [0.2] their er [0.3] brothers and sisters and so on [0.4] and 
remember if it's an inbred strain these mice are all genetically identical [0.
4] so really transferring the cells from one mouse to another [0.3] will not 
make any difference there shouldn't be any nasty responses as a result [0.6] 
okay so you've got some lethally irradiated mice [0.6] and [0.4] you [0.2] 
populate them [0.2] with [0.3] or repopulate them with lymphocytes of different 
sorts [0.6] and give them an antigen [0.2] sheep red blood cells S-R-B-C [1.1] 
so you inoculate [0.2] one mouse [0.3] or possibly if it's experimental you'd 
have to have some replicates of course [0.5] inoculate T-cells [0.2] and sheep 
red blood cells [0.4] you don't get any antigen [0.2] any antibodies pretty 
obviously [1.9] if you inoculate them with B-cells [1.7] you take your mouse [0.
3] your lethally irradiated mouse [0.6] put in some B-cells [0.5] and then give 
it sheep red blood cells as the antigen [0.5] you get a bit of I-G-M [0.4] and 
no I-G-G [1.0] little bit of I-G-M not very much [0.3] and some I-G-G [2.5] and 
[0.5] you do the third experiment [0.7] this lucky mouse gets both T and B-
cells [1.3] and [0.2] you give it sheep red blood cells [0.6] and it produces a 
lot of I-G-M [0.2] and I-G-G [0.7] which suggests that although the B-cells [0.
4] do produce [0.2] antibodies [0.5] you need some help [0.2] from T-cells [0.
4] to produce adequate 
quantities of antibodies [0.3] that is these T-helper cells [0.3] are required 
[0.2] T-helper cells [0.3] are required [5.1] and [0.3] the same sort of thing 
[2.0] can happen [0.4] in [1.1] mice which are genetically deprived of their 
thymus [1.5] in the mouse world there are some mice known as [3.2] nude mice 
jolly chilly but they they certainly [0.2] haven't got any hair [1.6] nude mice 
have no hair but that's not the important thing [0.6] the important things 
about nude mice is that they don't have a thymus [0.7] they're [0.3] thymus-
deficient they're athymic as it's called [4.6] oops [0.9] pen seems to be on 
the way out [1.8] athymic [2.3] genetically don't have a thymus [0.4] so 
they've got B-cells [1.3] but no T-cells so they're a bit like these mice here 
although they're not at death's door [0.8] but they haven't got a thymus [0.5] 
but if you get some nude mice [0.3] and put T-cells into them from [0.3] 
another inbred mouse which is normal very similar to them but normal [0.8] then 
[0.2] these [0.2] athymic mice these nude mice instead of [0.3] not producing 
antibodies [0.3] will suddenly start to produce antibodies so 
you can give nude mice [0.2] which haven't got their T-cells so you give them T-
cells of the right sort [0.6] and [0.2] they'll start to produce antibodies 
whereas they didn't produce antibodies before [1.6] so [1.0] T-cells and B-
cells then [0.3] have to cooperate to produce an immune response [3.6] okay [1.
2] so what about macrophages [0.5] antigen presenting cells [0.6] and similar 
sorts of [0.4] er cells [0.6] are possibly important as well [0.9] and you can 
show this by [0.2] various [0.3] er [0.2] culture experiments [1.3] as is shown 
[0.2] here [3.0] you can separate out the spleen cells [0.5] don't worry about 
the technique but you can separate spleen cells out [0.9] and [0.2] you can [0.
5] er [0.8] isolate them and grow them in culture and so on quite happily in a 
petri dish [0.7] as i say the metho-, [0.3] the methodology doesn't matter [0.
5] you can divide them into two populations you can divide them [0.3] into 
those that stick to glass [0.2] glass adherent [0.3] cells [0.4] and you can [0.
