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Abbas: Basic Immunology, 4th Edition
Chapter 01: Introduction to the Immune System
- The principal function of the immune system is:
- Defense against cancer
- Repair of injured tissues
- Defense against microbial infections
- Prevention of inflammatory diseases
- Protection against environmental toxins
The immune system has evolved in the setting of selective pressures imposed by microbial infections. Although immune responses to cancer may occur, the concept that “immunosurveillance” against cancer is a principal function of the immune system is controversial. Repair of injured tissues may be a secondary consequence of the immune responses and inflammation. Although the immune system has regulatory features that are needed to prevent excessive inflammation, prevention of inflammatory diseases is not a primary function. The immune system can protect against microbial toxins, but it generally does not offer protection against toxins of nonbiologic origin.
- Which of the following infectious diseases was prevented by the first successful vaccination?
In 1798, Edward Jenner reported the first intentional successful vaccination, which was against smallpox in a boy, using material from the cowpox pustules of a milkmaid. In 1980, smallpox was reported to be eradicated worldwide by a vaccination program. Effective vaccines against tetanus toxin, rubella virus, and poliovirus were developed in the 20th century and are widely used. There is no effective vaccine against Mycobacterium tuberculosis.
- A previously healthy 8-year-old boy is infected with an upper respiratory tract virus for the first time. During the first few hours of infection, which one of the following events occurs?
- The adaptive immune system responds rapidly to the virus and keeps the viral infection under control.
- The innate immune system responds rapidly to the viral infection and keeps the viral infection under control.
- Passive immunity mediated by maternal antibodies limits the spread of infection.
- B and T lymphocytes recognize the virus and stimulate the innate immune response.
- The virus causes malignant transformation of respiratory mucosal epithelial cells, and the malignant cells are recognized by the adaptive immune system.
The innate immune response to microbes develops within hours of infection, well before the adaptive immune response. B and T lymphocytes are components of the adaptive immune response, and they would not be able to respond to a newly encountered virus before the innate immune response. An 8-year-old boy would no longer have maternal antibodies from transplacental passive transfer and is unlikely to be breast-feeding, which is another potential source of maternal antibodies. Malignant transformation takes months or years to develop.
- Which of the following is a unique property of the adaptive immune system?
- Highly diverse repertoire of specificities for antigens
- Self-nonself discrimination
- Recognition of microbial structures by both cell-associated and soluble receptors
- Protection against viral infections
- Responses that have the same kinetics and magnitude on repeated exposure to the same microbe
Highly diverse repertoires of specificities for antigens are found only in T and B lymphocytes, which are the central cellular components of the adaptive immune system. Both the innate and the adaptive immune systems use cell-associated and soluble receptors to recognize microbes, display some degree of self-nonself discrimination, and protect against viruses. On repeated exposure to the same microbe, the adaptive immune response becomes more rapid and of greater magnitude; this is the manifestation of memory.
- Antibodies and T lymphocytes are the respective mediators of which two types of immunity?
- Innate and adaptive
- Passive and active
- Specific and nonspecific
- Humoral and cell-mediated
- Adult and neonatal
Both B and T lymphocytes are principal components of adaptive immunity. B lymphocytes produce antibodies, which are the recognition and effector molecules of humoral immune responses to extracellular pathogens. T cells recognize and promote eradication of intracellular pathogens in cell-mediated immunity. Passive and active immunity both can be mediated by either B or T lymphocytes. Specific immunity is another term for adaptive immunity. Both B and T lymphocytes participate in adult adaptive immunity but are still developing in the neonatal period.
- A standard treatment of animal bite victims, when there is a possibility that the animal was infected with the rabies virus, is administration of human immunoglobulin preparations containing anti–rabies virus antibodies. Which type of immunity would be established by this treatment?
- Active humoral immunity
- Passive humoral immunity
- Active cell-mediated immunity
- Passive cell-mediated immunity
- Innate immunity
Humoral immunity is mediated by antibodies. The transfer of protective antibodies made by one or more individuals into another individual is a form of passive humoral immunity. Active immunity to an infection develops when an individual’s own immune system responds to the microbe. Cell-mediated immunity is mediated by T lymphocytes, not antibodies, and innate immunity is not mediated by either antibodies or T lymphocytes.
- At 15 months of age, a child received a measles-mumps-rubella vaccine (MMR). At age 22, she is living with a family in Mexico that has not been vaccinated and she is exposed to measles. Despite the exposure, she does not become infected. Which of the following properties of the adaptive immune system is best illustrated by this scenario?
