I 2 Autoimmunity Review Qtns ABBAS
What are the principal classes of lymphocytes, and how do they differ in function?
> B lymphocytes express surface immunoglobulin, which functions as their antigen receptor, and mediate humoral immunity. > Following activation, lymphocytes differentiate into antibody-secreting plasma cells. > T lymphocytes express the T cell antigen receptor and most express CD4 or CD8, and mediate cell-mediated immune responses. > After activation by peptide antigens displayed by cell surface MHC molecules, T cells secrete cytokines, membrane-bound activating ligands, and cytotoxic proteins. > These molecules induce inflammation, enhance the functions of phagocytes, promote B cell antibody responses, and induce death of infected cells.
What are the important differences among naive, effector, and memory T and B lymphocytes?
> Naive lymphocytes are mature B or T cells that have not yet encountered a foreign antigen. Following activation, naive lymphocytes differentiate into cells that acquire the ability to protect against or eliminate pathogens. These lymphocytes are known as effector cells. Most effector cells die, but a small subset of activated lymphocytes acquires the ability to live for extended periods, known as memory cells. Memory lymphocytes not only self-renew and survive indefinitely but also respond more rapidly and vigorously when challenged by antigen.
How do naive and effector T lymphocytes differ in their patterns of migration?
> Naive lymphocytes home to secondary lymphoid organs and recirculate between these organs. > Effector lymphocytes are generated in lymph nodes but home to the tissue site where the activating antigen may be located.
What are the two types of adaptive immunity, and what types of microbes do these adaptive immune responses combat?
> cell-mediated immunity and humoral immunity. > Cell-mediated immunity, mediated by T cells, is essential for protection against intracellular pathogens. > Humoral or antibody-mediated immunity provides protection primarily against extracellular pathogens.
How do CD8+ CTLs kill cells infected with viruses?
Activated CD8+ T cells secrete *perforin* and *granzymes*, which enter the infected cells recognized by the T lymphocytes and induce apoptosis of these infected cells.
What are the mechanisms by which T cells activate macrophages, and what are the responses of macrophages that result in the killing of ingested microbes?
Activated helper T cells secrete cytokines such as interferon-γ that activate macrophages. These helper T cells also express CD40 ligand (CD154), which can activate macrophages by engaging CD40. Activated macrophages then induce NADPH oxidase activity to generate reactive oxygen species, and nitric oxide synthase to make nitric oxide. These free radicals can destroy ingested microbes. Activated macrophages also produce increased amounts of lysosomal enzymes, which help to destroy microbes, and other molecules that promote inflammation and call in more leukocytes into the reaction.
Chapter 2 Review: _Innate Immunity_
All multicellular organisms contain intrinsic mechanisms of defense against infections, which constitute innate immunity. > The mechanisms of innate immunity respond to microbes and not to nonmicrobial substances, are specific for structures present on various classes of microbes, are mediated by receptors encoded in the germline, and are not enhanced by repeat exposures to microbes. > Toll-like receptors (TLRs), expressed on plasma membranes and in endosomes of many cell types, are a major class of innate immune system receptors that recognize different microbial products, including bacterial cell wall constituents and viral nucleic acids. Some receptors of the NLR family recognize microbes, products of damaged cells (ATP), and other substances, and these receptors signal through a cytosolic multiprotein complex, the inflammasome, to induce secretion of the proinflammatory cytokine interleukin-1. The principal components of innate immunity are epithelia, phagocytes, dendritic cells, natural killer cells, cytokines, and plasma proteins, including the proteins of the complement system. Epithelia provide physical barriers against microbes, produce antibiotics, and contain lymphocytes that may prevent infections. The principal phagocytes—neutrophils and monocytes/macrophages—are blood cells that are recruited to sites of infection, where they are activated by engagement of different receptors. Activated macrophages destroy microbes and dead cells and initiate tissue repair; these functions may be carried out by different populations of macrophages. Natural killer (NK) cells kill host cells infected by intracellular microbes and produce the cytokine interferon-γ (IFN-G), which activates macrophages to kill phagocytosed microbes. The complement system is a family of proteins that are activated sequentially on encounter with some microbes and by antibodies (in humoral arm of adaptive immunity). Complement proteins coat (opsonize) microbes for phagocytosis, stimulate inflammation, and lyse microbes. Cytokines of innate immunity function to stimulate inflammation (TNF, IL-1, chemokines), activate NK cells (IL-12), activate macrophages (IFN-γ), and prevent viral infections (type I IFNs). Inflammation consists of recruiting phagocytes to sites of infection and tissue damage, a process mediated by binding to endothelial adhesion molecules that are induced by the cytokines TNF and IL-1, phagocytes also respond to soluble chemoattractants, including chemokines, complement fragments, and bacterial peptides. This is followed by ingestion and destruction of microbes and damaged cells. Antiviral defense is mediated by type I interferons, IFNa Type I IFN inhibit viral replication, and NK cells, which kill infected cells. In addition to providing early defense against infections, innate immune responses provide signals that work together with antigens to activate B and T lymphocytes. The requirement for these second signals ensures that adaptive immunity is elicited by microbes (the inducers of innate immune reactions) and not by self or nonmicrobial substances.
