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HDM Final > Humoral Immune Responses > Flashcards

Humoral Immune Responses Flashcards

1
Q

Mature Naive B Cells

A

Resting mature naive B cells express

BCR: IgM, IgD, Iga &IgB
Co-BCR: CD19, CD81 & CR2 (CD21)
HLA-Class II
CD40
CD45R(A)
CD20

B cells can be divided into two major subsets
B1 and B2
B2 cells can also be divided into two major subsets
-Follicular B cells are re-circulating B cells (majority)
-Marginal B cells reside in the spleen blood-borne polysaccharide Ags

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2
Q

Migration of Naive B cells

A 
Travel to Secondary Lymphoid Tissue (SLT)
- Primary lymphoid follicles
-spleen: enter via blood
-Lymph nodes: enter via Lymphatics 
Passage through SLT
-enter through HEV
- no Ag, migrate to primary follicle (CXCR5)
-receive signal to survive (FDCs)
-exit through efferent lymphatic vessel

Competition for Survival Signals

  • took nay B cells, not enough FDCs to provide survival signals
  • naive B cells die within weeks in absence of Ag
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3
Q

B Cell Activation and Expansion Ag dependent phase

A
  • Response initiated by recognition of Ag (epitope) by B cell specific for that Ag (idiotope)
  • Ag binds to mIg on naive cells and activates these cells
  • Activation can occur in a T dependent or T-independent manner
  • -Complete activation requires 2 signals
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4
Q

B Cell Activation: First Signal

A

-Ag recognition by miss
-Must crosslink 2 or more BCR
-Signaling occurs through Iga and IgB cytoplasmic tails
—the IC signaling steps in B-cell activation are identical to those of T cells. The only differences lie in the SRC-family kinases involved in the initial IC signaling steps

-Prepares cell for interaction with 2nd signal
—process Ag
—Biochemical signaling

Ag binds to BCR —> turns on ITAM —> Fyn, Lyn, Blk phosphorylates Iga and IgB —> Syk comes and binds to IgB —> PLCy activation —> inositol triphostae —> increased cytosolic Ca2+ —> ca2+ dependent enzymes —> Myc and NFAT
PLCy activation —> diacylglycerol (DAG) —> PKC —> NFAT and NFkB

Blk, Lyn, Fyn phospharyaltes Syk —> Syk phosphorylates adapter proteins —> GTP/GDP exchange on Ras, Rac —> Ras GTP, RAC GTP —> ERK, JNK —> AP-1

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5
Q

B Cell Activation: First Signal cont

A
  • Cross-linking of BCR by Ag generates a signal that is necessary but NOT sufficient to activate naive B cells
  • Ag with bound C3d recognized by miGs & CR2
  • CR2 provides cross-linkage for signaling
  • Signaling occurs through Iga and IgB CR2, &CD19 cytoplasmic tails (BCR co-receptor complex)
  • If C3d is attached to protein Ag Ag is 1000x fold more immunogenic
  • TLR signaling through cytoplasmic domains

Microbial Ag binds to BCR and bound CD3 —> BCR signaling and enhancement of BCR signaling —> proliferation of differentiation

Microbial Ag binds to BCR —> PAMP from microbe activates TLR —> TLR signaling along with BCR signaling —> proliferation and differentiation

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6
Q

Outcomes of First Signal

A

Ag binding to cross-linking of membrane Ig —> Changes in activated B cells
—> expression of proteins that promote survival and cell cycling —> increased survival proliferation

—> Ag presentation increased B7 expression—> Interaction with helper T cells

—> Increased expression of cytokine receptors —> Responsiveness to cytokines

—>increased expression of CCR7. Secretion of IgM —> Migration from follicle to T cell areas

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7
Q

Migration of Activated B Cells

A
  • After activation by Ag in the follicular area, B cells change their chemokine receptor expression and migrate to the edge of the follicular zone
  • Activated B cells secrete low levels of IgM and increase expression of co-stimulators molecules and cytokine receptors

Ag presentation, T cell activation —> CCR7 decreases and CXCR5 increases (B cell chemokine, allows them to move towards B cell) ) and migration of activated T cells to edge of follicle—> B cells present Ag to activated helper T cells —> Ag uptake and processing, B cell activation, increase CCR7 (allows them to move towards T cells) and migration of activated B cells to edge of follicle —> B cells present Ag to activated helper T cells —> Ag uptake and processing, B cell activation, CCR7 (allows them to move towards T cells) increases and migration of activated B cells to edge of follicle