3] also have [0.4] non-glass adherent cells [0.8] and the glass adherent cells 
are the macrophages they have the ability to stick to glass or plastic [0.4] as 
long 
as it's clean [0.9] and [0.4] non-glass adherent cells will include the 
lymphocytes [2.1] okay so you take your mouse [0.2] you take out the spleen you 
separate the cells [0.6] and you do the following experiment [0.7] again using 
sheep red blood cells if you like as the antigen [0.2] perfectly possible [0.8] 
so you take your mouse spleen cells [1.2] you divide them into three lots you 
have a complete set [0.8] you have some glass adherent ones [0.5] and you have 
glass non-adherent ones [1.8] and if you have the complete cells you present 
these cells with sheep red blood cells as the antigen [0.7] you get antibodies 
produced in due course [2.5] you have the glass adherent ones [0.5] you present 
antigen [0.9] no antibody [1.0] you have [0.2] glass non-adherent ones [0.3] 
you present antigen [0.3] you get no antibody [1.0] if you remix the sets the 
glass adherent ones and glass non-adherent ones [0.6] you get antibody produced 
[0.8] so clearly glass adherent cells [0.7] er [0.3] are necessary for the 
production of antibody [0.6] but no one would say that macrophages actually 
produce it but they're clearly important for 
its production [0.4] and so [0.6] the glass non-adherent ones [0.3] need the 
glass adherent ones [0.3] to make the antibody macrophages are needed to 
produce antibody [2.6] 
so these are cells [0.2] from a [0.6] line of mice [0.8] from [0.3] strain of 
mice [1.5] and [1.8] so they're all from one mouse basically you can take [0.5] 
one [0.4] spleen of one mouse and do this experiment [1.3] and [3.2] not sure 
this is going to work actually [0.2] okay [0.9] er [3.0] move it up a bit [0.2] 
sorry we'll take the top off here [7.4] so these are all all [1.7] the same [0.
9] all [0.3] cells from one mouse [0.9] and so because they're from one mouse 
they're all going to have the same [0.3] M-H-C group [0.5] let's say for the 
sake of argument [0.5] they're all [0.2] H-two-K [0.5] they're all of the M-H-C 
same M-H-C type [0.4] major histocompatibility complex remember [3.3] all cells 
[0.2] from one animal [0.3] will have the sem-, same M-H-C type [2.1] and 
similarly with an inbred strain of mice if you got a lot of siblings of one 
inbred strain they'll all be of the same M-H-C type so you could take [0.4] the 
glass adherent [0.3] cells from one mouse [0.4] and the 
glass non-adherent cells from another mouse all of the same inbred line [0.2] 
and you'd still get the same response when you mix them [0.3] you've got [0.4] 
antibodies produced [2.4] but if we do a devious experiment where we take [1.3] 
two lines of mice [0.4] one of one M-H-C type [0.4] and one of another M-H-C 
type [0.5] say [0.3] H-two-K [0.4] and H-two-D [0.9] and then we try and get 
the cells to cooperate [2.1] as in below the line here [1.7] okay [0.7] so 
you've got glass adherent cells which are H-two-K from one mouse which is H-two-
K [0.6] glass non-adherent cells [0.3] from a mouse which is H-two-D now [0.9] 
and you put them together [2.5] you don't get any antibodies produced [0.7] you 
don't get antibodies produced [0.5] when the macrophages and the lymphocytes [0.
3] come from [0.2] mice of different [0.2] M-H-C type [2.8] and this is what is 
called [0.7] M-H-C-two [0.4] or [0.2] sorry M-H-C restriction [3.2] the 
response is M-H-C restricted [0.8] okay [2.3] because the macrophages [0.7] and 
the lymphocytes have to be of the same [0.2] M-H-C type [0.2] and in fact [0.3] 
it's M-H-C-two restricted [1.0] because it's that molecule [0.4] 
which is the important one [0.2] it's the M-H-C-two molecules that are 
important [0.5] for reasons which i [0.7] won't explain in detail here but will 
become obvious a bit later on so it's M-H-C-two [0.3] restriction that's 
applying here [0.7] it [0.3] the cells [0.2] have to be of the same [0.3] M-H-C 
ti-, type [0.5] before you get [0.2] the response [3.9] okay [0.5] so [2.3] 
what goes on [0.9] between these cells you've got three sorts of cells you got 
T-helper cells [0.3] you got [0.3] antigen presenting cells or macrophages [0.
