Microbiology Module 13.2

• B-Cell and Antibodies
• T-Cells and T-Cell Receptors
• MHC ( major histocompatibility Complex)
• Macrophage-like cells bridge innate and adaptive systems using MHC molecules

B-Cells mature in bone marrow and circulate w/surface IgM until they encounter antigen, spending most of their time in lymphatic structures (nodes, spleen, etc.)

Lymphatic system circulate in and out of the blood. One-way system

Once antigen is encountered, they produce many kinds of Ig's and long-lived memory cells

Self reactive B-Cells are neutralized in bone marrow. By definition Ig's on B-Cells are only made toward foreign entities

T-Cells produced in bone marrow but migrate to thymus where they mature into several types of diff. functions

Also circulate until they encounter antigen, spending most of their time in lymphatic structures as B-Cells

Self-reactive T-Cells are destroyed in thymus

Function is to produce antibodies to mark foreign antigens for destruction or to neutralize their ability to function

• Each antigen can have many antigenic determinants or EPITOPES (make direct contact with Igs)
• Epitopes are 3D regions of antigen, size: 10-15AA
• Antibodies that bind to antigen undergo conformational changes that activate effector functions

All Igs contain 2 identical heavy and 2 identical light chains

Heavy and light chains contain variable and constant regions

Variable regions from 1 heavy and 1 light chain combine to form antigen-binding sites

Fc regions responsible for special effector functions (complement fixation, opsonization. Only activated (exposed) after antigen is bond

Light chain genes randomly rearrange to bring single variable region next to one of several J regions

A single constant region is linke to the J's

Total of over 400 V genes and > 6 J genes

Can have over 2400 diff. combos but only need about 406 diff. coding sequences

Heavy chain genes have 4 segments that are recombined: V, D, J, and C (200 V, 20 D, 6J)

IgM is always the first Ig heavy chain rearragement, using C(u) constant gene and is expressed initially as a membrane protein

Later other constant regions are used by further rearragements to replace C(u) w/other C genes

10^13 total possible H & L antibodies, > 10^8 circulate at any given time

• T-cells bind to antigens via T-Cell receptors.
• Difference between T-cell receptors and Ig is that receptors always work as membrane bound proteins. Only have 2 different chain of equal molecular weight (no L and H)

Each TCR is composed of 2 diff. chains, (A) and (B)

Each chain has constant and variable regions, made by recombinations of genetic segments analogous to Ig genes

Variable regions of (A) and (B) chains combine to bind to antigen

T-cell w/ "functional" TCRs mature in thymus into several types

Helper T-cells- T(h)0 have surface CD4 proteins and cytotoxic T-lymphocytes (CTLs) have surface CD8 proteins

Any T-cell w/a TCR that binds to a self-antigen is eliminated

MHC molecules found on ALL cells, help immune system fo focus on foreign invaders (viruses, microbes, cancer)

ALL MHC molecules bind to potential intracellular antigens and transfer them to cell surface

• Class 1 MHC: loaded w/molecules from ER, typically will be antigenic only in virally infected/cancerous cells
• 2 chains: MHC and B-Microglobulin

Class 2 MHC: loaded with peptides from the phagolysosome (usually antigenic)

MHC molecules are plymorphic and each cell co-expresses 6 diff. molecules/pairs, 3 from each parent

Class 1 MHC proteins found on all nucleated cells and responsible for graft rejection

Class 2 MHC proteins found ONLY on antigen-presenting cells (APC's) of immune system (macrophage-like cells, B-cells)

Phagocytosis by macrophage-like antigen-presenting cells (APC's)

Antigen presentation on Class 2 MHC molecules and debris are expelled

T(h)0 cells bind via several interactions of T-cell and APC: TCR-antigen, CD4-MHC 2, CD28 and B7

T(h)0 are then activated to proliferate & differentiate into T(h)1, T(h)2, other types, all w/same TCR as original T(h)0

Various memory cells produced

B-cells have IgMs that bind to EC debris from macrophage-like cells

Debris is internalized (phagosomes --> phagolysosomes)

B-cells are APCs that load Ag from phagolysosomes onto MHC2 molecules

T(h)2 cells bind to Ag/MHC2 molecules on B-cells, CD4-MHC2 also occur

Cytokines (signaling molecules) are produced, large amounts of Ig's are secreted by activated plasma cells

Interactions of macrophages, B-cells and T-cells all occur in lymph nodes

After B-cell activation B-cells secrete IgM and divide

Some B-cell progeny further rearrange genes to make new classes of H-chains= class switch

Memory B-cells produced: long-lived, have surface Ig and will immediately secrete antibody after future encounters with antigen

IgGs and IgMs fix complement and bond to receptors on phagocytic cells, IgAs are found in secretions, IgEs mediate allergic responses

All classes deactivate and inhibit pathogen binding to cell surface

T-Cells that kill any cells that are virally infected

Must have 2 encounters w/Ag: First a T(h)0 cell interacts with APC, producing a T(h)1

Then the T(h)1 must interact w/an APC, producing cytokines that pre-activates CTLs

CTLs circulate to locate host cells w/cognate Ag, then kill the infected cells

Binding of activated CTL requires CD8-MHC1 binding in addtion to TCR-Ag

CTLs kill transformed or infected cells by secreting perforins (self assembling proteins that make pore on infected cells and lyse them), granzymes (trigger suicde pathways) or via CD95L-CD95 (found on most cells) interaction

Granzymes triggers apoptosis of host cells

CD95/FAS is common surface molecule; CTLs release CD95L/FASL in microvesicels, triggering apoptosis

Dendritic cells are super APCs derived from 2 separate lineages (myeloid and lymphoid)

Are able to directly activate CTLs via Ag-presentation on MHC1 molecules (no T(h)1 intermediate involved)

Cytokines are soluble proteins made and released by one cell that acts as signaling molecules

Many diff. types of cytokines

Maybe involved in anti-inflammatory and immunosuppresant research.

Some are chematactic, induces apoptosis, proliferation, etc.