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8
Q

Second Signal

A

TI-1 Ag (B cell)
-mitogen

TD Ag (B cell)

  • T cell dependent to activate, has to be a protein Ag —> only thing T cells recognize
  • contact dependent
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9
Q

Cellular Sequence of B cell Activation

A
  1. APC (DC) HLA class II to interact w/T-Cell (CD4) (MHC binds with TCR)
  2. B7 of DC binds with CD28 of Th Cell
  3. CD40 of DC binds with CD40L (provides 2nd signal)
    - All of these make up the immune synapse —> proliferation and expansion
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10
Q

T Dependent Immune Synapse

A
  • The costimulatory signals are generated through the interactions of CD40:CD40L and adhesion molecules
  • Th cytokine modulated class switching
  • Inuced expression of activation-induced delaminates (AID) enzyme
  • Affinity maturation (somatic hyermutation) of secreted Abs (the last 2 happen at the same time)
  • -Class switching and affinity maturation often occur at the same time

TCR of T cell binds to MHC class II of B cell —> CD28 of T cell binds to B7 of B cell —> CD40L of T cell binds to CD40

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11
Q

Migration of Activated B Cells

A

Had the meet and greet w/T cell, now is fully activated

After receiving T cell help, B cells change their chemokine receptor expression and migrate to the follicular area and establish germinal centers in the follicules

Activated B cells begin cytokine modulated class switching and affinity maturation of receptors

Successful re-arrangements are selected/supported by Tfh and follicular dendritic cells (IgM is coming out)

  1. DC binds with naive CD4+ T cell —> T cell activation —> helper T cells —> Initial T-B interaction —> short lived plasma cells (extrafollicular focus) —> germinal center reaction

OR

  1. B cell activation —> initial T-B interaction —> short-lived plasma cells —> (extrafollicular helper T cells) —-> germinal center reaction (follicular dendritic cell and follicular helper T cell)
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12
Q

T Follicular Helpers

A

Tfh

  • CD4+/low levels of CD25 expression (been activated by DC)
  • ICOS/ICOS-L essential for germinal center reaction
  • Secrete IL-2L facilitates differentiation from B cell to plasma blasts
  • Provides IFN-y and IL-4 for cytokine switching
  1. DC binds naive CD4+ T cell —> activates T cell (expresses CXCR5) —> Tfh cell expresses ICOS binds with ICOS-L activated B cell —> germinal center B cell bound with follicular dendritic cell
    Tfh cell —> follicular helper T cell (while bound with B cell at TCR-MHC II and CD4-;CD40L, follicular helper T cell (secretes IL-21)
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13
Q

Class Switching in the Germinal Center

A
  • Cytokines released by Th cells promote two general functions
  • The first is to induce H chain class switching
  • The second function is to augment C cell differentiation and proliferation
  • There is great redundancy in this system as many cytokines have overlapping functions

-Each cytokines has multiple effects and acts on multiple cell types

Helper T cell (binds with activated B cell with CD40:CD40L and TCR-MHC II)
—> IgM B cell —> IgM - complement activation
—> ? —> IgG subclasses (IgG1, IgG3) - opsonization and phagocytosis; complement activation; neonatal immunity (placental transfer)
—> IL-4 —> IgE and IgG4 — Immunity against helminths, mast cell degranulation (immediate hypersensitivity)
—> (mucosal tissues, cytokines (e.g. TGF-B, APRIL, BAFF, others) —> IgA — mucosal immunity (transport of IgA through epithelia)

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14
Q

Switch Recombination

A

CD40:CD40L ligation and cytokines trigger isotype switching and affinity maturation by:

  • modulation of switch regions
  • Increasing the accessibility of the DNA at a specific C region
  • T-dependent Ag
  • Expression of activation-induced delaminates (AID)

Rearranged VDJ gene segment recombined with a downstream C region gene and the intervening DNA is deleted

*Cannot go back after you have spliced past gene, AID aids in the splicing (like RAG)

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15
Q

Affinity Maturation

A

-Introduction of point mutations in the switch regions of the variable areas of the Ig genes resulting in an expansion of the Ab repertoire to generate high-affinity Ag-specific antibodies

Somatic Hypermutation: 10^3 to. 10^4 times higher than normal spontaneous mutation rates

Key enzyme: AID, converts Cs to Us allowing APE I endonuclease to relate double-stranded breaks in the DNA —> thereby causing a low-affinity Ab to become a high-affinity Ab by creating point mutations

