Diseases Of The Immune System

Question 1

Define immunity

. Deficiencies in immune defenses result in an increased susceptibility to infections, which can be life-threatening if the deficits are not corrected.on the other hand the immune system is itself capable of causing great harm and is the root cause of some of the most vexing and intractable diseases of the modern world.
True or false

Answer 1

Immunity refers to protection against infections, and the immune system is the collection of cells and molecules that are responsible for defending the body against the count- less pathogenic microbes in the environment.

True

Question 2

Defense against microbes consists of two types of reactions
Name them and explain

What are the major components of the innate response

The innate immune response is able to prevent and control many infections. However, many pathogenic microbes have evolved to overcome the early defenses, and protection against these infections requires the more spe- cialized and powerful mechanisms of adaptive immunity (also called acquired, or specific, immunity true or false

What are the components of the adaptive immunity

By convention, the terms “immune system” and “immune response” refer to adaptive immunity. True or false

State the types of adaptive immunity and what they are mediated by

How do T cells work

When the immune system is inappropriately triggered or not properly controlled, the same mechanisms that are involved in host defense cause tissue injury and disease. The reaction of the cells of innate and adaptive immunity may be manifested as inflammation. True or false

Antibodies provide protection against extracellular microbes in the blood, mucosal secretions, and tissues. True or false

Answer 2

Innate immunity (also called natural, or native, immunity) is mediated by cells and proteins that are always present and poised to fight against microbes, being called into action immediately in response to infection.

The major components of innate immunity are epithelial barriers of the skin, gastrointestinal tract, and respiratory tract, which prevent microbe entry; phagocytic leukocytes (neutrophils and macrophages); a specialized cell type called the natural killer (NK) cell; and several circulating plasma proteins, the most important of which are the proteins of the comple- ment system.

True

Adaptive immunity is normally silent and responds (or “adapts”) to the presence of infectious microbes by becoming active, expanding, and generating potent mechanisms for neutral- izing and eliminating the microbes.

The components of the adaptive immune system are lymphocytes and their products.

There are two types of adaptive immune responses: humoral immunity, mediated by soluble proteins called antibodies that are produced by B lymphocytes (also called B cells), and cell-mediated (or cellular) immunity, mediated by T lymphocytes (also called T cells).

T lymphocytes are important in defense against intracellular microbes. They work by either directly killing infected cells (accomplished by cytotoxic T lymphocytes) or by activat- ing phagocytes to kill ingested microbes, via the produc- tion of soluble protein mediators called cytokines (made by helper T cells).

Question 3

The cells of the immune system consist of?

What are the two remarkable features of the immune system

Lymphocytes are present in the circulation and in various lymphoid organs. Although all lymphocytes appear mor- phologically identical, there are actually several function- ally and phenotypically distinct lymphocyte populations.
True or false

Where do lymphocytes develop from
Where do T and B lymphocytes mature in the body

Answer 3

The cells of the immune system consist of lymphocytes, which recognize antigens and mount adaptive immune responses; specialized antigen-presenting cells (APCs),

Two remarkable features of the immune system are the specialization of the cells to perform diverse functions, and the precise control mechanisms that permit useful responses when needed and prevent potentially harmful ones.

True

Lymphocytes develop from precursors in the generative lymphoid organs; T lymphocytes are so called because they mature in the thymus, whereas B lymphocytes mature in the bone marrow.

Question 4

Each T or B lymphocyte expresses recep- tors for a single antigen, and the total population of lym- phocytes (numbering about 1012 in humans) is capable of recognizing tens or hundreds of millions of antigens.
How are they able to do so?

Why is the demonstration of antigen receptor gene rearrangements by molecular methods (e.g., poly- merase chain reaction [PCR] assay) a definitive marker of T or B lymphocytes?

Answer 4

This enormous diversity of antigen recognition is generated by the somatic rearrangement of antigen receptor genes during lymphocyte maturation, and variations that are introduced during the joining of different gene segments to form antigen receptors.

These antigen receptors are rearranged and expressed in lymphocytes but not in any other cell. Because each lymphocyte has a unique DNA rearrangement (and hence a unique antigen receptor), molecular analysis of the rearrangements in cell populations can distinguish polyclonal (non-neoplastic) lymphocyte proliferations from monoclonal (neoplastic) expansions.

Question 5

Thymus-derived, or T, lymphocytes are the effector cells of cel- lular immunity and the “helper cells” for antibody responses to protein antigens. T cells constitute 60% to 70% of the lym- phocytes in peripheral blood and are the major lymphocyte population in splenic periarteriolar sheaths and lymph node interfollicular zones.
True or false

T cells do not detect free or cir- culating antigens.instead what do they do?

It is now known that the normal function of MHC molecules is to display peptides for recognition by T lym- phocytes. By forcing T cells to see MHC-bound peptides on cell surfaces the system ensures that T cells can recognize antigens displayed by other cells. True or false

How do T cells function by interacting with others cells

Answer 5

True

Instead, the vast majority (greater than 95%) of T cells recognize only peptide fragments of protein antigens bound to proteins of the major histocompatibility complex (MHC).

True

either to kill infected cells or to activate phagocytes or B lymphocytes that have ingested protein antigens.

Question 6

What is the MHC restriction

TCRs are noncovalently linked to a cluster of five invari- ant polypeptide chains, the γ, δ, and ε proteins of the CD3 molecular complex and two ζ chains (Fig. 4–2, A). The CD3 proteins and ζ chains do not themselves bind antigens; instead what do they do?

CD4 and CD8 serve as what on the T cell receptor

During antigen recognition, what do CD4 cells do?

Answer 6

In each person, T cells recognize only peptides displayed by that person’s MHC molecules, which, of course, are the only MHC molecules that the T cells normally encounter. Peptide antigens presented by self MHC mol- ecules are recognized by the T cell receptor (TCR),

they are attached to the TCR and deliver intracel- lular biochemical signals after TCR recognition of antigen.

CD4 and CD8 are expressed on distinct T cell subsets and serve as coreceptors for T cell activation.

CD4 molecules on T cells bind to invariant portions of class II MHC molecules (see later) on selected APCs; in an analogous fashion, CD8 binds to class I MHC molecules.

Question 7

CD4 is expressed on 50%–60% of mature T cells, whereas CD8 is expressed on about 40% of T cells. The CD4- and CD8-expressing T cells—are called ?

Why are CD4+ T cells called helper T cells?

Why are CD8+ T cells called cytotoxic T lymphocytes?

Other important invari- ant proteins on T cells include CD28, which functions as the receptor for molecules that are induced on APCs by microbes (and are called costimulators), and various adhe- sion molecules that strengthen the bond between the T cells and APCs and control the migration of the T cells to differ- ent tissues. True or false

Answer 7

CD4+ and CD8+ cells, respectively

CD4+ T cells are “helper” T cells because they secrete soluble molecules (cytokines) that help B cells to produce antibodies (the origin of the name “helper” cells) and also help macrophages to destroy phagocytosed microbes.

CD8+ T cells can also secrete cyto- kines, but they play a more important role in directly killing virus-infected or tumor cells, and hence are called “cytotoxic” T lymphocytes (CTLs)

True

Question 8

What is the human MHC (in the The Peptide
Display System of Adaptive Immunity )called

The HLA system is highly polymorphic; that is, there are several alternative forms (alleles) of a gene at each locus (estimated to number about 3500 for all HLA genes and about 1100 for HLA-B alleles alone) true or false

Several other proteins are encoded in the MHC locus, some of which have been called “class III molecules.” These include complement components (C2, C3, and Bf) and the cytokines tumor necrosis factor (TNF) and lymphotoxin. These molecules do not form a part of the peptide display system and are not discussed further. True or false

On the basis of their chemical structure, tissue distribu- tion, and function, MHC gene products fall into two main categories: name them and explain them based on their chemical structure,tissue distribution and function

Lymphocytes are the mediators of adaptive immunity and the only cells that produce specific and diverse receptors for antigens.
• T (thymus-derived) lymphocytes express TCRs that rec- ognize peptide antigens displayed by MHC molecules on the surface of APCs. True or false

Answer 8

Human Leukocyte Antigen complex(HLA). It consists of a cluster of genes on chromosome 6

True

Class I MHC molecules :are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C .Each of these molecules is a heterodimer, con- sisting of a polymorphic 44-kDa α chain noncovalently associated with an invariant 12-kDa β2-microglobulin polypeptide (encoded by a separate gene on chromo- some 15). The extracellular portion of the α chain
contains a cleft where the polymorphic residues are located and where foreign peptides bind to MHC mol- ecules for presentation to T cells, and a conserved region that binds CD8, ensuring that only CD8+ T cells can respond to peptides displayed by class I molecules. 

In general, class I MHC molecules bind and display pep- tides derived from proteins synthesized in the cyto- plasm of the cell (e.g., viral antigens). Because class I MHC molecules are present on all nucleated cells, all virus-infected cells can be detected and eliminated by CD8+ CTLs.

• Class II MHC molecules are encoded by genes in the HLA-D region, which contains at least three subregions: DP, DQ, and DR. Class II MHC molecules are heterodi- mers of noncovalently linked polymorphic α and β sub- units (Fig. 4–3). The extracellular portion of the class II MHC heterodimer contains a cleft for the binding of antigenic peptides and a region that binds CD4. Class II MHC expression is restricted to a few types of cells, mainly APCs (notably, dendritic cells [DCs]), macro- phages, and B cells. In general, class II MHC molecules bind to peptides derived from proteins synthesized outside the cell (e.g., those derived from extracellular bacteria) and ingested into the cell. This property allows CD4+ T cells to recognize the presence of extracellular pathogens and to orchestrate a protective response.

Question 9

Each person inherits one HLA allele from each parent; typi- cally, then, two different molecules are expressed for every HLA locus. Cells of a heterozygous person can therefore express six different class I HLA molecules: three of mater- nal origin and three of paternal origin. Similarly, a given individual expresses maternal and paternal alleles of the class II MHC loci; because some HLA-D α and β chains can mix and match with each other, each class II–expressing cell can have as many as 20 different class II MHC mole- cules. Different MHC alleles bind to different peptide frag- ments; the expression of many different MHC molecules allows each cell to present a wide array of peptide antigens.

True or false

What is HLA haplotype
What is the implications of HLA polymorphism
What are antigens so called?

The ability of any given MHC allele to bind the peptide antigens generated from a particular pathogen will determine whether a specific person’s T cells can actually “see” and respond to that pathogen. True or false

The inheritance of particular alleles influences both protective and harmful immune responses. Give an example that explains this

Answer 9

The com- bination of HLA alleles for each person is called the HLA haplotype.

The implications of HLA polymorphism are obvious in the context of transplantation—because each person has HLA alleles that differ to some extent from every other person’s, grafts from virtually any donor will evoke immune responses in the recipient and be rejected (except, of course, for identical twins).

This ability of MHC molecules to trigger immune responses is the reason these molecules are often called antigens

For example, if the antigen is ragweed pollen and the response is an allergic reaction, inheritance of some HLA genes may make individuals susceptible to “hay fever,” the colloquial name for ragweed allergy. On the other hand, responsiveness to a viral antigen, deter- mined by inheritance of certain HLA alleles, may be benefi- cial for the host.

Question 10

Why are B lymphocytes the effector cells of humoral immunity

B cells make up 10% to 20% of the circulating peripheral lymphocyte population. They also are present in bone marrow and in the follicles of peripheral lymphoid tissues (lymph nodes, spleen, tonsils, and other mucosal tissues) true or false

How do B cells and T cells recognize an antigen

How is the diversity of antibodies generated

B cells express several invariant molecules that are responsible for signal trans- duction and for activation of the cells . State some of the invariant molecules

After stimulation of B cells what happens to them

State the five classes of immunoglobulins

IgG, IgM, and IgA constitute more than 95% of circulating antibodies. True or false
Which is the major isotype in mucosal secretions ,which is expressed on the surface of B cells but not secreted,which is present at low concentrations in circulation

Answer 10

Cuz Bone marrow–derived B lymphocytes are the cells that produce antibodies

B cells recognize antigen by means of membrane-bound antibody of the immunoglobulin M (IgM) class, expressed on the surface together with signaling molecules to form the B cell receptor (BCR) complex (Fig. 4–2, B). Whereas T cells can recognize only MHC-associated peptides, B cells can recognize and respond to many more chemical structures, including soluble or cell-associated proteins, lipids, polysaccharides, nucleic acids, and small chemicals; furthermore, B cells (and antibodies) recognize native (properly folded) forms of these antigens.

