1. B cell immunity

2. B-cell activation requires crosslinking of surface immunoglobulin
Activation of B cells usually requires
1) Crosslinking of BCR
2) CD19 co-receptor on B cell
3) CD40 receptor on B cell

3. B-cell activation requires crosslinking of surface immunoglobulin
1) Crosslinking of BCR
IgM molecules in the B cell receptor (BCR) on the surface of the B cell are crosslinked when they bind the epitope on the surface of the pathogen.
(Crosslinking of surface Ig is analogous to T cell receptor clustering in T cell activation.)

4. B-cell activation requires crosslinking of surface immunoglobulin
2) CD19 co-receptor on B cell
The B cell has a co-receptor that is required to give a signal for activation.
The co-receptor is composed of CD19 and 2 other surface molecules.
Binding of the co-receptor to complement components increases the BCR signal by 1,000 to 10,000 fold.

5. B-cell activation requires crosslinking of surface immunoglobulin
3) CD40 receptor on B cell
A co-stimulatory signal from a T cell, given when CD 40 ligand on the T cell binds CD40 receptor on the B cell, is usually needed for the B cell to be activated.

6. Thymus-independent antigens
Thymus-independent antigens (TI antigens)–can stimulate B cells to produce antibodies without T cell help.
TI antigens are usually bacterial surface molecules with highly repetitive epitopes.
The need for the co-stimulatory signal is overridden for one of two reasons:
bacterial components like LPS bind to other receptors on B cells
repetitive epitopes of TI antigens crosslink many BCRs on the cell surface.

7. Thymus-independent antigens
However, because Thymus independent (TI) response doesn’t involve T cells, they do not have the attributes that require T cell help:
No isotype switching.
No somatic hypermutation.
No memory B cell formation.

8. Most TI antigens activate B cells regardless of their antigenic specificity
Mitogens – Nonspecifically activate T and/or B cells
At high concentrations
Polyclonal in nature
B cells
T cells
B and T cells
Bacterial polysaccharides
- Lipopolysaccharide (LPS)
Plant glycoproteins
Concanavalin A (Con A)
Phytohemagglutinin (PHA)
Pokeweed mitogen

9. Nonspecific activation of T cells
Superantigens – Antigens that bind simultaneously to TCR and MHC-II of APC in the absence of a specific peptide antigen.
Example: a) Toxic Shock Syndrome
Staphylococcus aureus
Elicits massive T cell activation
Induces large cytokine release

10. Thymus-dependent antigens

11. Interaction with T cells is required for isotype switching in B cells.
Is initiated by T cell cytokines.
The isotype that a B cell switches to is determined by cognate interactions with helper T cells.
The particular isotypes are determined by cytokines released by the helper T cell.

12. Interaction with T cells is required for isotype switching in B cells.
Isotype switching requires interaction between CD40 receptor on the B cell with CD40 ligand on the T cell.
Hyper-IgM syndrome–a condition in which there are unusually high amounts of IgM and very few other isotypes.
Hyper-IgM is caused by a failure to isotype switch due to the absence of CD40 ligand on T cells.

13. Antibody Effector Functions
Isotype switching diversifies the constant region (Fc region) of the Ig.
The Fc region has 2 functions:
To deliver antibodies to sites that would otherwise be inaccessible.
To link antigen to proteins or cells of the immune system that will cause its destruction.

14. IgM, IgG, and IgA antibodies protect the blood and extracellular fluids.
IgM and IgG predominate in the plasma where they protect the body from septicemia–infections of the blood.
IgG and monomeric Ig A made in the lymph nodes or spleen predominate in the extracellular spaces.
Dimeric IgA is made in the secondary lymphoid tissue underlying mucosal surfaces and predominates in secretions across epithelium including in breast milk.

15. Transfer of antibodies from mother to child
A newborn is protected from pathogens that it will encounter in the environment after birth by passive immunity – the transfer of pre-formed Igs from one individual or organism to another.
Antibodies are transferred from the mother to the baby in two ways:
1) IgA against pathogens to which the mother has been exposed are secreted in breast milk and protect the baby from pathogens in the gut.
2) IgG is transported across the placenta from the mother directly into the blood stream of the fetus.

16. Antibody production is deficient in very young infants.
The mother's IgG is gradually broken down in the infant.
The infant only begins making its own Igs after about 6 months.
Consequently IgGs are lowest in infants between 3 and 6 months.

17. High affinity IgG and IgA are used to neutralize microbial toxins and animal venom.
Toxoids – modified forms of microbial toxins that are used as a vaccination to stimulate a protective response against toxins. Examples: diphtheria toxin, tetanus toxin
High affinity antibodies to toxins prevent them from binding to receptors on the cell surface.

18. High affinity IgG and IgA are used to neutralize microbial toxins and animal venom.
People who have been exposed to animal venoms can be protected through passive immunity by injection with antibodies against the venom.
In this case the pre-formed antibodies are isolated from the serum of large domesticated animals that have been vaccinated with venom.

