L20- Adaptive Immunity Pt 2

B cell overview

• B cell are produced from stem cells in the bone marrow.

• B cell maturation also occurs in the bone marrow.

• A selection process removes all B cells that recognize self antigens.

• Once out of the bone marrow, B cells make their way to the secondary lymphatic tissue until they encounter an antigen presenting cell.

• Activated B cells cells result in antibody production.
  Antibody producing B cells are known as plasma cells.

Once out of the bone marrow…

• B cells make their way to the secondary lymphatic tissue until they encounter an antigen presenting cell.

  • Activated B cells cells result in antibody production.

  • Antibody producing B cells are known as plasma cells.

Antibody variability

• Humans can make antibodies to as many as 10^13 different antigens.

• This allows the host to respond to as many antigens as needed throughout their life.

Properties of Antibodies

• Single Y shaped antibody is called a monomer

• Variable

• Constant

• Heavy Chain

• Light Chain

• Disulfide bridge

Variable:

Generates the antigen binding site.

Constant:

• determines the class.

• Identical in humans.

Heavy chain

• Identical 440 amino acids.

• Has a variable and constant domain

Light Chain

• Identical

• Held to heavy chain by disulfide bonds.

• Has a variable and constant domain.

5 classes of heavy chain

• There are 5 classes of heavy chain antibodies

1. IgG

2. IgA

3. IgM

4. IgD

5. IgE

What regions do antibody shape depend?

• Depends on the kind of constant region.

IgG components

• The main class found in the blood (20% of
  all plasma protein, 80% of immunoglobulin
  pool).

• Largest quantities are produced in
  secondary response

• Antigen binding site: Binds antigen, Tissue-
  binding sites attach to receptors on
  phagocytic cells. Binds microorganism to
  engulfing cells. Can opsonize bacteria,
  viruses, toxins.

• Is the only antibody that can cross the
  placenta. Also found in milk and colostrum.

IgG Antigen Binding site

• Binds antigen, Tissue- binding sites attach to receptors on phagocytic cells. Binds microorganism to engulfing cells.

• Can opsonize (to coat a pathogen like bacteria or a virus) with special molecules called opsonins (such as antibodies or complement proteins to mark it for destruction), viruses, toxins

IgM components

• Makes up 5% of the immunoglobulin pool.

• Found as a monomer on the surface of B cells (BCR) and is secreted as a pentamer by plasma cells.

• Monomers are arranged in a pinwheel held together by a disulfide bond and a joining(J) chain.

Where is IgM found?

• Found as a monomer on the surface of B cells (BCR) and is secreted as a pentamer by plasma cells.

IgM important info

• Soluble, pentameric antibody is the 1st antibody secreted in primary response after antigen stimulation.

• Only antibody produced following T- cell independent B-cell activation.

  • 1st antibody made by fetus.

  • Too large to cross the placenta.

  • Stays in the blood.

IgA components

• Makes up about 12% of immunoglobulin.

• Small amount in blood (Monomeric) but very abundant in mucus membrane secretions.

• Secretion IgA consists of 2 monomers held together by a J chain (join chain) which has a secretory component (protects against proteolytic cleave).

• Guards entrance into the body by binding to antigens on microorganisms before they enter the blood.

• Immune barrier.

Where are igA usually found?

• Small amount in blood (Monomeric) but very abundant in mucus membrane secretions.

• High concentration in colostrum where it provides mucosal immunity.

IgD components

• Found on B-cell membranes (BCR) like IgM.

• Is rarely secreted.

• It may help initiate immune responses and some allergic reactions.

• In addition, IgD levels rise in some autoimmune conditions.

Where is IgD usually found?

• on B-cell membranes (BCR) like IgM.

IgE components

• High Affinity for receptors on the plasma membranes of
  basophils in the blood or mast cells in the tissues (via
  tissue binding site).

• The antigen-binding sites is free to bind antigens to
  which humans can develop allergies, such as drugs,
  pollens, and certain foods.

• When IgE is triggered by an antigen, the associated
  basophils or mast cells secrete various inflammatory
  mediators, such as histamine, which produces allergy
  symptoms.

• High levels in body fluids and skin/tissue.

• Rare in the blood.

Where us IgE usually found?

• on the plasma membranes of basophils in the blood or mast cells in the tissues

• High levels in body fluids and skin/tissue.

• Rare in the blood.

B cell receptors components

• Composed of IgM or IgD antibodies.

• They do not span the full
  membrane.

• They work by signal transduction
  using the accessory proteins (Ig-
  a/Ig-b to transmit the signal

2 B cell activation components

1. T-cell dependent B-cell activation
   Vs.

2. T-cell independent B-cell activation

T-cell dependent B-cell

activation

• T-cells required

• Memory cells generated

• IgM and IgG produced

T-cell independent B-cell activation

• No T-cells required

• No memory cells generated

• Only IgM produced

T-cell dependent B- cell activation components

• B cell receptor binds antigen --> internalized via endocytosis.

• The internalized antigen is broken down and presented on B-cell MHC class II and move to the B-cell surface.

• The presented antigen is recognized by CD4 helper T cells.

  • The activated TH2 cells release cytokines that stimulate proliferation of B cells.a

T-cell dependent B- cell activation components CONTINUED

• After several round of replication, the activated TH2 cells stimulate production of memory B cells. Subsequent exposures.