The diver- sity of antibodies is generated during somatic rearrange- ments of immunoglobulin genes.

Some are the signaling molecules attached to the BCR; another example is CD21 (also known as the type 2 complement receptor, or CR2), which recognizes a complement break- down product that frequently is deposited on microbes and promotes B cell responses to microbial antigens.

After stimulation, B cells differentiate into plasma cells, which secrete large amounts of antibodies, the mediators of humoral immunity.

There are five classes, or isotypes, of immunoglobulins: IgG, IgM, and IgA constitute more than 95% of circulating antibodies. IgA is the major isotype in mucosal secretions; IgE is present in the circulation at very low concentrations and also is found attached to the surfaces of tissue mast cells; and IgD is expressed on the surfaces of B cells but is not secreted.

Question 11

What are natural killer cells

Why don’t NK cells have specificities as diverse as Do T or B cells ?

What types of receptors do NK have

How do they function

Normally, the effects of the inhibitory receptors dominate over those of the activating receptors, thereby preventing activation of the NK cells. Infections (especially viral infections) and stress are associated with reduced expression of class I MHC molecules, thus releasing the NK cells from inhibition. At the same time, there is increased engagement of the activating receptors. The net result is that the NK cells are activated and the infected or stressed cells are killed and eliminated true or false

Answer 11

Natural killer (NK) cells are lymphocytes that arise from the common lymphoid progenitor that gives rise to T and B lymphocytes.

However, NK cells are cells of innate immunity and do not express highly variable and clonally distributed receptors for antigens.

two types of receptors—inhibitory and activating.

The inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells, whereas the acti- vating receptors recognize molecules that are expressed or upregulated on stressed or infected cells or cells with DNA damage.

Question 12

What are antigen presenting cells of APc

What are dendritic cells

Cells with dendritic morphology (i.e., with fine dendritic cytoplasmic processes) occur as two functionally distinct types. Name them and how they function

Where are they both found?

One subset of DCs is called plasmacytoid DCs because of their resemblance to plasma cells. These cells are present in the blood and lymphoid organs, and are major sources of the antiviral cytokine type I interferon, produced in response to many viruses. True or false

Name some other APCs and their functions

• APCs capture microbes and other antigens, transport them to lymphoid organs, and display them for recognition by lymphocytes. The most efficient APCs are DCs, which are located in epithelia and most tissues true or false

Answer 12

cell types that are specialized to capture microbial antigens and display these to lymphocytes.

Foremost among these APCs are dendritic cells (DCs), the major cells for displaying protein antigens to naive T cells to initiate immune responses.

Dendritic cells (DCs), sometimes called interdigitat- ing DCs, express high levels of class II MHC and T cell costimulatory molecules and function to capture and present antigens to T cells. 
The second type of cells with dendritic morphology are follicular dendritic cells (FDCs). FDCs bear receptors for the Fc tails of IgG molecules and for complement proteins and hence effi- ciently trap antigens bound to antibodies and complement. These cells display antigens to activated B lymphocytes in lymphoid follicles and promote secondary antibody responses, but are not involved in capturing antigens for display to T cells.

DCs reside in and under epithe- lia, where they are strategically located to capture entering microbes; an example is the Langerhans cell of the epider- mis. DCs also are present in the T cell zones of lymphoid tissues, where they present antigens to T cells circulating through these tissues, and in the interstitium of many non- lymphoid organs, such as the heart and lungs, where they are poised to capture the antigens of any invading microbes.

follicular dendritic cells (FDCs) are located in the germinal centers of lymphoid follicles in the spleen and lymph nodes.

Macrophages ingest microbes and other particulate anti- gens and display peptides for recognition by T lympho- cytes. These T cells in turn activate the macrophages to kill the microbes, the central reaction of cell-mediated immu- nity. B cells present peptides to helper T cells and receive signals that stimulate antibody responses to protein antigens.

Question 13

What cells are front liner effector cells,which cells are effector cells of humoral immunity and which are effector cells for cell mediated immunity

Macrophages, as described in Chapter 2, bind microbes that are coated with antibodies or complement and then phagocytose and destroy these microbes, thus serving as effector cells of humoral immunity. Macro- phages also respond to signals from helper T cells, which improves their ability to destroy phagocytosed microbes, thus serving as effector cells of cellular immunity. T lym- phocytes secrete cytokines that recruit and activate other leukocytes, such as neutrophils and eosinophils, and together these cell types function in defense against various pathogens. True or false

NK cells kill cells that are infected by some microbes or are stressed and damaged beyond repair. NK cells express inhibitory receptors that recognize MHC molecules that are normally expressed on healthy cells, and are thus prevented from killing normal cells.
True or false

Answer 13

NK cells are front-line effector cells in that they can rapidly react against “stressed” cells. Antibody-secreting plasma cells are the effector cells of humoral immunity. T lymphocytes, both CD4+ helper T cells and CD8+ CTLs, are effector cells of cell-mediated immunity.

Question 14

The lymphoid tissues of the body are divided into ?

Give some examples of the types of lymphoid tissues

The cells of the immune system are organized in tissues. Some of these tissues are the sites of mature lymphocyte production (the generative lymphoid organs, the bone marrow and thymus), while others are the sites of immune responses (the peripheral lymphoid organs, including lymph nodes, spleen, and mucosal lymphoid tissues). True or false

Answer 14

genera- tive (primary) organs, where lymphocytes express antigen receptors and mature, and peripheral (secondary) lym- phoid organs, where adaptive immune responses develop.

The generative organs are the thymus and bone marrow, and the peripheral organs are the lymph nodes, spleen, and mucosal and cutaneous lymphoid tissues. Mature lympho- cytes recirculate through the peripheral organs, hunting for microbial antigens that they can respond to. An important characteristic of these organs is that T and B lymphocytes are anatomically organized in a manner that facilitates the adaptive immune response, a process that is described later

Question 15

What is the The Early Innate Immune Response to Microbes as a normal immune response

Answer 15

The principal barriers between hosts and their environ- ment are the epithelia of the skin and the gastrointestinal and respiratory tracts. Infectious microbes usually enter through these routes and attempt to colonize the hosts. The mechanisms of innate immunity operate at every step in a microbe’s attempt to invade. At the site of entry, epithelia serve as physical barriers to infections and eliminate microbes through production of peptide antibiotics and the actions of intraepithelial lymphocytes. If microbes are able to survive and traverse these epithelia, they encounter phagocytes, including neutrophils, which are rapidly recruited from the blood into tissues, and macrophages, which live in tissues under epithelia. The function of these phagocytic cells is to ingest microbes and destroy them by producing microbicidal substances. In response to recogni- tion of microbes, phagocytes, DCs, and many other cell types secrete proteins called cytokines (described later), which promote inflammation and microbial killing and enhance protective immune responses. Cells use several receptors to sense microbes; foremost among these are the Toll-like receptors (TLRs), so named because of homology with the Drosophila Toll protein, that recognize bacterial and viral components (Chapter 2). NK cells kill virus- infected cells and produce the macrophage-activating cyto- kine IFN-γ. If the microbes enter the blood, many plasma proteins, including the proteins of the complement system, recognize the microbes and are activated, and their
products kill microbes and coat (opsonize) the microbes for phagocytosis. In addition to combating infections, innate immune responses stimulate subsequent adaptive immu- nity, providing signals that are essential for initiating the responses of antigen-specific T and B lymphocytes.

Question 16

In capture and display of microbial agents as a normal immune response what happens when microbes enter the epithelia

Answer 16

Microbes that enter through epithelia, along with their protein antigens, are captured by DCs that are resident in and under these epithelia. Antigen-bearing DCs then migrate to draining lymph nodes (Fig. 4–4). Protein anti- gens are proteolytically digested in the APCs to generate peptides that are displayed on the surface of the APCs bound to MHC molecules. Antigens in different cellular compartments are presented by different MHC molecules and are recognized by different subsets of T cells. Antigens that are ingested from the extracellular environment are processed in endosomal and lysosomal vesicles and then are displayed bound to class II MHC molecules. Because CD4 binds to class II MHC molecules, CD4+ helper T cells recognize class II–associated peptides. By contrast, anti- gens in the cytoplasm are displayed by class I MHC molecules and are recognized by CD8+ cytotoxic T cells, because CD8 binds to class I MHC. This segregation of different antigens is key to the specialized functions of CD4+ and CD8+ T cells; as we discuss below, the two classes of T cells are designed to combat microbes that are located in different cellular compartments. Protein anti- gens, as well as polysaccharides and other nonprotein anti- gens, can also be recognized directly by B lymphocytes in the lymphoid follicles of the peripheral lymphoid organs.
Before being recognized by B and T cells, the microbe elicits an innate immune response. This response activates APCs to express costimulatory molecules and secrete cyto- kines that stimulate the proliferation and differentiation of T lymphocytes. The principal costimulators for T cells are the B7 molecules (CD80 and CD86) that are expressed on APCs and recognized by the CD28 receptor on naive T cells. The innate immune response to some microbes and polysaccharides also results in the activation of comple- ment, generating cleavage products that enhance the proliferation and differentiation of B lymphocytes. Thus, antigen (signal 1 in Fig. 4–2) and molecules produced during innate immune responses (signal 2 in Fig. 4–2) func- tion cooperatively to activate antigen-specific lymphocytes. The requirement for microbe-triggered signal 2 ensures that the adaptive immune response is induced by microbes and not by harmless substances.

Question 17

Explain Cell-Mediated Immunity:Activation of T Lymphocytes and Elimination of Cell-Associated Microbes

Although different cytokines have diverse actions and functions, they all share some common features. State them

Cytokines may be grouped into several classes on the basis of their biologic activities and functions. State those classes

Answer 17

Naive T lymphocytes are activated by antigen and costimulators in peripheral lymphoid organs, and prolifer- ate and differentiate into effector cells, most of which migrate to any site where the antigen (microbe) is present (Fig. 4–4). Upon activation, T lymphocytes secrete soluble proteins called cytokines, which function as growth and differentiation factors for lymphocytes and other cells, and mediate communications between leukocytes. Because of the important roles of cytokines in both beneficial immune responses and in inflammatory diseases, it is important to understand their properties and actions.

Cytokines are synthesized and secreted in response to external stimuli, which may be microbial products, antigen recognition, or other cytokines. Their secretion typically is transient and is controlled by transcription and post-translational mecha- nisms. The actions of cytokines may be autocrine (on the cell that produces the cytokine), paracrine (on adjacent cells), and, less commonly, endocrine (at a distance from the site of production) (Chapter 2). The effects of cytokines tend to be pleiotropic (one cytokine can have diverse biologic activities, often on many cell types) and redundant (mul- tiple cytokines may have the same activity). Molecularly defined cytokines are called interleukins, referring to their ability to mediate communications between leukocytes.

