Adaptive Immunity Part 1 & 2

• Adaptive immunity is being discussed
• This is part 1 and 2

Session Objectives

• The session will outline the structure of immunoglobulins and their types
• The session will explain the role of MHC, TCR, and BCR receptor molecules
• The session will discuss how different lymphocytes are activated
• The session will compare and contrast the four types of hypersensitivity reactions
• The session will compare and contrast the humoral and cell-mediated immune responses, discussing the roles of key cells like Th1, Th2, and Th17
• The session will discuss the regulation of the immune response

Molecules of Adaptive Immunity

• Immunoglobulins, also known as B cell receptors (BCR), are key molecules
• Major Histocompatibility Complexes (MHCs) are also essential
• T cell receptors (TCR) play a vital role
• Cellular interactions involve:
  • Cytokines and chemokines
  • Adhesion molecules
  • CD molecules

Immunoglobulins (Igs)

• Immunoglobulins are soluble, humoral molecules specific to an epitope
• Antigen-antibody reactions immobilize, cross-link, neutralize, and opsonize

Antigen-Antibody (Ag-Ab) Reactions

• The precipitin reaction is one type of Ag-Ab reaction
• Agglutination/cross-linking occurs with IgM and IgA antibodies
• Neutralization is achieved with IgG and IgA antibodies
• Opsonization (phagocytosis) enhances the engulfment of pathogens

Immunoglobulin Structure

• Immunoglobulins consist of 4 polypeptides: 2 heavy and 2 light chains, linked by disulfide (S-S) bonds
• There are 5 types of heavy chains: µ, ɣ, α, δ, and ε, known as isotypes
• Papain digestion yields:
  • Fab, the antigen-binding fragment
  • Fc, the constant fragment

Immunoglobulin Isotypes: IgM and IgD

• IgM has two forms:
  • Pentamer when secreted
  • Monomer on the B-cell surface
• IgM is the first antibody produced
• It causes agglutination and immobilization
• IgM activates complement but does not cross the placenta
• IgD is monomeric and functions as a B cell receptor (BCR)

Immunoglobulin Isotypes: IgG and IgA

• IgG is the most common antibody in serum and is found as a monomer on cell surfaces and secreted
• It is the second antibody released
• IgG can neutralize, opsonize, activate complement, and contribute to hypersensitivity and antibody-dependent cell-mediated cytotoxicity
• It crosses the placenta
• IgA exists as:
  • Monomer in serum
  • Dimer in secretions like tears, saliva, and milk
• It is the most produced antibody daily and is associated with mucosal immunity (MALT)

Immunoglobulin Isotype IgE

• IgE is the least common antibody in serum and exists as a monomer
• It binds to mast cells and eosinophils, targeting worms
• IgE mediates immediate hypersensitivity (Type I)

Antibody-Dependent Cell-Mediated Cytotoxicity

• Antibody-dependent cell-mediated cytotoxicity involves:
  • Antibodies tagging bacteria, parasites, or worms
  • Natural killer (NK) cells and eosinophils being attracted to the tagged cells

Hypersensitivity Type I

• It is an immediate reaction mediated by antibodies
• IgE binds to mast cells and basophils
• This type is associated with asthma, allergies, and anaphylaxis

Hypersensitivity Type II

• Type II hypersensitivity is antibody-dependent and involves cell-mediated cytotoxicity
• IgG and IgM interact with cell membranes or extracellular matrix
• Complement and NK cells are involved
• Hemolytic anemia can result from a mismatch
• Binding to the basement membrane leads to inflammation and tissue injury
• Antibodies block function, seen in Graves' disease and Myasthenia Gravis and play a role in rheumatic fever

Hypersensitivity Type III

• Involves immune complexes
  • Circulating antigen-antibody complexes (IgG) lead to vasculitis
  • Localized reactions (Arthus reaction) cause abscesses or necrotizing vasculitis
  • Systemic reactions (serum sickness) can be:
    • Exogenous, triggered by non-human antibodies or drugs, like penicillin
    • Endogenous, such as in systemic lupus erythematosus (SLE)

Major Histocompatibility Complex (MHC) Molecules

• MHC molecules are also known as Human Leukocyte Antigens (HLA)
• There are 3 classes:
  • MHC Class I
  • MHC Class II
  • MHC Class III (complement components)

MHC Class I and II

• MHC Class I:
  • Found on all nucleated cells
  • Functions in self-reporting for viral-infected and tumor cells
  • Includes HLA-A, B, and C, with 100 alleles at each locus
• MHC Class II:
  • Primarily expressed on antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages (MΦ)
  • Also found on B-cells, some activated T-cells, and specialized epithelial cells in the thymus and intestine
  • Involved in antigen presentation