3] and you got B-cells [0.3] and somehow you've got to get them together [0.3] 
to make antibodies [3.5] well [1.9] early on [1.8] the theory was [0.4] that 
you got a response [0.2] something like this this is what you would find [0.5] 
in many early [0.3] textbooks [3.8] you have [0.7] an antigen here [1.3] which 
consists of [0.6] a complicated molecule [1.7] it could for instance consist of 
a carrier protein such as [0.4] er [0.6] chicken gamma globulin [3.6] can 
somebody stop talking at the back please [3.2] chicken gamma globulin C-G-G [0.
7] and [0.6] it's known that you can make artificial antigens by sticking a [0.
2] the small 
molecular group on [0.3] called a hapten [0.6] for instance dinitrophenol [0.8] 
and i expect [1.3] Professor namex has told you about that [2.2] dinitrophenol 
[0.6] and it's known that the antibody will recognize the dinitrophenol [0.3] 
as long as it's attached to a carrier molecule if it's free on its own [0.4] 
the B-cell won't recognize it [0.3] the B-cell won't recognize the 
dinitrophenol on its own [0.4] but it'll recognize it and make antibodies [0.3] 
if it's atch-, attached to chicken gamma globulin [2.1] and of course the 
hapten [0.4] could be replaced in nature [0.8] by a normal epitope antigenic 
determinant [0.7] so the picture was something like this that you had T-helper 
cells recognizing one end of the molecule [1.4] the B-cell recognizing the bit 
that one's interested in against which will make the antibody [0.5] and [0.2] 
the T-helper cell [0.2] helps the B-cell [0.4] whatever help might mean [4.7] 
okay and that's described by the way in Weir and er Stewart [0.4] thirty-nine 
and page thirty-nine and forty [0.5] and Roitt Brostoff and Male [0.2] on pages 
one-four-two 
and one-four-three if you're interested in that [3.3] so that was the early 
picture [1.3] you've got the T-helper cell and the B-cell cooperating [3.3] but 
you've got a third sort of cell an antigen presenting cell and can anyone see 
what the problem is [5.9] remembering [0.4] that obviously this gap here [0.3] 
is vastly magnified i mean this T-helper cell would be much closer to the B-
cell than i've shown but can anyone see [0.4] what the problem is [1.2] if you 
got the third cell as well coming into it [2.7] pretty naive [1.1] problem 
really but you may not notice it [2.6] you can't haven't got enough space for 
anything to be going on because this T-helper cell will be close to the B-cell 
[0.3] how do you get a macrophage putting its paw in so to speak or its er [0.
2] er pseudopodium in [0.5] to [0.6] get [0.2] this [0.2] to get into contact 
with the antigen so there's [0.4] something wrong with this story [0.9] because 
there must be more to it than that because you've got a third cell [0.3] and 
how does it make contact [1.1] okay [0.2] so let's try to explain [0.4] what 
actually goes on [1.8] let's start just by saying one or two things about 
antigen presenting cells [1.2] you've seen this picture before [2.2] but [0.2] 
an antigen presenting cell [4.2] can present [0.2] antigen in a variety of ways 
it can present it on its surface [1.2] just as a lump [0.2] attached by say 
complement [3.1] so you get the antigen presenting cell [2.1] some complement 
[1.4] and then the antigen stuck on the surface like that for example [0.8] you 
could have [0.3] er simple lumps of antigen presented in that way [0.3] with 
complement [0.5] but also [0.4] you can have the antigen taken in [0.3] and 
processed [0.5] and [0.3] remember [0.2] during the processing it can be 
exposed or reprocessed and put on the surface [0.8] in [0.8] the cleft [0.2] in 
the M-H-C-two molecule [0.3] the M-H-C-two molecule [0.3] is assembled inside 
[0.4] er er [0.7] er [0.2] er little vacuoles inside the macrophage [0.4] bits 
of antigen are stuck in the cleft [0.3] it's exocytosed [0.3] and exposed on 
the surface so [0.5] presentation can be [0.5] in the form of [0.2] M-H-C-two 
[1.8] there's a bit of antigen [0.4] in that [0.3] cleft there [0.3] a little 
bit of processed antigen this is much larger this bit here this is a little bit 
of processed antigen okay [1.2] 
a few [0.2] amino acids for example [1.0] so there are at least two ways in 
which antigen presenting cells [0.4] can [0.3] present [0.2] antigen [0.2] on 
their surface [1.8] so [1.1] if you could look at the diagram that i gave the 
early-comers unfortunately i haven't got enough copies of it to go round i 
thought it was photocopied more than that i'll get you copies of it [0.8] er [0.
