Genes and ImmunityGenes and Immunity

Immune response systemImmune response system is remarkably adaptive defense is remarkably adaptive defense system system a. protects against pathogens and cancer a. protects against pathogens and cancer b. immune recognition or b. immune recognition or specificityspecificity is the hallmark of is the hallmark of IRS IRS c. distinguishes between c. distinguishes between selfself versus versus non-self non-self d. effect or response-calls in a variety of cells and d. effect or response-calls in a variety of cells and proteins (B cells, T cells etc) proteins (B cells, T cells etc) e. exhibits e. exhibits memory-memory--protection against second invasion -protection against second invasion    

                                eg polio vaccine eg polio vaccine

Problems with immune system Type I diabetes (B cells and insulin cells are killed by the Type I diabetes (B cells and insulin cells are killed by the immune system) immune system)

Pioneers:Pioneers: Discipline of immunology has its roots in the early observations and Discipline of immunology has its roots in the early observations and experiments by experiments by Edward JennerEdward Jenner and  and Louis PasteurLouis Pasteur (human medicine and (human medicine and veterinary medicine) veterinary medicine)

Edward JennerEdward Jenner, 1898---viral etiology , 1898---viral etiology

country physician country physician smallpox--40-50% fatality smallpox--40-50% fatality observations for almost 20 years--milk maids no pock marks on theirobservations for almost 20 years--milk maids no pock marks on theirbody from small pox body from small pox cowpox--blisters on their hands, did not get small pox cowpox--blisters on their hands, did not get small pox fluid from cowpox blister--inoculated 8 year old boy, waited and inoculated fluid from cowpox blister--inoculated 8 year old boy, waited and inoculated with smallpox--did not get small pox with smallpox--did not get small pox established procedure for preventing smallpox throughout Europe established procedure for preventing smallpox throughout Europe

Louis Pasteur-Louis Pasteur--chance observation--1880, -chance observation--1880,

experimenting with chicken cholera--major disease of chickens experimenting with chicken cholera--major disease of chickens left preparation of cholera bacteria on shelf 2 weeks left preparation of cholera bacteria on shelf 2 weeks injected chickens--did not die--re-injected with live bacteria-did not die injected chickens--did not die--re-injected with live bacteria-did not die 1881--injected sheep with attenuated anthrax--gave live anthrax-did not die 1881--injected sheep with attenuated anthrax--gave live anthrax-did not die

Duality of the IRS:Duality of the IRS:Elie Metchnikoff, 1883 Elie Metchnikoff, 1883 cellular immunitycellular immunity (T cells) (T cells)

Emil von Behring, 1890--Emil von Behring, 1890--humoral immunityhumoral immunity (Ab's) (Ab's)

Today's thinking is that IRS is combination of Today's thinking is that IRS is combination of cellularcellular and andhumoralhumoral                                   

Thymus-Thymus-----------------------T cells (----------------------T cells (cellularcellular)) (T helper/killer)(T helper/killer)

Bone Marrow -----Bone Marrow -----

Bursa Equiv-Bursa Equiv-------------------B cells (------------------B cells (humoralhumoral))

T cellsT cells are present in all areas of the body and ask the are present in all areas of the body and ask the question: question: self or non-self?self or non-self?

Without T helper cells there would be not B cell response.Without T helper cells there would be not B cell response.                       

Take home lessonTake home lesson

These two systems are not independent of each other, but are inThese two systems are not independent of each other, but are inconstant communication..constant communication..

Where do our immune cells come Where do our immune cells come from?from?

  Formation and development of RBC’s Formation and development of RBC’s and WBC’s (leukocytes)and WBC’s (leukocytes)

All blood cells arise from one type of All blood cells arise from one type of cell called the cell called the hematopoietichematopoietic stem stem cellcell

Stem cells have the ability to Stem cells have the ability to differentiate into a number of different differentiate into a number of different cell types.cell types.

They are self renewing and maintain They are self renewing and maintain their populations via division.their populations via division.

