Topic 7    B-cell maturation, activation, and differentiation 

Introduction

The marvelous array of deftly interacting cells that defend the body against microbial and viral invaders arises from a few precursor cells that first appear about nine weeks after conception.  From that point onward, the cells of the immune system go through a continuously repeated cycle of development.  The step cells on which the immune system depends both reproduce themselves and give rise to many specialized lineage-B cells, macrophages, killer T cells, helper T cells, inflammatory T cells and others.

Specificity and memory are two properties of an adaptive immune system that evolved to protect us against disease-causing organisms.  Execution of immune responses depends upon coordinated interplay among several components which include instigating antigenic signals, responding cells, and the products of these cells.   We have referred to some aspects of B-cell developmental processes in previous lessons.  Here we describe in sequence, the overall pathway, beginning with the earliest distinctive B-lineage cell.    In the differentiation of  B-cells occurring in the adult bone marrow, the first stage is rearrangement of the V, D, and J genes of the H chain in the germ line DNA and formation of a cytoplasmic ΅-chain.  This event is followed by rearrangement of the genes for L chains and formation of an IgM molecule, which appears on the surface of the cell.  These events define the cell as a B cell with a particular specificity.  Further development depends on exposure to a  specific antigen, which leads to proliferation and differentiation of the B cell into  plasma cells or memory cells.   After these developmental events are described, recent evidence concerning the regulation of B-cell development at various stages is presented.  We show that development and differentiation of at least some of the activated B lymphocytes depends on many different signals.  Finally, we describe the mechanism which protects us against induction of immune responses by self-antigens.

This section is usually found hard by many, because it contains a large amount of very detailed information. Don’t let this discourage you.  In fact, although very detailed and complex, this information is organized into a logical flow.  The developmental steps in B-cell “life time” are temporally and spatially separated. My recommendation is that you divide the process of  B-cell development into smaller parts.  Try to draw an idea map, or a visualizing concept representing the interactions occurring during the particular steps in B-cell activation, maturation or differentiation. Finally you may use multiple, smaller idea maps, to construct a final picture, just like you would with jig- saw puzzle.  I find this method useful because it makes me think about the correct arrangement of interactions. It reinforces the material and emphasizes understanding of it rather than mechanical memorization.   More importantly, very often it makes me notice some of the relations I would otherwise miss.

Objectives

On completion of this section and the required reading, you should be able to:

n  describe the sequential development of the humoral immune response;

n  draw a contemporary model for T cell and B cell macrophage interaction;

n  describe antigen processing and presentation by B cells;

n  outline the sequence of helper (T/(TH)) cell involvement in antibody production;

n  describe the interplay between TH1 and TH2 cells in the development of immune responses.

Required Reading

Please refer to the textbook key for specific readings for this section.   

P Key Words

•    affinity maturation

•    apotosis

•    anergic

•    avidity

•    B-cell coreceptor

•    B-cell receptor

•    clonal deletion

•    capping

•    carrier effect

•    cell mediated immunity

•    Cytotoxic T cells

•    Helper T cells

•    TH1 cells

•    TH2 cells

•    humoral immunity

•    immunologic memory

•    negative selection

•    progression signals

•    perforin

•    plasma cells

•    primary antibody

•    progenitor

•    precursor

•    programmed cell death

•    secondary antibody

•    thymus dependent antigens

•    thymus independent antigens

P Key Concepts

n  Lymphocytes possess receptors that trigger specific immune responses following binding of antigenic determinants for which they have specific affinity.

n  Development of B cells involves antigen-independent maturation in the bone marrow and antigen-dependent activation and differentiation of mature B cells in the periphery, resulting in antibody -secreting plasma cells and memory B cells

n  Modulation of humoral immune responses is achieved by T suppressor cells, genes, antibodies, immune complexes, cytokines, and neuroendocrine products.

n  Antibody diversity is achieved through recombination of variable germline genes, junction diversity, somatic hyper-mutation, and the random pairing of heavy and light immunoglobulin chains.

n  Lymphocytes potentially reactive with “self” are deleted or in some way inactivated.  This ensures that no immune response is mounted against self components.