What are the differences in the types of antigens recognized by antibodies and TCRs?
Antibodies can recognize all types of molecules, including small molecules, proteins, carbohydrates, lipids, and nucleic acids. In proteins, antibodies can recognize *conformational* or linear epitopes. TCRs can recognize only linear peptides bound to the clefts of MHC molecules
What are the functionally distinct domains (regions) of antibody and TCR molecules? What features of the amino acid sequences in these regions are important for their functions?
Antibody and T cell receptor (TCR) chains contain *variable* domains that are involved in *antigen* recognition and constant domains that, in the case of antibodies, mediate effector functions (Fc Regions). Variable domains contain residues that contribute to antigen recognition.
Summarize the links among antigen recognition, the major biochemical signaling pathways in T cells, and the production of transcription factors.
Antigen recognition results in co-receptors in T cells bringing the Lck tyrosine kinase in proximity to CD3 and ζ chain ITAMs. Phosphorylation of the ITAMs results in the recruitment and activation of ZAP-70 tyrosine kinase, which in turn initiates different signaling pathways by activating different downstream enzymes. Activation of phospholipase Cγ results in the calcium signaling and the subsequent activation of the NFAT transcription factor. Activation of PKCθ results in the activation of the NF-κB transcription factor. Activation of MAP kinases leads to the production of the AP-1 transcription factor.
When antigens enter through the skin, in what organs are they concentrated? What cell type(s) play important roles in this process of antigen capture?
Antigens that enter through the skin are captured by dendritic cells that reside in the epidermis (LANGERHANS) and dermis and transported to skin draining lymph nodes, where the antigens are concentrated and displayed to lymphocytes.
Where are T and B lymphocytes located in lymph nodes, and how is their anatomic separation maintained?
B lymphocytes reside in follicles or B cell zones in secondary lymphoid organs. T cells reside in the T cell zone in the parafollicular cortex of lymph nodes. B and T cells are maintained in these locations by specific cytokines secreted by stromal cells in the follicle and the parafollicular cortex, respectively.
What are the major subsets of CD4+ helper T cells, and how do they differ?
CD4+ helper T cell subsets include TH1 cells that produce interferon-γ, which stimulates the microbicidal activities of phagocytes. TH2 cells secrete IL-4, IL-5, and IL-13 and mediate allergic and antihelminthic responses(IL-5 = Eosinophils). TH17 cells make IL-17 and contribute to neutrophil recruitment to sites of infection.
Which subsets of T cells recognize antigens presented by class I and class II MHC molecules? What molecules on T cells contribute to their specificity for either class I or class II MHC-associated peptide antigens?
CD4+ helper T cells recognize antigens displayed by class II molecules, and CD8+ cytotoxic T lymphocytes recognize MHC class I-peptide complexes. The CD4 co-receptor of helper T cells can bind to MHC class II molecules, and the CD8 co-receptor of cytotoxic T cells binds to MHC class I molecules.
What signals are required to induce the responses of CD8+ T cells?
CD8+ T cells are activated by peptide-class I MHC antigens, costimulatory signals, and cytokines (e.g., IL-12) and differentiate into cytotoxic T cells.
