Innate Immunity

• DR NEGAR SHAFIEI SABET is an ASSOCIATE PROFESSOR at SEGI UNIVERSITY, reachable at [email protected], with an MSc in Medical Microbiology and a Ph.D.

Innate Immunity

• Epithelial barriers are the first line of defense against microbes, including the skin and mucosal epithelium.
• Sentinel cells in blood and tissues, such as tissue DCs, macrophages, and endothelial cells, alert the system when barriers are breached.
• Phagocytes like neutrophils and monocytes are recruited into tissues to resolve problems.
• Plasma proteins like complement and collectins leak into tissues to help.
• The most important effector mechanism of innate immunity upon activation is inflammation
• Inflammation is defined as the recruitment of leukocytes and plasma proteins from the blood to sites of infection and tissue injury.
• Acute inflammation combats extracellular bacterial and fungal infections.
• Acute inflammation includes increased vascular permeability, protein-rich exudate leakage into tissue, and migration/activation of phagocytes to kill microbes and amplify the inflammatory response.
• Histamine causes endothelial cell contraction, creating gaps in blood vessels, enabling proteins to exit.
• Microbes are killed by reactive oxygen, nitrogen species, and proteolytic enzymes.
• Inducible nitric oxide synthase (iNOS) produces nitric oxide (NO).
• Reactive oxygen species are known as ROS.

Phagocytosis and Killing of Microbes

• Microbes attach to phagocyte receptors, the phagocyte membrane encloses the microbe, forming a phagosome, which then fuses with a lysosome to form a phagolysosome.

Complement System

• The complement system is composed of serum and cell surface proteins that work together to eliminate microbes.
• Complement proteins are typically inactive.
• Activation involves a series of sequential proteolysis events of complement proteins, resulting in enzyme complexes with proteolytic activity.
• Regulatory proteins on normal host cells inhibit complement activation, whereas microbes lack these inhibitory proteins.
• Activation results in inflammation (C3a, C5a), opsonization and phagocytosis (C3b), and microbe lysis.
• The classical pathway is activated by certain isotypes of antibodies bound to antigens.
• The alternative pathway is activated by microbial cell surfaces in the absence of antibodies.
• The lectin pathway is activated by a plasma lectin that binds to mannose residues on microbes.
• Cell-bound C3b acts as an opsonin to enhance phagocytosis of coated cells.
• Proteolytic products C5a, C3a, and (to a lesser extent) C4a stimulate leukocyte recruitment and inflammation.
• The MAC lyses cells.

Functions of Innate Immunity

• Innate immunity functions by facilitating inflammation.
• Innate immunity functions by inducing antiviral defense through type I interferon production.
• Innate immunity functions by stimulating adaptive immunity.
• Innate immunity functions by facilitating Phagocytosis/opsonization.
• Innate immunity functions by activating the complement system

Antigen-Presenting Cells (APCs)

• Dendritic cells, macrophages, and B cells are antigen-presenting cells(APCs).
• Dendritic cells initiate T cell activation.
• Macrophages induce the activation of macrophages (cell-mediated immunity).
• B cells induce the activation of B cells and antibody production (humoral immunity).
• Dendritic cells are efficient APCs because they are located at microbe entry sites, express receptors for capturing and reacting to microbes, migrate to T cell zones in lymphoid organs, and convert from antigen capture to antigen presentation/ T cell activation.
• T cells recognize MOLECULES of HLA (MHC; Major Histocompatibility Complex) on the surface of other cells
• T cells don't see antigens in the circulation.
• APCs display antigens
• CD40L enhances APC function, but does not provide costimulatory signals to T cells directly. IL-2 plays key roles in the growth, survival, differentiation and regulation of T lymphocytes.
• IL-2 also plays a key role in maintaining regulatory T cells.

T Cell Activation Signals

• Antigen recognition (first signal): involves regulated movement of signaling receptors and adhesion molecules (immune synapse)
• Costimulators (second signal)

Cytokines

• Cytokines are produced by APCs or T cells, stimulate T cell expansion, and induce differentiation into effector cells.

