SABS I Lecture 21: Immune Regulation

bone marrow, negative

B-cell regulation begins in the __________ ___________ with __________ selection

lymphoid progenitor, stromal

interactions between ____________ ____________ ___________ cells and ___________ cells is required to promote B-cell differentiation

- releasing cytokines

- checking receptors

What are some things that the stromal cells do in the bone marrow?

- early pro-B cells

- pro-B cells

- pre-B cells

- immature B cells

What are the 4 developmental stages of B cells in the bone marrow?

moving around pieces of DNA to make a fully functional protein

as the first 3 developmental stages of B cells occurs, what is happening?

immature B cell

At what developmental stage does it have a fully functional antibody on the surface of the B cell - IgM antibody with 2 heavy chains and 2 light chains?

immature B cell

What B cell developmental stage gets a challenge inside of the bone marrow (negative selection event)?

stromal

If the IgM antibody interacts with any of the __________ cells as it is being challenged during negative selection, it must be fixed or stopped

about 25%

What percentage of immature B cells do not have a problem and can continue with maturation within the bone marrow?

- successfully rearranged heavy chain allele and light chain allele

- express IgM on surface

- capable of receptor editing if antibody is self-reactive (negative selection)

at the first functional immunoglobulin checkpoint, immature B cells are checked to have (3):

mature B cells

What do we call naïve B cells that still need to be activated but are fully mature?

IgM and IgD

What antibodies do mature B cells express?

IgM

Which antibody on mature B cells is taller and less flexible?

IgD

Which antibody on mature B cells is shorter and more flexible?

yes

Do IgM and IgD bind the same antigen exactly the same way?

they go to a lymph node and continue circulating until they find a lymph node with an activation event

What do the 25% of mature B cells do after they complete the process of maturation in the bone marrow?

soluble monovalent, anergy

self-reactive B cells that recognize __________ __________ antigens may not undergo receptor editing, and these cells are placed into an arrested state known as ____________ where that do not respond to antigen

released from bone marrow to circulate for a few days and then deleted

What happens to self-reactive B cells that recognize soluble monovalent antigens and are anergized?

receptor editing, deleted

If the antigen is multivalent (at least 2 antibodies can attach) and not soluble, the antigen can undergo ___________ ___________ or is ____________

deleted

if activation signal of self-antigen that is multivalent is powerful, the B cell is ____________ because it will cause an autoimmune problem

receptor editing

if activation signal of self-antigen that is multivalent is moderate, the B cell undergoes _________ ___________

B cell goes back to light-chain antibody gene and changes it by moving DNA around

What is receptor editing?

in transitional cells once the B cell leaves the bone marrow and is going to the spleen

When does receptor editing occur?

another negative selection event to make sure it's no longer self-reactive

What happens when a mature B cell that underwent receptor editing reaches the spleen?

survival signal that is a positive selection (without this signal it can't protect you)

If the mature B cell is no longer self-reactive in the spleen, what does it get?

IgD

Once a mature B cell is activated, what does it lose?

spleen

B-cell maturation is completed in the ___________ if they had to go here due to a negative selection event

- filter/cleanse blood

- second negative selection and positive selection (survival signal) of B cells

2 major functions of the spleen:

self-regulation

the first level of regulation is ___________

CD22

a B-cell surface molecule that regulates activation

ITIM motif (immunoreceptor tyrosine-based inhibitory motif)

the cytoplasmic tail of CD22 contains an _________ __________

regulatory B cells (Bregs)

anti-inflammatory cells that develop in the peripheral lymphoid tissues or at the site of inflammation

- IL-6

- IL-21

- IL-35

- IL-1beta

- T cells expressing CD40L and CTLA-4

regulatory B cells (Bregs) are activated by (5):

IL-10, TGF-beta, helper T cells, B cells

regulatory B cells (Bregs) secrete _________ and _________ (anti-inflammatory cytokines) and use direct cell-to-cell contact to regulate __________ ______ _______ and can regulate other _________ ________ too