7] in time for the [0.4] er [0.7] video at [0.2] eleven o'clock i'll get you 
some more copies of it [0.6] but you've got a picture like this which 
summarizes what goes on [0.8] and [0.9] so just note [0.2] could you that 
you've got [0.3] a T-helper cell and the B-cell cooperating [0.6] and [0.2] two 
antigen presenting cells [0.3] here [0.2] and here [0.3] okay and we'll go 
through this story and if you haven't got the picture [0.4] you can certainly 
get [0.5] most of this copied down [0.3] from the [0.3] pictures as i put them 
up in sequence [1.3] okay so let's go through the stages first of all talking 
about this side [0.8] then this side [0.3] and then [0.2] the interaction 
between the two [0.3] this side [0.4] that side [0.3] then the interaction 
between the two [1.0] so let's start with the T-helper cell [5.0] somewhere [0.
2] in the lymph node [0.4] probably [0.2] in the paracortex [0.4] there are T-
helper cells [0.7] which will be [1.1] specific [0.4] for the antigen [0.2] 
there's specificity of fit between the T-cell receptor [0.3] and the antigen [0.
3] and the M-H-C-two molecule here [0.2] okay [0.5] you get [0.3] specificity 
of fit [0.9] there's a few of these T-helper cells [0.3] somewhere [0.3] in the 
paracortex of a lymph node [1.1] and an antigen presenting cell [0.6] presents 
this antigen then [0.3] in combination with M-H-C-two [0.3] on its surface [1.
3] and the T-cell receptor [0.3] recognizes [0.5] the [0.2] antigen [0.2] and 
the M-H-C [0.8] like [0.6] as is shown there there is a fit [0.2] between the M-
H-C and the antigen [0.3] and the T-cell receptor [0.3] there's also a 
subsidiary molecule [0.3] C-D-four [0.3] which helps the connection [0.8] don't 
worry too much if you don't understand that at this stage [0.4] i'll ex-, have 
to explain that to you [0.3] in a later lecture [2.0] so the T-helper cell [0.
8] connects up to the antigen presenting 
cell [0.5] because of this specificity of fit across here [1.2] and [0.2] 
messages are exchanged between the two cells that's what these squiggly arrows 
mean [1.0] and [0.2] the T-helper cell [0.3] becomes stimulated [1.4] will 
undergo mitosis [0.9] will undergo maturation [0.3] and will produce a clone of 
daughter cells [0.3] okay so the T-helper cell [0.3] receives some of this 
antigen after it's processed by an antigen presenting cell [0.6] showing it in 
in the M-H-C-two context [1.0] and [0.9] mitosis and maturation result [0.4] 
and you'll notice M-H-C-two is important [0.4] and that's why it's M-H-C-two 
restricted because [0.3] the T-cell receptor [0.3] will only recognize its own 
M-H-C-two sort [0.5] so [0.3] an H-two-K T-helper cell [0.3] will recognize an 
H-two-K [0.2] antigen presenting cell [0.4] but an H-two-K T-helper cell [0.3] 
will not recognize [0.2] an H-two-D [0.3] type [0.2] antigen presenting cell 
that's why there's M-H-C- [0.3] two restriction [0.4] okay [0.5] so [0.3] the T-
helper cell [0.6] produces a clone of daughter cells [0.2] as a result of that 
stimulation [1.3] and some of them [0.2] will probably migrate to those 
follicles that we keep talking 
about [2.5] but remember it takes some time for this to take place it isn't an 