CHAPTER 5 Review: T Cell-Mediated Immunity Activation of T Lymphocytes by Cell-Associated Antigens
Cell-mediated immunity (CMI) The form of adaptive immunity that is mediated by T lymphocytes and serves as the defense mechanism against microbes that survive within phagocytes or infect nonphagocytic cells. CMI responses include CD4+ T cell-mediated activation of macrophages that have phagocytosed microbes and CD8+ CTL-mediated killing of infected cells. SUMMARY: T lymphocytes are the cells of cell-mediated immunity, the arm of the adaptive immune system that combats intracellular microbes, which may be microbes that are ingested by phagocytes and live within these cells or microbes that infect nonphagocytic cells. T lymphocytes also mediate defense against some extracellular microbes and help B lymphocytes to produce antibodies. The responses of T lymphocytes consist of sequential phases: recognition of cell-associated microbes by naive T cells, expansion of the antigen-specific clones by proliferation, and differentiation of some of the progeny into effector cells and memory cells. T cells use their antigen receptors to recognize peptide antigens displayed by MHC molecules on antigen-presenting cells (APCs), which accounts for the specificity of the ensuing response, and polymorphic residues of the MHC molecules, accounting for the MHC restriction of T cell responses. Antigen recognition by the T cell receptor (TCR) triggers signals that are delivered to the interior of the cells by molecules associated with the TCR (CD3 and ζ chains) and by the coreceptors CD4 and CD8, which recognize class II and class I MHC molecules, respectively. The binding of T cells to APCs is enhanced by adhesion molecules, notably the integrins, whose affinity for their ligands is increased by antigen recognition by the TCR. APCs exposed to microbes or to cytokines produced as part of the innate immune reactions to microbes express costimulators that bind to receptors on T cells and deliver necessary second signals for T cell activation. The biochemical signals triggered in T cells by antigen recognition and costimulation result in the activation of various transcription factors that stimulate the expression of genes encoding cytokines, cytokine receptors, and other molecules involved in T cell responses. In response to antigen recognition and costimulation, T cells secrete cytokines that induce proliferation of the antigen-stimulated T cells and mediate the effector functions of T cells. CD4+ helper T cells may differentiate into subsets of effector cells that produce restricted sets of cytokines and perform different functions. TH1 cells, which produce IFN-γ, activate phagocytes to eliminate ingested microbes, and stimulate the production of opsonizing (IgG ) and complement-binding antibodies. TH2 cells, which produce IL-4 and IL-5, stimulate IgE production and activate eosinophils, which function mainly in defense against *helminths*. TH17 cells, which produce IL-17, play a role in defense against extracellular bacterial and *fungal* infections and are implicated in several inflammatory diseases. CD8+ T cells recognize peptides of *intracellular* (cytosolic) protein antigens and may require help from CD4+ T cells to differentiate into effector CTLs. The function of CTLs is to kill cells producing cytoplasmic microbial antigens.
How is central tolerance induced in T lymphocytes and B lymphocytes?
Central tolerance is the elimination or inactivation of self-reactive T and B cells during their development in the thymus or bone marrow, respectively. Central tolerance is induced in immature T cells in the thymus after they express T cell receptors. If a developing T cell recognizes with high avidity either self MHC molecules or peptides derived by self proteins bound to self MHC presented by thymic antigen-presenting cells, signals will be generated that lead to apoptosis of the T cell (called clonal deletion or negative selection), and surviving CD4+ T cells may develop into harmless and protective regulatory T cells. Furthermore, some proteins mainly expressed by cells in a particular peripheral tissue type or organ may be also expressed by thymic medullary epithelial cells (TMECs) under the control of the AIRE protein. The developing T cells that recognize peptides from these self proteins in complex with self MHC are deleted. Central tolerance develops in immature B cells after they express a functional membrane B cell receptor complex. Immature B cell recognition of self antigens will lead to apoptosis or to receptor editing, whereby a new round of VDJ recombination in the light-chain genes will generate new specificities that are not self-reactive.
What is costimulation? What is the physiologic significance of costimulation? What are some of the ligand-receptor pairs involved in costimulation?
Costimulation refers to signals delivered to a lymphocyte that are *required* for lymphocyte activation but are *independent* of antigen receptor signaling. Costimulatory signals are commonly referred to as a "second signal" and provide lymphocytes with the information that the antigen they are recognizing may be of microbial origin. B7-1 and B7-2 are the major costimulators on antigens presenting cells that bind to CD28 on T cells.
Why do differentiated effector T cells (which have been activated by antigen) migrate preferentially to tissues that are sites of infection and not to lymph nodes?
Differentiated effector T cells lose expression of *L-selectin* and *CCR7* (both of which are present on naive T cells) and can no longer home to lymph nodes. Effector cells express LFA 1&2 (CD18/CD11a) bind to adhesion molecules on endothelium (I-CAM) exposed to inflammatory cytokines and respond to chemokines produced at sites of inflammation, thus preferentially migrating to these sites.
How is functional anergy induced in T cells? How may this mechanism of tolerance fail to give rise to autoimmune disorders?
Functional anergy, a mechanism of peripheral tolerance, is a long-lasting condition in which a T cell will not respond to antigen stimulation. Anergy is induced in naive T cells when they recognize peptide-MHC antigen without costimulation. The mechanisms of anergy include blocks in signaling downstream from the T cell receptor or the preferential engagement of inhibitory receptors. Anergy may also occur when "tolerogenic" dendritic cells, which have not been exposed to microbial stimuli, process and present self peptide-MHC to T cells. Such DCs will not express sufficient levels of B7-1, B7-2, or other molecules to provide costimulation, and therefore the self-reactive T cell will become anergic. Anergy may fail during an infection, when a T cell recognizes self peptide-MHC on a DC that has been activated by innate responses to the microbe.