Cytokines involved in innate immunity and inflammation, the earliest host response to microbes and dead cells. The major cytokines in this group are TNF and interleukin-1 (IL-1) and a group of chemoattractant cyto- kines called chemokines. IL-12, IFN-γ, IL-6, IL-23, and several other cytokines also participate in the early innate immune response. Major sources of these cyto- kines are activated macrophages and DCs, as well as endothelial cells, lymphocytes, mast cells, and other cell types. These were described in Chapter 2.
• Cytokines that regulate lymphocyte responses and effector functions in adaptive immunity. Different cytokines are involved in the proliferation and differentiation of lym- phocytes (e.g., IL-2, IL-4), and in the activation of various effector cells (e.g., IFN-γ, which activates macrophages; IL-5, which activates eosinophils). The major sources of these cytokines are CD4+ helper T lymphocytes stimu- lated by antigens and costimulators. These cytokines are key participants in the induction and effector phases of adaptive cell-mediated immune responses (see later).
• Cytokines that stimulate hematopoiesis. Many of these are called colony-stimulating factors. They function to increase the output of leukocytes from the bone marrow and to thus replenish leukocytes that are consumed during immune and inflammatory reactions

Question 18

Explain the effector functions of T lymphocytes in cell mediated immunity

Answer 18

Effector Functions of T Lymphocytes
One of the earliest responses of CD4+ helper T cells is secre- tion of the cytokine IL-2 and expression of high-affinity receptors for IL-2. IL-2 is a growth factor that acts on these T lymphocytes and stimulates their proliferation, leading to an increase in the number of antigen-specific lympho- cytes. Some of the progeny of the expanded pool of T cells differentiate into effector cells that can secrete different sets of cytokines and thus perform different functions. The best- defined subsets of CD4+ helper cells are the TH1, TH2, and TH17 subsets (Fig. 4–5). TH1 cells produce the cytokine IFN-γ, which activates macrophages and stimulates B cells to produce antibodies that activate complement and coat microbes for phagocytosis. TH2 cells produce IL-4, which stimulates B cells to differentiate into IgE-secreting plasma cells; IL-5, which activates eosinophils; and IL-13, which activates mucosal epithelial cells to secrete mucus and expel microbes, and activates macrophages to secrete growth factors important for tissue repair. TH17 cells produce the cytokine IL-17, which recruits neutrophils and thus promotes inflammation; TH17 cells play an important role in some T cell–mediated inflammatory disorders. These effector cells migrate to sites of infection and accom- panying tissue damage. When the differentiated effectors again encounter cell-associated microbes, they are acti- vated to perform the functions that are responsible for elimination of the microbes. The key mediators of the func- tions of helper T cells are various cytokines and the surface molecule called CD40 ligand (CD40L), which binds to its receptor, CD40, on B cells and macrophages. Differentiated CD4+ effector T cells of the TH1 subset recognize microbial peptides on macrophages that have ingested the microbes. The T cells express CD40L, which engages CD40 on the macrophages, and the T cells secrete the cytokine IFN-γ, which is a potent macrophage activator. The combination of CD40- and IFN-γ–mediated activation results in the induction of potent microbicidal substances in the macro- phages, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbes. TH2 cells elicit cellular defense reactions that are dominated by eosinophils and not macrophages. As discussed later, CD4+ helper T cells also stimulate B cell responses by CD40L and cytokines. Some CD4+ T cells remain in the lymphoid organs in which they were activated and then migrate into follicles, where they stimulate antibody responses; these cells are called follicular helper T cells.
Activated CD8+ lymphocytes differentiate into CTLs, which kill cells harboring microbes in the cytoplasm. These microbes may be viruses that infect many cell types, or bacteria that are ingested by macrophages but have learned to escape from phagocytic vesicles into the cytoplasm (where they are inaccessible to the killing machinery of phagocytes, which is largely confined to vesicles). By destroying the infected cells, CTLs eliminate the reservoirs of infection.

Question 19

Explain humoral Immunity:Activation of B Lymphocytes and Elimination of Extracellular Microbes(what’s re the major mechanisms of B cells,how does the humoral response combat microbes)

Answer 19

Upon activation, B lymphocytes proliferate and then dif- ferentiate into plasma cells that secrete different classes of antibodies with distinct functions (Fig. 4–6). There are two major mechanisms of B cell activation.
• T cell–independent. Many polysaccharide and lipid anti- gens have multiple identical antigenic determinants
ANTIBODY PRODUCTION
(epitopes) that are able to engage several antigen recep- tor molecules on each B cell and initiate the process of B cell activation.
• T cell–dependent. Typical globular protein antigens are not able to bind to many antigen receptors, and the full response of B cells to protein antigens requires help from CD4+ T cells. B cells also can act as APCs—they ingest protein antigens, degrade them, and display peptides bound to class II MHC molecules for recognition by helper T cells. The helper T cells express CD40L and secrete cytokines, which work together to activate the B cells.

Some of the progeny of the expanded B cell clones differ- entiate into antibody-secreting plasma cells. Each plasma cell secretes antibodies that have the same specificity as the cell surface antibodies (B cell receptors) that first recog- nized the antigen. Polysaccharides and lipids stimulate secretion mainly of IgM antibody. Protein antigens, by virtue of CD40L- and cytokine-mediated helper T cell actions, induce the production of antibodies of different classes (IgG, IgA, IgE). This production of functionally dif- ferent antibodies, all with the same specificity, is called heavy-chain class (isotype) switching; it provides plasticity in the antibody response, allowing antibodies to serve many functions. Helper T cells also stimulate the produc- tion of antibodies with higher and higher affinity for the antigen. This process, called affinity maturation, improves the quality of the humoral immune response.
The humoral immune response combats microbes in numerous ways (Fig. 4–6).
• Antibodies bind to microbes and prevent them from infecting cells, thereby “neutralizing” the microbes.

IgG antibodies coat (“opsonize”) microbes and target them for phagocytosis, since phagocytes (neutrophils and macrophages) express receptors for the Fc tails of IgG molecules.
• IgG and IgM activate the complement system by the classical pathway, and complement products promote phagocytosis and destruction of microbes. Production of most opsonizing and complement-fixing IgG antibodies is stimulated by IFN-γ, typically produced by TH1 helper cells, which respond to many bacteria and viruses, and IgG antibodies are important mechanisms of defense against these microbes.
• IgA is secreted in mucosal tissues and neutralizes microbes in the lumens of the respiratory and gastroin- testinal tracts (and other mucosal tissues).
• IgG is actively transported across the placenta and pro- tects the newborn until the immune system becomes mature. This is called passive immunity.
• IgE coats helminthic parasites and functions with mast cells and eosinophils to kill them. As mentioned earlier, TH2 helper cells secrete cytokines that stimulate the pro- duction of IgE and activate eosinophils, and thus the response to helminths is orchestrated by TH2 cells.
Circulating IgG antibodies have half-lives of about 3 weeks, which is much longer than the half-lives of most blood proteins, as a consequence of special mechanisms for recy- cling IgG and reducing its catabolism. Some antibody- secreting plasma cells migrate to the bone marrow and live for years, continuing to produce low levels of antibodies.

Question 20

Explain Decline of Immune Responses and Immunologic Memory

Answer 20

majority of effector lymphocytes induced by an infec- tious pathogen die by apoptosis after the microbe is elimi- nated, thus returning the immune system to its basal resting state. This return to a stable or steady state, called homeostasis, occurs because microbes provide essential stimuli for lymphocyte survival and activation, and effec- tor cells are short-lived. Therefore, as the stimuli are elimi- nated, the activated lymphocytes are no longer kept alive.
The initial activation of lymphocytes also generates long-lived memory cells, which may survive for years after the infection. Memory cells are an expanded pool of antigen-specific lymphocytes (more numerous than the naive cells specific for any antigen that are present before encounter with that antigen), and memory cells respond faster and more effectively against the antigen than do naive cells. This is why the generation of memory cells is an important goal of vaccination.

Question 21

In the general over view of normal immune responses,The early reaction to microbes is mediated by the mecha- nisms of innate immunity, which are ready to respond to microbes. These mechanisms include epithelial barriers, phagocytes, NK cells, and plasma proteins (e.g., of the complement system).The reaction of innate immunity is often manifested as inflammation.
• The defense reactions of adaptive immunity develop slowly, but are more potent and specialized.
• Microbes and other foreign antigens are captured by DCs and transported to lymph nodes, where the antigens are recognized by naive lymphocytes. The lymphocytes are activated to proliferate and differentiate into effector and memory cells.
• Cell-mediated immunity is the reaction of T lymphocytes, designed to combat cell-associated microbes (e.g., phago- cytosed microbes and microbes in the cytoplasm of infected cells). Humoral immunity is mediated by antibod- ies and is effective against extracellular microbes (in the circulation and mucosal lumens).
• CD4+ helper T cells help B cells to make antibodies, activate macrophages to destroy ingested microbes, stim- ulate recruitment of leukocytes, and regulate all immune responses to protein antigens. The functions of CD4+ T cells are mediated by secreted proteins called cytokines. CD8+ CTLs kill cells that express antigens in the cyto- plasm that are seen as foreign (e.g., virus-infected and tumor cells).
• Antibodies secreted by plasma cells neutralize microbes and block their infectivity, and promote the phagocytosis and destruction of pathogens. Antibodies also confer passive immunity to neonates
True or false

Answer 21

True

Question 22

How are hypersensitivity disorders

What are the causes of hypersensitivity reactions

Answer 22

Immune responses that normally are protective are also capable of causing tissue injury. Injurious immune reac- tions are grouped under hypersensitivity, and the resulting diseases are called hypersensitivity diseases. This term originated from the idea that persons who mount immune responses against an antigen are “sensitized” to that antigen, so pathologic or excessive reactions represent manifestations of a “hypersensitive” state. Normally, an exquisite system of checks and balances optimizes the eradication of infecting organisms without serious injury to host tissues. However, immune responses may be inad- equately controlled or inappropriately targeted to host tissues, and in such situations, the normally beneficial response is the cause of disease.

Pathologic immune responses may be directed against different types of antigens and may result from various underlying abnormalities. Autoimmunity: reactions against self antigens. Normally, the immune system does not react against self-generated antigens. This phenomenon is called self tolerance, implying that the body “tolerates” its own antigens. On occasion, self-tolerance fails, resulting in reactions against the body’s own cells and tissues; collectively, such reactions constitute autoimmunity. The diseases caused by autoimmunity are referred to as autoimmune diseases. We shall return to the mechanisms of self- tolerance and autoimmunity later in this chapter.
• Reactions against microbes. There are many types of reac- tions against microbial antigens that may cause disease. In some cases, the reaction appears to be excessive or the microbial antigen is unusually persistent. If antibodies are produced against such antigens, the antibodies may bind to the microbial antigens to produce immune com- plexes, which deposit in tissues and trigger inflamma- tion; this is the underlying mechanism of poststreptococcal glomerulonephritis (Chapter 13). T cell responses against persistent microbes may give rise to severe inflamma- tion, sometimes with the formation of granulomas (Chapter 2); this is the cause of tissue injury in tubercu- losis and other infections. Rarely, antibodies or T cells reactive with a microbe cross-react with a host tissue; such cross-reactivity is believed to be the basis for rheu- matic heart disease (Chapter 10). In some instances, the disease-causing immune response may be entirely normal, but in the process of eradicating the infection, host tissues are injured. In viral hepatitis, the virus that infects liver cells is not cytopathic, but it is recognized as foreign by the immune system. Cytotoxic T cells try to eliminate infected cells, and this normal immune response damages liver cells.
• Reactions against environmental antigens. Most healthy people do not react strongly against common environ- mental substances (e.g., pollens, animal danders, or dust mites), but almost 20% of the population are “allergic” to these substances. These individuals are genetically predisposed to make unusual immune responses to a variety of noninfectious, and otherwise harmless,
Table 4–1 Mechanisms of Hypersensitivity Reactions
antigens to which all persons are exposed but against which only some react.
In all of these conditions, tissue injury is caused by the same mechanisms that normally function to eliminate infectious pathogens—namely, antibodies, effector T lym- phocytes, and various other effector cells. The problem in these diseases is that the response is triggered and maintained inappropriately. Because the stimuli for these abnormal immune responses are difficult or impossible to eliminate (e.g., self antigens, persistent microbes, or envi- ronmental antigens), and the immune system has many intrinsic positive feedback loops (amplification mecha- nisms), once a pathologic immune response starts it is difficult to control or terminate it. Therefore, these hyper- sensitivity diseases tend to be chronic and debilitating, and are therapeutic challenges. Since inflammation, typically chronic inflammation, is a major component of the pathol- ogy of these disorders, they are sometimes grouped under the rubric immune-mediated inflammatory diseases.

