Adaptive Immunity and MHC

• The module covers foundations of immunology, specifically adaptive immunity and the major histocompatibility complex (MHC).

Adaptive Immunity Overview

• 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: Antibodies block microbe binding to cells, inhibiting infection and spread, and prevent toxins from binding to cellular receptors.
• Opsonization: IgG antibodies coat microbes, promoting phagocytosis by binding to Fc receptors on neutrophils and macrophages.
• Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): IgG binds infected cells via Fab regions, and Fc regions bind Fc receptors on NK cells, activating them to kill the cells. IgE binds helminthic parasites via Fab regions, and Fc regions bind Fc receptors on eosinophils, causing degranulation and parasite death.
• Complement Activation: IgG and IgM activate the complement system.
• Mucosal Immunity: IgA in mucosal secretions (GIT and RT) neutralizes microbes and toxins by blocking their entry.
• Neonatal Immunity: Maternal IgG antibodies are transported across the placenta, and antibodies in ingested milk protect newborns.

Primary Immune Response

• Upon first exposure to an antigen, there is a lag of about ten days before a specific antibody is detectable.
• The primary antibody produced is IgM.
• Antibody levels decline after a short time.

Secondary Immune Response

• Re-exposure to the same antigen results in a rapid antibody appearance and greater amount.
• The main antibody class is IgG.
• Antibodies remain detectable for months or years.
• Simultaneous exposure to a new antigen leads to a primary response for that antigen.
• The immune system possesses immunologic memory for antigens.
• During the primary response, some B lymphocytes become long-lived memory cells.
• Class switching from IgM to IgG is required for the secondary response.

Cell-Mediated Immunity

• Cell-mediated immunity eradicates intracellular microbes.
• Consists of activating naive T cells to proliferate and differentiate into effector cells, including CD4+ T helper cells and CD8+ cytolytic cells (CTLs), which eliminates intracellular microbes

Types of Cell-Mediated Immunity

• CD4+ T cells differentiate into two effector cells based on cytokine production: IL-12 leads to Th1, and IL-4 leads to Th2.
• Th1 secretes IFN-γ, which activates phagocytes to kill microbes.
• Th2 secretes IL-4 and IL-5 stimulating eosinophil and mast cell degranulation in allergy and helminthic infection.

CD8+ T Cells

• CD8+ T cells kill any cell containing intracellular microbes or microbial proteins through direct cell cytotoxicity, eliminating the reservoir of infection.

T Cell Activation

• T cells are activated by two signals.
• Signal 1: Peptide + MHC on APCs is recognized by TCR-CD3.
• Signal 2: Interaction of B7 molecule on APCs with CD28 on T cells provides a co-stimulatory signal.
• Absence of the second signal leads to T-cells to enter anergy (unresponsiveness).

Steps of CD8+ CTL Killing

• CTLs recognize class I MHC + peptides on the surface of infected target cells.
• Tight adhesions (“conjugates”) are formed with these cells.
• CTLs are activated by IL-2 & IFN-γ to release their granule contents, leading to granule exocytosis.
• Granule contents include perforin, which forms pores in the target cell membrane.
• Granzymes enter cells through the pores and induce apoptosis by activating capases
• CTL detaches to kill other cells
• Target cell death occurs.

Major Histocompatibility Complex (MHC)

• MHC is a group of genes on the short arm of chromosome 6, and these produce MHC molecules.
• MHC molecules are present on cell surfaces.
• MHC is responsible for displaying protein antigens to T cells; it is also called human leucocytic Ag = HLA.

Classification of Genes (MHC)

• Class I MHC genes include HLA-A, HLA-B, and HLA-C and are involved in antigen presentation to Tc cells.
• Class II MHC genes include HLA-D region genes (HLA-DR, HLA-DP, and HLA-DQ) promoting antigen presentation to Th cells.
• Class III MHC genes lie between class I & II and produce some complement components and TNF-α but do not produce MHC.

Structure and Distribution of MHC Molecules

• MHC molecules are membrane proteins expressed on cells.
• Both class I & II molecules consist of an extracellular part, a transmembrane part, and a cytoplasmic part to anchor the molecule to the cell.

Class I MHC Molecules

• Two polypeptide chains form Class I MHC molecules.
• The alpha chain has three domains (α1, α2, α3), attached to β2 microglobulin outside MHC.
• α1 and α2 domains create a cleft or groove that binds to peptides.
• It presents antigens to CD8+ T cells.
• Class I molecules are expressed on all nucleated cells.

Class II MHC Molecules

• Class II MHC molecules are made of two polypeptide chains, an alpha chain (α1 & α2) and a beta chain (β1 & β2).
• The α1 and β1 domains form the peptide-binding cleft.
• Class II is expressed on APCs only.

Additional Information

• B7 molecules on APCs bind with CD28 on T cells during T cell activation.
• Class I MHC presents antigen to Th (CD4), NK, Tc (CD8), monocytes and macrophges.