CHAPTER 4 REVIEW: _Antigen Recognition in the Adaptive Immune System_
In the adaptive immune system, the molecules responsible for specific recognition of antigens are antibodies and T cell antigen receptors. Antibodies (also called immunoglobulins) may be produced as membrane receptors of B lymphocytes and as proteins _secreted_ by antigen-stimulated B cells that have differentiated into antibody-secreting [[plasma]] cells. Secreted antibodies are the effector molecules of _humoral_ immunity, capable of neutralizing microbes and microbial toxins and eliminating them by activating various effector mechanisms. T cell receptors (TCRs) are membrane receptors and are not secreted. The core structure of antibodies consists of two identical heavy chains and two identical light chains forming a disulfide-linked complex. Each chain consists of a variable (V) region, which is the portion that [[recognizes]] [[antigen]], and a constant (C) region, which provides structural stability and, in [[heavy]] [[chains]], performs the effector functions of antibodies. The V region of one heavy chain and of one light chain together form the [[[antigen-binding]] site, and thus the core structure has two identical antigen-binding sites. T cell receptors consist of an α chain and a β chain. Each chain contains one V region and one C region, and [[both]] chains participate in the recognition of antigens, which for most T cells are peptides displayed by MHC molecules. The V regions of immunoglobulin (Ig) and TCR molecules contain [[hypervariable]] segments, also called complementarity-determining regions [[CDRs]], which are the regions of contact with antigens. The genes that encode antigen receptors consist of multiple segments separate in the [[germline]] and brought together during maturation of lymphocytes. In B cells, the Ig gene segments undergo [[recombination]] as the cells mature in the bone marrow, and in T cells the TCR gene segments undergo recombination during maturation in the [[thymus]]. Receptors of different specificities are generated in part by different combinations of V, D, and J gene segments. The process of recombination introduces variability in the nucleotide sequences at the sites of recombination by adding or removing _nucleotides_ from the junctions by *TdT*. The result of this introduced variability is the development of a diverse repertoire of lymphocytes, in which clones of cells with different antigen specificities express receptors that differ in sequence and recognition, and most of the differences are concentrated at the regions of gene recombination. During their maturation, lymphocytes are selected to survive at several checkpoints; only cells with complete functional antigen receptors are preserved and expanded. In addition, T lymphocytes are _positively_ selected to recognize peptide antigens displayed by self MHC molecules and to ensure that the recognition of the appropriate type of MHC molecule matches the co-receptor preserved. Immature lymphocytes that strongly recognize self antigens are [[negatively]] selected and prevented from completing their maturation, thus eliminating cells with the potential of reacting in harmful ways against self tissues.
What are some possible mechanisms by which infections promote the development of autoimmunity?
Infections may promote the development of autoimmunity by (a) inducing costimulatory molecule expression by APCs that present self antigens to lymphocytes; (b) causing inflammation and tissue damage, which exposes normally sequestered self antigens to the immune system; and (c) molecular mimicry, if the microbe expresses an antigen molecularly similar to a self antigen, and thereby simulating an immune response (antibodies or T cells) that cross-reacts with self antigens.
How do innate immune responses enhance adaptive immunity?
Innate immune responses induce the expression of [[costimulators on dendritic cells]] that can provide _second signals for T cell activation._ Innate immune cells make cytokines that modulate the adaptive immune response. Complement activation as part of the innate immune response can lead to the generation of complement fragments that enhance B lymphocyte activation.
How does the specificity of innate immunity differ from that of adaptive immunity?
Innate immunity is directed against microbes and the products of damaged cells and is mediated by cell surface receptors and secreted proteins of limited diversity that recognize microbial patterns and products of damaged cells. Adaptive immunity uses an extremely large and diverse set of antigen receptors to recognize a wide variety of microbial and nonmicrobial antigens.
Chapter 6 REVIEW QUESTIONS: What are the types of T lymphocyte-mediated immune reactions that eliminate microbes that are sequestered in the vesicles of phagocytes and microbes that live in the cytoplasm of infected host cells?
Intracellular microbes that reside in *phagosomes* are eliminated by helper T cells, especially those of the TH1 subset that activate phagocytes to destroy ingested microbes (IFNgamma - M-phage). Microbes that reside in the cytoplasm may be eliminated by CD8+ T cell-mediated killing of the infected cells, thus eliminating the reservoir of infection.
What are examples of microbial substances recognized by the innate immune system, and what are the receptors for these substances?