-Can be useful, sometimes not

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16
Q

Somatic Hypermutation

A

Day 7 of primary response - heavy chains and light chains only show one point mutation

Day 14 of primary
-Both chains show more point mutations

Secondary
-about 3x as many point mutations in both regions

Tertiary
-Many more point mutations in both regions

By the time you get the tertiary response the affinity is very high, gets “better, better, and better” diversity also increases

17
Q

Cytokine Influence of Class Switching

A

Naive B cell or Naive B cell +LPS —> no isotpye switching

Naive B cell+LPS+IL-4 —> isotype switching to epsilon + gamma

Naive B cell+LPS+TGF-B —> alpha and gamma 2

*switch to one or another, not both

18
Q

Selection Checkpoint

A

Checking to make sure the point mutations still bind with the epitope- otherwise they will be deleted

  • Selective survival of the B cells producing the highest affinity Abs occurs in the germinal center(s)
  • FDC and Tfh are interactions with high affinity B cells is necessary for survival-if not they will die
  • FDCs provide intact Ag in the form of complexes called immune complexes
19
Q

T-Independent Ag B cell Activation

A

B-1 cells respond to T independent responses (non-protein) Ag in mucosal tissues
-Marginal zone B cells (B-2) in spleen recognize blood-borne polysaccharides

T dependent
Follicular B cells binds with protein Ag —> Helper T cell binds with B cell —-> isotype-switched; high affinity Ab, memory B cells, long lived plasma cells+IgG, IgA, and IgE

T independent
B1 cells, marginal zone B cells binds with polysaccharide Ag —> other signals i.e. complement protein, microbial product —> Mainly IgM, low affinity Ab, short lived plasma cells+IgM
-Secrete natural Ab—> IgM in response to mucosal biome (commensal in gut) that interact with blood—> why you react with other blood

20
Q

Plasma Cells

A
  • Terminally differentiated effector B cell
  • Short versus long-lived
  • Cell markers- decrease CD19 and CD20, HLA class I, increase CD27, sIg class dependent
  • Secrete Abs at rates ranging from hundreds to thousands of Ab per second per cell!
  • Expansion of ER in cytoplasm
  • Abs: effector molecules of humoral immunity
21
Q

Memory B cells

A
  • only for PROTEIN Ag
  • T DEPENDENT process
  • Survive for long periods of time without additional Ag stimulation
  • Express high levels of the anti-apoptotic protein Bcl-2, which contributes to their long life span
  • Surface markers: CD27 and CD45R(0)
  • sIg (=BCR) class DEPENDENT to what they switched to
  • Capable of mounting a rapid response to subsequent exposure to same Ag (secondary immune response)
22
Q

Antibody feedback

A

-turn it down

  • Control mechanism triggered by secreted AB that blocks further AB production
  • IgG ONLY
  • Ab excess
  • Bind to Fc -> ITIM (blocks further activation)

(FYI ITAM turns it on —> interact with Syk instead of ZAP70)

A. BCR signaling leads to PIP3 formation, which binds other signaling molecules, leading to activation
Polyvalent Ag —> Syk binds —> PI3K —-> leads to phosphorylation PIP2 to PIP3 —> BTK, PLCy, PDK1

B. Fc receptor-associated phosphates, SHIP, converts PIP3 to PIP2 in B cell - receptor complex, blocking downstream signaling
Polyvalent Ag makes Ab-antigen complex —> SHIP turned on, turns on ITIM —> PIP3 to PIP2 —> Block in B cell receptor signaling, no activation

23
Q

Clinical Blue Box-DM

A

3yo, high temperature, high RR, low O2 saturation, enlarged neck and axillae LN
—> from this we know there’s an infection- acute inflammation response (innate)

What do you want to know?

  • sick contacts?
  • happened before?
  • travel

PMH- 10 previous episodes of otitis media, had pneumonia once before, received DTap vaccine

Now what more info do you want?
-FH
No sibs, no relevant med history in family
-Doesn’t tell us much

24
Q

Clinical Blue Box- DM

Labs

A

High WBC
High IgM
Low IgG
IgA and IgE- undetectable

Blood- positive for streptococcus pneumoniae

Now what do you think?
-she’s not class switching
Has proper response to IgM titter, IgG was undetectable- not class switching
She had no specific IgG Ab against tetanus toxoid
-This tells us she’s not responding to protein Ag (TD-Ag, T cell activation needed for class switching)
She is responding to TI-Ag —> polysaccharide
25
Q

Clinical Blue Box- Lymph Nodes??