Question 23

Explain the types of hypersensitivity reactions

State the types of reactions,immune mechanisms,histopathologic lesions and protypical disorders

Answer 23

Hypersensitivity reactions are traditionally subdivided into four types based on the principal immune mechanism responsible for injury; three are variations on antibody-mediated injury, whereas the fourth is T cell–mediated (Table 4–1). The rationale for this classification is that the mechanism of immune injury is often a good predictor of the clinical manifestations and may even help to guide the therapy. However, this classification of immune-mediated diseases is not perfect, because several immune reactions may coexist in one disease.
•

Immediate (type I) hypersensitivity, often called allergy, results from the activation of the TH2 subset of CD4+ helper T cells by environmental antigens, leading to the production of IgE antibodies, which become attached to mast cells. When these IgE molecules bind the antigen (allergen), the mast cells are triggered to release media- tors that transiently affect vascular permeability and induce smooth muscle contraction in various organs, and that also may stimulate more prolonged inflamma- tion (the late-phase reaction). These diseases are com- monly called allergic, or atopic, disorders.
• Antibody-mediated (type II) hypersensitivity disorders are caused by antibodies that bind to fixed tissue or cell surface antigens, promoting phagocytosis and destruc- tion of the coated cells or triggering pathologic inflam- mation in tissues.
• Immune complex–mediated (type III) hypersensitivity disor- ders are caused by antibodies binding to antigens to form complexes that circulate and deposit in vascular beds and stimulate inflammation, typically as a consequence of complement activation. Tissue injury in these diseases is the result of the inflammation.
• T cell–mediated (type IV) hypersensitivity disorders are caused mainly by immune responses in which T lym- phocytes of the TH1 and TH17 subsets produce cytokines that induce inflammation and activate neutrophils and macrophages, which are responsible for tissue injury. CD8+ CTLs also may contribute to injury by directly killing host cells.

Type
Immune Mechanisms
Histopathologic Lesions
Prototypical Disorders
Immediate (type I)
Production of IgE antibody → immediate hypersensitivity release of vasoactive amines and other
mediators from mast cells; later recruitment of inflammatory cells
Histopathological lesions:Vascular dilation, edema, smooth muscle contraction, mucus production, tissue
injury, inflammation
Pro typical disorders:Anaphylaxis; allergies; bronchial, asthma (atopic forms)

Antibody-mediated (type II)
Production of IgG, IgM → binds to antigen hypersensitivity on target cell or tissue → phagocytosis or
lysis of target cell by activated complement or Fc receptors; recruitment of leukocytes

Histopathological:Phagocytosis and lysis of cells; in some diseases functional derangements
without cell or tissue injury

Protypical disorders:Autoimmune hemolytic anemia; inflammation;, Goodpasture syndrome

Immune complex–mediated (type III)
hypersensitivity →

Deposition of antigen–antibody complexes leading to complement activation → recruitment
of leukocytes by complement products and Fc receptors → release of enzymes and other toxic molecules
Histopathological:Inflammation, necrotizing vasculitis (fibrinoid necrosis)

Protypical disorder:Systemic lupus erythematosus; some forms of glomerulonephritis; serum sickness;Arthus reaction

Cell-mediated (type IV)

Activated T lymphocytes → (1) release of hypersensitivity cytokines, inflammation and macrophage
activation; (2) T cell–mediated cytotoxicity

Histopathological:Perivascular cellular infiltrates; edema; granuloma formation; cell destruction

Protypical:Contact dermatitis; multiple sclerosis; type 1 diabetes; tuberculosis

Question 24

Explain type 1 hypersensitivity

What’s re the sequence of events in immediate hypersensitivity reactions

Answer 24

Immediate (Type I) Hypersensitivity
Immediate hypersensitivity is a tissue reaction that occurs rapidly (typically within minutes) after the interaction of antigen with IgE antibody that is bound to the surface of mast cells in a sensitized host. The reaction is initiated by entry of an antigen, which is called an allergen because it triggers allergy. Many allergens are environmental substances that are harmless for most persons on exposure. Some people apparently inherit genes that make them susceptible to allergies. This susceptibility is manifested by the propen- sity of such persons to mount strong TH2 responses and, subsequently, to produce IgE antibody against the aller- gens. The IgE is central to the activation of the mast cells and release of mediators that are responsible for the clinical and pathologic manifestations of the reaction. Immediate hypersensitivity may occur as a local reaction that is merely annoying (e.g., seasonal rhinitis, or hay fever), severely debilitating (asthma), or even fatal (anaphylaxis).

Most hypersensitivity reactions follow the same sequence of cellular responses (Fig. 4–7):
• ActivationofTH2cellsandproductionofIgEantibody.Aller- gens may be introduced by inhalation, ingestion, or injection. Variables that probably contribute to the strong TH2 responses to allergens include the route of entry, dose, and chronicity of antigen exposure, and the genetic makeup of the host. It is not clear if allergenic substances also have unique structural properties that endow them with the ability to elicit TH2 responses. Immediate hypersensitivity is the prototypical TH2-mediated reaction. The TH2 cells that are induced secrete several cytokines, including IL-4, IL-5, and IL-13, which are responsible for essentially all the reactions of immediate hypersensitivity. IL-4 stimulates B cells specific for the allergen to undergo heavy-chain class switching to IgE and to secrete this immunoglobulin isotype. IL-5 acti-
vates eosinophils that are recruited to the reaction, and
IL-13 acts on epithelial cells and stimulates mucus secre-
tion. T 2 cells often are recruited to the site of allergic H
reactions in response to chemokines that are produced locally; among these chemokines is eotaxin, which also recruits eosinophils to the same site.
• Sensitization of mast cells by IgE antibody. Mast cells are derived from precursors in the bone marrow, are widely distributed in tissues, and often reside near blood vessels and nerves and in subepithelial locations. Mast cells express a high-affinity receptor for the Fc portion of the ε heavy chain of IgE, called FcεRI. Even though the serum concentration of IgE is very low (in the range of 1 to 100 μg/mL), the affinity of the mast cell FcεRI recep- tor is so high that the receptors are always occupied by IgE. These antibody-bearing mast cells are “sensitized” to react if the antigen binds to the antibody molecules. Basophils are the circulating counterparts of mast cells. They also express FcεRI, but their role in most immedi- ate hypersensitivity reactions is not established (since these reactions occur in tissues and not in the circula- tion). The third cell type that expresses FcεRI is eosino- phils, which often are present in these reactions and also have a role in IgE-mediated host defense against hel- minth infections, described later.
• Activation of mast cells and release of mediators. When a person who was sensitized by exposure to an allergen is reexposed to the allergen, it binds to multiple specific IgE molecules on mast cells, usually at or near the site of allergen entry. When these IgE molecules are cross- linked, a series of biochemical signals is triggered in the mast cells. The signals culminate in the secretion of various mediators from the mast cells. Three groups of mediators are the most important in different immediate hypersensitivity reactions (Fig. 4–8):
 Vasoactive amines released from granule stores. The gran- ules of mast cells contain histamine, which is released within seconds or minutes of activation. Histamine causes vasodilation, increased vascular permeability, smooth muscle contraction, and increased secretion of mucus. Other rapidly released mediators include adenosine (which causes bronchoconstriction and inhibits platelet aggregation) and chemotactic factors for neutrophils and eosinophils. Other mast cell granule contents that may be secreted include several neutral proteases (e.g., tryptase), which may damage tissues and also generate kinins and cleave comple- ment components to produce additional chemotactic and inflammatory factors (e.g., C3a) (Chapter 2). The granules also contain acidic proteoglycans (heparin, chondroitin sulfate), the main function of which seems to be as a storage matrix for the amines.
 Newly synthesized lipid mediators. Mast cells synthesize and secrete prostaglandins and leukotrienes, by the same pathways as do other leukocytes (Chapter 2). These lipid mediators have several actions that are important in immediate hypersensitivity reactions. Prostaglandin D2 (PGD2) is the most abundant media- tor generated by the cyclooxygenase pathway in mast cells. It causes intense bronchospasm as well as increased mucus secretion. The leukotrienes LTC4 and LTD4 are the most potent vasoactive and spasmo- genic agents known; on a molar basis, they are several thousand times more active than histamine in increas- ing vascular permeability and in causing bronchial smooth muscle contraction. LTB4 is highly chemotac- tic for neutrophils, eosinophils, and monocytes.
 Cytokines. Activation of mast cells results in the syn- thesis and secretion of several cytokines that are important for the late-phase reaction. These include TNF and chemokines, which recruit and activate leu- kocytes (Chapter 2); IL-4 and IL-5, which amplify the TH2-initiated immune reaction; and IL-13, which
stimulates epithelial cell mucus secretion.
In summary, a variety of compounds that act on blood vessels, smooth muscle, and leukocytes mediate type I hypersensitivity reactions (Table 4–2). Some of these com- pounds are released rapidly from sensitized mast cells and are responsible for the intense immediate reactions associ- ated with conditions such as systemic anaphylaxis. Others, such as cytokines, are responsible for the inflammation seen in late-phase reactions.
Often, the IgE-triggered reaction has two well-defined phases (Fig. 4–9): (1) the immediate response, characterized by vasodilation, vascular leakage, and smooth muscle spasm, usually evident within 5 to 30 minutes after expo- sure to an allergen and subsiding by 60 minutes; and (2) a second, late-phase reaction that usually sets in 2 to 8 hours later and may last for several days and is characterized by inflammation as well as tissue destruction, such as mucosal epithelial cell damage. The dominant inflammatory cells in the late-phase reaction are neutrophils, eosinophils, and lymphocytes, especially TH2 cells. Neutrophils are recruited by various chemokines; their roles in inflammation were described in Chapter 2. Eosinophils are recruited by eotaxin and other chemokines released from TNF-activated epithe- lium and are important effectors of tissue injury in the late-phase response. Eosinophils produce major basic protein and eosinophil cationic protein, which are toxic to epithelial cells, and LTC4 and platelet-activating factor, which promote inflammation. TH2 cells produce cytokines that have multiple actions, as described earlier. These recruited leukocytes can amplify and sustain the inflamma- tory response even in the absence of continuous allergen exposure. In addition, inflammatory leukocytes are respon- sible for much of the epithelial cell injury in immediate hypersensitivity. Because inflammation is a major compo- nent of many allergic diseases, notably asthma and atopic dermatitis, therapy usually includes anti-inflammatory drugs such as corticosteroids.

Question 25

State the mast cell mediators in type 1 hypersensitivity and their actions

Answer 25

Action
Mediators

Vasodilation, increased vascular permeability :PAF, Histamine
Leukotrienes C4, D4, E4
Neutral proteases that activate
complement and kinins ,Prostaglandin D2

Smooth muscle spasm: Leukotrienes C4, D4, E4 Histamine
Prostaglandins PAF

Cellular infiltration :Cytokines (e.g., chemokines, TNF) Leukotriene B4
Eosinophil and neutrophil chemotactic factors (not defined biochemically)

Question 26

What’s re the clinical and pathological manifestations of type 1 hypersensitivity reaction

Answer 26

An immediate hypersensitivity reaction may occur as a systemic disorder or as a local reaction. The nature of the reaction is often determined by the route of antigen exposure. Systemic exposure to protein antigens (e.g., in bee venom) or drugs (e.g., penicillin) may result in sys- temic anaphylaxis. Within minutes of the exposure in a sensitized host, itching, urticaria (hives), and skin ery- thema appear, followed in short order by profound respira- tory difficulty caused by pulmonary bronchoconstriction and accentuated by hypersecretion of mucus. Laryngeal edema may exacerbate matters by causing upper airway obstruction. In addition, the musculature of the entire gas- trointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation with a fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes.
Local reactions generally occur when the antigen is con- fined to a particular site, such as skin (contact, causing urticaria), gastrointestinal tract (ingestion, causing diar- rhea), or lung (inhalation, causing bronchoconstriction). The common forms of skin and food allergies, hay fever, and certain forms of asthma are examples of localized aller- gic reactions. However, ingestion or inhalation of allergens also can trigger systemic reactions.
Susceptibility to localized type I reactions has a strong genetic component, and the term atopy is used to imply familial predisposition to such localized reactions. Patients who suffer from nasobronchial allergy (including hay fever and some forms of asthma) often have a family history of similar conditions. Genes that are implicated in susceptibil- ity to asthma and other atopic disorders include those encoding HLA molecules (which may confer immune responsiveness to particular allergens), cytokines (which may control TH2 responses), a component of the FcεRI, and ADAM33, a metalloproteinase that may be involved in tissue remodeling in the airways.
The reactions of immediate hypersensitivity clearly did not evolve solely to cause human discomfort and disease. The immune response dependent on TH2 cells and IgE—in particular, the late-phase inflammatory reaction—plays an important protective role in combating parasitic infections. IgE antibodies are produced in response to many helmin- thic infections, and their physiologic function is to target helminths for destruction by eosinophils and mast cells. Mast cells also are involved in defense against bacterial infections. And snake aficionados will be relieved to hear that their mast cells may protect them from some snake venoms by releasing granule proteases that degrade the toxins. Why these beneficial responses are inappropriately activated by harmless environmental antigens, giving rise to allergies, remains a puzzle.

