7/26/2019 Unit 04.docx

1/31

Unit 04

Patients with AIDS suffer from a variety of infectious diseases, including Pneumocystis

carinii pneumonia, Toxoplasma gondiiencephalitis, and enteritis caused by a variety of

organisms, including Candida, Cryptosporidium, Giardia andAmoeba. These infectionsultimately lead to the death of the patient.

Why does a person with AIDS ac!uired immune deficiency syndrome" develop these

infections, with organisms which ordinarily do not cause problems in most individuals#

The body has several mechanisms which allow it to resist foreign invaders,

both nonspecific and specific. The ac!uired immune deficiency syndrome causes a failure

in the specific mechanisms by which the body resists infection $ in other words, there is a

failure in the immune response.

The immune response is characterized by its specificity$ the ability to direct reactivity

toward the inducing agent through recognition of specific surface molecular mar%ers

termed antigens" $ but also by its ability to &remember& the inducing agent, and respond in

an enhanced way when the agent is again encountered. In this way, it differs from the acute

inflammatory response, which we discussed in the previous unit. Inflammation is

nonspecific$ the inflammatory response is similar regardless of the initiating in'ury.

In truth, this (nit should be called the Ac!uired Immune )esponse. When the terms

&Immune )esponse* and &Immunity* are discussed, we are referring to the Ac!uiredImmune response. +ou might recall from Unit 03that we discussed something called the

&Innate Immune )esponse*, wherein phagocytes could recognie surface molecules on

pathogens PA-Ps". Innate immunity provides a muchneeded overlap in function between

inflammation and ac!uired immunity, and as such was discussed under Acute Inflammation.

In this unit we will cover the following:

nonspecific defense mechanisms

characteristics of the immune response antigens

cells of the immune response

antibodies

antigen/antibody interaction and complement activation

7/26/2019 Unit 04.docx

2/31

the types of immune response $ immunologic memory

immuniation

serology

hypersensitivity reactions

transplantation

autoimmune disorders

immunodeficiency

AIDS

At the end of this section you should be able to:

briefly describe some nonspecific defense mechanisms

describe what characteries the immune response

describe what an antigen is, and give e0amples of e0trinsic and intrinsic antigens

describe the concept of selftolerance

define the terms T and 1 cells

describe what happens when both 1 and T cells comes into contact with their

specific antigen

describe the ma'or functions of macrophages in the immune response

e0plain what effector T cells do

list and briefly describe the five immunoglobulin classes

describe antibody production by 1 cells

describe how passive immunity is naturally ac!uired

describe the function of lymph nodes

describe the mechanisms which can be initiated by antibodyantigen interactions,

including agglutination, opsoniation, and complement fi0ation

outline the primary and secondary immune response

describe active and passive immuniation

define hypersensitivity reactions

outline the mechanisms of the four types of hypersensitivity reactions, and give

clinical e0amples of each

describe the factors affecting the outcome of tissue transplantation

7/26/2019 Unit 04.docx

3/31

outline how the human immunodeficiency virus causes AIDS, and why

opportunistic infections are problems in AIDS patients

1efore we move into a discussion on the immune response, I would li%e to spend a little bit

of time discussing nonspecific protective mechanisms. These can be considered the &first

line* of defense.

Nonspecific defense mechanisms

The s%in and mucous membranes have an important function as a physical barrier to

foreign agents. 2ells are routinely sloughed from the surfaces of both, helping to remove

organisms which might have gained a foothold. The s%in surface normally has a

slightly acidic pHwhich helps prevent the growth of some organisms. The mucus secreted

by membranes of the digestive, urogenital and respiratory tracts acts as a protective

coating. Cilia help move foreign particles out of the respiratory tract by their directional

movement, sweeping out a film of mucus and any entrapped particles. The cough

mechanism helps to e0pel such material more forcefully.

A variety of substances produced by these membranes also have protective

functions. ysozyme in tears, acid in the stomach, digesti!e enzymes... all help prevent

foreign agents from gaining a foothold.

