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Pathology Fall 2015 > Humoral Immunity > Flashcards

Humoral Immunity Flashcards

1
Q

Key Points about Antibodies

A
  • Antibodies Neutralize or Eliminate Extracellular microbes and their Soluble Products (Toxins).
  • Circulating Antibodies Neutralize microbes by **Blocking their entrance into Host cells, before they proliferate and spread.
  • Antibodies are produced against Proteins, Lipids, Nucleic Acids, Carbohydrates, and Polysaccharides, and small chemicals.
  • Antibodies are particularly effective against microbes with Capsules rich in Polysaccharides and Lipids.
  • Most Effective Vaccines Stimulate Antibody Production.
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2
Q

How to Develop Circulating Antibodies

A

Congenital: Passive

  • -Newborns acquire Antibodies Transplacentally prior to Birth
  • -And from Milk after birth.
  • -Providing immunity in infancy.

Infections: Active
–Primary Immune Response leaves Memory B cells that secrete low levels of Antibody for Months or even many Years.

Immunization by Vaccination:
–Whole Microbe or Part or its toxin is given under controlled circumstances to Induce a Primary Immune Response –> To Prevent Subsequent Infection.

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3
Q

B cell Maturation

A

Occurs in Bone Marrow.

Progenitors give rise to Pro-B cells.

1) Pro-B cells undergo Ig Heavy chain Recombination, mediated by VDJ Recombinase.

2) Pre-B cells are those that contain Ig mu Heavy chain protein in cytoplasm.
- –They then express the Pre-BCR Complex on Cell Surface, composed of mu Heavy chain (with 2 surrogate light chains and with the Ig alpha and beta signaling molecules).
- –Pre-BCR complex delivers intracellular signals: (1) Promote survival and proliferation; (2) Ig Light chain Recombination.
- –(3) Allelic Exclusion inhibits VDJ Recombinase from acting at other chromosome’s heavy chain.

3) Immature B cell: Expresses a complete IgM Antigen Receptor on cell surface, composed of a mu Heavy chain and a Light chain (kappa or lambda).
4) Mature B cell: Expresses both IgM and IgD on cell surface.

5) Positive Selection of Weak Self-Antigen Recognition.
- -Negative selection of strong or no recognition of self antigen.

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4
Q

Immunoglobulin Structure

A

4 Polypeptide Chains: 2 identical Heavy (H) chains; 2 identical Light (L) chains.

  • -Each Light chain is attached to 1 Heavy chain.
  • -The 2 Heavy chains are attached to each other.

Light Chains contain 1 Variable region and 1 Constant region.

Heavy Chains contain 1 Variable region and 3-4 Constant regions.

Each Variable region of the either chain contains 3 Hypervariable regions (CDRs).

  • -CDR3 has the greatest variability.
  • -CDR3 is located at the junction of the V and C regions.

Light Chains are not attached to cell membrane.

Heavy Chains are either membrane-bound or part of soluble Ig.

Light chains do not switch and remain fixed throughout the life of that B cell. They do not affect Antibody function.

2 Types of Light Chains (by Constant regions): Kappa and Lambda

5 Classes/Isotypes of Heavy Chains (by Constant regions):
IgA (alpha type C region)
IgM (mu type C region)
IgG (gamma type C region)
IgE (epsilon type C region)
IgD (delta type C region)
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5
Q

Fab Regions

A

Fab Region (Fragment, Antigen-Binding):

  • —Region of the Antibody that contains a whole Light chain attached to the V and first C domains of a Heavy chain.
  • —Is the portion of the Antibody required for Antigen Recognition.

There are 2 identical Fab regions on an Ig.

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6
Q

Fc Region

A

Fc Region (Fragment, Crystalline)

There is one Fc region on the Ig.

It is the region of the Antibody containing the remaining Heavy chain C domains.

Function:

  • -**Most of the biologic activity and Effector functions of the Antibody.
  • -**Binds to cells on their Fc Receptors only if Fab is Bound to Antigen!!
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7
Q

Hinge Region

A

Located between the Fab and Fc regions.

Flexible.

Allows the two Antigen-binding Fab regions to move independently of each other, enabling them to simultaneously bind Antigen Epitopes that are separated from one another.

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8
Q

Epitope / Antigenic Determinant

A

The region of the Antigen recognized by Variable Domains.

  • Each Antibody typically recognizes 1 Epitope.
  • Because there are 2 Fab sites on a given Ig, this can bind to 2 Identical Antigen Epitopes.
  • Microbes have multiple Antigen, each one with multiple Epitopes.
  • -Some may be *Highly Repetitive.
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9
Q

Affinity

A

= Fab binding strength to an Antigen Epitope.

