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Essentials of Immunology

Overview of the Immune Response Cells and Organs of the Immune System

All the cells involved in immunity originate from common stem ells in the bone marrow (!igure 22"#).

The blood and lymph systems (!igure 22"2) circulate cells and proteins that are important for a functional immune system. Whole blood is composed of plasma, a liquid containing proteins and a variety of other solutes and suspended cells.

utside the body, plasma quic!ly forms an insoluble clot. "lasma remains liquid only when an anticoagulant is added. After clotting, the remaining fluid, called serum, contains no cells or clotting proteins. #erum does, however, contain a high concentration of other proteins, including soluble antibody proteins, and is widely used in immunological investigations. The use of serum antibodies to detect antigens in vitro is called serology. A variety of leu$o ytes participate in immune responses.

The Innate Immune Response%

The innate immune response is mediated by phago ytes. "hagocytes recogni$e pathogen&asso iated mole ular patterns 'PA(Ps) via a family of membrane%bound pattern&re ognition mole ules 'PR(s) (!igure 22"*).

&nteraction of the "A'"s with "('s activates phagocytes to produce metabolic products that !ill the pathogen or limit its effects (!igure 22"+). 'any pathogens have developed mechanisms to inhibit phagocytes.

Inflammation% !ever% and Septi Sho $

Inflammation is characteri$ed by pain, swelling (edema), redness (erythema), and heat. The inflammatory response is a normal and generally desirable outcome of an immune response. )ncontrolled systemic inflammation, called septic shoc!, can lead to serious illness and death.

The first inflammatory cell to arrive at the scene of an infection or tissue in*ury is the neutrophil. These phagocytic cells are attracted to the site of an active infection or tissue in*ury by soluble chemoattractants called chemo!ines.

+or e,ample, &-%. (interleu$in%.), a small protein in the chemo!ine family, is produced by damaged host cells. /eutrophils migrate toward the cells secreting &-%. and are activated by the interaction with &-%..

The Adaptive Immune Response

&n adaptive immunity, nonspecific phagocytes present antigen to specific T ells, triggering the production of effector T cells and antibodies. &mmune T cells and antibodies react directly or indirectly to neutrali$e or destroy the antigen.

The adaptive immune response is characteri$ed by spe ifi ity for the antigen, the ability to respond more vigorously when ree,posed to the same antigen (memory), and the ability to discriminate self antigens from nonself antigens (toleran e) (!igure 22",).

Anti-ody&mediated immunity is particularly effective against pathogens such as viruses and bacteria in the blood or lymph and also against soluble pathogen products such as to,ins.

#ome T cells, the T0 (T%cytoto,ic) cells, directly attac! and destroy antigen%bearing cells. ther antigen%activated T cells, the T 12 or T%helper 2 cells, act indirectly by secreting proteins called cyto!ines that activate other cells such as macrophages to destroy the antigen%bearing cells.

This ell&mediated immunity leads to !illing of pathogen%infected cells through recognition of pathogen antigens found on infected host cells.

Antigens% T Cells% and Cellular Immunity Immunogens and Antigens

Immunogens are foreign macromolecules that induce an immune response. 'olecular si$e, comple,ity, and physical form are intrinsic properties of immunogens. 'olecular si$e is an important component of immunogenicity. +or e,ample, low% molecular%weight compounds called haptens cannot induce an immune response but can bind to antibodies. 3ecause haptens are bound by antibodies, they are antigens even though they are not immunogenic. When foreign immunogens are introduced into a host in an appropriate dose and route, they initiate an immune response.

Antigens are molecules recogni$ed by antibodies or T& ell re eptors 'TCRs) (!igure 22"#.).

Anti-odies recogni$e conformational determinants4 T0(s recogni$e linear peptide determinants (!igure 22"/).

The antibody or T0( does not interact with the antigenic macromolecule as a whole but only against a distinct portion of the molecule called an antigeni determinant or epitope.

Presentation of Antigen to T 0ympho ytes

T cells recogni$e antigens presented by antigen&presenting ells 'APCs) or by pathogen%infected cells.
At the molecular level, T0(s bind peptide antigens presented by ma1or histo ompati-ility omple2 '(HC) proteins. Class I (HC proteins are found on the surfaces of all nucleated cells. Class II (HC proteins are found only on the surface of 3 lympho ytes, ma rophages, and dendriti ells, all of which are A"0s (!igure 22"##).

These molecular interactions stimulate T cells to !ill antigen%bearing cells or to produce cell%stimulating proteins !nown as yto$ines . !igure 22"#2 illustrates antigen presentation by '10 & and '10 && proteins.

T&Cytoto2i Cells and 3atural 4iller Cells

T%cytoto,ic (T0) cells recogni$e antigens on virus%infected host cells and tumor cells through antigen%specific T0(s. Antigen% specific recognition triggers !illing via perforin and gran$ymes (!igure 22"#5).