Lipopolysaccharide (LPS) recognized by Toll-like receptor-4 (TLR-4), flagellin recognized by TLR-5, double-stranded DNA recognized by TLR-9, and mannans recognized by the mannose receptor as well as by mannose-binding protein.
Describe the sequence of events by which class I and class II MHC molecules acquire antigens for display.
MHC class II α and β chains are produced in the [[endoplasmic reticulum]], where they assemble with each other and with an [[invariant]] [[chain]] that occludes the antigen binding cleft. The MHC class II-invariant chain complex is transported to a late endosomal/lysosomal compartment where the invariant chain is degraded (HDR), leaving a peptide called [[CLIP]] in the cleft. Proteins internalized by the _endocytic_ pathway are degraded in late endosomes and lysosomes into peptides. Specific peptides displace CLIP and bind tightly to the cleft of the MHC class II molecule, which is then transported to the cell surface.
What are MHC molecules? What are human MHC molecules called? How were MHC molecules discovered, and what is their function?
Major histocompatibility complex (MHC) molecules are cell surface proteins that present antigenic peptides to T cells. Human MHC proteins are called HLA molecules. They were initially discovered as products of polymorphic genes that mediate transplant rejection. Their physiologic function is antigen presentation.
What are some of the molecules in addition to the TCR that T cells use to initiate their responses to antigens, and what are the functions of these molecules?
Molecules other than the TCR used by T cells to respond to antigens include the CD4 and CD8 co-receptors, which bind to class II and class I MHC molecules, respectively; costimulatory receptors such as CD28, which bind to costimulators B7 expressed on activated APCs; and adhesion molecules such as the integrin LFA-1 (CD18 + 11a), which mediate cell-cell adhesion to ICAM and control the migration of the T cells.
Where do regulatory T cells develop, and how do they protect against autoimmunity?
Most regulatory T cells are CD4+ T cells that express the IL-2 receptor protein CD25 and the transcription factor FoxP3. Tregs develop in the thymus from immature thymocytes as a consequence of self antigen recognition (called "natural" Tregs). Tregs can also differentiate from mature naive T cells in peripheral lymphoid tissues, as a result of antigen recognition together with signals from cytokines such as TGF-β (called "adaptive" or "induced" Tregs). Regulatory T cells protect against autoimmunity by suppressing activation of self-reactive T cells by antigen-presenting cells (APCs), or by directly inhibiting the T cells. The mechanisms by which Tregs suppress APCs or T cells involve both direct cell-cell contact and secretion of cytokines (e.g., TGF-β, IL-10).
What is the role of MHC molecules in the recognition of infected cells by NK cells, and what is the physiologic significance of this recognition?
NK cells express inhibitory receptors that recognize MHC class I molecules on host cells and can then dampen NK cell activation. _In virally infected cells, MHC class I molecules are downregulated and therefore fail to engage inhibitory receptors, and thus NK cells can be activated to kill these infected cells._
What is the phenomenon of negative selection, and what is its importance?
Negative selection results in the deletion or editing of *strongly* self-reactive lymphocytes. This process mediates self tolerance in the thymus for T cells and in the bone marrow for B cells.
What are the differences between the antigens that are displayed by class I and class II MHC molecules?
Proteins that are produced in or enter the cytosol are presented by MHC class I molecules. Proteins internalized into [[vesicles]] by endocytosis are presented by MHC class II molecules.