Question 27

Immediate (Type I) Hypersensitivity
• Also called allergic reactions, or allergies
• Induced by environmental antigens (allergens) that stimu-
late strong TH2 responses and IgE production in geneti-
cally susceptible individuals
• IgE coats mast cells by binding to Fcε receptors; reexpo-
sure to the allergen leads to cross-linking of the IgE and
FcεRI, activation of mast cells, and release of mediators.
• Principal mediators are histamine, proteases, and other granule contents; prostaglandins and leukotrienes; and
cytokines.
• Mediators are responsible for the immediate vascular and
smooth muscle reactions and the late-phase reaction
(inflammation).
• The clinical manifestations may be local or systemic, and
range from mildly annoying rhinitis to fatal anaphylaxis.

True or false

Answer 27

True

Question 28

What are type 2 hypersensitivity reactions

What is the mechanism of antibody mediated disorders

Answer 28

Antibody-mediated (type II) hypersensitivity disorders are caused by antibodies directed against target antigens on the surface of cells or other tissue components. The antigens may be normal molecules intrinsic to cell membranes or in the extracellular matrix, or they may be adsorbed exoge- nous antigens (e.g., a drug metabolite). Antibody-mediated abnormalities are the underlying cause of many human diseases; examples of these are listed in Table 4–3. In all of these disorders, the tissue damage or functional abnormali- ties result from a limited number of mechanisms.
Mechanisms of Antibody-Mediated Diseases
Antibodies cause disease by targeting cells for phagocyto- sis, by activating the complement system, and by interfer- ing with normal cellular functions (Fig. 4–10). The antibodies that are responsible typically are high-affinity antibodies capable of activating complement and binding to the Fc receptors of phagocytes.
• Opsonization and phagocytosis. When circulating cells, such as erythrocytes or platelets, are coated (opsonized) with autoantibodies, with or without complement pro- teins, the cells become targets for phagocytosis by neutrophils and macrophages (Fig. 4–10, A). These phagocytes express receptors for the Fc tails of IgG anti- bodies and for breakdown products of the C3 comple- ment protein, and use these receptors to bind and ingest opsonized particles. Opsonized cells are usually elimi- nated in the spleen, and this is why splenectomy is of clinical benefit in autoimmune thrombocytopenia and
some forms of autoimmune hemolytic anemia.
• Inflammation.Antibodiesboundtocellularortissueanti- gens activate the complement system by the “classical” pathway (Fig. 4–10, B). Products of complement activa- tion serve several functions (see Fig. 2–18, Chapter 2), one of which is to recruit neutrophils and monocytes, triggering inflammation in tissues. Leukocytes may also be activated by engagement of Fc receptors, which rec- ognize the bound antibodies. This mechanism of injury is exemplified by Goodpasture syndrome and pemphi-
gus vulgaris.
• Antibody-mediated cellular dysfunction. In some cases,
antibodies directed against cell surface receptors impair or dysregulate cellular function without causing cell injury or inflammation (Fig. 4–10, C). In myasthenia gravis, antibodies against acetylcholine receptors in the motor end plates of skeletal muscles inhibit neuromuscular transmission, with resultant muscle weakness. Antibodies can also stimulate cellular
responses excessively. In Graves disease, antibodies against the thyroid-stimulating hormone receptor stim- ulate thyroid epithelial cells to secrete thyroid hormones, resulting in hyperthyroidism. Antibodies against hor- mones and other essential proteins can neutralize and block the actions of these molecules, causing functional derangements.

Question 29

Name some examples of antibody mediated diseases in type 2,their target antigen,mechanism of disease and clinipathological manifestation

Answer 29

Disease
Target Antigen
Mechanisms of Disease
Clinicopathologic Manifestations

Autoimmune hemolytic anemia

Red cell membrane proteins (Rh blood group antigens, I antigen)
Opsonization and phagocytosis of erythrocytes
Hemolysis, anemia

Autoimmune thrombocytopenic purpura

Platelet membrane proteins (GpIIb/IIIa integrin)
Opsonization and phagocytosis of platelets
Manifestation:Bleeding

Pemphigus vulgaris
Proteins in intercellular junctions of epidermal cells (epidermal
desmoglein)

Antibody-mediated activation of proteases, disruption of
intercellular adhesions

Skin vesicles (bullae)

Vasculitis caused by ANCA :
Neutrophil granule proteins, presumably released from activated neutrophils
Neutrophil degranulation and inflammation
Manifestation:Vasculitis

Goodpasture syndrome
Noncollagenous protein (NC1) in basement membranes of kidney glomeruli and lung alveoli
Complement- and Fc receptor mediated inflammation
Nephritis, lung hemorrhage

Acute rheumatic fever
Streptococcal cell wall antigen; antibody cross-reacts with
myocardial antigen
Mechanism of disease:Inflammation, macrophage activation
Myocarditis

Myasthenia gravis
Acetylcholine receptor
Antibody inhibits acetylcholine binding, downmodulates receptors

Muscle weakness, paralysis

Graves disease (hyperthyroidism)
TSH receptor
Antibody-mediated stimulation of TSH receptors
Hyperthyroidism

Insulin-resistant diabetes
Insulin receptor
Antibody inhibits binding of insulin Hyperglycemia, ketoacidosis

Pernicious anemia
Intrinsic factor of gastric parietal Neutralization of intrinsic factor, cells decreased absorption of vitamin B12
Abnormal myelopoiesis, anemia

Question 30

Explain type 3 hypersensitivity reaction

Explain systemic and local immune complex disease

Answer 30

Immune Complex Diseases (Type III Hypersensitivity)
Antigen–antibody (immune) complexes that are formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation. The antigens in these com- plexes may be exogenous antigens, such as microbial pro- teins, or endogenous antigens, such as nucleoproteins. The mere formation of immune complexes does not equate with hypersensitivity disease; small amounts of antigen– antibody complexes may be produced during normal

immune responses and are usually phagocytosed and destroyed. It is only when these complexes are produced in large amounts, persist, and are deposited in tissues that they are pathogenic. Pathogenic immune complexes may form in the circulation and subsequently deposit in blood vessels, or the complexes may form at sites where antigen has been planted (in situ immune complexes). Immune complex–mediated injury is systemic when complexes are formed in the circulation and are deposited in several organs, or it may be localized to particular organs (e.g., kidneys, joints, or skin) if the complexes are formed and deposited in a specific site. The mechanism of tissue injury is the same regardless of the pattern of distribution; however, the sequence of events and the conditions leading to the formation of systemic and local immune complexes are different and are considered separately in the following descriptions.

Systemic Immune Complex Disease
The pathogenesis of systemic immune complex disease can be divided into three phases: (1) formation of antigen– antibody complexes in the circulation and (2) deposition of the immune complexes in various tissues, thereby initiat- ing (3) an inflammatory reaction in various sites through- out the body (Fig. 4–11).
Acute serum sickness is the prototype of a systemic immune complex disease. It was first described in humans when large amounts of foreign serum were administered for passive immunization (e.g., in persons receiving horse serum containing antidiphtheria antibody); it is now seen only rarely (e.g., in patients injected with rabbit or horse antithymocyte globulin for treatment of aplastic anemia or graft rejection, or patients with snakebite given anti-venom antibody made in animals). Although serum sickness is no longer common, the study of its pathogenesis sheds light on the mechanisms of human immune complex diseases. Approximately 5 days after the foreign protein is injected, specific antibodies are produced; these react with the antigen still present in the circulation to form antigen– antibody complexes. The complexes deposit in blood vessels in various tissue beds, triggering the subsequent injurious inflammatory reaction.
Several variables determine whether immune complex forma- tion leads to tissue deposition and disease. Perhaps foremost among these factors is the size of the complexes. Very large complexes or complexes with many free IgG Fc regions (typically formed in antibody excess) are rapidly removed from the circulation by macrophages in the spleen and liver and are therefore usually harmless. The most pathogenic complexes are formed during antigen excess and are small or intermediate in size and are cleared less effectively by phagocytes and therefore circulate longer. In addition, the charge of the complex, the valency of the antigen, the avidity of the antibody, and the hemodynamics of a given vascular bed all influence the tendency to develop disease. The favored sites of deposition are kidneys, joints, and small blood vessels in many tissues. Localization in the kidney and joints is explained in part by the high hemody- namic pressures associated with the filtration function of the glomerulus and the synovium. For complexes to leave the circulation and deposit within or outside the vessel wall, an increase in vascular permeability also must occur. This is probably triggered when immune complexes bind to leukocytes and mast cells by means of Fc and C3b recep- tors and stimulate release of mediators that increase vas- cular permeability.
Once complexes are deposited in the tissue, the third phase, the inflammatory reaction, ensues. During this phase (approximately 10 days after antigen administration), clini- cal features such as fever, urticaria, arthralgias, lymph node enlargement, and proteinuria appear. Wherever immune complexes deposit, characteristic tissue damage occurs. The immune complexes activate the complement system, leading to the release of biologically active frag- ments such as the anaphylatoxins (C3a and C5a), which increase vascular permeability and are chemotactic for neutrophils and monocytes (Chapter 2). The complexes also bind to Fcγ receptors on neutrophils and monocytes, activating these cells. Attempted phagocytosis of immune complexes by the leukocytes results in the secretion of a variety of additional pro-inflammatory substances, includ- ing prostaglandins, vasodilator peptides, and chemotactic substances, as well as lysosomal enzymes capable of digest- ing basement membrane, collagen, elastin, and cartilage, and reactive-oxygen species that damage tissues. Immune complexes can also cause platelet aggregation and activate Hageman factor; both of these reactions augment the inflammatory process and initiate formation of micro- thrombi, which contribute to the tissue injury by producing local ischemia (Fig. 4–11). The resultant pathologic lesion is termed vasculitis if it occurs in blood vessels, glomerulo- nephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints, and so on.
Predictably, the antibody classes that induce such lesions are complement-fixing antibodies (i.e., IgG and IgM) and antibodies that bind to phagocyte Fc receptors (IgG). During the active phase of the disease, consumption of complement may result in decreased serum complement levels. The role of complement- and Fc receptor–dependent inflammation in the pathogenesis of the tissue injury is supported by the observation that experimental depletion of serum complement levels or knockout of Fc receptors in mice greatly reduces the severity of lesions, as does deple- tion of neutrophils.

Local Immune Complex Disease
A model of local immune complex diseases is the Arthus reaction, in which an area of tissue necrosis appears as a result of acute immune complex vasculitis. The reaction is produced experimentally by injecting an antigen into the skin of a previously immunized animal (i.e., pre-formed antibodies against the antigen are already present in the circulation). Because of the initial antibody excess, immune complexes are formed as the antigen diffuses into the vas- cular wall; these are precipitated at the site of injection and trigger the same inflammatory reaction and histologic appearance as in systemic immune complex disease. Arthus lesions evolve over a few hours and reach a peak 4 to 10 hours after injection, when the injection site develops visible edema with severe hemorrhage, occasionally fol- lowed by ulceration.

Question 31

Give some examples of diseases that are immune complex mediated ,the antigen involved and clinicopathological manifestation

Answer 31

Disease
Antigen Involved
Clinicopathologic Manifestations

Systemic lupus erythematosus
Nuclear antigens
Nephritis, skin lesions, arthritis, others

Poststreptococcal glomerulonephritis Streptococcal cell wall antigen(s); may be “planted” in glomerular basement membrane
Nephritis

Polyarteritis nodosa
Hepatitis B virus antigens in some cases Systemic vasculitis

Reactive arthritis
Bacterial antigens (e.g., Yersinia)
Acute arthritis

Serum sickness 
Various proteins (e.g., foreign serum protein such as horse antithymocyte globulin)

Arthritis, vasculitis, nephritis

Arthus reaction (experimental)
Various foreign proteins
Cutaneous vasculitis

Question 32

What is the morphology of type three hypersensitivity reactions

SUMMARY
Pathogenesis of Diseases Caused by Antibodies and Immune Complexes
• Antibodies can coat (opsonize) cells, with or without complement proteins, and target these cells for phagocy- tosis by macrophages, which express receptors for the Fc tails of IgG molecules and for complement proteins.The result is depletion of the opsonized cells.
• Antibodies and immune complexes may deposit in tissues or blood vessels, and elicit an acute inflammatory reaction by activating complement, with release of breakdown products, or by engaging Fc receptors of leukocytes. The inflammatory reaction causes tissue injury.
• Antibodies can bind to cell surface receptors or essential molecules, and cause functional derangements (either inhibition or unregulated activation) without cell injury.