instantaneous thing [0.5] for instance mitosis will take some time for a start 
[0.8] [9.1] okay [3.1] now [1.0] let's go to the other side of the story [1.8] 
this is [0.5] in the follicle [5.2] you've got an antigen presenting cell there 
like the dendritic follicular cell [1.3] this time it presents antigen in a 
different way [0.5] bound to the surface perhaps with the aid of complement or 
something or other [0.4] but it presents a blob of antigen [1.0] not in [0.2] 
terms of M-H-C-two now but just [0.6] on the surface so you've got a distinct 
blob of antigen [0.7] presented to the B-cell [1.0] you get cross-linking as i 
said early on [0.5] the I-G cross-links [0.4] capping [0.4] endocytosis [1.6] 
and the antigen molecule or er it's more than a molecule it's a lump [0.4] is 
taken into the B-cell [0.9] okay the antigen's taken into the B-cell [0.6] and 
it's broken up [0.3] it's broken up into small fragments [2.5] that's what this 
is supposed to represent this is broken up into that [1.1] and these small 
fragments are small 
enough [0.4] to be expressed [0.4] on the M-H-C-two molecule [0.3] on the B-
cell [1.3] okay so the B-cell [0.3] has M-H-C-two molecules just like that 
antigen presenting cell that we had over this side before [0.8] and [0.4] it 
expresses bits of [0.5] antigen [0.2] in the M-H-C-two cleft [2.2] so the B-
cell [0.2] has started to [0.4] be doing things with the antigen [0.8] and 
you'll notice that this response down here [0.2] is not M-H-C-two restricted 
because there's no M-H-C-two involved down here [0.4] there's M-H-C-two up here 
[0.3] but not down here [1.6] [12.3] so [0.2] the B-cell [0.2] has started to 
process the antigen for which it is specific [1.0] and it's presented some of 
this antigen in its M-H-C-two [1.9] and so [1.0] when these T-helper cells come 
along [1.9] which [0.5] is a bit of a mind-boggling event because how does a 
rare cell meet another rare cell i don't know [0.5] but this is what is said to 
occur [2.1] you've got this B-cell now with the antigen in its cleft [0.3] it 
recognizes a T-helper cell which has still got the same T-cell receptor 
specific for it it's the same one as [0.3] recognized the [0.4] antigen 
presenting cell way back down here [1.3] the two come along [0.7] they 
interconnect [1.0] there's the antigen there's the M-H-C- [0.5] two [0.3] 
there's the T-helper cell [0.8] and [0.9] you find then [0.6] that [0.5] once 
the T-helper cell [0.3] makes contact with the B-cell [1.5] it then gives the T-
helper s-, the T-helper cell then gives the B-cell [0.2] some help [3.2] okay 
[1.0] so the antigen is broken down by the B-cell [0.4] put into the M-H-C-two 
cleft [0.5] T-helper cell recognizes it with its T-cell receptor [1.5] for 
which it speci-, it's specific for this M-H-C [0.4] antigen pattern there [1.3] 
also C-D-four is involved [0.6] and once that connection is made there are in 
fact a number of other surface molecules but [0.4] as long as that connection 
is made [0.4] you then get help [0.3] going abro-, across from the T-helper 
cell [0.4] to the B-cell [0.9] and once that occurs the B-cell [0.3] is then 
stimulated [0.4] to produce a clone or [0.7] memory cells [0.9] plasma cells [0.