CHAPTER 6 Effector Mechanisms of T Cell-Mediated Immunity Functions of T Cells in Host Defense
SUMMARY: Cell-mediated immunity is the arm of adaptive immunity that eradicates infections by cell-associated microbes, and utilizes two types of T cells. CD4+ helper T cells recruit and activate phagocytes to kill ingested and some extracellular microbes, and CD8+ cytotoxic T lymphocytes (CTLs) kill cells harboring microbes in their cytosol, eliminating reservoirs of infection. Effector T cells are generated in peripheral lymphoid organs, mainly lymph nodes draining sites of microbe entry, by the activation of naive T lymphocytes. The effector T cells are able to migrate to any site of infection. The migration of effector T cells is controlled by adhesion molecules and chemokines. Various adhesion molecules are induced on the T cells after activation and bind to their ligands, which themselves are induced on endothelial cells by microbes and by cytokines produced during innate immune responses to microbes. The migration of T cells is independent of antigen, but cells that recognize microbial antigens in tissues are retained at these sites. Effector cells of the TH1 subset of CD4+ helper T cells recognize the antigens of microbes that have been ingested by macrophages. These T cells express CD40 ligand (CD 154) and secrete IFN-γ, which function cooperatively to activate macrophages. Activated macrophages produce substances, including reactive oxygen species, nitric oxide, and lysosomal enzymes, that kill ingested microbes. Macrophages also produce cytokines that induce inflammation and some macrophages produce cytokines that promote fibrosis and tissue repair. TH17 cells enhance *neutrophil* and monocyte recruitment and acute inflammation, which is essential for defense against certain extracellular bacteria and fungi. Effector CD4+ T helper cells of the TH2 subset stimulate eosinophilic inflammation by secreting IL-5, and *inhibit* the microbicidal functions of activated macrophages. Eosinophils are important in host defense against *helminthic* parasites. The balance between activation of TH1 and TH2 cells determines the outcomes of many infections, with TH1 cells promoting and TH2 cells suppressing defense against intracellular microbes. CD8+ T cells differentiate into CTLs that kill infected cells, mainly by inducing DNA fragmentation and apoptosis. CD4+ and CD8+ T cells often function cooperatively to eradicate intracellular infections. Many pathogenic microbes have evolved mechanisms to resist cell-mediated immunity. These mechanisms include inhibiting *phagolysosome* fusion, escaping from the vesicles of phagocytes, inhibiting the assembly of class I MHC-peptide complexes, and producing inhibitory cytokines or decoy cytokine receptors.
CHAPTER 7 Humoral Immune Responses Activation of B Lymphocytes and Production of Antibodies
SUMMARY: Humoral immunity is mediated by antibodies that bind to extracellular microbes and their toxins, which are *neutralized* or targeted for destruction by phagocytes and the *complement system*. Humoral immune responses to nonprotein antigens are initiated by recognition of the antigens by specific immunoglobulin receptors of naive B cells. The binding of multivalent antigen cross-links Ig receptors of specific B cells, and biochemical signals are delivered to the inside of the B cells by Ig-associated signaling proteins. These signals induce B cell clonal expansion and *IgM* secretion. Humoral immune responses to a *protein antigen*, called *T-dependent* responses, are initiated by binding of the protein to specific Ig receptors of naive B cells in *lymphoid follicles*. This results in the generation of signals that prepare the B cell for interaction with helper T cells. In addition, the B cells internalize and process that antigen and present *class II MHC-displayed peptides* to activated helper T cells also specific for the antigen. The helper T cells express CD40L and secrete cytokines, which function together to stimulate high levels of B cell proliferation and differentiation. Some helper T cells, called *follicular* helper T cells (TFH) migrate into *germinal centers* and are especially effective at stimulating isotype switching and *affinity maturation*. Heavy-chain isotype switching (or class switching) is the process by which the isotype, but not the *specificity*, of the antibodies produced in response to an antigen changes as the humoral response proceeds. Isotype switching depends on the combination of *CD40L and cytokines*, both expressed by helper T cells. Different cytokines induce switching to different antibody isotypes, enabling the immune system to respond in the most effective way to different types of microbes. Affinity maturation is the process by which the affinity of antibodies for protein antigens increases with prolonged or repeated exposure to the antigens. The process is initiated by signals from TFH cells, resulting in migration of the B cells into follicles and the formation of *germinal centers*. Here the B cells proliferate rapidly, and their Ig V genes undergo somatic *Hypermutation*. The antigen complexed with secreted antibody is displayed by *follicular dendritic cells* FDCs in the *germinal centers*. B cells that recognize the antigen with high affinity are selected to survive, giving rise to affinity maturation of the antibody response. The early T-dependent humoral response occurs in *extrafollicular* foci and generates low levels of antibodies, with little isotype switching, that are produced by short-lived plasma cells. The later response develops in germinal centers and leads to extensive isotype switching and affinity maturation, generation of long-lived plasma cells that secrete antibodies for many years, and development of long-lived memory B cells, which rapidly respond to reencounter with antigen by proliferation and secretion of high-affinity antibodies. Polysaccharides, lipids, and other nonprotein antigens are called *T-independent* antigens because they induce antibody responses without T cell help. Most T-independent antigens contain multiple identical epitopes that are able to cross-link many Ig receptors on a B cell, providing signals that stimulate B cell responses even in the absence of helper T cell activation. Antibody responses to T-independent antigens show less heavy-chain class switching and affinity maturation than typical for responses to T-dependent protein antigens. Secreted antibodies form immune complexes with residual antigen and shut off B cell activation by engaging an inhibitory Fc receptor on B cells.
What are some of the genes that contribute to autoimmunity? How may MHC genes play a role in the development of autoimmune diseases?
