BMS172 Adaptive Immunity & MHC

• Adaptive immunity and MHC Module: Foundations of Immunology BMS172

Instructor Information

• Contact the instructor, Professor Doctor Mohammed Mahmoud El-Naggar at [email protected]
• The department is Medical Microbiology and Immunology
• The instructor's mobile number is 01126625177
• Academic hours are Sundays from 10:00 AM to 12:00 AM

Learning Outcomes

• Describe types of adaptive immunity
• Identify functions of antibody isotypes
• Compare primary and secondary humoral immune responses
• Identify types of cell-mediated immunity
• Define MHC
• Describe MHC classes
• Describe MHC structure
• Describe MHC distribution
• Describe MHC function

Lecture Outline

• Types of adaptive immunity (humoral and cellular)
• Primary and secondary humoral immune response
• Types of cell-mediated immunity
• Major histocompatibility complex

Adaptive Immunity Types

• Adaptive immunity includes humoral and cell-mediated immunity

Humoral Immunity

• Humoral immunity is mediated by secreted antibodies
• It defends against extracellular microbes and microbial toxins

Functions of Antibody Isotypes

• Neutralization of microbes and microbial toxins involves antibodies blocking microbe binding to cells, thus preventing infection
• Neutralization involves antibodies inhibiting microbe spread from infected to adjacent cells
• Neutralization involves antibodies blocking toxin binding to cellular receptors, inhibiting toxin's pathological effects
• Antibodies of the IgG isotype coat microbes promoting their phagocytosis by binding to Fc receptors on phagocytic cells like neutrophils and macrophages
• IgG binds to infected cells via Fab regions and to Fc receptors on NK cells via Fc regions, activating NK cells to kill
• IgE binds to helminthic parasites via Fab regions and to Fc receptors on eosinophils via Fc regions which activates eosinophils to release granule contents that kill the parasites

Activation of the Complement

• IgG and IgM activate the complement system

Antibody Function

• Mucosal immunity is where IgA, the major antibody class produced by mucosa-associated lymphoid tissues (MALT) in the GIT and RT, is transported to organ lumens
• In mucosal secretions, IgA binds to and neutralizes microbes and toxins by blocking their entry
• Neonatal immunity is where neonates are protected from infection by maternal IgG antibodies transported across the placenta, and by ingested milk antibodies transported across the gut epithelium

Primary Immune Response

• There is a lag of about 10 days before a specific antibody becomes detectable after the first exposure to an antigen
• The primary response antibody is IgM
• Antibody levels decline after a short time

Secondary Immune Response

• Re-exposure to the same antigen induces a more rapid antibody appearance
• A greater amount of antibody is produced
• The antibody class is IgG
• Antibodies remain detectable for months or years
• Exposure to a different antigen at the same time results in a primary response to the new antigen

Primary vs Secondary Immune Response

• The immune system possesses specific immunologic memory for antigens
• The secondary response is possible because of the immune system possessing specific immunologic memory for antigens
• B lymphocytes become memory cells during the primary response leading to class switching from IgM to IgG during the secondary response

Cell-Mediated Immunity

• Cell-mediated immunity eradicates infections by intracellular microbes
• Naïve T cells activate, proliferate, and differentiate into effector cells e.g. CD4+ T helper cells and CD8+ cytolytic cells (CTLs)
• Then intracellular microbes are eliminated

Types of Cell-Mediated Immunity

• CD4+ T cells differentiate into two effector cell types based on cytokine production by the antigen-presenting cell
• IL-12 leads to Th1 differentiation
• IL-4 leads to Th2 differentiation
• Th1 cells secrete IFN-γ, activating phagocytes to kill microbes
• Th2 cells secrete IL-4 and IL-5, stimulating eosinophil and mast cell degranulation in allergy and helminthic infection
• CD8+ T cells kill cells containing microbes or microbial proteins in the intracellular by direct cell cytotoxicity, eliminating the reservoir of infection

Activation of T Cells

• Peptide + MHC on the surface of APCs are recognized by TCR-CD3
• The interaction of B7 molecules on APCs with CD28 on T cells.
• Exposure of T cells to an antigen in the absence of a second signal i.e. co-stimulatory signal leads to unresponsiveness or anergy

Killing of Infected Cells

• CD8+ CTLs recognize class I MHC + peptides on the surface of infected "target" cells"
• Tight adhesions form between CTLs and target cells
• CTLs are activated by IL-2 and IFN-γ to release their granule contents toward the target cell via exocytosis

Granule Contents

• Perforin forms pores in the target cell membrane
• Granzymes enter target cells through the pores, inducing apoptosis by activating caspases
• CTLs detach from target cells to kill other target cells
• Target cells die

Major Histocompatibility Complex Definition

• MHC is a group of genes on the short arm of chromosome 6
• MHC produces molecules present on cell surfaces
• MHC is responsible for displaying protein Ag to T cells
• MHC is also called human leucocytic Ag = HLA

Classification of Genes

Structure and Distribution of MHC Molecules

• They consist of an extracellular, transmembrane, and cytoplasmic part that anchors the molecule to the cell
• MHC molecules are membrane proteins expressed on cells

Class I Molecules

• Includes two polypeptide chains, an α chain of 3 domains (α1, α2, α3), attached to a β2 microglobulin encoded by a gene outside MHC
• Alpha 1 and alpha 2 domains form the peptide-binding cleft
• Class I presents antigen to CD8+ cells
• Class I molecules are expressed on all nucleated cells

Class II Molecules

• Includes two polypeptide chains, an α chain (α1 & α2) and β chain (β1 & β2)
• Alpha 1 and beta 1 domains form the peptide-binding cleft
• Class II presents antigen to CD4+ cells
• Class II is expressed on APCs only

Case Study

• A 65-year-old man with chronic renal failure received a kidney transplant from a blood group-matched friend
• Two weeks post-transplant, the man's creatinine levels rose continuously and he was told that he would have to go back to renal dialysis

Potential Questions to Consider

• What is the proper diagnosis?
• What test should you concentrate on for the next operation for this man?