The Major PlayersThe Major Players

B cells (Humoral)B cells (Humoral) produce antibodies produce antibodies

which bind to pathogens which bind to pathogens and disable them or flag and disable them or flag them for destruction them for destruction

T cells (Cellular)T cells (Cellular) kill infected cellskill infected cells coordinate entire coordinate entire

adaptive responseadaptive response

Humoral BranchHumoral Branch

Antibodies are immune system-related Antibodies are immune system-related proteins called proteins called immunoglobulinsimmunoglobulins. .

Antibody consists of four polypeptides– two Antibody consists of four polypeptides– two heavy chains and two light chains joined to heavy chains and two light chains joined to form a "Y" shaped molecule. form a "Y" shaped molecule.

The amino acid sequence in the tips of the The amino acid sequence in the tips of the "Y“ varies greatly among different "Y“ varies greatly among different

antibodies.antibodies.

•This variable region, give the antibody its specificity for binding antigen. This variable region, give the antibody its specificity for binding antigen. The variable region includes the ends of the light and heavy chains. The variable region includes the ends of the light and heavy chains.

•The The constantconstant region (Fc) determines the mechanism used to destroy region (Fc) determines the mechanism used to destroy antigen (secondary biological function)antigen (secondary biological function)

fivefive major classes, IgM, IgG, Iga, IgD and IgE major classes, IgM, IgG, Iga, IgD and IgE

IgA about 15% of total antibody countIgA about 15% of total antibody count. Found in mucous secretions and . Found in mucous secretions and mother’s milkmother’s milk

IgD less than 1%IgD less than 1%Appears to have a role in activating and suppressing lymphocyte activityAppears to have a role in activating and suppressing lymphocyte activityFound in large quantities in the cell walls of many B-cells. IgD has a single Found in large quantities in the cell walls of many B-cells. IgD has a single binding site.binding site.

  IgE less than 1%IgE less than 1%

Mediator in allergic responses. Most importantly activates histamine Mediator in allergic responses. Most importantly activates histamine secreting cells. Also appears to play a role in parasitic infection. secreting cells. Also appears to play a role in parasitic infection.

IgG- composes 75% of our immunoglobulin pool.IgG- composes 75% of our immunoglobulin pool. IgG stimulates IgG stimulates high immune response. Most importantly, it is the only antibody that high immune response. Most importantly, it is the only antibody that can cross the placenta and confer immunity on the fetus. can cross the placenta and confer immunity on the fetus.

  IgM - makes up 10% of our total antibodies.IgM - makes up 10% of our total antibodies. This is the predominant This is the predominant

early antibody; the one that first activates in an initial attack of early antibody; the one that first activates in an initial attack of antigen. antigen. Because of its high number of antigen binding sites (5), it is an Because of its high number of antigen binding sites (5), it is an effective agglutinator of antigen . This is important in the initial effective agglutinator of antigen . This is important in the initial activation of B-cells, macrophages, and the complement system.activation of B-cells, macrophages, and the complement system.

Explaining Ab specificity.Explaining Ab specificity.

ImmunoGlobulin (Ig) molecules ImmunoGlobulin (Ig) molecules Thousands on surface of each B cell Thousands on surface of each B cell Ig are essentially just bound antibodiesIg are essentially just bound antibodies

What do Antibodies bind to?What do Antibodies bind to?

An An antigenantigen is defined as "anything that can be is defined as "anything that can be bound by an antibody". This can be an enormous bound by an antibody". This can be an enormous range of substances from simple chemicals, sugars, range of substances from simple chemicals, sugars, small peptides to complex protein complexes such small peptides to complex protein complexes such as viruses. as viruses.

In fact antibodies interact specifically with relatively In fact antibodies interact specifically with relatively small parts of molecules. These are known as small parts of molecules. These are known as antigenic antigenic determinantsdeterminants or or epitopesepitopes..

Antibody diversityAntibody diversity

How is this astonishing diversity How is this astonishing diversity generated? generated? This problem has been resolved over This problem has been resolved over the past 20 years by the the past 20 years by the demonstration that demonstration that Ig genes Ig genes rearrangerearrange during B cell during B cell development. development. light chains- two types k or λlight chains- two types k or λ

contain V J C gene segmentscontain V J C gene segments Rearranged V J segments encode the Rearranged V J segments encode the

variable region of the light chain.variable region of the light chain.

heavy chain family contains V D J C heavy chain family contains V D J C genes segmentsgenes segments

Rearranged V D J segments encode the Rearranged V D J segments encode the variable region of the heavy chain.variable region of the heavy chain.