- Nonreactivity to self
Protection against infections after vaccination is due to immunologic memory of the adaptive immune system. Memory is manifested as a more rapidly developing and vigorous response on repeat exposure to an antigen compared with the first exposure. Specificity and diversity are properties related to the range of antigenic structures recognized by the immune system, and specialization is the ability of the adaptive immune system to use distinct effector mechanisms for distinct infections.
- A vaccine administered in the autumn of one year may protect against the prevalent strain of influenza virus that originated in Hong Kong that same year, but it will not protect against another strain of influenza virus that originated in Russia. This phenomenon illustrates which property of the adaptive immune system?
- Cultural diversity
Adaptive immune responses are highly specific for distinct molecular structures, which may be present in a vaccine and be produced by one strain of virus but not by a closely related strain. Amnesia, although generally not used in immunology, implies lack of memory, but the efficacy of the vaccine against the Hong Kong strain implies it has induced memory. The same effector mechanisms would be required to combat different strains of influenza, and therefore failure of a vaccine to protect against two different strains of virus is not related to specialization of effector functions.
- The two major functional classes of effector T lymphocytes are:
- Helper T lymphocytes and cytotoxic T lymphocytes
- Natural killer cells and cytotoxic T lymphocytes
- Memory T cells and effector T cells
- Helper cells and antigen-presenting cells
- Cytotoxic T lymphocytes and target cells
T cells can be classified into effector subsets that perform different effector functions. Most effector T cells are either helper T lymphocytes, which promote macrophage and B cell responses to infections, or cytotoxic T lymphocytes, which directly kill infected cells. Natural killer cells are not T lymphocytes. Antigen-presenting cells usually are not T cells. Memory T cells are not effector T cells.
- Which of the following cell types is required for all humoral immune responses?
- Natural killer cells
- Dendritic cells
- Cytolytic T lymphocytes
- B lymphocytes
- Helper T lymphocytes
Humoral immune responses are antibody-mediated immune responses, and all antibodies are made by B lymphocytes and by no other cell type.
- During a humoral immune response to a newly encountered bacterial infection, B cells are first stimulated to proliferate and then secrete antibodies specific for the bacterium. The antibodies may then bind to the bacteria and facilitate ingestion of the microbes by phagocytic cells. In what phase of the humoral immune response does the binding of secreted antibodies to bacteria occur?
- Recognition phase
- Activation phase
- Effector phase
- Homeostatic phase
- Memory phase
The effector phase of an immune response occurs when cells or molecules eliminate the microbe or microbial toxin. In a humoral immune response, the effector phase includes secretion of antibody, binding of the antibody to the microbe or toxin, and subsequent antibody-dependent elimination of the microbe or toxin. The recognition phase is the initial binding of the antigen by the naive lymphocyte. The activation phase includes proliferation and differentiation of lymphocytes in response to antigen recognition. The homeostatic phase follows the effector phase, during which the response wanes. In the memory phase, memory B cells and antibodies secreted by long-lived antibody-secreting cells are “waiting” for a repeat exposure to the microbe.
- Which of the following statements is consistent with the process of clonal selection?
- The specificity of a lymphocyte antigen receptor changes to accommodate the structure of an antigen that binds to it.
- Many different antigen receptors with different specificities are expressed on each lymphocyte.
- Lymphocytes do not express antigen receptors on their cell surfaces until after exposure to antigen.
- The diversity of the lymphocyte repertoire for antigens is very small before exposure to antigen but increases significantly after antigen exposure.
- The diversity of the lymphocyte repertoire for antigens is very large before exposure to antigen, with millions of different clones of lymphocytes, each having a different specificity.
The clonal selection hypothesis accurately predicted that individuals possess large numbers of different clones of lymphocytes before antigen exposure, with cells in each clone expressing antigen receptors with a single identical specificity, but with different specificities from other clones. Thus, the diversity of the lymphocyte repertoire is very large even before antigen exposure. These receptors are expressed before antigen exposure, and their specificities generally do not change in response to antigen.
- Which of the following best describes clonal expansion in adaptive immune responses?