Inflammation, the sub'ect of the last unit, is a further e0ample of a nonspecific defense

mechanism. The cells of the inflammatory response, the neutrophils and macrophages,

have important roles asphagocytes$ this nonspecific phagocytosis has an important early

role in defense. This phagocytic role can be enhanced by &opsoniation* $ we3ll return to

this later. The macrophages also have important roles in the immune response."

What characteries the immune response#

The immune response is first characteried by its specificity$ the fact that reactivity is

directed specifically toward the foreign &agent*, through recognition of specific surface

molecular mar%ers, termed antigens. 1y this I3m referring to infectious agents such as

bacteria, viruses, fungi, protooa...we3ll discuss these in (nit 4, Infection", as well as a

variety of macromolecules...we3ll return to antigens shortly."

The second defining characteristic of the immune response is its memory$ this specific

antigen is &remembered* by the body after its initial e0posure, and so is recognied when itis encountered again.

Finally, the immune response is characterized by an enhanced response on this

second exposure to the antigen$ this is termedamplification.

Antigens

7/26/2019 Unit 04.docx

4/31

ntigens are molecules which evo!e an immune response when introduced into a

host" The term is also used more narrowly, to describe molecules which induce

an antibody response, with the term immunogen being used to indicate molecules which

elicit an immune response."

They are large molecules, typically protein or polysaccharide in nature. Smaller moleculestermed haptens" can also become antigenic if they comple0 with larger carrier molecules.

"oreign #extrinsic$ antigens include infectious agents such as bacteria, viruses, protooa,

and fungi $ we will discuss these in unit 5I", transplanted foreign cells eg. blood

transfusions, tissue transplantations", and a variety of other particles that may gain entry

into the body.

Components of the body can also become antigenic under certain circumstances. 6or

e0ample, when cells undergo neoplastic transformation become cancerous" they may be

recognied as being foreign by the body $ this is beneficial as the body can then &combat*the tumour. 7ormal molecules in the body may be altered by the binding of a hapten, so the

body begins reacting against them. 2ertain antigens eg. lens protein in the eye" are

normally separated from the immune system since early embryonic life, so tolerance to

them doesn3t develop $ if these are released in later life eg. due to lens in'ury", an immune

response to them may develop.

How does the body know what is foreign?

8ow does the body %now what to react against $ why doesn3t it destroy its own tissues# To

be able to react against something, it must first be able to recognie what is foreign, or

%non&self'. -any molecules in the body will induce an immune response if introduced intoanother individual, whereas in the body of origin they are tolerated. #elf $or natural%

tolerance refers to this lac! of response to our own antigens"

How does self tolerance develop?

The mechanisms of self tolerance are not completely understood, but several theories have

been developed to e0plain how it occurs. 9ne of the more accepted of these theories is that

of clonal deletion central tolerance", which suggests that during embryonic development

our lymphocytes go through a selection procedure in the thymus those that are potentiallyreacting against self antigens are deleted. There are also several :bac%up3 mechanisms in

the peripheral tissues which can help prevent potentially self reactive T cells which have

escaped central deletion" from having an effect.

7/26/2019 Unit 04.docx

5/31

The immune response is !uite comple0, with numerous interactions occurring between

different cell types. I thought it might help if I first gave a brief overview, so you can have

some idea of where we3re headed;

A brief overview of the immune response

When an antigen enters the body, it is first processed by antigen&presenting cells, then

presented to lymphocytes, the ma'or effector cells of the immune system. This causes the

lymphocytes T cells and 1 cells" to proliferate and transform>=>? of

your te0tboo%, and complete the following discussion.

1cells 1lymphocytes" Te0t pp. =>C=>"

).cells are characterized as a group by the presence of a cell surface antibody.

receptor complex $termed the ).cell receptor complex, or )/%" When these

antibodies Ab" come into contact with their specific antigen Ag", the Ab/Ag interaction

causes the 1cell to first proliferate termed &2lonal E0pansion*", and then differentiate into

two populationsJ of mature Tcells. 2DH Tcells are

termed &helper* Tcells or Thcells" because they secrete cyto%ines which

influence most of the other cells in the immune system, upregulating the immune

response. 8elper Tcells can be further subdivided into ThC and ThF subtypes,

based on the spectrum of different cyto%ines they secrete, with defines the type of

response they incur of your te0t and complete the following in your te0tboo%, what are the two ma'or types of dendritic cells, andwhat are their features#