Phases of T Cell Response

• T Cell Response starts with antigen recognition, then lymphocyte activation, then clonal expansion resulting in differentiation of the T cell Effector functions are
• Activation of macrophages, B cells and other cells; results in inflammation
• Killing of infected "target cells"; macrophage activation

Effector T cell subsets role in Host Defense

• Helps classify the role of subsets CD4+ T helper cell in host defense
• TH1 cells produce IFNy which helps activates macrophages and IgG production for Intracellular elimination of microbes
• TH2 cell produce IL-4, IL-5, and IL-13 activating Mast cells, eosinophil, and IgE production. This eliminate helminthic parasites
• TH17 cells produce IL-17A, IL-17F, and IL-22 activating neutrophilic, monocytic inflammation. This eliminate extracellular bacteria and fungi
• The antigens need to be recognized by T cell (antigen recognition), T cell can see the antigens when it is presented by antigen presenting cells (APC). (Soluble antigen cannot be seen by T cells).
• Antigen presenting cells (APC) have MHC I & MHC II that present antigen to T cell.
• Two signals required for T cell activation, 1st signal goes to T cell by antigen recognition, the 2nd is called costimulation.
• Upon antigen recognition the T cell expresses CD 40 ligand (CD 40 L) that binds to CD 40 on the surface of APC.
• Then costimulation occurs by expression of B7 on APC then B7 will attaches to CD 28 on T cell.
• Then APC start secreting cytokines (IL-2) that will attach to cytokine receptor on the T cell.
• Cytokines helps on proliferation of T cells & differentiation.
• Upon differentiation T cells will be Effectors T cells.

Effector Helper T cells

• Effort Helper T cells help phagocytes to kill ingested microbes & help B cells to make antibodies (activations of Macrophages & B cell) and help with inflammation
• Effector Cytotoxic T lymphocytes (CTLs) kill infected Cells & eliminate reservoirs of infection and activations of Macrophages.
• Regulatory T cells suppress/inhibit APCs or other Lymphocytes.
• Outcome of cell mediated immune response is generation of memory T cells.

Adaptive immunity phases

• Adaptive immunity phases starts with antigen recognition, then lymphocyte activation then antigen elimination. Contraction will lead to memory.
• Humoral immunity and T-dependent responses require antigen recognition by specific B lymphocytes, where multivalent antigens can activate B cells directly through the B cell receptor (BCR), leading to limited isotype switching and no affinity maturation
• Antigen is internalized then presented to T helper cells by B lymphocytes
• Activated B cells differentiate into plasma cells that secrete antibodies, which leads to isotype switching and affinity maturation
• B-cell process occurs.

Humoral Immunity Phases

• Humoral immunity starts with, resting IgM and IgD mature B cells then Antigen will result in, activated B cells with Helper T cells. Followed by Clonal expansion and isotype switching, affinity maturation resulting in plasma cells and memory B cells.

Heavy Chain Isotype Switching involves

• CD40 ligand, CD40,
• IgM+ B cells,
• cytokines,
• Activated B cells.
• Mucosal tissues and cytokines,
• IgM,
• IgG subclasses (IgG1, IgG3),
• IgE,
• IgA.
• Principal effector functions includes Complement activation, FcR-dependent phagocyte responses, immunity against helminths, and Mucosal immunity.

Affinity Maturation

• Involves mutations in immunoglobulin V genes, resulting in selection of high-affinity B cells
• Primary responses are smaller, with IgM > IgG, lower average affinity, and are induced by all immunogens
• Secondary responses are larger, with an increase in IgG and, higher average affinity, and are induced by only protein antigens
• Secondary response, Memory cells produce antibodies with greater affinity to their antigens
• Rapid response time
• A greater number of antibodies are produced

Functions of Antibodies

• Functions of antibodies include, neutralization of microbes and toxins, opsonization and phagocytosis of microbes, antibody-dependent cellular cytotoxicity, phagocytosis of microbes opsonized with complement fragments, inflammation, and lysis of microbes.