Introduction to the immune system

Innate immunitythe “front line” of defensenon specific

Acquired immunitymechanisms- antigen specificityimmunological memoryprinciples of vaccination

Important features of the immune system

Must be able to distinguish foreign antigens fromself antigens (what is an antigen?)

Must have memory (responds slowly to firstexposure, but more rapidly to subsequentexposures TO THE SAME ANTIGEN)

What does the immune system actually do?

Phagocytes- kill and remove foreign ordamaged cells

Antibodies- “tag” invading cells or viruses for destruction

Cytotoxic cells- killed altered cells

Regulate the immune response

What/where is the immune system?

Barriers

Circulating blood cells

Tissue-fixed cells

Lymphatic system

p. 375, physical barriers to infection

p. 377, origin of lymphoid cells

Cells with immune function (p. 378)GranulocytesNeutrophils

most common leukocyte (50-70%)most potent phagocyte

Eosinophils (2-4%)probably phagocyticinvolved in allergic responses, parasitic infections

Basophils (0-1%)mostly found in tissues (mast cells)release inflammatory molecules

Agranulocytes

Monocytes (5-10%)more common in tissues

In tissues:macrophages- phagocytes; help regulateimmune response (“antigen presenting cells”)

dendritic cells- present antigen to lymphocytes

Lymphocytes (20-40%)B cells- make antibodiesT cells- some are cytotoxic, some are regulatory

Where are the lymphoid cells?

In the blood

In the tissues

In the lymphoid system

Can be recruited to site of injury or infection

p. 396, the lymphoid system

The lymphoid system parallels the circulatorysystem

Primary lymphoid organs- where lymphoid cellsdevelopbone marrow (ALL blood cells)

thymus- T cells mature there (become cytotoxic or helper T cells) and thencirculate

Secondary lymphoid organsPurpose: to trap antigen and present it to lymphocytesMost lymphocytes actually reside in these tissues

Lymph nodes- “filter” antigen from lymph

Spleen- “filters” antigen from blood

Lymphoid tissue in mucosa, gut and skin

Innate defenses

If they are “non-specific” how are they actually activated-appropriately??

Barriersskinantimicrobial chemicals

lysozyme (in tears and salivastomach acidoxygen metabolites

normal flora (“healthy competition”)

If barrier is breached- then what?

Pattern recognition- something is perceived asabnormal

Damaged tissue

Structures associated with bacteria (peptidoglycan,LPS, etc.)toll-like receptors on phagocytes, endothelialcells- some recognizes viruses, tooCell is then activated in response

Toll-like receptors, p. 381

Complement proteins- circulate in blood

Are normally inactive, but become active when binding to antigen, or antigen-antibody complexes

What happens next?

A series of reactions, resulting in:destruction of antigeninflammationenhanced phagocytosis of antigen

Complement system, p. 382

Phagocytosis; how do the cells know whence toengulf?

detectors of microbes and/or damaged cells(pattern recognition)

response to cytokines (produced by damagedcells and other immune cells

complement receptors

What happens in phagocytosis?

Process of phagocytosis, p. 384

Neutrophils are more potent killers, but die quickly

Macrophages can present antigen; amplifyimmune responsecan prolong activity by regenerating lysosomes

Both contribute to inflammatory response toinfection and/or damage

What is the inflammatory process?

What triggers the inflammatory process?

What are the outcomes of inflammation?

What is apoptosis, and how does it preventinflammation?

Inflammatory process, p. 387

Inflammation is triggered by infection or injuryPurpose: to contain damage (and response)

repair damage

“Cardinal signs of inflammation”:swelling, redness, heat, pain

Why swelling?

Chemical signals are released by damaged tissue

Neutrophils, monocytes recruited to the site andenter tissuesfluid enters tissues, too

Why redness?

Chemicals promote vasodilation Blood vessel walls relax; more blood (and

therefore more blood cells) can bebrought to the region

Why heat?Chemicals raise temperature at the spot(pyrogens)Increased temperature kills microbes

phagocytes are more activemore cells are formed

Effect can be systemic (fever)

Why pain?

Chemicals effect free nerve endings (painreceptors)Pain inhibits mobility; can help localizedamage

Inflammation can cause a lot of “bystanderdamage”

Ideally, damaged is confined to the site of injury

Some sites are more sensitive to damage thanothers

Damage can be systemic (septic shock, dueto blood infections: loss of blood volume,tissue damage, excess clot formation

Not all cell death causes inflammation

Apoptosis: programmed cell death

Under genetic control

(In immune response a large number of cells areformed to fight the infection- what happens tothem after the infection is cleared?)

