BIOS5050_Week_26_Lecture_1_and_2_slides

Antigen and Antibodies Overview

Definition of Antigen

• Antigens are substances that elicit an immune response, typically comprising proteins or carbohydrates derived from pathogens such as bacteria, viruses, and fungi. These molecules are recognized by the immune system as foreign, triggering the production of antibodies.

Structure of Antibodies

• Antibodies, also known as immunoglobulins, consist of four polypeptide chains, which include two heavy chains and two light chains.

• They have distinct structural regions:

  • Variable (Fab) Regions: These regions are specifically designed for antigen binding, allowing antibodies to recognize a diverse array of antigens. The variability in these regions allows for high specificity towards different antigens.

  • Constant (Fc) Regions: These regions mediate interactions with other components of the immune system, such as binding to receptors on immune cells or complement proteins that aid in pathogen destruction.

Antibody/Antigen Interactions

• Antibody-antigen interactions depend on complementary shapes, sizes, and a range of non-covalent forces including hydrogen bonds, ionic bonds, and hydrophobic interactions, facilitating a strong but reversible binding.

• Bivalent binding, where an antibody binds to two antigen sites, enhances stability (avidity) compared to monovalent binding by increasing the likelihood of remaining attached during immune responses.

Classes of Antibodies

Different Antibody Classes:

• IgG: This is the most abundant antibody in serum, constituting about 75% of the immunoglobulin in the body. It plays a critical role in the immune system by providing the majority of antibody-based immunity against invading pathogens.

• IgM: This antibody is the first type produced during an initial immune response and often exists as a pentamer, which allows it to bind effectively to multiple antigens.

• IgA: Primarily found in mucosal areas such as the gut, respiratory tract, and secretions like saliva and tears, IgA provides a first line of defense against pathogens at mucosal surfaces.

• IgE: Involved in allergic responses and defense against parasitic infections, IgE binds to allergens and triggers histamine release from mast cells and basophils.

• IgD: Functions mainly as a receptor on B cells and plays a role in the activation and regulation of B cell responses.

Production of Secreted IgA

• IgA is the primary antibody class found at mucosal surfaces and is usually secreted in a dimeric form, which binds to a specifically designated receptor for transport across epithelial layers to provide localized immune protection.

Monoclonal vs Polyclonal Antibodies

• Monoclonal Antibodies: These are identical antibodies derived from a single clone of cells and are specific to one epitope, allowing for targeted therapies and diagnostics.

• Polyclonal Antibodies: These consist of a mixture of antibodies produced by different B cell lines, allowing them to target various epitopes on the same antigen, which may enhance the immune response.

Adaptive Immune System Details

• The adaptive immune system includes T lymphocytes, B lymphocytes, and soluble antibodies.

• Function of Antibodies: Antibodies specifically recognize and bind to antigens, flagging them for destruction or neutralization by other immune cells, including phagocytes.

• Vaccination: Vaccines stimulate T and B cells to generate memory, allowing long-term immunity against specific pathogens, exemplified by the eradication of smallpox in 1979 and effective management of diseases like polio.

Antibody Interactions and Strength

Affinity vs. Avidity:

• Affinity: Refers to the strength of binding between a single antigenic site and antibody binding site, crucial for the initial stages of immune recognition.

• Avidity: Reflects the overall strength of binding when an antibody binds multiple identical epitopes, enhancing the binding stability and effectiveness of immune responses against pathogens with repetitive structures.

Mechanism of Antibody Binding

Multivalent Binding:

• Antibodies can bind multiple identical epitopes present on pathogens, which significantly increases bond stability and is essential for efficient recognition and targeting of pathogens.

Important Non-Covalent Forces in Antibody Binding

• Hydrogen Bonds: Formed between electronegative atoms and are crucial for the specificity of antigen binding.

• Ionic Bonds: Created between positively and negatively charged residues, contributing to the strength of the antibody-antigen interaction.

• Hydrophobic Interactions: Driven by water-facilitated clustering of hydrophobic groups, these interactions significantly enhance binding affinity.

• Van der Waals Forces: Weak attractions that occur when electron clouds of closely positioned atoms overlap, aiding in the overall binding process.

Antibody Functions and Effector Mechanisms

Major Effector Functions:

• Neutralization: Prevents pathogens from entering host cells, thereby inhibiting infection.

• Opsonization: Marks pathogens for destruction by phagocytes and enhances their uptake and elimination by immune cells.