Pairing of different combinations Pairing of different combinations of Ig heavy and light chains. of Ig heavy and light chains. Recombination of V, D and J Recombination of V, D and J segments (VJ for light chains)segments (VJ for light chains) Together these potentially Together these potentially generate some 5x10generate some 5x1066 different different antibodies.antibodies.

Cellular BranchCellular Branch

T cellsT lymphocytes constitute the "cellular" arm of immunity.

There are two major subsets of T lymphocytes that differ There are two major subsets of T lymphocytes that differ in in functionfunction

Specificity of T cellsSpecificity of T cells

Each T cell has a unique Each T cell has a unique surface molecule called a T surface molecule called a T cell receptor (TCR)cell receptor (TCR)

Specificity through similar Specificity through similar process of DNA splicing...process of DNA splicing...Like Ig’s, each cell’s TCRs Like Ig’s, each cell’s TCRs recognizes a unique pattern recognizes a unique pattern (10^7 TCR types)(10^7 TCR types)

TH cells are activated and proliferate only TH cells are activated and proliferate only when presented with the antigen via when presented with the antigen via self self MHC.MHC.

MHC genes are organized into regions that MHC genes are organized into regions that encode 3 classes of moleculesencode 3 classes of molecules

Class IClass I – present on the surface of nearly all – present on the surface of nearly all nucleated cells.nucleated cells.Major function is to present antigens to Tc cellsMajor function is to present antigens to Tc cells

Class IIClass II – present on APC’s – present on APC’s Major function to present antigens to TH cellsMajor function to present antigens to TH cells

APC –Dendritic Cells (can present with APC –Dendritic Cells (can present with either class I or class II). They are the major APC either class I or class II). They are the major APC

in our bodyin our body MacrophagesMacrophages

Establishing Self ToleranceEstablishing Self Tolerance

T cells originate in the bone marrow then migrate to the T cells originate in the bone marrow then migrate to the TThymus where they maturehymus where they mature

Selection of T cells through binding to common MHC-self Selection of T cells through binding to common MHC-self peptides in thymuspeptides in thymus

strong binders are killed (clonal deletion)strong binders are killed (clonal deletion) weak binders die from lack of stimulation (clonal selection)weak binders die from lack of stimulation (clonal selection) They then go on to make either Tc or TH cells, but 95% of all They then go on to make either Tc or TH cells, but 95% of all

cells entering the thymus undergo apoptosis. cells entering the thymus undergo apoptosis.

Remaining T cells are not self-reactiveRemaining T cells are not self-reactive

Bringing it all togetherBringing it all together

Typical Immune Typical Immune ResponseResponse

Ex. Polio Ex. Polio

Initial response started Initial response started out by IgM out by IgM

IgG activated later IgG activated later

Low ResponseLow Response

IgMIgM response. response.

T cell independentT cell independent

Taking a closer look at Taking a closer look at cell involvement.cell involvement.

Clonal ExpansionClonal Expansion

High ResponseHigh Response

T cell dependentT cell dependent

IgG now becomes IgG now becomes involvedinvolved

How do T cells get How do T cells get involved in the IRS?involved in the IRS?

In order for a T cell to get involved in the IRS, it needs to be presented the antigen in a very specific manner. This is made possible via presentation of the antigen by an Antigen Presenting Cell (APC)•Macrophages •B cells•Dendritic cells

Sequence of EventsSequence of EventsAg recognized by Ab on B cellAg recognized by Ab on B cellIngested by (APC), immunogen Ingested by (APC), immunogen broken downbroken downSelect peptides of immunogen Select peptides of immunogen presented on surface of APC via presented on surface of APC via MHCMHCPeptide is presented to T helper cell Peptide is presented to T helper cell via TCR.via TCR.Cytokine release (chemical signals)Cytokine release (chemical signals)Cytokine release from T helper cell Cytokine release from T helper cell telling B cell to continue making telling B cell to continue making Ab's that are specific to the Ab's that are specific to the immunogen.immunogen.