Summary

Innate defense consists of barriers, phagocytesurveillance, and mechanisms to detectinfection or damage

Inflammation is the first line response to infection

Lymphocytes may be activated during this processwhich will respond more rapidly and inten-sively to subsequent infections

Adaptive immunity

SpecificityMemoryDistinguishes self from non-self

Components of adaptive immunity:Humoral

Cell-mediated

Principles of vaccinationImmune deficiency and its consequences

Adaptive immunity takes several days todevelop (to first exposure to antigen)

Cells proliferateAntibodies are producedCytokines (signaling molecules) are produced

Meanwhile, innate mechanisms act

Adaptive mechanisms respond if infection hasnot been eliminated

What are the adaptive mechanisms?

Humoral immunity against “extracellular”antigens (bacteria, free viruses,toxins, etc.)antibodies and other molecules

Cell-mediated against “intracellular” antigens(virus-infected cells; tumor cells)

Responses are orchestrated by helperT cells

p. 395 (be sure to come back to this slide)

How does humoral immunity work?

B cells proliferate (in lymphatic tissues) andmake antibodies

Antibodies circulate and bind to antigen

Neutralization; immobilizationImmune complexesFacilitates phagocytosisFacilitates complement-mediated lysis

B cells are activated clonally

p. 401How antibodies work

Applies to T cells, too (p. 403)

In bone marrow

In the system

Clonal selection theory

Antibodies have certain features in commonbut different classes (isotypes) havedifferent properties.

p. 398

Variable region is unique, because each bindsto a different antigen

Constant regions fall into five classes

(table 16.1, p. 399)

What happens in the primary response thatleads to antibody production?

T cells respond to antigen; produce cytokines

These cause B cells to proliferate and becomeplasma cells (antibody-producing cells)

They become more able to react with antigenClass-switching (for appropriate response)

from IgM to IgA, IgG, IgE (unclear about IgD)Memory cells- more of them; they respond faster

in subsequent responses

p. 405

What about the memory cells?

• There are more of them in the circulation• Antigen specificity does not change• They have already gone through

development so can become active right away (note the secondary response on previous slide)

• Both T and B memory cells have been identified

• Memory cells can live for years

T cells also have an antigen-specific receptor

Receptor is NOT released

T cell must come in direct contact with antigen-presenting cell

Major antigen-presenting cells:macrophagedendritic cellB cell

How do these cells present antigen (and where)?

What are the different types of T cells

CD4(helper) and CD8 (cytotoxic)

Both have antigen-specific receptorsCD4 and CD8 molecules help with antigen

presentation

CD4 cells “see” antigen + MHC Class II(helper T cells)

CD8 cells “see” antigen + MHC Class I (cytotoxic T cells)

What is MHC? (major histocompatibilitycomplex)

Groups of cell- surface proteins, inherited

When cells process antigen they return fragments(peptides) to the surface, bound to eitherMHC Class I or Class II

MHC Class I is found on most cells

MHC Class II on antigen-presenting cells (andlevels can vary)

How do cells present antigen?

Class II-bearing cells take up and “process” antigen, then antigen is expressed on cell surface bound to MHC Class IIRemember, only certain cell types express MHCClass II- so not all cells can do thisLots of antigen-presenting cells in lymphoid tissues!

Class I-bearing cells (remember, virtually all cells),if infected or transformed, will express antigen boundto MHC Class I

When T cells are activated they proliferateand produce cytokines

Dozens of cytokines have been identified(and other cells can produce them, too)

Cytokines bind to neighboring cells and activate them

Recall that immune response is characterizedby rapid proliferation and activation ofcells!

(And: you don’t want cells activated all the time)

What do T cells actually do?

T helper cells- cytokine production(Some are engaged in “delayed-type hypersen-

sitivity)

Cytotoxic T cells- cause apoptosis in targets

What about natural killer cells?similar targets as CTLsno antigen-specific receptorno memory responsehave antibody receptorsprobably immune surveillance

Natural killer cells vs cytotoxic T cells

• Natural killer cells part of innate immune system

• Early protection against transformed cells or virus-infected cells (Same targets as cytotoxic T cells)

• Cytotoxic T cells become activated if natural killer cells cannot eliminate these cells

How DO immune cells avoid reacting withself antigens?

Remember that T cells regulate the immuneresponse

Most self-reactive cells are eliminated in thethymus

Antigen-presenting cells seem to be key

Model of antigen presentationNotice the APC has MHC ClassII and other molecules requiredto present antigen

APC: antigen presenting cell

Summary, p. 412

Immune system responds to antigens thatenter body in course of infection

Vaccination: antigens are DELIBERATELYintroduced to body to generate a specificimmune response (and memory)

Immune system normally distinguishes “harmful”antigens from self antigens or harmlesssubstances

What happens if it does not?

What happens if immune system is deficient?