True or false

Answer 32

The morphologic appearance of immune complex injury is dominated by acute necrotizing vasculitis, microthrombi, and superimposed ischemic necrosis accompanied by acute inflammation of the affected organs. The necrotic vessel wall takes on a smudgy eosinophilic appearance called fibrinoid necrosis, caused by protein deposition (see Fig. 1–13, Chapter 1). Immune complexes can be visualized in the tissues, usually in the vascular wall (examples of such deposits in the kidney in lupus are shown in Fig. 4–18, E). In due course, the lesions tend to resolve, especially when they were brought about by a single exposure to antigen (e.g., in acute serum sickness or acute poststreptococcal glomerulo- nephritis) (Chapter 13). However, chronic immune complex disease develops when there is persistent antigenemia or repeated exposure to an antigen. This occurs in some human diseases, such as systemic lupus erythematosus (SLE). Most often, even though the morphologic changes and other find- ings strongly implicate immune complex disease, the inciting antigens are unknown.

Question 33

Explain type 4 hypersensitivity reactions

Explain the inflammatory reactions elicited by CD4+ T cells

Answer 33

T Cell–Mediated (Type IV) Hypersensitivity
Several autoimmune disorders, as well as pathologic reactions to environmental chemicals and persistent microbes, are now known to be caused by T cells (Table 4–5). The occurrence and significance of T lymphocyte–mediated tissue injury have been increasingly appreciated as the methods for detecting and purifying T cells from patients’ circulation and lesions have improved. This group of diseases is of great clinical interest because many of the new, rationally designed biologic therapies for immune-mediated inflam- matory diseases have been developed to target abnormal T cell reactions. Two types of T cell reactions are capable of causing tissue injury and disease: (1) cytokine-mediated inflammation, in which the cytokines are produced mainly by CD4+ T cells, and (2) direct cell cytotoxicity, mediated by CD8+ T cells (Fig. 4–12). In inflammation, exemplified by the delayed-type hypersensitivity (DTH) reaction, CD4+ T cells of the TH1 and TH17 subsets secrete cytokines, which recruit and activate other cells, especially macrophages, and these are the major effector cells of injury. In cell-mediated cytotoxicity, cytotoxic CD8+ T cells are responsible for tissue damage.

Inflammatory Reactions Elicited by CD4+ T Cells
The sequence of events in T cell–mediated inflammatory reactions begins with the first exposure to antigen and is essentially the same as the reactions of cell-mediated immunity (Fig. 4–4). Naive CD4+ T lymphocytes recognize peptide antigens of self or microbial proteins in association with class II MHC molecules on the surface of DCs (or macrophages) that have processed the antigens. If the DCs produce IL-12, the naive T cells differentiate into effector cells of the TH1 type. The cytokine IFN-γ, made by NK cells and by the TH1 cells themselves, further promotes TH1 dif- ferentiation, providing a powerful positive feedback loop. If the APCs produce IL-1, IL-6, or IL-23 instead of IL-12, the CD4+ cells develop into TH17 effectors. On subsequent exposure to the antigen, the previously generated effector cells are recruited to the site of antigen exposure and are activated by the antigen presented by local APCs. The TH1 cells secrete IFN-γ, which is the most potent macrophage- activating cytokine known. Activated macrophages have
increased phagocytic and microbicidal activity. Activated macrophages also express more class II MHC molecules and costimulators, leading to augmented antigen presenta- tion capacity, and the cells secrete more IL-12, thus stimu- lating more TH1 responses. Upon activation by antigen, TH17 effector cells secrete IL-17 and several other cytokines, which promote the recruitment of neutrophils (and mono- cytes) and thus induce inflammation. Because the cyto- kines produced by the T cells enhance leukocyte recruitment and activation, these inflammatory reactions become chronic unless the offending agent is eliminated or the cycle is interrupted therapeutically. In fact, inflammation occurs as an early response to microbes and dead cells (Chapter 2), but it is greatly increased and prolonged when T cells are involved.
Delayed-type hypersensitivity (DTH), described next, is an illustrative model of T cell–mediated inflammation and tissue injury. The same reactions are the underlying basis for several diseases. Contact dermatitis is an example of tissue injury resulting from T cell–mediated inflammation. It is evoked by contact with pentadecylcatechol (also known as urushiol, the active component of poison ivy and poison oak, which probably becomes antigenic by binding to a host protein). On reexposure of a previously exposed person to the plants, sensitized TH1 CD4+ cells accumulate in the dermis and migrate toward the antigen within the epidermis. Here they release cytokines that damage kera- tinocytes, causing separation of these cells and formation of an intraepidermal vesicle, and inflammation manifested as a vesicular dermatitis. It has long been thought that several systemic diseases, such as type 1 diabetes and mul- tiple sclerosis, are caused by TH1 and TH17 reactions against self antigens, and Crohn disease may be caused by uncon- trolled reactions involving the same T cells but directed against intestinal bacteria. T cell–mediated inflammation also plays a role in the rejection of transplants, described later in the chapter

Question 34

Explain delayed type hypersensitivity and T cell mediated cytotoxicity

Mechanisms of T Cell–Mediated Hypersensitivity Reactions
• Cytokine-mediated inflammation: CD4+ T cells are acti- vated by exposure to a protein antigen and differentiate into TH1 and TH17 effector cells. Subsequent exposure to the antigen results in the secretion of cytokines. IFN-γ activates macrophages to produce substances that cause tissue damage and promote fibrosis, and IL-17 and other cytokines recruit leukocytes, thus promoting inflammation.
• T cell–mediated cytotoxicity: CD8+ CTLs specific for an antigen recognize cells expressing the target antigen and kill these cells. CD8+ T cells also secrete IFN-γ.

True or false

Answer 34

Delayed-Type Hypersensitivity
DTH is a T cell–mediated reaction that develops in response to antigen challenge in a previously sensitized individual. In contrast with immediate hypersensitivity, the DTH reac- tion is delayed for 12 to 48 hours, which is the time it takes for effector T cells to be recruited to the site of antigen chal- lenge and to be activated to secrete cytokines. The classic example of DTH is the tuberculin reaction, elicited by chal- lenge with a protein extract of M. tuberculosis (tuberculin) in a person who has previously been exposed to the tuber- cle bacillus. Between 8 and 12 hours after intracutaneous injection of tuberculin, a local area of erythema and indura- tion appears, reaching a peak (typically 1 to 2 cm in diam- eter) in 24 to 72 hours and thereafter slowly subsiding. On histologic examination, the DTH reaction is characterized by perivascular accumulation (“cuffing”) of CD4+ helper T cells and macrophages (Fig. 4–13). Local secretion of cyto- kines by these cells leads to increased microvascular per- meability, giving rise to dermal edema and fibrin deposition; the latter is the main cause of the tissue induration in these responses. DTH reactions are mediated primarily by TH1 cells; the contribution of TH17 cells is unclear. The tubercu- lin response is used to screen populations for people who have had previous exposure to tuberculosis and therefore have circulating memory T cells specific for mycobacterial proteins. Notably, immunosuppression or loss of CD4+ T cells (e.g., resulting from HIV infection) may lead to a nega- tive tuberculin response even in the presence of a severe infection.
Prolonged DTH reactions against persistent microbes or other stimuli may result in a special morphologic pattern
of reaction called granulomatous inflammation. The initial perivascular CD4+ T cell infiltrate is progressively replaced by macrophages over a period of 2 to 3 weeks. These accumulated macrophages typically exhibit morphologic evidence of activation; that is, they become large, flat, and eosinophilic, and are called epithelioid cells. The epitheli- oid cells occasionally fuse under the influence of cytokines (e.g., IFN-γ) to form multinucleate giant cells. A micro- scopic aggregate of epithelioid cells, typically surrounded by a collar of lymphocytes, is called a granuloma (Fig. 4–14, A). The process is essentially a chronic form of TH1-mediated inflammation and macrophage activation (Fig. 4–14, B). Older granulomas develop an enclosing rim of fibroblasts and connective tissue. Recognition of a granuloma is of diagnostic importance because of the limited number of conditions that can cause it (Chapter 2).
T Cell–Mediated Cytotoxicity
In this form of T cell–mediated tissue injury, CD8+ CTLs kill antigen-bearing target cells. As discussed earlier, class I MHC molecules bind to intracellular peptide antigens and present the peptides to CD8+ T lymphocytes, stimulat- ing the differentiation of these T cells into effector cells called CTLs. CTLs play a critical role in resistance to virus infections and some tumors. The principal mechanism of killing by CTLs is dependent on the perforin–granzyme system. Perforin and granzymes are stored in the granules of CTLs and are rapidly released when CTLs engage their targets (cells bearing the appropriate class I MHC–bound peptides). Perforin binds to the plasma membrane of the target cells and promotes the entry of granzymes, which are proteases that specifically cleave and thereby activate cellular caspases. These enzymes induce apoptotic death of the target cells (Chapter 1). CTLs play an important role in the rejection of solid-organ transplants and may contribute to many immunologic diseases, such as type 1 diabetes (in which insulin-producing β cells in pancreatic islets are destroyed by an autoimmune T cell reaction). CD8+ T cells may also secrete IFN-γ and contribute to cytokine-mediated inflammation, but less so than CD4+ cells.

Question 35

State some cell mediated diseases ,specificity of pathogenic T cells,principal mechanism of tissue injury,clinicopathological manifestations

Answer 35

Rheumatoid arthritis
Collagen?; citrullinated self proteins
Inflammation mediated by TH17 (and TH1?)? cytokines; role of antibodies and immune
complexes?
Chronic arthritis with inflammation, destruction of articular cartilage and bone

Multiple sclerosis
Protein antigens in myelin (e.g., myelin basic protein)
Inflammation mediated by TH1 and TH17 cytokines, myelin destruction by activated
macrophages
Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions

Type 1 diabetes
Antigens of pancreatic islet β mellitus cells (insulin, glutamic acid
decarboxylase, others)
T cell–mediated inflammation, destruction of islet cells by CTLs
Insulitis (chronic inflammation in islets), destruction of β cells; diabetes

Hashimoto thyroiditis
Thyroglobulin, other thyroid proteins Inflammation, CTL-mediated killing of
thyroid epithelial cells
Hypothyroidism

Inflammatory bowel disease
Enteric bacteria; self antigens?
Inflammation mediated mainly by TH17 cytokines
Chronic intestinal inflammation, ulceration, obstruction

Autoimmune myocarditis
Myosin heavy chain protein
CTL-mediated killing of myocardial cells; inflammation mediated by TH1 cytokines
Cardiomyopathy

Contact sensitivity
Various environmental chemicals (e.g., urushiol from poison ivy
or poison oak)
Inflammation mediated by TH1 (and TH17?) cytokines
Epidermal necrosis, dermal inflammation with skin rash and blisters
*

