Humoral Immune Responses in Immunology

Humoral Immune Responses

• B cell activation leads to proliferation and differentiation into plasma cells (antibody secreting) and memory cells
• T cells assist in B cell activation in T-dependent antibody responses
• T-independent responses are less conventional, and involve B cell activation directly by certain antigens

Primary and Secondary Humoral Immune Responses

• Responses to protein antigens differ in magnitude and quality between primary and secondary exposures
• Primary responses are slower and less effective
• Secondary responses are faster, more robust, and involve higher affinity antibodies due to memory cells

Antibody Delivery to Follicular B Cells

• Antigens can reach follicular B cells via direct entry, transport by antigen presenting cells, or through lymph nodes
• Follicular B cells are specialized for antigen capture and processing

B Cell Activation

• B cells are activated by antigen binding to the B cell receptor (BCR)
• BCR triggering can be augmented by complement receptor 2 (CR2) and Toll-like receptors (TLRs)
• These receptors recognize specific molecular patterns present on pathogens

Effects of BCR Engagement

• BCR engagement initiates B cell proliferation and differentiation
• Multivalent antigens trigger stronger signals, leading to rapid division
• Protein antigens require T cell help for effective activation

Humoral Immune Response to T-dependent Protein Antigens

• B cells internalize protein antigens and process them into peptides
• Peptides are presented to helper T cells via MHC class II molecules
• Helper T cells recognize the MHC-peptide complexes and activate specific B cells

Antigen Presentation to Helper T Cells

• B cells present processed antigens to helper T cells, initiating a T-dependent response
• Hapten-carrier conjugates involve B cell recognition of the hapten and T cell recognition of the carrier protein
• Certain haptens can trigger autoimmune reactions, such as hydralazine (causing drug-induced lupus), halothane (inducing hepatitis), and penicillin analogs (leading to autoimmune hemolytic anemia)

Role of CD40L:CD40 Interaction in T-dependent B Cell Activation

• CD40 ligand (CD40L) on helper T cells binds to CD40 on B cells
• This interaction provides essential costimulatory signal for optimal B cells activation

Germinal Center Reaction

• Germinal centers form within lymph nodes during T-dependent responses
• They are specialized structures where B cells undergo affinity maturation, isotype switching, and generate memory cells and long-lived plasma cells
• The germinal center reaction is a complex process of B cell diversification and selection for the most effective immune response

Heavy Chain Isotype Switching

• Activated B cells undergo isotype switching to produce different antibody classes (IgG, IgA, IgE)
• Switching involves DNA recombination and changes in the constant region of the antibody heavy chain
• Each isotype has specialized functions

Affinity Maturation

• B cells undergo somatic mutations in their variable regions, leading to increased affinity for a specific antigen
• This occurs within germinal centers
• B cells with higher affinity antibodies gain a survival advantage

B Cell Selection in Germinal Centers

• B cells compete for limited resources and survival signals
• B cells with the highest affinity for antigens receive better survival signals
• This process shapes the immune repertoire towards high-affinity antibody producers

Membrane and Secreted µ Chains

• Early B cell development involves the production of both membrane-bound and secreted forms of the µ chain of IgM
• This allows B cells to express IgM as a receptor and later secrete it as a soluble antibody

Antibodies (Immunoglobulins)

• Antibodies are glycoproteins produced by B cells
• They bind to specific antigens and trigger effector functions
• Effector functions include neutralization, inflammation, phagocytosis, complement activation, and direct cell killing

Antibody Structure

• Antibodies have a basic structure of two identical heavy chains and two identical light chains
• Light chains are either kappa (κ) or lambda (λ)
• Each chain contains Ig domains, folded units responsible for structure and function
• Each antibody has a variable region (V region) and a constant region (C region)

Hypervariable Region of Immunoglobulins

• The V region is responsible for antigen binding
• It contains hypervariable regions called complementarity-determining regions (CDRs)
• CDRs are crucial for antigen recognition and specificity

Antigen-Antibody Binding

• CDRs on the antibody interact with the antigen through shape and chemical complementarity
• This interaction is highly specific

General Features of Antibody Structure

• All antibodies share a core structure of two heavy chains and two light chains
• Heavy and light chains have domains
• Domains are independently folded units of about 110 amino acids, containing conserved sequences and disulfide bonds

Antibodies Characterization

• Antibodies can be analyzed using gel electrophoresis
• Under non-reducing conditions, antibodies migrate as intact molecules
• Under reducing conditions, the disulfide bonds are broken, separating the heavy and light chains

Features of Immunoglobulin Binding Antigen

• Antibody binding is specific and saturable
• Antibody binding follows the law of mass action
• Antibody binding can be affected by pH and temperature

Human Immunoglobulin Repertoire

• Humans produce a vast array of antibodies, each with unique antigen specificity
• Antibodies are classified into isotypes based on their C region of the heavy chain
• The five main antibody isotypes in humans are IgM, IgD, IgG, IgE, and IgA

Human Antibody Isotypes

• Antibodies can switch isotypes through genetic recombination
• Switching is irreversible and changes the effector functions of the antibody
• The isotype switch is triggered by external signals, such as cytokines

Clonal Expansion

• Lymphocytes exposed to their specific antigen undergo clonal expansion
• This increases the number of antigen-specific cells, allowing the immune system to keep pace with rapidly dividing pathogens

Memory

• Repeated exposure to an antigen generates memory cells
• Memory cells are more efficient at responding to the antigen than naïve lymphocytes
• Memory cells produce antibodies with higher affinity than those produced in the primary response

Changes in Antibody Structure during Immune Response

• Antibodies undergo changes in structure during the immune response
• These changes lead to increased affinity and altered effector functions
• Antibody structure can reflect the history of exposure to antigens

Monoclonal Antibodies

• Monoclonal antibodies are produced from a single clone of B cells
• They recognize a single antigenic determinant
• Used in research, diagnostics, and therapeutics

Revised Monoclonal Antibody Nomenclature

• A revised nomenclature scheme for monoclonal antibodies was developed in 2017
• This scheme helps to standardize the naming of monoclonal antibodies

Limitations of Monoclonal Antibodies

• Not orally bioavailable, requiring injection for administration
• Difficult to target intracellular targets due to barriers
• Can elicit anti-drug antibodies (ADA) if recognized as foreign by the immune system
• Manufacturing can be challenging due to the complexity of the molecules

Anti-Drug Antibodies (ADA)

• ADA can neutralize monoclonal antibodies and reduce their effectiveness
• ADA can also lead to side effects
• ADA can occur in patients receiving monoclonal antibody therapies

Recombinant Antibodies

• Recombinant antibodies are produced using genetic engineering techniques
• They are designed to reduce immunogenicity
• Often used as therapeutic antibodies

Recombinant Antibodies: Anti-CD20

• Rituximab is a chimeric antibody targeting CD20 on B cells used in non-Hodgkin lymphoma
• Ofatumumab is a fully humanized anti-CD20 antibody used in chronic lymphocytic leukemia (CLL)
• Obinutuzumab is a glycoengineered anti-CD20 antibody with improved efficacy compared to rituximab

Second and Third Generation Anti-CD20 mAbs

• Second-generation anti-CD20 antibodies are humanized to reduce immunogenicity
• Third-generation anti-CD20 antibodies have engineered Fc regions to increase their binding affinity for FcγRIIIa receptors
• Third-generation antibodies are under development for improved cancer treatment

Explore the intricate processes of humoral immune responses, including B cell activation, proliferation, and the differences between primary and secondary immune responses. This quiz delves into the roles of T cells, antigens, and how antibodies are delivered to follicular B cells.