B10 B cells

_____ ______ _______ are a functionally defined regulatory B cell subset that secrete IL-10

antibody-mediated suppression

the presence an antibody to an antigen can suppress the immune response to that antigen is known as

over-production of antibody

antibody-mediated suppression is a natural feedback mechanism to prevent

negative

antibody-mediated suppression can be known as _________ regulation of B cell activation as a result of binding antigen already complexed with antibody

vaccines, passive immunization

antibody-mediated suppression is relevant to ___________ and __________ __________

presence of passively transferred maternal antibody due to breastfeeding (mom's antibodies block the child's immune system from making memory cells)

Why can't some vaccines be given early?

at the same time or immediately after tetanus immune globulin (anti-tetanus antibody)

When should the tetanus vaccine not be given?

thymus, negative

T-cell regulation begins in the __________ with ___________ selections

T cells

If you don't have a thymus, what else do you not have?

thymus

in the _________, there is a point where CD8 and CD4 are being expressed at the same time but they should not be released expressing both

they are challenged to see if they are functional

As T cells move from cortex to medulla, what happens?

T cells interact with MHC class I and MHC class II

What is the first challenge in the thymus for T cells?

self-MHC

only T cells that have some ability to recognize __________ continue to mature

apoptosis

T cells with too low of an affinity for self-MHC undergo __________ within the thymus

cTECs

double positive T cells roll around the ___________ that express MHC class I and class II using your own peptides on the surface not intended to activate cells, just challenge them

positive

__________ selection results in self-MHC restriction

1st negative selection

the ___________ __________ _________ assesses how tightly the MHC/TCR complex interacts (how much activation signal is sent)

T cell

the ______ _______ decides what protein to keep: CD4 or CD8

medulla

the second negative selection for T cells is in the __________

interaction of TCR with self-peptide

What does the second negative selection for the T cells assess?

mTECs

in the second negative selection, the ________ express a regulatory element that lets them put proteins on their surface that should not be in the thymus

self-tolerance

the second negative selection for T cells is ___________

central tolerance

the positive selection and two negative selection events = ___________ ___________ for T cells

no; different from B cells

Do the T cells fix their genes?

survival

positive selection is always a __________ signal for a lymphocyte

negative

___________ selection results in self-tolerance for T cells to some extent, but we need other regulation mechanisms in the periphery

Tregs

during negative selection event in the cortex, some cells get recruited and promoted to become __________ because they are potentially self-reactive in the thymus

regulate other cells that try to perform like they would

What do Tregs do?

peripheral tolerance

not all antigens are expressed in the thymus - there are mechanisms of __________ __________ and immune regulation also

- undergo apoptosis

- anergized

- recruited to be peripheral Tregs

When the T cells bind to self-antigen in the periphery what do they do?

CD4, Foxp3

Tregs express ____________ have transcription factor ________ which blocks T cell from responding to IL-2 (blocks T cell from being activated)

IL-2

naturally occuring Tregs will go into places with lots of _______ and bind to it but Foxp3 blocks them from being activated by it

IL-2 sinks (drain IL-2 from sites)

Tregs are also called

T cells, professional APCs

Tregs regulate other _______ ________ and ___________ _______

CTLA4, B7 (CD80/86)

activated T cells eventually express ________, an inhibitory receptor which has a binding with __________ that is 20 times stronger than the bond between CD28 and B7 (CD80/86)

yes

Do Tregs also have CTLA4 on their surface?

neutrophils

___________ are a key orchestrator of immune processes, shaping the immune response and contributing to immune homeostasis

neutrophils

__________ release cytokines that can activate or suppress both innate and adaptive responses (directors of response)

macrophages, T cells

neutrophils influence the behavior of ____________ and _______ _________

N1

Which neutrophils drive inflammation?

N2

Which neutrophils suppress inflammation?

macrophages

_____________ are central regulators of the immune system and can also release cytokines that can activate or suppress both innate and adaptive responses

M1

macrophages that drive inflammation

M2

macrophages that suppress inflammation