Question 36

What are autoimmune diseases and immunologic tolerance

Answer 36

Immune reactions to self antigens (i.e., autoimmunity) are the underlying cause of numerous human diseases. Auto- immune diseases currently are estimated to affect 2% to 5% of the population in developed countries, and appear to be increasing in incidence. The evidence that these diseases are indeed the result of autoimmune reactions is more per- suasive for some than for others. For instance, in many of these disorders, multiple high-affinity autoantibodies have been identified, and in some cases these antibodies are known to cause pathologic abnormalities (Table 4–6). Simi- larly, with improving technology, there is growing evi- dence for the activation of pathogenic self-reactive T cells in some of these diseases. In addition, experimental models have proved very informative, providing circumstantial evidence supporting an autoimmune etiology. Neverthe- less, it is fair to say that for many disorders traditionally classified as autoimmune, this etiologic origin is suspected but not proved.
Presumed autoimmune diseases range from those in which specific immune responses are directed against one particular organ or cell type and result in localized tissue damage, to multisystem diseases characterized by lesions in many organs and associated with multiple autoantibod- ies or T cell–mediated reactions against numerous self anti- gens. In many of the systemic diseases that are caused by immune complexes and autoantibodies, the lesions affect principally the connective tissue and blood vessels of the various organs involved. Therefore, these diseases are often referred to as “collagen vascular” or “connective tissue” disorders, even though the immunologic reactions are not specifically directed against constituents of connec- tive tissue or blood vessels.
Normal persons are unresponsive (tolerant) to their own (self) antigens, and autoimmunity results from a failure of self-tolerance. Therefore, understanding the pathogenesis of autoimmunity requires familiarity with the mechanisms of normal immunologic tolerance.
Immunologic Tolerance
Immunologic tolerance is unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen. Self- tolerance refers to a lack of immune responsiveness to one’s own tissue antigens. Billions of different antigen receptors are randomly generated in developing T and B lymphocytes, and it is not surprising that during this process, receptors are produced that can recognize self antigens. Since these antigens cannot all be concealed from the immune system, there must be means of eliminating or controlling self-reactive lymphocytes. Several mechanisms work in concert to select against self-reactivity and to thus prevent immune reactions against the body’s own antigens. These mechanisms are broadly divided into two groups: central tolerance and peripheral tolerance (Fig. 4–15).
Central tolerance. The principal mechanism of central tol- erance is the antigen-induced deletion (death) of self- reactive T and B lymphocytes during their maturation in central (generative) lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). In the thymus, many autologous (self) protein antigens are pro- cessed and presented by thymic APCs in association with self MHC. Any immature T cell that encounters such a self antigen undergoes apoptosis (a process called deletion, or negative selection), and the T cells that complete their maturation are thereby depleted of self-reactive cells (Fig. 4–15). An exciting advance has been the identifica- tion of putative transcription factors that induce the expres- sion of peripheral tissue antigens in the thymus, thus making the thymus an immunologic mirror of self. One such factor is called the autoimmune regulator (AIRE); mutations in the AIRE gene are responsible for an autoim- mune polyendocrine syndrome in which T cells specific for multiple self antigens escape deletion (presumably because these self antigens are not expressed in the thymus), and attack tissues expressing the self antigens. Some T cells that encounter self antigens in the thymus are not killed but differentiate into regulatory T cells, as described later.
Immature B cells that recognize self antigens with high affinity in the bone marrow also may die by apoptosis. Some self-reactive B cells may not be deleted but may undergo a second round of rearrangement of antigen receptor genes and then express new receptors that are no longer self-reactive (a process called “receptor editing”).
Unfortunately, the process of deletion of self-reactive lymphocytes is not perfect. Many self antigens may not be present in the thymus, so T cells bearing receptors for such autoantigens can escape into the periphery. There is similar “slippage” in the B cell system as well, and B cells that bear receptors for a variety of self antigens, including thyro- globulin, collagen, and DNA, can be found in healthy persons.
Peripheral tolerance. Self-reactive T cells that escape negative selection in the thymus can potentially wreak havoc unless they are deleted or effectively muzzled. Several mechanisms in the peripheral tissues that silence such potentially autoreactive T cells have been identified (Fig. 4–15):
• Anergy:Thistermreferstofunctionalinactivation(rather than death) of lymphocytes induced by encounter with antigens under certain conditions. As described previ- ously, activation of T cells requires two signals: recogni- tion of peptide antigen in association with self MHC molecules on APCs, and a set of second costimulatory signals (e.g., through B7 molecules) provided by the APCs. If the second costimulatory signals are not deliv- ered, or if an inhibitory receptor on the T cell (rather than the costimulatory receptor) is engaged when the cell encounters self antigen, the T cell becomes anergic and cannot respond to the antigen (Fig. 4–15). Because costimulatory molecules are not strongly expressed on most normal tissues, the encounter between autoreac- tive T cells and self antigens in tissues may result in anergy. B cells can also become anergic if they encounter antigen in the absence of specific helper T cells.
• Suppression by regulatory T cells: The responses of T lym- phocytes to self antigens may be actively suppressed by regulatory T cells. The best-defined populations of regu- latory T cells express CD25, one of the chains of the receptor for IL-2, and require IL-2 for their generation and survival. These cells also express a unique transcrip- tion factor called FoxP3. This protein is necessary for the development of regulatory cells, and mutations in the FOXP3 gene are responsible for a systemic autoimmune disease called IPEX (immune dysregulation, polyendo- crinopathy, enteropathy, X-linked syndrome), which is associated with deficiency of regulatory T cells. Several mechanisms have been proposed to explain how regula- tory T cells control immune responses, including secre- tion of immunosuppressive cytokines (e.g., IL-10, transforming growth factor-β [TGF-β]), which can dampen a variety of T cell responses, and competitive blocking of B7 molecules on APCs.
• Activation-induced cell death: Another mechanism of peripheral tolerance involves apoptosis of mature lym- phocytes as a result of self-antigen recognition. One mechanism of apoptosis involves the death receptor Fas
(a member of the TNF receptor family), which can be engaged by its ligand coexpressed on the same or neigh- boring cells. The same pathway is important for the deletion of self-reactive B cells by Fas ligand expressed on T cells. The importance of this pathway of self- tolerance is illustrated by the discovery that mutations in the FAS gene are responsible for an autoimmune disease called the autoimmune lymphoproliferative syn- drome (ALPS), characterized by lymphadenopathy and multiple autoantibodies including anti-DNA. Defects in Fas and Fas ligand are also the cause of similar autoim- mune diseases in mice. The mitochondrial pathway of apoptosis, which does not depend on death receptors, may also be involved in the elimination of self-reactive lymphocytes.

Question 37

Explain the mechanisms of autoimmunity and genetic factors in autoimmunity

Answer 37

Mechanisms of Autoimmunity
Proceeding from the foregoing summary of the principal mechanisms of self-tolerance, we can ask how these mecha- nisms might break down to give rise to pathologic autoim- munity. Unfortunately, there are no simple answers to this question, and the underlying causes of most human auto- immune diseases remain to be determined. As mentioned earlier, certain mutations can compromise one or another pathway of self-tolerance and cause pathologic autoim- munity. Study of these single-gene mutations is extremely informative, and such research helps to establish the bio- logic significance of the various pathways of self-tolerance. The diseases caused by such mutations are rare, however, and most autoimmune diseases cannot be explained by defects in single genes.

It is believed that the breakdown of self-tolerance and devel- opment of autoimmunity result from a combination of inherited susceptibility genes, which influence lymphocyte tolerance, and environmental factors, such as infections or tissue injury, that alter the display of self antigens (Fig. 4–16).
Genetic Factors in Autoimmunity
There is abundant evidence that susceptibility genes play an important role in the development of autoimmune diseases.
• Autoimmune diseases have a tendency to run in fami- lies, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins.
• Several autoimmune diseases are linked with the HLA locus, especially class II alleles (HLA-DR, -DQ). The fre- quency of a disease in a person with a particular HLA allele, compared with that in people who do not inherit that allele, is called the odds ratio or relative risk (Table 4–7). The relative risk ranges from 3 or 4 for rheumatoid arthritis (RA) and HLA-DR4 to 100 or more for ankylos- ing spondylitis and HLA-B27. However, how MHC genes influence the development of autoimmunity is still not clear, especially because MHC molecules do not distinguish between self and foreign peptide antigens. It is also worthy of note that most people with a susceptibility-related MHC allele never develop any disease, and, conversely, people without the relevant MHC gene can develop the disease. Expression of a particular MHC gene is therefore but one variable that can contribute to autoimmunity.
• Genome-wideassociationstudiesandlinkagestudiesin families are revealing many genetic polymorphisms that are associated with different autoimmune diseases (Table 4–8). Some of these polymorphisms seem to be associated with several diseases, suggesting that the genes involved influence general mechanisms of self- tolerance and immune regulation. Others are disease- specific and may influence end-organ sensitivity or display of particular self antigens. There is great interest in elucidating how these genes contribute to autoim- munity, and many plausible hypotheses have been pro- posed (Table 4–8), but the actual role of these genes in the development of particular autoimmune diseases is not established.

Question 38

Explain the role of Role of Infections and Tissue Injury in autoimmune diseases

Answer 38

Role of Infections and Tissue Injury
A variety of microbes, including bacteria, mycoplasmas, and viruses, have been implicated as triggers for autoim- munity. Microbes may induce autoimmune reactions by several mechanisms Viruses and other microbes may share cross-reacting epitopes with self antigens, such that responses may be induced by the microbe but may attack self tissues. This phenome- non is called molecular mimicry. It is the probable cause of a few diseases, the best example being rheumatic heart disease, in which an immune response against streptococci cross-reacts with cardiac antigens. It is not known if more subtle mimicry plays a role in other auto- immune diseases.
• Microbialinfectionswithresultanttissuenecrosisandinflam- mation can cause upregulation of costimulatory molecules on APCs in the tissue, thus favoring a breakdown of T cell anergy and subsequent T cell activation.
There is no lack of possible mechanisms to explain how infectious agents might participate in the pathogenesis of autoimmunity. At present, however, no evidence is avail- able that clearly implicates any microbe in the causation of human autoimmune diseases. Adding to the complexity are recent suggestions (based largely on epidemiologic data) that infections may paradoxically protect affected persons from some autoimmune diseases, notably type 1 diabetes and multiple sclerosis. The possible mechanisms underlying this effect are not understood.
The display of tissue antigens may be altered by a variety of environmental insults, not only infections. As discussed later, ultraviolet (UV) radiation causes cell death and may lead to the exposure of nuclear antigens, which elicit patho- logic immune responses in lupus; this mechanism is the proposed explanation for the association of lupus flares with exposure to sunlight. Smoking is a risk factor for RA, perhaps because it leads to chemical modification of self antigens. Local tissue injury for any reason may lead to the release of self antigens and autoimmune responses.
Finally, there is a strong gender bias of autoimmunity, with many of these diseases being more common in women than in men. The underlying mechanisms are still not well
understood, and may include the effects of hormones and other factors.
An autoimmune response may itself promote further autoimmune attack. Tissue injury caused by an autoim- mune response or any other cause may lead to exposure of self antigen epitopes that were previously concealed but are now presented to T cells in an immunogenic form. The activation of such autoreactive T cells is called “epitope spreading,” because the immune response “spreads” to epitopes that were not recognized initially. This is one of the mechanisms that may contribute to the chronicity of autoimmune diseases.