Several rare autoimmune diseases are caused by single-gene mutations that interfere with mechanisms of tolerance. These include mutations in the genes encoding AIRE, FoxP3, FAS, and complement C4. Multiple genes likely contribute the development of common autoimmune diseases. Particular MHC alleles are frequently associated with autoimmunity. MHC genes may be important in development of autoimmunity because they are central to thymic selection processes required for central tolerance during T cell development and for presentation of self peptides to mature T cells. Certain alleles may be more likely to bind certain self peptides than other alleles.
What are some of the mechanisms by which intracellular microbes resist the effector mechanisms of cell-mediated immunity?
Some intracellular microbes evade immunity by preventing phagolysosomal fusion. Other intracellular microbes express molecules that can inactivate host complement responses. Some microbes are encapsulated and can resist phagocytosis and complement.
What are the roles of TH1, TH17, and TH2 cells in defense against intracellular microbes and helminthic parasites?
TH1 cells eliminate intracellular pathogens by activating macrophages. TH2 cells can secrete IL-5 induce class switching to IgE and activate eosinophils to secrete proteins that kill helminths. TH17 cytokines enhance gut motility, which can help clear intestinal parasites. TH17 cells stimulate the production of anti-microbial substances, called *defensins*, that function like locally produced endogenous antibiotics.
What are the roles of the cytokines TNF, IL-12, and type I interferons in defense against infections?
TNF stimulates inflammation in part by helping to _recruit neutrophils and monocytes to sites of infection._ [[ IL-12 made by macrophages and dendritic cells contributes to NK cell and T cell activation.]] Type I interferons inhibit viral replication (the antiviral state).
What are the components of the TCR complex? Which of these components are responsible for antigen recognition and which for signal transduction?
The T cell receptor (TCR) complex is made up of the TCR α and β chains responsible for antigen recognition and the CD3 complex and ζ homodimers required for signal transduction.
What is immunological tolerance? Why is it important?
The adaptive immune system does not normally mount effective immune responses to self molecules. This state of immune unresponsiveness to self is called tolerance and is important because the adaptive immune system will develop T and B cells expressing antigen receptors that recognize self antigens, and these lymphocytes must be controlled or killed to prevent autoimmune disease. Also, the mechanisms of tolerance induction may be exploited to inhibit harmful immune responses to allergens, self antigens, and transplants.
What are some of the checkpoints during lymphocyte maturation that ensure survival of the useful cells?
The first checkpoint in B and T cell maturation involves the selection of pre-B and pre-T cells that have productively rearranged the µ heavy-chain gene in the case of B lineage cells and the TCR β chain gene in the case of developing T cells. Positive selection is a process in which T cells that can recognize self MHC molecules weakly are allowed to survive and express the type of co-receptor that matches the type of MHC molecule recognized.
Chapter 3 Review: _Antigen Capture and Presentation to Lymphocytes_
The induction of immune responses to the _protein_ antigens of microbes depends on a specialized system for capturing and displaying these antigens for recognition by the rare naive T cells specific for any antigen. Microbes and microbial antigens that enter the body through epithelia are captured by [[dendritic cells located in the epithelia]] and transported to regional lymph nodes, or by [[dendritic cells in lymph nodes]] and spleen. The protein antigens of the microbes are displayed by the antigen-presenting cells (APCs) to naive T lymphocytes that recirculate through the lymphoid organs. Molecules encoded in the major histocompatibility complex (MHC) perform the function of displaying peptides derived from protein antigens. MHC genes are highly polymorphic. Their major products are class I and class II MHC molecules, which contain peptide-binding clefts, where the polymorphic residues are concentrated, and [[invariant regions,]] which bind the co-receptors CD8 and CD4, respectively. Proteins that are ingested by APCs from the extracellular environment are proteolytically degraded within the _vesicles_ of the APCs, and the peptides generated bind to the clefts of newly synthesized class II MHC molecules. CD4 binds to an invariant part of class II MHC, because of which CD4+ helper T can only be activated by class II MHC-associated peptides derived mainly from extracellular proteins. Proteins that are produced in the cytoplasm of infected cells, or that enter the cytoplasm from phagosomes, are degraded by [[proteasomes]], transported into the endoplasmic reticulum by [[TAP]], and bind to the clefts of newly synthesized class I MHC molecules. CD8 binds class I MHC molecules, so CD8+ cytotoxic T lymphocytes can be activated only by class I MHC-associated peptides derived from cytosolic proteins. The role of MHC molecules in antigen display ensures that T cells only recognize cell-associated protein antigens, and that the correct type of T cell (helper or cytotoxic) responds to the type of microbe the T cell is best able to combat. Microbes activate APCs to express membrane proteins (costimulators) and to secrete cytokines that provide signals functioning in concert with antigens to stimulate specific T cells. The requirement for these second signals ensures that T cells respond to microbial antigens and not to harmless, nonmicrobial substances. B lymphocytes recognize proteins as well as [[nonprotein]] antigens, even in their [[native]] conformations. [[Follicular]] dendritic cells (FDC'S) display antigens to _germinal_ _center_ B cells and select high-affinity B cells during humoral immune responses.
