U3L3: Mature B cell responses I

What are the main distinctions between mature B cell subsets?

• patterns of cell surface marker expression

• developmental origin

• anatomic niches

• roles in antibody response

what do B1 cell subsets develop from?

from fetal liver-derived stem cells

What do B2 cell subsets develop from?

HSCs in bone marrow

when are most B1 cells generated

during fetal development

how do B1 cells maintain themselves is they are only generated during fetal development?

self-renewal in the periphery

what is special about the B1 BCR repetoire?

it is selected for self- (apoptotic) antigens and polyreactivity (microbial antigens) → this is specical because this is the only subset that intentionally recognizes some form of self

What are the two types of B1 cells

B-1a and B-1b

how to differentiate between the two types of B1 cells

B-1a cells express CD5; B-1b cells LACK CD5

Where are B-1b cells resdominantly found

peritoneal cavity but also the lung pleura as these are potential sites of invasion by bacteria and other miocrobes

What is the major source of “natural” IgM antibodies?

B-1 cells

natural antibodies

antibodies that are spontaneously produced by B-1 cells in the apparent absence of infection

significance of natural antibodies

provide a pool of antibodies that acts as a first line of antibody mediated defense

When do B2 cells develop

arise from bone marrow precursor cells AFTER birth and are continuously produced in children and adults

What are the types of B-2 cells

Marginal zone (MZ) and follicular B cells

abundance of MZ cells right after birth

low abundance right after birth, full development does not occur until ~2 years of age

difference in IgD expression between MZ and folliculat B cells

follicular B cells display higher IgD expression, where MZ B cells express low IgD and high levels of complement receptors

What does the white pulp of the spleen consist of?

T cell zones and B cell follicles

what does the marginal zone of a spleen consist of

surrounds the white pulp and contains MZ b cells, marginal zone macrophages, and reticular cells

where do blood and leukocytes enter the spleen and where do they go from there?

they enter through branches of the central arteriole, which ends in marginal sinus and red pulp

important roles of marginal zone b cells

IMMUNE SURVEILLANCE OF THE CIRCULATORY SYSTEM; provide first line of defense by rapidly producing IgN and some low affinity IgG in response to blood-borne viruses and encapsulated bacteria→ high sensitivity to TLR stimulation

What is the most abundant B cell subset?

follicular B cells (70% of B cells in spleen, and 80-90% of B cells in LNs) —> localize to follicles in spleen, lymph node, and MALT

What kind of antibodies to follicular B cells mainly produce

can produce isotype switched, high-affinity antibodies → due to germinal center reaction initiated by helper T cell interactions

When are B-1 cells first produced

fetus

When are follicular b cells first produced

after birth

When are marginal zone B cells first produced

after birth → take a while to fully develop

primary location of B1 cells

body cavities (peritoneal and pleural)

Where are follicular B cells primarily located

secondary lymphoid organs

Where are marginal B cells primarily located 

spleen

do B1 cells depend on IL-7

NO

do follicular B cells depend on IL-7

YES

Do marginal Zone B cells depend on IL-7

YES

how are B1 cells renoewed

self-renewed

how are follicular B cells renewed

replaced from the bone marrow

how are marginal zone B cells renewwed

long-lived

isotypes secreted by B1 cells

IgM >> IgG → remember the naturally secreted IgM as a first line of defense

isotype secreted by follicular B cells

IgG>IgM

isotypes secreted by marginal zone B cells

IgM » IgG

do B1 cells require T cell help

no

What cell types are major responders of T-indendent antigens?

Marginal B cells

What are the major responders to T-dependent antigens?

follicular B cells

what are teh signals involved in inducing B cell responses

1. BCR clustering induces BCR signaling cascade

2. co-stimulation amplifies BCR mediated activation, promotes differentiation and survival

3. cytokines drive proliferation, differentiation and class switching

Minimum signals needed for B cell activation

1 and 2

Where can signal 2 come from in B cell activation

CD4 T cells or TLR activation depending on the type of antigen

what antigens are folllicular B cells exposed to

antigens that are transported into the B cell zones of the lymph nodes and spleen

steps in BCR signaling through Syk activation

1. membrane bound BCRs cluster upon antigen binding

2. the ITAMs BCR adaptor proteins are phosphorylated by Lyn kinases and intracellular signaling cascades are initiated

3. Syk is attracted to phosphorylated ITAMS

4. Syk is phosphorylated and activated → this induces further signaling cascades

In the BCR signaling cascade, what happens after Syk is activated?

1. SLP65 (scaffold protein) interacts with other proteins and promotes signalsome assembly

2. Syk then phosphorylates BTK and other proteins

3. PLCy2 is activated and cleaves PIP2 to generate IP3 and DAG

   1. IP3 leads to increased intracellular Ca2+ and DAG leads to activation of PKC

4. Vav and Grb2 are recruited to signalsome → RAS pathway is activated

5. FINALLY, activation of NFkb, NFAT, and AP-1

thymus dependent antigens

require CD4 T cell cooperation to synthesize specific antibodies; need to interact with BCR and TCR

Thymus independent antigens

able to activate B cells without CD4 T cells; often contain repeating epitopes

B cell signal 2 when responding to TI antigens

provided by components of the innate immune system

What are the types of TI antigens

TI-1 and TI-2

TI-1 antigens

include mitogenic stimuli that can activate B cells nonspecifically through TLR recognition and induce B cell activation; activate B cell regardless of the specificity of the BCR

TI-2 antigens

bacterial polysaccharides and polymerized flagellin and can crosslink BCR and induce activation

key features of TI responses

• rapid antibody production

• secreted antibody is mainly IgM

• no CD4 T cell help → no germinal center response

• relatively short lived response

• no memory is generated