Question 39

State some organ specific diseases and systemic diseases

Immunologic Tolerance and Autoimmunity
• Tolerance (unresponsiveness) to self antigens is a funda- mental property of the immune system, and breakdown of tolerance is the basis of autoimmune diseases.
• Central tolerance: Immature lymphocytes that recognize self antigens in the central (generative) lymphoid organs are killed by apoptosis; in the B cell lineage, some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive.
• Peripheral tolerance: Mature lymphocytes that recognize self antigens in peripheral tissues become functionally inactive (anergic), or are suppressed by regulatory T lym- phocytes, or die by apoptosis.
• The factors that lead to a failure of self-tolerance and the development of autoimmunity include (1) inheritance of sus- ceptibility genes that may disrupt different tolerance path- ways and (2) infections and tissue alterations that may expose self-antigens and activate APCs and lymphocytes in the tissues.
True or false

Answer 39

Organ-Specific
 Systemic
 Diseases Mediated by Antibodies
 Autoimmune hemolytic anemia
 Autoimmune thrombocytopenia
 Autoimmune atrophic gastritis of pernicious anemia
 Myasthenia gravis
 Graves disease
 Goodpasture syndrome

Systemic: Systemic lupus erythematosus

Diseases Mediated by T Cells*
Type 1 diabetes mellitus
Multiple sclerosis

Hashimoto thyroiditis
Crohn disease

Systemic: Rheumatoid arthritis, Systemic sclerosis (scleroderma)

Sjögren syndrome(systemic for the last two diseases)

Diseases Postulated to Be of Autoimmune Origin†
Primary biliary cirrhosis -systemic:Polyarteritis nodosa
Autoimmune (chronic active) hepatitis -
Systemic:Inflammatory myopathies

Question 40

What are allografts and what happens in transplant rejection

Answer 40

REJECTION OF TRANSPLANTS
The major barrier to transplantation of organs from one individual to another of the same species (called allografts) is immunologic rejection of the transplanted tissue. Rejec- tion is a complex phenomenon involving both cell- and antibody-mediated reactions that destroy the graft. The key to successful transplantation has been the development of therapies that prevent or minimize rejection. Discussed next is how grafts are recognized as foreign and how they are rejected.
Immune Recognition of Allografts
Rejection of allografts is a response mainly to MHC molecules,
which are so polymorphic that most individuals in an outbred population differ in at least some of the MHC molecules they express (except, of course, for identical twins). There are two main mechanisms by which the host immune system recognizes and responds to the MHC mol- ecules on the graft (Fig. 4–23):
• Directrecognition.HostTcellsdirectlyrecognizetheallo- geneic (foreign) MHC molecules that are expressed on graft cells. Direct recognition of foreign MHC seems to violate the rule of MHC restriction, which states that in every individual, all of the T cells are educated to recog- nize foreign antigens displayed by only that individual’s MHC molecules. It is postulated that allogeneic MHC molecules (with any bound peptides) structurally mimic self MHC and foreign peptide, and so direct recognition of the allogeneic MHC is essentially an immunologic cross-reaction. Because DCs in the graft express high levels of MHC as well as costimulatory molecules, they are believed to be the major culprits contributing to direct recognition. The most important consequence of direct recognition is the activation of host CD8+ T cells that recognize class I MHC (HLA-A, -B) molecules in the graft. These T cells differentiate into CTLs, which kill the cells in the graft. Host CD4+ helper T cells may be trig- gered into proliferation and cytokine production by rec- ognition of donor class II MHC (HLA-D) molecules and drive an inflammatory response.
• Indirect recognition. In this pathway, host CD4+ T cells recognize donor MHC molecules after these molecules are picked up, processed, and presented by the host’s own APCs. This sequence is similar to the physiologic processing and presentation of other foreign (e.g., microbial) antigens. The activated CD4+ T cells then recognize APCs displaying graft antigens and secrete cytokines that induce inflammation and damage the graft. The indirect pathway is also involved in the pro- duction of antibodies against graft alloantigens; if these antigens are proteins, they are picked up by host B cells, and peptides are presented to helper T cells, which then stimulate antibody responses.

Question 41

What’s re the effector mechanisms of graft rejection

Recognition and Rejection of Organ Transplants (Allografts)
• The graft rejection response is initiated mainly by host T cells that recognize the foreign HLA antigens of the graft, either directly (on APCs in the graft) or indirectly (after uptake and presentation by host APCs).
• Types and mechanisms of rejection comprise the following:
 Hyperacute rejection: Pre-formed antidonor antibodies bind to graft endothelium immediately after transplanta- tion, leading to thrombosis, ischemic damage, and rapid graft failure.
 Acute cellular rejection: T cells destroy graft parenchyma (and vessels) by cytotoxicity and inflammatory reactions.
 Acute humoral rejection: Antibodies damage graft vasculature.
 Chronic rejection: Dominated by arteriosclerosis, this type is probably caused by T cell reaction and secretion of cytokines that induce proliferation of vascular smooth muscle cells, associated with parenchymal fibrosis.

True or false

Answer 41

Effector Mechanisms of Graft Rejection
Both T cells and antibodies reactive with the graft are involved in the rejection of most solid-organ allografts (Fig. 4–23).
T Cell–Mediated Rejection
CTLs kill cells in the grafted tissue, causing parenchymal and endothelial cell death (the latter resulting in thrombo- sis and graft ischemia). Cytokine-secreting CD4+ T cells trigger inflammatory reactions resembling DTH in the tissues and blood vessels, with local accumulation of mononuclear cells (lymphocytes and macrophages). Acti- vated microphages can injure graft cells and vasculature. The microvascular injury also results in tissue ischemia, which contributes to graft destruction.
Antibody-Mediated Rejection
Although T cells are of paramount importance in allograft rejection, antibodies also mediate some forms of rejection. Alloantibodies directed against graft MHC molecules and other alloantigens bind to the graft endothelium and cause vascular injury through complement activation and recruit- ment of leukocytes. Superimposed on the resulting endo- thelial damage and dysfunction is thrombosis, adding further ischemic insult to the injury.
Hyperacute rejection is a special form of rejection occur- ring if pre-formed anti-donor antibodies are present in the circulation of the host before transplantation. This may happen in multiparous women who have anti-HLA anti- bodies against paternal antigens encountered during preg- nancy, or in individuals exposed to foreign HLA (on platelets or leukocytes) from previous blood transfusions. Obviously, such antibodies also may be present in a patient who has previously rejected an organ transplant. Subse- quent transplantation in such patients will result in imme- diate rejection (within minutes to hours) because the
circulating antibodies rapidly bind to the endothelium of the grafted organ, with resultant complement activation and vascular thrombosis. With the current practice of screening potential recipients for pre-formed anti-HLA antibodies and cross-matching (testing recipients for the presence of antibodies directed against the donor’s lym- phocytes), hyperacute rejection occurs in less than 0.4% of transplant recipients.

Question 42

Explain the morphology of transplant rejection

Answer 42

On the basis of the time course and morphology of rejection reactions, they have been classified as hyperacute, acute, and chronic (Fig. 4–24). This classification is helpful for under- standing the mechanism of rejection, because each pattern is caused by a different type of dominant immunologic reaction. The morphology of these patterns is described in the context of renal transplants; however, similar changes are encoun- tered in other vascularized organ transplants.
Hyperacute Rejection
Hyperacute rejection occurs within minutes to a few hours after transplantation in a presensitized host and typically is recognized by the surgeon just after the vascular anastomosis is completed. In contrast with a nonrejecting kidney graft, which regains a normal pink color and tissue turgor and promptly excretes urine, a hyperacutely rejecting kidney rapidly becomes cyanotic, mottled, and flaccid and may excrete only a few drops of bloody fluid. The histologic picture is characterized by widespread acute arteritis and arteriolitis, vessel thrombosis, and ischemic necrosis, all resulting from the binding of preformed antibodies to graft endothelium. Virtually all arterioles and arteries exhibit char- acteristic acute fibrinoid necrosis of their walls, with narrow- ing or complete occlusion of the lumens by precipitated fibrin and cellular debris Acute Rejection
Acute rejection may occur within days to weeks of transplan- tation in a nonimmunosuppressed host or may appear months or even years later, even in the presence of adequate immunosuppression. Acute rejection is caused by both cel- lular and humoral immune mechanisms, and in any one patient, one or the other may predominate, or both may be present. On histologic examination, cellular rejection is marked by an interstitial mononuclear cell infiltrate with asso- ciated edema and parenchymal injury, whereas humoral rejection is associated with vasculitis.
Acute cellular rejection most commonly is seen within the first months after transplantation and typically is accom- panied by clinical signs of renal failure. Histologic examination usually shows extensive interstitial CD4+ and CD8+ T cell infiltration with edema and mild interstitial hemorrhage (Fig. 4–24, B). Glomerular and peritubular capillaries contain large numbers of mononuclear cells, which also may invade the tubules, leading to focal tubular necrosis. In addition to tubular injury, CD8+ T cells also may injure the endothelium, causing an endothelitis. Cyclosporine (a widely used immu- nosuppressive agent) is also nephrotoxic and induces so- called arteriolar hyaline deposits. Renal biopsy is used to distinguish rejection from drug toxicity. Accurate recogni- tion of cellular rejection is important, because patients typi- cally respond promptly to increased immunosuppressive therapy.
Acute humoral rejection (rejection vasculitis) caused by antidonor antibodies also may participate in acute graft rejection. The histologic lesions may take the form of necro- tizing vasculitis with endothelial cell necrosis; neutrophilic infiltration; deposition of antibody, complement, and fibrin; and thrombosis. Such lesions may be associated with isch- emic necrosis of the renal parenchyma. Somewhat older subacute lesions are characterized by marked thickening of the intima by proliferating fibroblasts, myocytes, and foamy macrophages (Fig. 4–24, C). The resultant narrowing of the arterioles may cause infarction or renal cortical atrophy. The proliferative vascular lesions mimic arteriosclerotic thickening and are believed to be caused by cytokines that stimulate proliferation of vascular smooth muscle cells. Local deposi- tion of complement breakdown products (specifically C4d) is used to detect antibody-mediated rejection of kidney allografts.
Chronic Rejection
Patients present with chronic rejection late after transplanta- tion (months to years) with a progressive rise in serum cre- atinine levels (an index of renal function) over a period of 4 to 6 months. Chronic rejection is dominated by vascular changes, interstitial fibrosis, and loss of renal parenchyma; there are typically only mild or no ongoing cellular parenchy- mal infiltrates. The vascular changes occur predominantly in the arteries and arterioles, which exhibit intimal smooth muscle cell proliferation and extracellular matrix synthesis (Fig. 4–24, D). These lesions ultimately compromise vascular perfusion and result in renal ischemia manifested by loss or hyalinization of glomeruli, interstitial fibrosis, and tubular atrophy. The vascular lesion may be caused by cytokines released by activated T cells that act on the cells of the vas- cular wall, and it may be the end stage of the proliferative arteritis described earlier.

Question 43

What are immune deficiency diseases and explain primary immune deficiency

Answer 43

Immune deficiency diseases may be caused by inherited defects affecting immune system development, or they may result from secondary effects of other diseases (e.g., infection, malnutrition, aging, immunosuppression, autoimmunity, or chemotherapy). Clinically, patients with immune deficiency present with increased susceptibility to infec- tions as well as to certain forms of cancer. The type of infec- tions in a given patient depends largely on the component of the immune system that is affected. Patients with defects in immunoglobulin, complement, or phagocytic cells typi- cally suffer from recurrent infections with pyogenic bacte- ria, whereas those with defects in cell-mediated immunity are prone to infections caused by viruses, fungi, and intra- cellular bacteria. Discussed next are some of the more important primary (congenital) immune deficiencies, fol- lowed by a detailed description of the acquired immuno- deficiency syndrome (AIDS), the most devastating example of secondary (acquired) immune deficiency.
Primary (Congenital) Immune Deficiencies
Primary immune deficiency states are fortunately rare, but their study has nevertheless contributed greatly to the current understanding of the development and function of the immune system. Most primary immune deficiency diseases are genetically determined and affect either adap- tive immunity (i.e., humoral or cellular) or innate host defense mechanisms, including complement proteins and cells such as phagocytes and NK cells. Defects in adaptive immunity are often subclassified on the basis of the primary component involved (i.e., B cells or T cells, or both); however, because of the interactions between T and B lym- phocytes, these distinctions are not clear-cut. For instance, T cell defects frequently lead to impaired antibody synthe- sis, and hence isolated deficiencies of T cells may be indis- tinguishable from combined deficiencies of T and B cells. Most primary immune deficiencies come to attention early in life (between the ages of 6 months and 2 years), usually because the affected infants are susceptible to recurrent infections. One of the most impressive accomplishments of modern molecular biology has been the identification of the genetic basis for many primary immune deficiencies (Fig. 4–25), laying the foundation for future gene replace- ment therapy.

Question 44

What is amyloidosis

Answer 44

Amyloidosis is a disorder characterized by the extracel- lular deposits of misfolded proteins that aggregate to form insoluble fibrils.
• The deposition of these proteins may result from exces- sive production of proteins that are prone to misfolding and aggregation; mutations that produce proteins that cannot fold properly and tend to aggregate; or defective or incomplete proteolytic degradation of extracellular proteins.
• Amyloidosis may be localized or systemic. It is seen in association with a variety of primary disorders, including monoclonal plasma cell proliferations (in which the amyloid deposits consist of immunoglobulin light chains); chronic inflammatory diseases such as RA (deposits of amyloid A protein, derived from an acute-phase protein produced in inflammation); Alzheimer disease (amyloid B protein); familial conditions in which the amyloid deposits consist of mutants of normal proteins (e.g., transthyretin in familial amyloid polyneuropathies); amyloidosis associ- ated with dialysis (deposits of β2-microglobulin, whose clearance is defective).
• Amyloid deposits cause tissue injury and impair normal function by causing pressure on cells and tissues.They do not evoke an inflammatory response.