3atural $iller '34) ells use the same effectors to !ill virus%infected cells and tumors. 1owever, /5 cells do not require stimulation, nor do they e,hibit memory. /5 cells respond in the absence of '10 proteins.

T&Helper Cells6 A tivating the Immune Response

T12 and T16 cells play pivotal roles in cell% mediated and antibody%mediated immune responses.

+ollowing the initial antigen e,posure, each antigen%stimulated 7 ell multiplies and differentiates to form both antibody%secreting plasma ells and memory cells (!igure 22"#8). T12 inflammatory and T16 helper cells each stimulate effector cells through the action of cyto!ines.

PART III Anti-odies and Immunity% p" 985 22"/ Anti-odies 'Immunoglo-ulins) % p" 988

Immunoglo-ulin 'Ig) (antibody) proteins consist of four chains, two heavy and two light (!igure 22"#*). 7ach &g8 light chain consists of two protein domains of equal si$e.

The amino%terminal region is a variable domain, meaning that the amino acid sequence in this structural region differs in each different antibody. The antigen%binding site is formed by the interaction of variable regions of heavy and light chains (!igure 22"#+).

7ach class of &g has different structural and functional characteristics (!igure 2"#9: Ta-le 22"2).

The structure of &g' is shown in !igure 22"#,. !igure 22"#/ shows the structure of &gA.

Anti-ody Produ tion

Antibody production is initiated by antigen contact with an antigen%specific 3 cell that processes the antigen and presents it to an antigen%specific T16 cell. The activated T16 cell then signals the antigen%specific 3 cell to produce antibody.

!igure 22"2. shows a typical rearrangement and e,pression pattern for the human !appa light chain.

Activated 3 cells live for years as memory cells and can rapidly produce large quantities (high titers) of antibodies upon ree,posure to antigen (!igure 22"2#).

"lasma cells are relatively short%lived (less than 2 wee!), but produce and secrete large amounts of &g' antibody in this primary anti-ody response. The memory 7 ells generated by the initial e,posure to antigen may live for years. &f ree,posure to the immuni$ing antigen occurs at a later time, memory cells need no T%cell activation4 they quic!ly transform to plasma cells and begin producing &g8. )pon ree,posure, the antibody titer rises rapidly to a level 29:299 times greater than the titer achieved following the first e,posure. This rise in antibody titer is referred to as the se ondary anti-ody response.

Complement% Anti-odies% and Pathogen ;estru tion

The omplement system cataly$es bacterial cell destruction and opsoni$ation (!igure 22"22).

0omplement is triggered by antibody interactions or by interactions with nonspecific activators. 0omplement is a critical component of both innate and adaptive host defense.

Immunity and Prevention of Infe tious ;isease 3atural Immunity

&nnate and adaptive immune responses are necessary for survival. -ac! of innate immunity results in death due to recurrent, uncontrollable infections. -ac! of adaptive immunity also results in uncontrollable infectious disease.

Artifi ial Immunity

&mmunity to infectious disease can be either passive or active, natural or artificial ( Ta-le 22"5).

'any e,oto,ins can be modified chemically so that they retain their antigenicity but are no longer to,ic. #uch a modified e,oto,in is called a to2oid.

Immuni<ation, a form of artificial active immunity, is widely employed to prevent infectious diseases (Ta-le 22"8: !igure 22"28).

'ost agents used for immuni$ation are either attenuated or inactivated pathogens or inactivated forms of natural microbial products.

3ew Immuni<ation Strategies

Alternative immuni$ation strategies using bioengineered molecules eliminate e,posure to microorganisms and, in some cases, even to protein antigen. Application of these strategies may provide safer and more targeted va ines.

Immune Response ;iseases Allergy% Hypersensitivity% and Autoimmunity

Hypersensitivity results when foreign antigens induce cellular or antibody immune responses, leading to host tissue damage. Ta-le 22"* lists the four types of hypersensitivity. Autoimmunity occurs when the immune response is directed against self antigens, resulting in host tissue damage.

&mmediate (Type &) hypersensitivity reactions, commonly called allergies, occur within minutes after e,posure to antigen (!igure 22"2*: Ta-le 22"+).

Type &; hypersensitivity, or delayed%type hypersensitivity (<T1), is cell%mediated hypersensitivity characteri$ed by tissue damage due to inflammatory responses produced by T12 inflammatory cells.
Typical antigens include certain microorganisms, a few self antigens (Ta-le 22"9), and several chemicals that bind covalently to the s!in, creating new antigens. Autoanti-odies are antibodies that react to self antigens.

Superantigens bind and activate large numbers of T cells in a novel fashion (!igure 22"29). #uperantigen%activated T cells are capable of producing systemic diseases characteri$ed by massive inflammatory reactions.