Lecture 7 - Development of the B cell repertoire

• Clonal selection and expansion of B cells

  Unique specificity of each lymphocyte receptor and the activation of lymphocytes upon interaction with a foreign molecule (antigen)
• Clonal selection and expansion of B cells

  1. Each lymphocyte has a single type of receptor with a unique specificity

  2. Interaction between an antigen and a lymphocyte receptor leads to the activation of that lymphocyte

  3. Daughter cells derived from an activated cell have receptors that are identical to those of the parental cell, leading to clonal expansion
• B cell development


  • B cells start their development in the bone marrow
  • Newly formed receptor is assessed for autoreactivity
  • B cells complete their development in the spleen or lymph node
• Newly Formed B cell receptor

  • Always of the IgM subclass
  • Reactivity of the newly formed B cell receptor for host antigens is tested through quality control steps in the bone marrow
• Receptor editing


  1. Immature B cells that express an autoreactive receptor re-initiate rearrangement of the receptor to form a new shape

  2. Immature B cells that express an autoreactive receptor die if the new receptor still has autoreactivity for self-antigens
• Central and peripheral tolerance

  Mechanisms for the immune system to prevent autoimmunity and safeguard the body from itself while maintaining an effective adaptive immune response to microbes
• Immunoglobulins (antibodies)


  Exist as a membrane receptor (B cell receptor [BcR]) that binds antigen, and as a secreted, fluid phase molecule that directs specific immune functions such as complement fixation, opsonisation, and neutralisation
• Structure of immunoglobulins


  • Two heavy chains and two light chains, connected by disulfide bonds and a hinge region
  • Constant regions of the heavy and light chains determine the isotype of the immunoglobulin, such as IgM, IgG, IgD, IgA, and IgE
  • Hyper-variable regions allow for diversity in binding to diverse antigens, following the "lock and key" principle for recognition
• Generation of immunoglobulin diversity

  1. Combinatorial diversity

  2. Heavy and light chain pairing

  3. Junctional diversity facilitated by the enzyme terminal deoxynucleotide transferase (TdT), which adds N-nucleotides to the DNA strand
• VDJ segments


  Variable (V), diversity (D), and joining (J) gene segments that undergo random rearrangement to generate diversity in the antigen-binding site of the immunoglobulin
• 12/23 rule


  Requirement for recombination signal sequences (RSS) with a 12-base-pair spacer to recombine with RSS with a 23-base-pair spacer, ensuring proper recombination of the V, D, and J gene segments
• Recombination activation genes 1 and 2 (RAG1 and RAG2)


  Facilitate the recombination process that results in the formation of a functional B cell receptor (BcR) with a unique specificity for antigens
• B cell development


  1. Occurs in the bone marrow, the spleen or lymph nodes

  2. In the bone marrow, the newly formed receptor is assessed for autoreactivity

  3. Immature B cells that express an autoreactive receptor have the option to re-initiate rearrangement of the receptor or die if the new receptor still has autoreactivity for self antigens
• Central tolerance


  Removal of developing adaptive immune cells with receptors specific for host proteins in the bone marrow
• The development of B cells in the bone marrow is tightly controlled and occurs in stages, resulting in the formation of a B cell receptor, which is always the IgM subclass
• After completing their development in the bone marrow, immature B cells migrate to the spleen to transition into the type of B cell they are to become, either marginal zone (MZ) or follicular (FO)
• Central tolerance also involves quality control steps, such as the testing of the reactivity of the newly formed B cell receptor for host antigens
• The immune system has evolved strategies to protect the body from itself, in addition to protecting it from microbes, through the concept of tolerance