The antigenprocessing role of macrophages and the amplification aspect of both the T and

1 cell response can be summaried in the following diagram

7/26/2019 Unit 04.docx

10/31

M 9pen @earning and Educational Support/D. Schaefer

+ou can see that the end result of the activation of T cells by antigen is the production of

effector T cells, but, what then#

#U11/6: Functions of ells within the Immune

#ystem

788 (67 FU9(I9

ntigen.resenting ells

$s%

N -acrophages =" 6iltration/Phagocytosis

F" Antigen Presentation to

Tcells

C" 2yto%ine secretion

N Interdigitating Dendritic

2ells

=" Antigen capture in

tissues

F" -igration to lymphoid

7/26/2019 Unit 04.docx

11/31

tissues

C" Antigen presentation to

lymphoid tissue Tcells

" 2yto%ine secretion

N 6ollicular Dendritic 2ells =" Antigen/antibody and

antigen/ complement

capture in lymphoid tissues

F" Antigen presentation to

lymphoid tissue 1cells

).cell 8ineage

N 1cells/-emory 2ells =" )ecognition of

circulating antigen

via 12)"

F" Proliferation into

Plasma 2ells and

-emory 2ells

N Plasma 2ells Production and secretion of

antigen

specific Immunoglobulin

(.cell 8ineage

N 2DH Tcells Tccells,

2ytoto0ic Tcells"

=" )ecognition of antigen

fragments on cell surface

-82 molecules

F" 2ytolysis/cytoto0icity

%ills affected cells"

N 2DH Tcells Thcells,

8elper Tcells"

=" )ecognition of antigen

fragments on cell surface

-82 molecules

F" Secretion of cyto%ines

that activate

7/26/2019 Unit 04.docx

12/31

1cells, Tccells

ther ell types

N 7atural Liller cells 7L

cells"

7onspecific cytolysis of

cells with atypical

surface antigens, loss of

normal -82I

antigens

)ead the section titled &8umoral Immunity< Activation of 1 @ymphocytes O Elimination ofE0tracellular -icrobes** on pp. =>=> of your te0tboo%, then complete the following< The

antibodies comprise a family of serum proteins called immunoglobulins, part of the globulin

fraction of serum. Three main classes of immunoglobulins are recognied.

What are the three main classes of immunoglobulins, and what are their %ey features#

I3ve included a schematic diagram of an immunoglobulin molecule below, to show the

&heavy* longer" and &light* chains. Each chain has both constant and variable parts. The

constant part is the same in all members of the same Ig class, and is shown as white. The

variable part shown as blac%" shows great variability in its amino acid se!uences $ it is this

region which gives the antibody its specificity. Thus, the antigenbinding sites are in these

variable regions. The constant region has receptors for complement, which we will discuss

shortly. 7ote also the 6c portion, the function of which will be described later."

7/26/2019 Unit 04.docx

13/31

Ig -olecule

M 9pen @earning and Educational Support/D. Schaefer

Antibody production

When the body is e0posed to an antigen, what steps must ta%e place before antibodies

appear in the serum#

)eview the activation and functions of 1cells.

This may ta%e up to two wee%s to occur. 7eonates are not yet capable of this response.

Instead, newborns humans" rely onpassi!ely ac4uired antibody from their mother",

predominantly Ig, which crosses the placenta in utero. During the first few wee%s of life the

lymphoid tissue develops, and immunoglobulins begin to be produced. The different classes

of immunoglobulins are synthesied at different rates.

The period at around age C months is when immunoglobulin levels are at their lowest, as

maternally derived antibodies are decreasing and actively produced antibody is still at low

levels.

In most domestic animals, the colostrum which is suc%led shortly after birth is of greater

importance as a source of passively ac!uired antibody. +oung piglets, calves, and foals

which fail to suc%le colostrum shortly after birth are at greatly increased ris% for a variety of

infectious diseases.

7/26/2019 Unit 04.docx

14/31

2olostrum is the thic%, yellow mil%y fluid secreted by the mammary gland of all mammals

including man" for a few days before and after parturition. It contains a high percentage of

protein, predominantly consisting of immunoglobulins derived from the maternal blood. The

gut of the neonate is especially able to absorb these proteins.