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10
Q

Affinity Maturation

A

During Immune responses, the quality of the Antibody improves, increase its Affinity.

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11
Q

Cross-Reactivity

A

A particular clone of B cells produces Antibody specific for 1 Antigen Epitope.

Antibody to one particular Antigen Epitope may also exhibit binding, although weaker, to another epitope that is structurally similar = cross reactivity.

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12
Q

Avidity

A

= The total strength of Antigen-Antibody binding, not just one interaction.

IgG exists as a monomer and thus can form 2 Ag-Ab bonds (b/c 2 V domains).

IgA forms a *Dimer; can bind 4 Antigens.

IgM forms a *Pentamer; can bind 10 Antigens; has Highest Avidity.

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13
Q

Polyclonal Antibody Production vs. Monoclonal Antibody Production

A

Polyclonal: Antibodies against microbes are made to Multiple Antigen Epitopes by Multiple Clones of B cells.

*Polyclonal B cells have an even kappa/lambda ratio.

Monoclonal: When only a single clone of B cells produces Antibody.

  • -> *This is Pathological and typical produced by B cell Tumors.
  • -Will show an unequal kappa/lambda ratio.
  • -Also done in lab via Hybridoma Technique: (1) Pregnancy Test that uses Antibodies to HCG;
    (2) Drugs, e.g. Herceptin, used to treat Breast Cancer.
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14
Q

IgD

A

Remains membrane-bound.
Never secreted.
Function: Antigen receptor on B cell.

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15
Q

IgM

A

IgM is the First Ig Secreted during Primary Immune Response.
–The Best Activator of Complement.
(–May opsonize, but less effectively than IgG.
–Not a good activator of NK cells.)

Effector Functions:
–Complement Activation (Classical) (Best!)

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16
Q

IgG

A

IgG is the *Most Abundant Ig in Blood. 4 subclasses: IgG1-4.

  • -*Best to Neutralize Microbes;
  • -*Best Antigen Opsonizer;
  • -An okay *Activator of Complement;
  • -Best NK cell Activator.

Effector Functions:
1) Neutralization of Microbes and Toxins (Best!)

2) Opsonization (Best!) for Fc Receptor-Dependent Phagocytosis: IgG1 and IgG3 bind to Fc receptors on Neutrophils and Macrophages specific for gamma Heavy chain.
3) Antibody-Dependent Activation of NK cells (Best!)
4) Complement Activation (Classical)
5) Feedback Inhibition of B cell Activation
6) Neonatal Immunity (Placental transfer)

17
Q

IgA

A

IgA is the Most Abundant Ig in the Whole Body. Is Located on Mucosal Surfaces.
–*Is Mainly Secreted into the Respiratory, Urinary, and Genital Tracts to provide “Mucosal Immunity.”

Effector Functions:
–Mucosal Immunity (IgA transported through epithelia)

IgA is produced by MALT in submucosa, then actively transported across the epithelia to Mucosal Surface to bind and *Neutralize Microbes (prevent them from penetrating epithelia).

The *Poly-Ig Receptor on *Basal Epithelial Cells binds IgA Fc region and triggers Endocytosis.

Locally produced TGF-beta promotes Isotype switch to IgA.

B1 B cells migrate to MALT and respond to Non-protein Antigen.

18
Q

IgE

A

IgE is typically *Bound to Mast Cells

  • -Mediates Cytotoxicity of Basophils, Mast Cells, and Eosinophils against Parasites, especially worms.
  • -Also involved in Allergic Reactions.

Effector Functions:

  • -Immunity against Helminths
  • -Mast Cell Degranulation (immediate hypersensitivity)

IgE activates *Mast cells and *Eosinophils against Helminthic Parasites and in *Allergic Reactions.

Eosinophils have *Fc-eRI and IL-5 Receptors; activation releases their granular contents and is toxic to Helminths.

*IgE binds to Fc-eRI on Mast cells, which secrete Histamine and Chemokines, *Attracting more Eosinophils.