What is the inflammasome, and how is it stimulated?
The inflammasome is a multiprotein complex found in the *cytoplasm* of phagocytes and some epithelial cells._ It proteolytically cleaves a precursor of the cytokine interleukin-1 (IL-1), generating an active proinflammatory form of IL-1 that is released from the cell. The inflammasome contains a [[NOD]] family molecule called NLRP3 and the proteolytic enzyme caspase-1. NLRP3 recognizes several different molecules that indicate cell infection or injury, leading to activation of [[caspase-1,]] which then cleaves the IL-1 precursor. Stimuli that activate the inflammasome include various bacterial products, viral DNA, intracellular crystals such as sodium urate, reduced potassium concentration, and reactive oxygen species.
What mechanisms contribute to the diversity of antibody and TCR molecules? Which of these mechanisms contributes the most to the diversity?
The joining of segments of antibody and TCR genes in developing lymphocytes @ *THYMUS*, known as VDJ recombination, is responsible for the diversity of antibodies and TCRs. Variations in nucleotide sequences introduced by the use of different V, D, and J segment combinations (combinatorial diversity) and during VDJ joining (junctional diversity) contribute to diversity, but *junctional alterations* make the largest contribution.
What is the principal growth factor for T cells? Why do antigen-specific T cells expand more than other (bystander) T cells on exposure to an antigen?
The major growth factor for T cells is interleukin-2 (IL-2). Antigen-specific T cells receive antigen receptor signals, costimulation and cytokine-mediated stimulation. T cells that have recognized antigens express increased levels of receptors for growth factors and are thus preferentially stimulated during immune responses to the antigens.
Chapter 1 Review: Introduction to Immune System
The physiologic function of the immune system is to protect individuals against infections. Innate immunity is the early line of defense, mediated by cells and molecules that are always present and ready to eliminate infectious microbes. Adaptive immunity is mediated by lymphocytes stimulated by microbial antigens, requires clonal expansion and differentiation of the lymphocytes before it is effective, and responds more effectively against each successive exposure to a microbe. Lymphocytes are the cells of adaptive immunity and are the only cells with clonally distributed receptors with fine specificities for different antigens. Adaptive immunity consists of humoral immunity, in which antibodies neutralize and eradicate extracellular microbes and toxins, and cell-mediated immunity, in which T lymphocytes eradicate intracellular microbes. Adaptive immune responses consist of sequential phases: antigen recognition by lymphocytes, activation of the lymphocytes to proliferate and to differentiate into effector and memory cells, elimination of the microbes, decline of the immune response, and long-lived memory. Different populations of lymphocytes serve distinct functions and may be distinguished by the surface expression of particular membrane molecules. B lymphocytes are the only cells that produce antibodies. B lymphocytes express membrane antibodies that recognize antigens, and the progeny of activated B cells, called plasma cells, secrete the antibodies that neutralize and eliminate the antigen. T lymphocytes recognize peptide fragments of protein antigens displayed on other cells. Helper T lymphocytes produce cytokines that activate phagocytes to destroy ingested microbes, recruit leukocytes, and activate B lymphocytes to produce antibodies. Cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm. Antigen-presenting cells (APCs) capture antigens of microbes that enter through epithelia, concentrate these antigens in lymphoid organs, and display the antigens for recognition by T cells. Lymphocytes and APCs are organized in peripheral lymphoid organs, where immune responses are initiated and develop. Naive lymphocytes circulate through peripheral lymphoid organs searching for foreign antigens. Effector T lymphocytes migrate to peripheral sites of infection, where they function to eliminate infectious microbes. Plasma cells remain in lymphoid organs and the bone marrow, where they secrete antibodies that enter the circulation and find and eliminate microbes.
What are the mechanisms by which the epithelium of the skin prevents the entry of microbes?
The skin provides a relatively impermeable epithelial barrier. These epithelial cells secrete antimicrobial peptide antibiotics, and the skin also contains protective intraepithelial lymphocytes.
How do phagocytes ingest and kill microbes?
To recognize microbes, phagocytes use a range of receptors that recognize microbial carbohydrates and *Fc receptors* that recognize microbes coated (opsonized) by antibodies. Microbes are internalized into phagosomes, which fuse with lysosomes, where the microbes are destroyed by reactive oxygen and nitrogen species and lysosomal enzymes.