A

LN biopsy revealed the presence of hyperplasia of the germinal centers

What is the cell type involved in the hyperplasia? -B1 TI B cell??
What type of defect can you rule out?
-We can rule out TI-Ag
-First signal (T activated B cells)

Further analysis of peripheral blood lymphocytes revealed normal expression of CD40L on activated T lymphocytes and normal expression of CD40 on the B lymphocytes. Her B lymphocytes failed at secreting IgG or IgE after stimulation with anti0CD40 monoclonal and IL-4
-So not a T cell thing (they are working/binding)

26
Q

Clinical Blue Box- DM

Genes

A

Sequencing of the cDNA of the B lymphocytes revealed a mutation on the AID gene

  • Not getting change in DNA repair
  • B cell defect in enzymatic pathway

Treatment
-started on IV Ab, had IVIG therapy which resulted in a marked decrease in frequency of infection

27
Q

Clinical Blue Box- DF (Dennis)

A

Dennis was 5, referred to childrens hospital with severe acute infection of sinus

What do you want to know?
-PMH- recurrent sirs infections, pneumonia at age 3
Has received normal series of childhood immunizations

What do you want to know now?
-FH- older brother and sister both healthy
Rule anything out? -Does NOT rule out x-linked disease

28
Q

Clinical Blue Box- Dennis

Labs

A

WBC- normal
Low count for neutrophils for infection, high amount of monocytes

Sinus future positive for streptococcus pyogenes

Ab levels
IgG- low
IgA- undetectable 
IgM- very high 
IgE undetectable

Titers found showed IgM class only

Now what do you want to know?
-LN (T cell) biopsy

29
Q

Clinical Blue Box- Dennis

Lymph Nodes

A

Absence of secondary follicles and germinal centers

Are you postulating T or B at this point? Why?
- T because not activating B (not receiving T cell activation
We have IgM

A booster DTap and Typhoid vaccine was administered
What do you want to see?
-Ab formation IgG
Primary and secondary challenge- looking for burst of IgG as a secondary response for DTaP and primary response to typhoid
-No detectable levels of Abs to tetanus or typhoid toxins were found 14 days later

Low CD19, high CD3, low CD56 and CD16

All CD19 cells had surface markers for Ig< and IgD only- no class switching

Lymphocyte Activation Assay:
Activated T cells did not bind soluble CD40
Normal expression of CD25 after activation
CD40L-CD40 problem (no binding)
Not IL-2 problem

Tx: started on IV antibiotics, started IVIG therapy

30
Q

Hype IgM syndromes

A

Both clinical cases have this

  • Five types: 5 genetic defects
  • all 5 lead to the inability to class switch
  • X linked HIgM, defect in CD40L expression (Dennis)
  • prone to a variety of infections
  • neutropenia, failure to thrive, thrombocytopenia and anemia are common
31
Q

HIgM Syndromes- the Basics

What was the major difference in the past medical history of the two patients that would lead you to T vs B cell defects

A
  • Difference of PMH
  • HIgM caused by a mutation in AID do not seem to suffer from opportunistic infections which are characteristic of CD40L deficiency

Why?

  • Neutrophils still working
  • B cells —> IgM
  • Do have active robust T cell response (for B def)- APC causes primary response??

DM had enlarged LN, patients with CD40L do not have enlarge
-Lack of 2nd signal to get clonal expansion

32
Q

HIgM Syndromes- The Basics

Cont.

A

Why are IgG class Abs more important against pyogenic bacteria than other class?

IgG more protective because
Functional activity
There are 4 versions of IgG

33
Q

HIgM syndromes: The Basics

A 
Cyclosporin A (graft rejection immunosuppressant) is widely used post transplant
Inhibits transcription of CD40L

Specifically how does this help the patient?
-B cells can’t be activated against graft tissues
What does it imply long term of the patient?
-opportunistic infections

34
Q

Newborn Immunnity

A

Presentation of genetically based immune deficients at around 3-6 months
Previously the baby was protected by maternal Ab and has not yet reached immunological maturity

35
Q

Opportunistic Infections

A
  • Infection cause by pathogens that take advantage of weakened or lacking immune response
  • Normally do not cause diseases in immunocompetent individual
  • Cadida (increased yeast infections)
  • C. Difficile
  • Pneumocystic jiroveci
  • Cryptosporidium
  • Toxoplasma gondii
  • cytomegalovirus

HDM Final (4 decks)

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