Second Line of Defense

(Adaptive, Acquired, Specific)

Two ways it can be acquired

Naturally acquired

by (either getting it from an infection, active exposure) or (receiving immunity through mothers)

Artificially acquired

by (either by raising immune response towards antigen through a vaccine) or (by preformed antibodies through the use of serum)

1.) Establishment of infection

2.) Induction of adaptive response

3.) Adaptive Immune Response

4.) Immunological memory

Absense of either the innate or specific immune response

Lacking innate immunity - there will be nothing present to keep the bacteria in check because the specific takes time to ramp up

Lacking specific immunity - the innate immunity will control the infection but can only accomplish so much and will be unable to monitor the bacterials constant growth

Specificity

Memory

Tolerance

Specificity

(component of adaptive immune system)

Immune cells recognize and react with individual molecules (antigens) that are recognized by surface immunoglobulins.

Ex. Immunoglobulins recognize only red antigens vs. blue or yellow

Tolerance

(with regards to specific immune system)

Immune cells are specific for nonself antigens

Immune cells dont touch or harm us

Self-reactive cells are destroyed during development of the immune system

APC's

What are they?

Antigen-presenting cells

Can be either macrophages, dendritic cells, or B cells

Process pathogen components into smaller pieces (antigens)

They present peptide antigens to T-cells through antigen-specific T cell Receptors (TCR)

3 kind of T-Cells

Cytotoxic T-cell - kills antigen bearing cells

T helper cell (TH1) secreted cytokines, activating Macrophages(indirect destruction)

T helper cell (TH2) interact antigen specific B cell stimulating them to make antibodies

B-cell antigen interaction

T-cell antigen interaction

Each B cell has unique antigen receptors

Cell surface receptors and the antibody is specific for a single antigen

When a T cell antigen interacts with a specific B cell it triggers the B cell to make a specific soluble antibody

-these antibodies neutralize, opsonize, and trigger complement activation

Cell-mediated immunity

(Component of Adaptive Immune System)

involves use of T cells only

-TH (T-helper) response

-activation of CTL (cytotoxic T-Lymphocytes)

doesnt involve antibodies or complement

-activates macrophages and NK cells

-stimulation of cells to release variety of cytokines

Humoral Immunity

involves antibodies that are secreted by terminally differentiated B cells (plasma cells) upon activation by antigen

begin life in bone marrow, growth cycle completes in Thymus

2 groupings

alpha/beta T cells that include CD4 and CD8 cells

delta/gamma T cells

Complete maturation in bone marrow

-get activated through antigens from T-cells  which are activated by a specific antigen that attaches to the TLR

What are antibodies (immunoglobulins)?

-They are glycoproteins capable of binding specifically to antigens

Produced by terminally differentiated B cells (plasma cells), in response to immune challenge

Produced in lymph nodes, spleen, and bone marrow and ciruculate in blood and lymph

two Antigen binding sites per immunoglobulin molecule

-each one has heavy and light chain

-Stalk is Fc region, arms is Fab regions

-All have same general structure, although can have some variations.

-Light chains only exist on outside portion of Fab regions, remainding segments are heavy chains

Antibody structure

(continued)

N-termini - located at end of Fab regions

C-termini - located at base of Fc region

Heavy chains are the inner portions of the Fab regions

-Linkage possible through disulfide bonds

Ab H and L chain structure

Upper regions  of H and L chain(variable)

Lower regions of H and L chain(constant)

Both chains have a variable (V) region and a constant (C) region

Variable regions  have a higher degree of variation in amino acid sequence between different antibodies

Constant regions have a limited degree of variation in amino acid sequence b/w different antibodies

Typically bind to intact components of the pathogen surface (glycoprotein,peptidoglycan)

Each antigen binding site binds to a specific part of an antigen called an EPITOPE

Typically bind to extracellular bacteria, virus, or toxins

Neutralization - antibody prevents bacterial adherence (bacterial is inactivated and toxin is neutralized)

Opsonization (Ig1 and Ig3) (Antibody promotes phagocytosis)

Complement Activation - Antibody activates complement, which enhances opsonization and lyses some bacteria. Group of serum proteins when activated participate in a controlled enzymatic cascade which destroy pathogenic organisms by formation of MAC.

IgG, IgA, and IgD have three constant domains

IgM and IgE have a fourth domain

these are blood proteins that circulate the system

IgG

(Serum Antibody)

Most common antibody

-monomer

4 subtypes: IgG1, IgG2, IgG3, and IgG4

IgG1 and IgG3 Odd for Opsonizing

IgG1/IgG3 - most abundant, opsonizing antibody

IgG2-poor opsonizer

IgG3/IgG1- opsonizing antibody

IgG1-IgG3 activates complement, NOT IgG4

IgG neutralizes targets and is the only antibody type that crosses placenta

IgM

(serum antibody)

-evolved a shape that overpower other antibodies

-first appearing serum antibody

-pentamer, five monomers are covalently linked to each other by disulfide bonds and J chain protein

-Pentamer equals bind up to 10 antigens and 5 Fc regions to cross link and activate complement

-Most effective activator of complement

-Binds to exotoxins and neutralizes them

IgE - allergy-associated antibody

(Serum Antibody)

-associated with allergy and metazoal (parasitic) infections

-monomer

-increased levels of IgE during parasitic infection are not always associated with protections against infections

-developed world has much cleaner living conditions (have less presense of IgE)

Secretory Antibodies

IgA (sIgA)

Secretory Antibody

sIgA is a dimer and often found in body secretions as a dimer consisting of two IgA proteins covalently linked to one another by J chain protein.