DID YOU KNOW?

The current understanding of how the various components of the immune system develop is almost completely at odds with beliefs that researchers held only three decades ago.  We now know that all immune systems are derived from a relatively small number of progenitors in the bone marrow and thymus.  Before the 1960s, immunologists thought all the different kinds of cells required for an immune response were produced locally in lymphoid organs such as the spleen, appendix and lymph nodes, which are distributed throughout the body.  That view began to change as a result of animal experiments and clinical observations of immune system dysfunctions. 

Perhaps the earliest of the pivotal events leading to the modern theories of immune cell origin were the atomic bomb attacks on Hiroshima and Nagasaki.  Many people exposed to radiation released by the explosions died 10-15 days later from internal bleeding or infection.  Animal experiments conducted to explore what happened to such casualties revealed that whole-body radiation kills the generative cells in blood-forming and lymphoid organs.  Without the cells responsible for clotting and for fighting invaders, the body dies.

Investigators found that the radiation syndrome could be treated by injecting a small sample of bone marrow cells from a genetically identical donor.  Further work with mice demonstrated that the entire blood and immune systems of mice that recovered from radiation were derived from donor cells.   A fraction of the newly reconstituted bone marrow from these irradiated mice could in turn save other mice exposed to radiation.  Clearly, the bone marrow contained cells capable both of differentiating into all blood lineages and of reproducing themselves.

How the immune system Develops. I. L. Weissman and M.D. Cooper. In: Life, Death and the Immune System, Scientific American - A Special Issue. W.H. Freeman and Company, New York, 1994

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 8.  The answers with explanations are available at the end of the textbook.

2.  Multiple Choice Questions

1.  Put the following in the correct sequence to elicit an antibody response:

A) T-H cell recognizes B cell;

B)  A.C. phagocytizes antigen;

C)  Antigen-digest goes to surface of A.C.;

D) T-H recognizes antigen-digest and MHC;

E)  B cell recognizes antigen.

     A) 1, 2, 3, 4, 5

     B)  2, 3, 4, 1, 5

     C)  None of these

     D) 5, 4, 3, 2, 1

     E)  3, 4, 5, 1, 2

2.  Germinal centers of lymphoid tissues largely contain:

A) macrophages

B)  neutrophils

C)  T-cells

D) B-cells

E)  plasma cells

3.  To induce an immune response, antigen-presenting cells must also secrete

A) IL-6

B)  IL-2

C)  TNF-a

D) IL-1

E)  IFN-y

4.  The B-cell antigen receptor typically consists of

A) CD3 and receptor immunoglobulin

B)    chain and receptor immunoglobulin

C)  Ig-a/B and CD3

D) Iga/B and receptor immunoglobulin

E)  ΅ chain and CD3

 

 

5.  Where in the lymph node are memory cells for antibody production generated?

A) subcapsular

B)  sinusoids

C)  primary follicles

D) germinal center

E)  paracortex

3. Definitions/Short Answer Questions.

1.  List the factors which determine the specificity of B-cells.

2.  Immature B lymphocytes  are the stage in development where contact with antigen may lead to unresponsiveness.  Explain.

3.  Differentiate between thymus-dependent and thymus independent antigens.

4.  Suggest experiments that might be used to determine the life span of memory  B cell.

5.  List the cytokines that are required in order for optimal T-cell-B-cell interaction to occur.

Where to Go from Here

Once you have completed the review, take some time and complete the objectives. If you are having trouble with any of the concepts, contact your instructor.

It is important that you get clarification on any of the topics or concepts that you are having difficulty with as soon as they arise. Many of the concepts build on each other so it is vital that you not only keep up with the schedule, but clear up any questions or problems as they arise. Remember to regularly check your Instructor and Assignment Information for assignments and due dates for completing them.

When you are confident that you can complete the objectives, proceed to the next topic.