• Complement Activation: Triggering of the complement system, leading to lysis of pathogens through the formation of the membrane attack complex.

• ADCC: Involves the triggering of immune cells to destroy pathogen-infected cells directly, utilizing mechanisms that involve interaction with antibodies.

Diversity and Specificity in Antibody Production

Recombination Mechanisms:

• RAG enzymes facilitate the cutting and pasting of gene segments for light and heavy chains, critical for generating a diverse repertoire of antibodies tailored to recognize a vast array of antigens. A lack of RAG enzymes can result in severe immunodeficiency, such as SCID (Severe Combined Immunodeficiency).

Class Switching and Somatic Hypermutation

• Class Switching: This process allows B cells to change their antibody class (e.g., from IgM to IgG) while retaining specificity for the same antigen, enhancing the effectiveness of the immune response.

• Somatic Hypermutation: Introduces mutations in the variable regions of antibodies during the immune response to increase their specificity and affinity towards particular antigens, optimizing the immune reaction.

MHC and Antigen Presentation

MHC Class I and II:

• Class I: Present on all nucleated cells, displaying endogenous peptides to CD8 cytotoxic T cells, which eliminates infected or malignant cells.

• Class II: Limited to antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells, displaying exogenous peptides to CD4 helper T cells for orchestrating adaptive immune responses.

Antigen Processing:

• Cytosolic Pathway for Class I: Involves the degradation of intracellular proteins by proteasomes, followed by transport of peptide fragments to the endoplasmic reticulum (ER) for MHC Class I loading.

• Endocytic Pathway for Class II: Involves the internalization of exogenous antigens, processing within endosomes, and subsequent loading onto Class II MHC molecules for presentation to CD4 T cells.

Antigen Processing Variants and TLR Role

• Immunoevasins: Viral proteins that interfere with MHC molecule processing and presentation to evade immune detection, presenting challenges for immune responses.

• Toll-like Receptors (TLRs): Components of the innate immune system that recognize pathogen-associated molecular patterns (PAMPs) and initiate adaptive immune responses, bridging innate and adaptive immunity.

C1q is an essential component of the classical complement pathway, involved in the immune response upon antibody binding. When antibodies like IgM or IgG bind to antigens on the surface of pathogens, they undergo structural changes that expose binding sites for C1q:

1. C1q Binding in IgM Activation:

   • IgM Structure: IgM is typically found as a pentamer, which allows for efficient binding to multiple antigens.

   • Activation Process: Upon binding to an antigen, IgM undergoes a conformational change that allows C1q to attach.

   • C1 Complex Formation: The binding of C1q leads to the activation of C1r and C1s, forming the C1 complex. C1s then cleaves C4 and C2, generating the C3 convertase (C4b2a).

2. C1q Binding in IgG Activation:

   • IgG Structure: IgG antibodies can exist as monomers but can also form networks when bound to multiple antigens.

   • Activation with IgG: Similar to IgM, when IgG binds to an antigen, it changes shape, allowing C1q to bind.

   • Complement Activation: The C1 complex initiates complement activation by cleaving C4 and C2, also forming the C3 convertase for opsonization and inflammation.

Overall, both IgM and IgG can activate the classical complement pathway through the binding of C1q, leading to a series of proteolytic events that facilitate pathogen elimination and enhance immune responses.

C1q is an essential component of the classical complement pathway, involved in the immune response upon antibody binding. When antibodies like IgM or IgG bind to antigens on the surface of pathogens, they undergo structural changes that expose binding sites for C1q:

1. C1q Binding in IgM Activation:

   • IgM Structure: IgM is typically found as a pentamer, which allows for efficient binding to multiple antigens.

   • Activation Process: Upon binding to an antigen, IgM undergoes a conformational change that allows C1q to attach.

   • C1 Complex Formation: The binding of C1q leads to the activation of C1r and C1s, forming the C1 complex. C1s then cleaves C4 and C2, generating the C3 convertase (C4b2a).

2. C1q Binding in IgG Activation:

   • IgG Structure: IgG antibodies can exist as monomers but can also form networks when bound to multiple antigens.

   • Activation with IgG: Similar to IgM, when IgG binds to an antigen, it changes shape, allowing C1q to bind.

   • Complement Activation: The C1 complex initiates complement activation by cleaving C4 and C2, also forming the C3 convertase for opsonization and inflammation.

Overall, both IgM and IgG can activate the classical complement pathway through the binding of C1q, leading to a series of proteolytic events that facilitate pathogen elimination and enhance immune responses.