B Cell Activation and Humoral Immune Responses Study Notes

B Cell Activation and Humoral Immune Responses Study Notes

Instructor and Course Overview

  • Instructor: Dr. Francina Towne

  • Course: IHL Course, RVU

  • Class: Class of 2029

  • Main Topic: B Cell Activation and Humoral Immune Responses

Quick Review of B Cell Development Phases

  1. Graduate to the periphery

  2. Pre-BCR “check” on surface

  3. Heavy chain rearrangement

  4. Expression of IgM BCR on the surface of the cell

  5. Light chain rearrangement

  6. “Check” for recognition of self in the bone marrow

  7. Correct Order Provided: C, B, E, D, F, A

Quiz Yourself: Negative Selection of B Cells

  • Negative selection importance:

    • Prevents an overabundance of circulating B cells competing for resources.

    • Only antigen-activated B cells leave the bone marrow.

    • Clonal expansion of B cells only occurs in response to infection.

    • BCRs that bind to normal body constituents are eliminated to prevent self-reactivity.

    • B cells do not leave secondary lymphoid tissues unless activated.

Purpose of Today's Lecture

  • Learn about:

    • Activation of B cells and their transformation into antibody-secreting plasma cells.

    • Regulation of B cell activation to ensure production of appropriate antibodies that target specific organisms.

    • The role of antibodies in combating infections in various body regions.

Reading Assignments

  • Basic Immunology: Functions & Disorders of the Immune System, by Abbas & Lichtman

    • Focus on Chapters 7 and 8: Humoral Immune Responses and Effector Mechanisms of Humoral Immunity

Chapter 7 Objectives - Humoral Immune Response

  1. Distinguish the different stages of B cell development.

  2. Describe the mechanisms of B cell activation (Thymus-Independent (TI) & Thymus-Dependent (TD)).

  3. Define Thymus-independent antigens and their role in B cell activation without T cell help.

  4. Discuss the immune system's process for selecting appropriate B cells for proliferation.

  5. Explain isotype switching, the importance of the switched region, and somatic hypermutation (SHM).

  6. Understand affinity maturation and the role of Follicular Dendritic Cells (FDCs) in T-dependent immune responses.

  7. Differentiate between plasma cells and B memory cells.

  8. Define polyclonal response.

Chapter 8 Objectives - Effector Mechanisms of Humoral Immunity

  1. Draw and describe the structure of immunoglobulin (Ig).

  2. Identify the five classes of antibodies, their locations, and typical forms (pentamer, dimer, monomer).

  3. Describe the role of the J chain in antibody functions and consequences of its absence.

  4. Discuss the primary and secondary immune responses, isotype switching, and their implications.

  5. Explain the functions of humoral immune responses, including neutralization, opsonization, complement fixation, and antibody-dependent cellular cytotoxicity (ADCC).

  6. Describe linked recognition in immune responses.

Overview of Lymphocyte Development

  • Lymphocyte types: B lymphocytes, T lymphocytes

  • B cells mature in the bone marrow and recirculate to lymph nodes and other peripheral lymphoid organs.

    • Key markers of mature B cells:

    • B cell receptors (BCR): Ig, Iga, Igb

    • Co-receptors: CD19, CD21 (CR2), CD80 (B7)

    • MHC I and II, CD40, CD20

Definition of Humoral Immunity

  • A branch of adaptive immunity mediated by B cells and antibodies produced by plasma cells.

  • Primary defense mechanism against extracellular pathogens.

B Cell Activation Overview

  • B Cells Response:

    • Respond to two types of antigens:

    • Thymus-independent (TI) antigens

      • Do not require T cell help, induce direct B cell activation.

      • Typically do not produce memory cells.

    • Thymus-dependent (TD) antigens

      • Require T cell help and significantly enhance humoral immune response, enabling memory cell formation.

Activation Steps in B Cells and T Cells

  1. Activation in LN (Lymph Nodes):

    • Naive CD4+ T cells activated by antigens from dendritic cells.

    • Activated B cells are trapped in T-cell zones.

    • B cells present antigen to T helper cells to form cognate interactions.

  2. Complete B Cell Activation Requires Three Signals:

    • Signal 1: BCR binding antigen and presenting it on MHC.

    • Signal 2: Interaction between MHC/TCR and CD40L/CD40.

    • Signal 3: Cytokines such as IL-2, IL-4, or IL-5.

    • Note: Lack of Signal 2 leads to B cell anergy (peripheral tolerance).

Step-by-Step B Cell Activation Through T Cells

  1. Antigen/BCR crosslinking (Signal 1).

  2. Antigen internalization and presentation via MHC II.

  3. B7 co-stimulation and formation of the B/T cell conjugate.

  4. T cell activation occurs; CD40L expression initiates Signal 2.

  5. Cytokine production (Signal 3) leading to B cell activation and proliferation.

  6. Clonal expansion of activated B cells.

T Cell Help for B Cells

  • When activated T helper cells encounter antigen-binding B cells, they upregulate CD40L, promoting B cell activation.

  • Cytokines from T cells induce heavy chain class switching and enhance B cell differentiation and proliferation.

Comparison of T Cell and B Cell Activation

  • T Cell Activation:

    • Involves recognition of MHC I-bound peptides via CD8 TCR.

    • Requires co-stimulation through B7 and CD28, and cytokines.

  • B Cell Activation:

    • Involves binding of native antigens via BCR.

    • Requires specific signals from T helper cells for optimal activation.

Memory B Cell Development

  • Crucial steps: isotype switching, clonal expansion, somatic hypermutation, and affinity maturation take place during germinal center formation.

Isotype Switching

  • T cells induce B cells to switch their isotype to better respond to antigens.

    • Specific constant regions such as IgM to IgG are changed while maintaining antigen specificity (VDJ variable region stays unchanged).

    • Cytokines like IL-4 and IFNg drive switches to IgE and IgG2a, respectively.

Somatic Hypermutation (SHM)

  • Random mutations occur about a week after immunization, selecting for high-affinity variants.

  • Mechanism requires transcription and activation-induced cytidine deaminase (AID).

Affinity Maturation

  • The goal is to produce the highest affinity antibodies, relying on competition among B cells for antigen presented by Follicular Dendritic Cells.

Polyclonal B Cell Response

  • Multiple B-cell lineages recognize different antigens on a given pathogen, leading to a polyclonal response that enhances clearance efficacy.

Immunoglobulin Classes and Functions

  • Types of Immunoglobulins:

    • IgM: Pentameric; primary response, highest complement activation.

    • IgG: Most abundant antibody in blood; important in secondary responses.

    • IgD: B cell surface expression, unsure of function in serum.

    • IgA: Dimeric in secretions like mucus; first line of mucosal protection.

    • IgE: Plays a key role in allergic reactions and parasitic infections.

Key Functions of Antibodies

  1. Neutralization: Block entry of pathogens into cells.

  2. Opsonization: Enhance phagocytosis via Fc receptor engagement.

  3. Complement Activation: Trigger lytic pathways against pathogens.

  4. ADCC: Direct killing of antibody-coated cells by NK cells.

Mechanisms of Waste Management

  • Immune complexes cleared by erythrocyte CR1 receptors to remove waste from circulation effectively.

Linked Recognition Concept

  • Linked recognition allows T cell help for B cells specific to non-protein antigens when paired with carrier proteins, facilitating memory formation.

Critical Thinking Prompt

  • Evaluate which proteins expressed by the influenza virus may generate stronger immune responses.

Conclusion

  • Understanding B cell activation, differentiation, and antibody production is crucial for therapeutic applications and developing effective vaccines against pathogens.