T Cell Receptor (TCR)

• TCR is a heterodimer, either αβ or ɣδ
• It associates with CD3 for signal transduction
• TCR is MHC-restricted, binding peptide fragments associated with MHC I & II, stabilized by CD4/CD8

Cellular Communication

• Cytokines are low molecular weight soluble messengers
• Chemokines are chemoattractant cytokines
• Adhesion molecules include integrins and selectins
• CD molecules:
  • Indicate function
  • Includes over 350 identified molecules
  • Includes CD3, CD4 & CD8

Lymphocyte Activation

• Lymphocyte activation is a time-consuming event with many checks and balances
• The main cell of the adaptive immune response is the T-helper cell
• Antigen presentation via MHC I or II is required for lymphocyte activation, and the TCR must be MHC-restricted

MHC Class II Presentation

• Dendritic cells (DCs) are the main antigen-presenting cells (APCs), acting as sentinels
• Presentation is actin-dependent phagocytosis
• Pattern Recognition Receptors (PRRs) engage Pathogen-Associated Molecular Patterns (PAMPs) which are extracellular antigens
• Antigens can be tagged with antibodies or complement
• Antigens are displayed on Major Histocompatibility Complex II (MHC II)
• MHC II displays both self and non-self antigens which is important for tolerance

MHC Class I Presentation

• Intracellular antigens are tagged with ubiquitin, leading to proteasome destruction
• Fragments enter the endoplasmic reticulum (ER), then the Golgi apparatus, and are displayed on MHC I
• CD8+ cells recognize the MHC I complex

T-Helper Cell Activation (CD4+)

• T-helper cells recognize MHC II-associated antigens
• An immunologic synapse forms between the naïve T-helper cell and the antigen-presenting cell (APC)
• Stabilization occurs via CD28 (a costimulatory molecule) which leads to signal transduction
• Absence of a costimulatory signal leads to anergy or apoptosis

T-helper Cell Differentiation and Function

• First contact with an antigen primes T-helper cells
• T-helper cells differentiate into Th1, Th2, or Th17 cells, influenced by cytokines from antigen-presenting cells (APCs)
  • Th1 cells: produce IFN-γ and IL-12
  • Th2 cells: produce IL-4 and IL-10
  • Th17 cells: produce IL-6 and TGF-β
• Some T-cells become memory T-cells with high expression of CD28

T-Cell Activation (CD8+)

• CD8+ T-cells recognize antigens on MHC Class I, leading to the expression of IL-2R
• It produces perforins and granzymes
• With help from Th1 cells, cytotoxic T-cells are produced

B-Cell Activation

• B-cells recognize antigens in association with MHC Class II or without MHC interaction
• Antigen binds to the B-cell receptor (BCR), leading to endocytosis, followed by antigen presentation on MHC to which CD4+ T-cells and cytokines engage for T-dependent activation
• T-independent antigens directly activate B-cells without T-cell help
  • Ti-1 antigens: polyclonal activators bind to receptors other than BCR, such as LPS, which are B-cell mitogens
  • Ti-2 antigens: multivalent polysaccharides which stimulate only mature B-cells

Arms of the Adaptive Immune Response

• Humoral Immune Response (IR):
  • Involves antibodies (Abs)
  • Targets extracellular pathogens
  • Associated with Type I, II, and III hypersensitivities
• Cell-Mediated Immunity (CMI):
  • Targets intracellular pathogens
  • Associated with Type IV hypersensitivity

Type IV Hypersensitivity

• Th1/macrophage (MΦ) induced inflammation
  • Topical exposure leads to contact dermatitis from substances like poison ivy, TNT, or nickel
  • Injected antigens or delayed-type hypersensitivity (DTH) responses occur 48-72 hours after exposure and are due to microbes like Mycobacteria, Leishmania, Candida, mumps virus, and many fungal skin tests

Immunologic Memory

• Primary (1°) vs. Secondary (2°) Immune Response (IR)
• Subsequent adaptive immune responses feature:
  • Isotype switching
  • Affinity maturation (hypermutations)

Immune Regulation

• Tolerance:
  • Anergy (CD28/B7 interaction)
  • T regulatory cells (Treg) (CD4, CD25 & FOXP3)
  • CD8+ suppressor cells (graft rejection; autoimmune diseases)
• Proinflammatory: Th17 (antagonists of IL-17 are effective in psoriasis)
• Th1/Th2 paradigm