4] and to produce antibodies [4.0] 
okay [14.9] so you end up with a picture which is on the sheet that i've [0.2] 
given at least some of you [2.5] slightly [1.2] drawn slightly differently but 
basically it's the same antigen presenting cell one [0.4] T-helper cell [0.4] B-
cell [0.2] and antigen presenting cell two [0.4] so you've had that bit of the 
story [0.4] then that bit of the story [0.3] then that bit of the story [0.5] 
and as a result the B-cells are stimulated to produce [0.3] a clone of daughter 
cells [0.3] memory cells and plasma cells [0.3] and the plasma cells [0.3] will 
produce [0.2] antibody [14.2] and if you find [0.2] that there are difficulties 
with that i mean don't hesitate to discuss it [0.5] in the discussion sessions 
[0.2] after the video [4.8] and you'll find that when i come to deal with T-
cells i'll give you a similar picture [0.7] er [0.5] and show that the process 
is approximately the same [0.5] with cell mediated immunity [3.8] okay [1.1] 
now the final thing i think we need to discuss this morning [0.9] is what this 
help is these dotted these 
jagged arrows [0.6] are in-, [0.4] intended to indicate help [0.6] help goes [0.
3] from the T-helper cell to the antigen presenting cell across here and back 
again i've shown it mainly going in that one way [0.4] and also [0.3] there's 
[0.3] er [0.3] cross-help [0.3] from the T-helper cell [0.3] to the B-cell [2.
1] there are two ways [0.7] in which help can be received in which one cell can 
stimulate another cell [2.2] you've got two cells here [1.9] let's call them A 
and B [1.5] help [0.2] is sometimes received [0.6] by [0.2] direct molecular 
interaction you get [0.2] receptors interacting between the two cells okay [0.
4] so they're in close proximity very close proximity [0.5] and [0.6] these 
receptors interact with each other they [0.5] fit each other perhaps in some 
way or another [0.3] and a message is sent across as a result [0.2] that's one 
way that help can be transferred [0.3] and in fact the help is often not just 
one way [0.3] it's two way [1.4] and the other way [0.4] the [0.3] this help 
occurs [0.8] is through molecules being secreted [4.1] and [0.2] molecules are 
secreted by cell A [0.5] and they act on receptors on cell B [2.7] and [0.6] so 
help can [0.4] be transferred in that way [0.4] and remember that in this 
picture [0.7] these cells are far closer together than i've shown here because 
these receptor groups are very small [0.3] and in fact a secretion [0.4] to 
diffuse across need only diffuse [0.3] a very very short distance [1.6] and 
these secreted factors [0.6] so far as immunology s-, is concerned [0.2] are 
called cytokines [4.2] cytokines okay [0.7] and most of them not all of them [0.
5] are [0.5] called by [0.9] the [0.2] er abbreviation I-L so you got I-L-one 
up to at least I-L-twenty and probably further okay [0.4] and I-L stands for 
interleukin [4.5] okay [1.0] which simply means between leukocytes [0.8] er 
though it's mainly between lymphocytes but certainly I-L-one for example [0.4] 
is secreted by [0.3] macrophages so [0.2] it's not always just lymphocytes that 
secrete [0.4] er [0.2] cytokines or interleukin [0.3] it can be other cells 
interleukin-one as i say [0.4] being secreted by [0.3] macrophages [2.1] and if 
you look at the [0.3] cytokines in bold [0.6] in this response here [0.7] they 
are [0.7] many [0.3] and quite complicated [2.2] but [0.6] just to [0.2] try to 
keep 
it relatively simple [0.8] they're as follows [0.6] you've got your antigen 
presenting cell the one that reacts with the T-helper cell called a T-helper-
two cell here [0.5] okay [0.6] and [1.0] the B-cell [0.4] which was stimulated 
by another antigen presenting cell [0.7] you'll notice then that the antigen 
presenting cell secretes I-L-one [0.6] as i've already said over there [0.6] it 
can act on the B-cell directly [0.5] can also act on the T-helper cell [2.3] 
and that stimulates the [0.2] both sets of cells [1.0] but notice the T-helper 