19. High affinity neutralizing antibodies prevent viruses and bacteria from infecting cells.
High affinity Igs prevent:
Viruses from binding to receptors on cell surfaces.

20. High affinity neutralizing antibodies prevent viruses and bacteria from infecting cells.
High affinity Igs prevent:
Bacteria from adhering to and colonizing the surface of epithelial cells.

21. The Fc receptors of hematopoietic cells are signaling receptors that bind Fc regions of antibodies.
Several different types of hematopoietic cells express Fc receptors that function as signaling receptors that induce a variety of responses.

22. Phagocyte Fc receptors facilitate the recognition, uptake, and destruction of antibody-coated pathogens.
The constant regions of circulating antibodies have low affinity for Fc receptors.
Once antigen is bound the region is capable of forming a strong interaction with Fc receptors on phagocytic cells. These interactions facilitate phagocytosis.
Some bacterial pathogens have adapted to evade phagocytosis and can only be phagocytosed if they have been opsonized with a coating of antibody.

23. IgE binds to high affinity Fc receptors on mast cells, basophils, and activated eosinophils.
The Fc receptor on mast cells, basophils, and eosinophils has such a high affinity for free IgE that they are almost always coated with IgE that is not bound to antigen.
Mast cells are like sentinels posted underneath the mucosa and the skin.
Mast cells, basophils, and eosinophils are filled with granules containing:
Histamines- bronchoconstriction, vascular permeability, gastric and mucus secretion
Inflammatory mediators–molecules that increase vascular permeability allowing molecules of the immune system to move out of the blood and into tissue

24. A mast cell becomes activated when antigens crosslink at least two IgE molecules on its surface.

25. IgE is effective against multicellular pathogens
Multicellular pathogens such as intestinal worms cannot be controlled by the mechanisms that work on microorganisms. However mechanisms involving IgE can be effective.
Inflammatory mediators cause smooth muscle contraction that can expel parasites from airways and the gut.
Increased blood vessel permeability supplies fluid to help flush out the pathogen.

26. Eosinophils can bind IgE on pathogens
If the pathogen stimulates an immune response and becomes coated with IgE,
eosinophils will bind IgE (via Fc receptor) causing them to pour out their toxic contents on the parasite.
In developed countries IgE most frequently lead to detrimental responses to
antigens that result in allergic responses or even anaphylaxis–a systemic life
threatening allergic response.
Anaphylaxis: common signs include difficulty breathing and drop in blood
pressure

27. Natural Killer Cells

28. NK cells provide an early defense against intracellular infections
Natural killer (NK) cells–a second type of cytotoxic lymphocyte.
Do not have T cell receptors or surface Ig.
Have cytotoxic granules.
NK cells:
Provide innate immunity against intracellular infections.
Are activated by cytokines released by macrophages early in infections.
Can terminate or contain infections during the time a CD8 cytotoxic T cell response is developing.

29. 2 things that can target cells for destruction by NK cells
1) Antibodies bound to the cell are recognized by Fc receptors on the NK cell and stimulate antibody-dependent cell-mediated cytotoxicity (ADCC)–the recognition and killing of cells coated with antibody.

30. 2 things that can target cells for destruction by NK cells
2) Reduced levels of MHC class I expression.

31. Complement

32. Complement Tags microorganisms for destruction
Complement system–a system of blood proteins that permanently marks a pathogen or antigen as foreign and targets it for removal by the immune system.

33. Complement components are plasma proteins with various functions.
The complement components are soluble proteins that are produced by the liver.
Many complement components are zymogens–an inactive form of an enzyme.
The initiation of the complement reaction starts a chain reaction that results in successive activation of zymogens by cleavage at specific sites.
Cleavage usually produces two fragments:
The larger fragment usually has enzymatic activity (activates the next component in the reaction.)
The smaller fragment stimulates inflammation.

34. Complement components are plasma proteins with various functions.
The complement system uses 3 different strategies to recognize pathogens, each of which activates the complement pathway:
Classical pathway–triggered by antibodies bound to the surface of the pathogen.
Alternative pathway–triggered directly by components of bacterial cell surfaces.
Lectin-mediated pathway–triggered by mannose binding proteins that are bound to molecules on the surface of pathogens.

35. C3a
(Mannose associated serine protease)
(Mannose binding lectin)

36. The most important and abundant complement molecule is C3.
All 3 complement pathways generate enzymes that act as C3 convertase–an enzyme that cleaves C3.

38. Small peptides released during complement activation induce local inflammation.
The smaller complement components C3a, C4a and C5a are known as anaphylatoxins
Anaphylatoxins induce anaphylaxis, an acute systemic inflammatory response
Order of potency: C5a > C3a > C4a

39. Complement Aids in Phagocytosis

40. Regulatory proteins in plasma limit the extent of complement activation
Various proteins inactivate enzymes at key steps in the complement pathways keeping the chain reaction from getting out of control e.g. C1INH (C1 esterase inhibitor)
Deficiency of C1 esterase inhibitor can cause Hereditary angioedema
Hereditary angioedema