• First class of antibodies generates are IgM. TH2 will stimulate the plasma cells to generate IgG, IgA or IgE in a process called class switching.

• Class switching occurs using a process of genetic rearrangement of the gene segments encoding one of the antibody regions.

Class switching

occurs using a process of genetic rearrangement of the gene segments encoding one of the antibody regions.

Primary response

• Is the first time the antigen encounters the B-cells.

  • This is a slower response

Secondary response

• is when the antibodies are produced by memory cells.

  • Very rapid and results in clearing the microorganism before you even begin to experience symptoms.

Primary response components

• After B-cell encounter, the B-cell divides to make plasma
  cells.

• Within a few days, antibodies are in the blood.
  Concentration increase over 10 weeks.

• 1st antibodies are IgM (directly binds foreign molecules).

• During T-cell–dependent activation, B cells undergo class switching, usually producing IgG or IgA. These antibodies bind more effectively than IgM.

• As the microorganisms are cleared, antibody production drops.

• B-cell proliferation results in production of memory B-cells (persist in lymphoid tissue). Can survive for months years without dividing.

Secondary Response components

• Antigen is recognized by memory b-cell.

• Because the memory cells are present in high number, they begin making antibodies quicker than 1st response.

• They can also begin dividing quicker and making antibodies in greater quantity faster.

  • IgM is produced before IgG.

  • IgM is produced in smaller quantities over a shorter period. IgG is produced sooner than primary response + in much larger quantities.

  • The secondary response is characterized by a rapid increase in antibodies, most of which are IgG.

Heterogeneity: Diversity

• The ability of the immune system to generate many kinds of antibodies which react to nearly 10 trillion epitopes.

• Humans have only 30,000 genes. How is this possible?

4 types of Antibody Diversity

1. Combinatorial Joining

2. Nucleotide Insertion

3. Splice-site Variability

4. Mutation

Combinatorial joining:

• Segments of DNA are removed during differentiation.

Nucleotide insertion:

During combinatorial joining, nucleotides are
inserted which increases diversity.

Splice-site variability:

CCTCCC + TGGTGG = CCGTGG. Can vary.

Mutation:

• Mutations in that occur during T-helper cell stimulation generate variation in antibodies

Clonal Cell Theory

• Lymphocytes express receptors to distinct antigen, determined before antibody-antigen interaction.

• Binding of antigen to antibody → proliferation of clone daughter cells.

5 Consequence of antibody binding to antigen

1. Precipitation

2. Neutralixsation

3. Complement Fixation

4. Aggulation

5. Osponization

Type I Hypersensitivity (Immediate / Allergy)

• Mechanism: IgE-mediated

• Trigger: Allergens (pollen, peanuts, animal
  dander, etc.)

• Cells involved: Mast cells and basophils

• Onset: Seconds to minutes

• Pathology: Degranulation → histamine
  release → vasodilation, bronchoconstriction

• Examples: Anaphylaxis, allergic rhinitis,
  asthma, hiv

Type II Hypersensitivity (Cytotoxic)

• Mechanism: IgG or IgM antibodies against
  cell-surface or extracellular matrix antigens

• Trigger: Self-antigens or foreign cell antigensCells involved: Complement, NK cells,
  macrophages

• Onset: Minutes to hours

• Pathology: Antibody binding leads to cell
  destruction (lysis), inflammation, or
  dysfunction

• Examples: Hemolytic anemia, Rh
  incompatibility. Graves disease (antibody-
  mediated dysfunction)

Type 1 Hypersensitivity overview

• IgE medicated stimulation of Mast cells.

• Mast cells are degranulated and release histamine.

Type 2 Hypersensitivity Overview

• Cytotoxic reaction that results in
  the destruction of host cells.

• IgG and IgM trigger cells within the
  host.

• This is seen during blood
  transfusion if wrong blood type
  is used.

Transplant and Tissue rejection

• Transplant from a genetically different person within the same species = allografts.

• Transplant from a different species = xenografts (heart valve).

• Typically, reactions do not occur in locations where there is little blood circulating like the eyes or heart valve.

• Unless all MHC proteins are the same between donor and recipient, the transplanted organ can be rejected. For example, like twins.
  • Organ rejection can occur in 1 or 2 ways:
  • Host versus graft disease
  • Graft versus host disease

Host versus graft disease: Self vs. non-self

• This can occur by two different mechanisms involving T
  cells.

  • First: This mechanism relies on the fact that MHC molecules on the surface of transplanted organs are different from those of the host.

    • Donor MHC class 1 are recognized as non-self by cytotoxic T-cells. CTL will destroy the donated tissue.

  • Second: Here, the T-helper cells recognize foreign MHC molecules and are triggered to release cytokines.

    • Cytokines will stimulate the recruitment
      of macrophages.

    • Macrophages will enter the graft and stimulate destruction of the organ.

    • It is nearly impossible to get 100% MHC I and II matching.

    • Match as close as you can, then treat
      receiving patient with immunosuppressors.

Graft versus host disease

• Here, the host cells are attached by the transplanted organ.

• Typically seen in bone marrow transplants.

• The foreign marrow recognizes the host as being foreign and mounts an immune response against their cells.

• Because bone marrow transplant include the introduction of stem cells, more matching criteria needs to be met.

• Still followed up with immunosuppressor drug