8ow does the antigen come into contact with macrophages andlymphocytes#

(p to this point the discussion has been rather abstract $ ho+ does the antigen come into

contact with macrophages and lymphocytes#

Antigens can enter the body in a variety of ways $ through the s%in if it has been in'ured, or

through the mucosal membranes of the respiratory tract, alimentary tract or urogenital tract.

@ocal nonspecific defenses, which I described at the beginning of this unit, may not be

ade!uate to stop the organism from gaining entry. 9nce &within* the body, the nonspecificinflammatory response with its associated phagocyte activity may be able to stop the

antigen from going further Unit 03;". 8owever, some antigens may be carried via lymphatic

flow to local lymph nodes, where they will first be e0posed to large numbers of

macrophages and lymphocytes.

Within the lymph node# the antigen is processed by macrophages and presented to T and

1 cells, leading to T cell transformation, T immunoblast formation and the production of

activated T cellsG 1 cells are transformed into plasma cells, which begin actively secreting

antibody. The end result of this is that antibody is secreted into the lymphatic vessels

leaving the node the efferent vessels", and ultimately enters the blood plasma via thethoracic duct.

The stimulation of lymphocyte activity within the lymph node also causes the lymph node to

become enlarged and possibly tender". This is why, for e0ample, the lymph nodes under

your 'aw which many people refer to as &glands*" may be enlarged in the case of a sore

throat. 5uch nodes, enlarged because of response to an antigenicstimulus, are referred to

as %reacti!e' or %hyperplastic'. The T and 1 cells are arranged in units called follicles $

enlarged, prominent follicles are characterictic of a reactive node.

We3ve spent some time discussing what antibodies are and how they are produced. The

most important thing about antibodies, however, is that they react with antigen.

The effect of antigenantibody interactions

6hen antigens #Ag$ interact +ith their specific antibodies #Ab$, they form an immune

comple', +hich may also contain other molecules such as complement.

7/26/2019 Unit 04.docx

15/31

Agglutination refers to the formation of large aggregates or &clumps* of Ag and

Ab. Agglutination occurs because of the two binding sites on antibody molecules

refer bac% to the diagram of an antibody Ig" molecule, on page =?4"G this cross

lin%s a number of antibody and antigen molecules, and ma%es it easier for

phagocytes to trap and consume the immune comple0es.

If the antigen is a to0in, then agglutination may serve to neutralie the to0in.

psoni)ation refers to the process of coating the antigen with antibody, allowing

increased phagocytosis by leu%ocytes having receptors for the antibody

particularly the 6c portion again, refer to the Ig molecule diagram on p.=?4".

This is the immune phagocytosis referred to in the last unit.

Complement fi'ation is one of the outcomes of

complement activation. 2omplement as opposed to a compliment" is a system of

nine plasma proteins 2=$2" which, similar to the clotting cascade, reactse!uentially. The C7890: complex, called the cytoto0ic comple0 or membrane

attac% comple0, -A2", can %punch' holes in cell membranes due to its

phospholipase$li%e activity...a cellular :-A2attac%3;

6or e0ample, a cell with an attached Ag/Ab comple0 initiates the complement cascade,

resulting in formation of the cytoto0ic comple0 and lysis of the cell.

Complement acti!ation also has other effects. It is closely associated with the inflammatory

response. 1oth 2Ca and 2?a contribute to vasodilation and increased vascular permeability,

as well as being chemotactic for neutrophils. 2Cb can act as an opsonin, inducing immune

phagocytosis by neutrophils and macrophages. 2omplement was introduced earlier, in Unit03.

7ote that agglutination and opsoniation occur when the antigenic stimulus is cellular,

bacteria, for e0ample". If the antigen is a macromolecule, Ag Ab comple0ing leads to

formation of a large macromolecular comple0, which is also more easily phagocytosed. The

activation and functions of the complement system are illustrated in 6ig. F=, on p. ?> of

your te0t.

To summarie, the formation of immune comple0es in !i!o in the living body" ultimately

leads to