19
Q

Follicular B cells

A

Follicular B cells:

  • -Located in Follicles of Spleen and other Lymphoid organs
  • -Recognize Protein Antigen with help from Helper T cells
  • -Undergo Isotype-Switching
  • -Produce High-Affinity Antibodies (Affinity Maturation)
  • -Are Long-lived Plasma Cells
  • -Can become Memory B cells
20
Q

Marginal Zone B cells

A
  • -Located in the Spleen and other Lymphoid Organs.
  • -Recognize Polysaccharides, Lipids, etc. (T-Independent)
  • -Have limited diversity Antigen Receptors
  • -Produce Mainly IgM
  • -Are Short-lived Plasma cells
  • -Cannot become Memory B cells
21
Q

B-1 cells

A
  • -Located in Mucosal Tissues and Peritoneal Cavity
  • -Recognize Polysaccharides, Lipids, etc. (T-independent)
  • -Have limited diversity Antigen Receptors
  • -Produce Mainly IgM
  • -Are Short-Lived Plasma cells
  • -Cannot become Memory B cells
22
Q

Primary Response vs. Secondary Response

A

Primary Response:

  • -First exposure of B cell to Antigen, regardless of type of Antigen.
  • -Low amount of Antibody produced; predominantly IgM.

Secondary Response:

  • -Repeated exposure
  • -Higher amount of Antibody; predominantly IgG
  • -Helper T cells cause Isotype Switching to occur and increased Affinity
23
Q

Antigen Recognition of B cells

A

1) Antigen is transported and concentrated in B cell rich Follicles and Marginal Zones of Peripheral Lymphoid Tissues.
2) B cells recognize whole, unprocessed Antigen via Membrane-Bound IgD Antigen Receptors.
3) IgAlpha and IgBeta accessory molecules of the BCR Complex transduce intracellular activation signals via their ITAMs motifs.
4) BCR complex clustering Cross-Links and Phosphorylates ITAMs, initiating signaling.

  • *Proteins initiate Weak B cell Signaling due to Limited Cross Linking: (Proteins rarely have repeated epitopes)
  • -> Therefore, T-Dependent

**Polysaccharides, Lipids, and Nucleic Acids contain High numbers of Identical Epitope, leading to Abundant Cross-Linking and strong activation signals on their own:
T-Independent

24
Q

Costimulation of B cells

A

Naive B cells require Costimulators.

1) Microbial Activation of Complement generates C3d.
2) C3d binds to Microbe.

3) Complement Receptor Type 2 (CR2) on B cells recognizes the C3d bound to the microbe, while IgD receptor recognizes the Antigen.
- -> Second Signal.

4) Microbes also produce Direct Second Signals:
- -B cells have Receptors for Microbial products, such as *TLR
- -Activation of these receptors stimulate B cell proliferation and Ig secretion.

25
Q

CD4+ Helper T cell Costimulate B cells

A

1) B cells recognize Unprocessed Protein Antigen as a whole, ingest it, digest it, and Display it on Class 2 MHC (Simultaneously acting as an APC)
2) CD4+ Helper T cells recognize it and activate B cell via CD40L - CD40 interaction and cytokine secretion.
3) Activated B cells express B7, Costimulator for T cell (CD28).

CD40L-CD40 interactions results in further Costimulation, lowering the threshold for B cell Activation, Ig Secretion, Heavy Chain Class Switching, and Affinity Maturation. (Analogous to T cell-mediated Macrophage Activation).

Although B cell and CD4+ T cells recognize different Epitopes of the Protein Antigen, Specificity is Maintain for the same Antigen Protein.

B cells are Very Efficient APCs.

B cell Ig receptor has very High Affinity and can Recognize Antigen in Very Low Concentrations.

Due to the Weak or complete lack of Antigen cross-linking, B cells recognizing Protein Antigen still cannot initiate signaling, even after Peptide Antigen is bound to BCR and Second Signals are delivered by Microbes and by Complement.

*Additional costimulation is required from CD4+ Helper T cells by binding of CD40L on T cell to CD40 on B cells.

This reduces signaling threshold, overcoming weak cross-linking and BCR clustering.

26
Q

Functional Consequences of B cell Activation

A

1) *Initiates B cell Proliferation and differentiation: Very strong for Polysaccharides and Lipids
2) *Sensitizes B cells for CD4+ Helper T cell interaction via expression of Cytokine Receptors for CD4+ Helper T cell-produced Cytokines.
3) *Increases B cell expression of B7, costimulators for CD4+ T cells.
4) *Decreases B cell expression of B cell Zone Chemokine Receptors
5) Low-level IgM secretion

27
Q

Heavy Chain Isotype Switch

A

CD4+ Helper T cells induce B cells to Isotype switch by CD40L mediated signals and Cytokine signals.

CD40 induces Activation-Induced Deaminase (AID) expression,
–> Switching VDJ recombination from C-mu to other Downstream C genes.

CD4+ Helper T cell Cytokines:
IFN-gamma –> IgG
IL-4 –> IgE

Cytokines produced by Mucosal tissues (e.g. TGF-beta) –> IgA

28
Q

Ig Affinity Maturation

A

Antibody Affinity for Antigen increases with Prolonged exposure to Antigen.