-A secretory protein component aids in transport of IgA across membrane of mucosal cells

-Fc portions of sIgA can bin to glycoproteins found in mucus

Major role is to attach to incoming microbes or microbial toxins and trap them in the mucin layer preventing them from reaching mucosa.

IgA (sIgA)

continued

Can neutralize but doesnt opsonize or activate complement

sIgA is secreted in breast milk as well as into mucus

-Serves important fucntion of protecting young infants from infections

Avidity

-determines the effectiveness of an antibody

-combination of affinity and valence

TCR consists of an alpha and beta chain anchored in T cell membrane

-Each chain has variable regions (outer segment) and constant regions (inner region anchored to membrane)
-Variable regions form the antigen-binding site

T cells that fight against infection

Cytotoxic T Cells

T helper Cells

T cells that fight intracellular infections

-also called CD8 T or CTL

-They bind to infected cells using CD8 and its TCR which recognize surface displayed antigens

1.) Triggers production of granzymes that trigger the infected cell to enter apoptosis (prog. cell death)

2.) Causes release of granules by the CTL which contain two proteins perforin and granulysin.

-Brought to the site of infection in granzymes that were produced by CTL-binding to the infected cell

-Creates pores in the infected cell membrane killing the host cell

-produced by CTL (CD8) binding to the infected cell and is housed in granzymes until binding occurs.

-Enters subcellular compartments through the pores that were created by perforin.

-Attaches to and kills the bacteria.

T Cells that fight extracellular infection

-also called CD4 or Th cells

-primarily bind to APC using CD4 and its TCR, which recognizes surface displayed antigens

1.) Causes activation and proliferation of T-helper cells, which make cytokines and chemokines that activate cytotoxic T cells and activate macrophages (Th1)

2.) Causes activation and proliferation of T-helper cells, which make cytokines and chemokines that cause activation and proliferation of B cells that make specific antibodies (Th2)

How do T cells "know" which cells to interact with

CD8 found on cytotoxic T cells bind specifically to MHC class 1 molecules (8*1=8)

CD4 found on T helper cells bind specifically to MHC class 2 molecules (4*2=8)

Named b/c they express CD8 glycoprotein on their surfaces

-this protein ensures that the CTL interacts ONLY with the correct cell type- those expressing MHC Class 1 (most cell types in the body that are infected)

CTL unlike NK cells kill intracellular bacteria and only kill cells infected with one kind of pathogen thats mediated by the variable region of TCR

CD4 T cells (Th cells)

Extracellular

-Express CD4 glycoprotein on their surface

-Help other cells to respond to extrcellular infection

-CD4 ensures Th cell interacts with correct cell type

-only those expressing MHC class 2 primarily APC

MHC Molecules

(major histocompatibility complex)

MHC 1: binding and transport of peptide antigens made in cytosol to cell surface for recognition by cd8 t cells.

MHC 2: binding and transport of peptide antigens made in endocytic vescicles to cell surface for recognition by cd4 t cells.

-presents lipids and glycolipid antigens rather then peptide antigens

-four forms CD1a, CD1b, CD1c, CD1d

Processing- pathogen derived proteins are degraded into peptides (within cell) to be recognized by T cells.

Presenting-Binding of the processed antigen (peptide) by MHC molecule and displayed at cell surface.

-APC phagocytoses external forein protein

1.) MHC2 proteins produced in ER assembled with blocking protein (li) preventing MHC2 binding to other peptides

2.)MHC2 containing vescicle fuses with phagolysosome.

3.)Digested peptide antigen loaded on MHC2 and complex is sent to cell surface.

4.)Complex interacts with TCR on Th cell

5.) CD4 receptor engages MHC2 molecule, Th cell becomes activated and releases cytokines and activates appropriate cell types.

-B cell functions as APC through recognizing antigens via BCR.

-Once Th/B-cell bind, cytokines released, cause B-cell to proliferate into plasma cell-> antibodies

-SOME activated b-cells become memory B cells

-Second exposure to antigen quickly converts memory to plasma cell.

T-independent production of antibodies

(for protec. against capsulated bacteria)

-crosslinking of antibodies

-causes Bcell to increase prod. of antibodies

-Lipid/polysaccharide antigens induce immune response not involving T-cells b/c they r characterized by repetitive epitopes that bind to antibodies on B-cell surface

-Cant be elicited in children under age 2

-Produces antibody response ONLYs

-Not strong or long lasting

-Only IgM and IgG2 produced

-

Mucosal Immunity

-not well understood

mucosal surface 1st step for microbe infection

-involves production of sIgA

-harmless to host, b/c occurs in mucin layer

GALT

-includes tonsils, adenoids, appendix, and small intestine (Peyer's Patch)

-collects antigen from epithelial surface of GI tract.

-M (microfold) cells collect pathogen and take it across gut lumen to APC's and Tcells.

-differ from enterocytes, lack microvilli

-get name, have broader microfolds on surface

-antigens released beneath M cells and taken up by dendritic cells or macrophages

Stimulation of memory T and B cells at GALT can migrate to other mucosal sites and vise versa leading to general mucosal immunity

IgA produced by plasma cells in GALT

IgA binds to polylg recepter on basal surface of mucosal cells

-Receptor-bound IgA goes to apical surface in vescicle

-IgA cleaved from receptor.

-portion of receptor remains attached to IgA making sIgA.

-some IgA's produced by plasma cell migrate to other mucosal surfaces

Both defense systems not made till 1-2years of age

-Birth to 1- maternal antibodies transferred through placenta or breast milk (passive immunization)

-Maternal antibodies can interfere with infant's immune system

-Reason why some vaccines given after age 1

-Transition from protection by maternal antibodies to child immune system open time frame where they are really vulnerable.