cells [0.2] remember they underwent mitosis [0.5] they can self-stimulate [0.8] 
they can stimulate themselves with the [0.2] s-, er [0.5] interleukin I-L-two 
[2.3] so [0.4] T-helper cells can stimulate themselves they're autostimulated 
[0.5] by [0.3] interleukin-two [1.0] and then [0.7] T-helper-two cells [0.6] 
can stimulate B-cells [0.6] by [0.5] a number of cytokines [0.4] some I-L-two 
but perhaps not very importantly but more importantly [0.4] I-L-four and I-L-
five [0.5] I-L-four and I-L-five stimulate B-cells [0.6] and I-L-six [0.4] 
encourages the actual secretion [0.2] of antibodies I-L-six [0.3] encourages 
the secretion of 
antibodies [0.4] so I-L-four and I-L-five [0.4] are the prime helpers [0.4] I-L-
two perhaps a bit [0.3] and I-L-six actually encourages the secretion of the 
antibodies [4.7] and then [0.3] finally [0.6] remember [0.3] that when you get 
[0.2] an immune response [0.7] you get a change of [1.3] I-G production [0.6] 
you start off with I-G-M [1.4] and then later on you get [0.2] I-G-G being 
produced there is a class switch remember [3.5] and the class switch from [0.6] 
I-G- [0.9] M [0.7] to I-G-G [0.6] is controlled [0.3] predominantly by [0.5] an 
increase of secretion [0.3] of I-L-four [0.3] the I-L-four level [0.4] converts 
the B-cells from being I-G-M secretors [0.3] to being I-G-G secretors [1.2] a 
predominance of I-G [0.6] of I-L-four [0.5] causes this class switch [0.3] from 
secreting I-G-M [0.4] to I-G-G [29.5] now i just want to leave you with the 
thought [0.7] about [0.6] these different sorts of B-cells remember that i 
talked about early on [0.9] that [1.2] B-cells in the follicles of the lymph 
node [0.5] are the normal ones that we've been discussing here using T-helper 
cells [0.7] but outside of the follicles you get B-cells these B-one cells 
that respond to strange [0.3] antigens things like these polymeric ones and so 
on [0.4] but they don't use T-cells at all [1.4] and [0.4] what you find is 
that [0.2] in the follicles the B-cells will produce [0.4] I-G-M [0.2] and then 
I-G-G just as we've described here [1.1] outside of the B-cell [0.8] outside of 
the follicle rather [0.3] these B-one B-cells [1.0] not using T-cells [0.6] 
only produce [0.2] I-G-M [2.0] and [0.7] the reason for this [1.2] is [0.6] 
that [1.4] since these B-cells are being stimulated on their own they may get 
some I-L-one help from antigen presenting cells [0.6] but they don't get any of 
this help because T-helper cells [0.3] are not involved [1.2] so these [0.3] B-
one [0.5] lymphocytes outside the follicle don't have T-cells [0.3] and they 
don't get any of this cytokine [0.3] help down here they might get some I-L-one 
coming from an antigen presenting cell [0.4] but they don't get any of this [0.
4] and therefore you find [0.6] that [0.4] this sort of [1.4] T-cell [0.5] will 
only produce I-G-M [0.2] it will never undergo [0.2] a class switch [3.9] so 
you get [0.3] a very deficient sort of response [0.4] against [0.3] things like 
polymeric antigens [0.4] er like the mitogenic ones and the complement ones [0.
3] which are [0.2] responded to by these B-one [0.5] B-cells only if if the 
antigen is not responded to by a B-two B-cell [0.4] it will only [0.3] produce 
an I-G-M response because you've got no T [0.4] T-helper cell help [0.5] 
therefore you haven't got these cytokines [0.4] so the B-cell stays at that 
position [0.2] and can't switch to that position [0.4] there [0.6] 
okay [2.6] so [0.4] with that [0.2] thought [0.7] that the end [0.8] just to 
put up [0.2] a [2.2] piece of paper about [0.2] what is relevant in the books 
[0.6] er Weir and Stewart in fact hasn't altered since last time because 
there's not a great deal in this area in that early part of chapter four [0.5] 
but i've added chapter eleven now to what you should have a look at [0.4] in 
Roitt Brostoff and Male some of it you won't understand but some of it is 
relevant to what i've said today [2.3] okay thank you very much [5.6] there is 
a handout [0.2] which i'll give you