Occurs in Germinal Centers where B cells divide quickly.

Process results from *Somatic Hypermutations in the Hypervariable Regions of Ig genes of Dividing B cells.

***AID plays a critical role by inducing Nucleotide Mutations.

1) B cell clones of varying affinities emerge.
2) *B cells undergo Apoptosis unless Primed by Antigen or Rescued by Helper CD4+ T cells.
3) *Circulating Antibody binds to Antigen and Complement to Form *Complexes.
4) *Follicular Dendritic Cells (FDCs) have Fc Receptors that bind to these Complexes and then Presents them to B cells.
5) *B cells uptake Antigen presented by FDC and present it to Helper CD4+ T cells who migrate to Germinal centers to provide Survival Signals to B cells.
6) *As the response proceeds, Antibody Increases and *Antigen Decreases to Low Concentrations.
7) *B cells with High Affinity Ig Receptors are Selected based on their Ability to Bind Antigen at Low Concentration and Survive.

29
Q

Evasion of Humoral Immunity

A

Microbes can resist Humoral immunity by *Variation on their Surface Macromolecules, such as Glycoprotein Coat.

Also, Inhibition of Complement Activation.

Or Resistance to Phagocytosis.

Resistant strains become selected by Antibody responses.

30
Q

Vaccination

A

*Purpose: Artificially induce protective immunity to Prevent Infection.

Can also *Prevent an Epidemic if enough people are immunized because microbe is less able to spread among population.

Instead of using “real”microbe, *Many vaccines use an agent that *Cannot Cause Disease, but that *Stimulates Specific Antibody Production using **Killed or *“Inactivated” Microbes or even **Toxins inactivated by *Heat or *Chemical treatment:

  • -*Toxoid: Inactivated Toxin
  • -*Killed Agent: Inactivated Bacteria or virus
  • -*Subunits: Protein subunit of bacteria or virus.

Other strategies use **Live “Attenuated” Microbial *Strains.

**To produce a Protective CD8+ CTL Immune Response against Viral infection, a Live “Attenuated” Vaccine must be given.

–Only live viral infection of APC will result in Class 1 MHC-Antigen peptide presentation and CTLs.

**“Inactivated” Vaccines tend to be Less Effective for Some Viruses, require *Larger Dose, and Periodic *“Boosters” to maintain immunity.

–“Inactivated” Vaccines are *Generally used Against Bacteria or Toxins.

31
Q

Active Immunization

A

With “Active” immunization, Vaccine is given prospectively to Initiate immune response with 2 Purposes:

1) To Prevent possible Disease in the person given the vaccine
2) To Create Immunity in Multiple Individuals to Decrease the Probability of Spreading/Epidemic.

32
Q

Passive Immunization

A

With “Passive” immunization, *Ig (preformed Antibody) is *Given to an individual at the Time of Infection to:

1) **Stop the Continuation of the Infection and Minimize Damage
2) May also be given to persons who have Poor Immune Responses because they are **Immunocompromised, to *Prevent Infection.

33
Q

Regulation of Humoral Immunity

A

–> Antibody Feedback:

*As Antigen declines, B cells die.

A special mechanism stops Ig secretion:
1) **Circulating IgG binds to Antigen, forming Complexes that bind to Fc Receptors on B cells
(Fc-gamma-RII Receptors; don’t need to know name)
2) These Fc Receptors provide *Inhibitory Signals when bound to IgG-Antigen Complexes
==> **Antibody Feedback Inhibition

34
Q

Neonatal Immunity

A

Newborns have incompletely developed immune system.

Maternal Antibodies are Actively transported across Placenta to Fetus and Intestinal Mucosa in Neonate, providing Passive Immunity.

**Transfer relies on Neonatal FcRn Receptor.

**Maternal IgG binds to FcRn in Placenta and is *Actively Transported into Neonatal Blood.

35
Q

Opsonization and Phagocytosis

A

Major mechanism of defense against Encapsulated Bacteria.

**Spleen contains large numbers of Phagocytes that clear Opsonized Bacteria.

**Splenectomy predisposes to infection by these bacteria.

36
Q

Antibody-Dependent Cellular Toxicity (ADCC)

A

**NK cells bind and lyse Antibody-coated Host Target cells.

They have Fc-gammaRIII Receptor (CD16), which binds to IgG bound to Host target cells and *Promotes ADCC.
(Marker for NK cells)

*How often Infected cells express surface molecules recognized by Antibody is Unknown.

Pathology Fall 2015 (16 decks)

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