- Increased number of different lymphocyte clones, each clone specific for a different antigen during the course of an infection
- Increased number of different lymphocyte clones, each clone specific for a different antigen during development of the immune system, before exposure to antigen
- Increased number of lymphocytes with identical specificities, all derived from a single lymphocyte due to nonspecific stimuli from the innate immune system
- Increased number of lymphocytes with identical specificities, all derived from a single lymphocyte stimulated by a single antigen
- Increased size of the lymphocytes of a single clone due to antigen-induced activation of the cells
Clonal expansion occurs during the activation phase of an adaptive immune response. A single lymphocyte is stimulated to divide by antigen, and the progeny go through several rounds of division until there are many lymphocytes, all with identical specificities, all derived from one cell. The number of different clones is not influenced by antigen exposure. Expansion does not refer to the size of the cells, although activated lymphocytes are larger than their naive precursors.
- The estimated number of distinct structures that can be recognized by the mammalian adaptive immune system is
Although the theoretical number of antigen specificities of the adaptive immune system is higher, estimates of the actual number of different antibody and T cell antigen receptor specificities are in the range of 107-109. This number is large enough to accommodate most of the diversity in molecular structures that the microbial world is capable of producing.
- Which of the following statements best describes the “two-signal requirement” for naive lymphocyte activation?
- Lymphocytes must recognize two different antigens to become activated.
- Lymphocytes must recognize the same antigen at two sequential times to become activated.
- Lymphocytes must recognize antigen and respond to another signal generated by microbial infection to become activated.
- Both naive B and naive T lymphocytes must simultaneously recognize antigen for either to be activated.
- When lymphocytes recognize antigen, the antigen receptors must activate two-signal transduction pathways to become activated.
Naive lymphocytes will not become activated by antigen alone (signal 1). In addition, they require “costimulatory” signals (signal 2), which are either microbial products or molecules on host cells induced by microbial infection. The molecules that provide signal 2 bind to receptors on the lymphocytes that are distinct from the clonally distributed antigen receptors. Each lymphocyte cannot generally recognize more than one antigen. Although lymphocyte activation may require recognition of antigen molecules by more than one antigen receptor, the two-signal requirement does not refer to this. There is no general requirement for both T and B cells to recognize the same antigen for activation of either to occur. The two-signal requirement does not refer to antigen receptor–associated signal transduction pathways.
- In addition to T cells, which cell type is required for initiation of all T cell–mediated immune responses?
- Effector cells
- Memory cells
- Natural killer cells
- Antigen-presenting cells
- B lymphocytes
T cell–mediated immune responses are initiated when naive T cells are activated. Antigen-presenting cells, such as dendritic cells, are required to display antigens (peptide-MHC molecule complexes) for naive T cell recognition and to express costimulatory molecules also needed for T cell activation. Memory cells, cytotoxic T cells, and B lymphocytes are not involved in the initial activation of naive T lymphocytes.
Abbas: Basic Immunology, 4th Edition
Chapter 05: T Cell–Mediated Immunity
- All of the following protein-protein interactions are involved in activation of naive helper T cells by antigen-presenting cells (APCs) EXCEPT:
- Binding of peptide-MHC complexes on the APC to the TCR on the T cell
- Binding of CD4 on the T cell to nonpolymorphic regions of class II MHC molecules on the APC
- Binding of integrins on the T cell with adhesion ligands on the APC
- Binding of B7-2 on the APC with CD28 on the T cell
- Binding of CD40L on the T cell with CD40 on the APC
CD40L is not expressed on naive T cells and is only up-regulated subsequent to activation by an antigen-presenting cell (APC). In the naive helper T cell, the TCR binds to the MHC-peptide complex whereas the CD4 coreceptor engages a conserved region on the MHC II molecule. Integrins on the T cell interact with adhesion ligands on the APC. This region of binding between the T cell and the APC is known as the immunologic synapse and also includes costimulatory interactions, such as CD28 on the T cell binding to B7 on the APC.
- Which one of the following statements about MHC-TCR interactions is NOT true?
- Antigen receptors on T cells bind to MHC molecules for only brief periods of time.
- The affinity of most TCRs for peptide-MHC complexes is similar to the affinity of antibodies for their antigens.
- Only 1% or less of the MHC molecules on any antigen-presenting cell (APC) display a peptide recognized by a particular T cell.
- T cells usually require multiple engagements with an APC before a threshold of activation is reached.
- A subthreshold number of MHC-TCR interactions can lead to T cell inactivation.
In general, the TCR binds to peptide-MHC complexes with lower affinity than antigen-antibody interactions. This relatively low-affinity interaction occurs briefly; thus, a T cell may need multiple engagements with the antigen-presenting cell (APC) before a threshold of activation occurs. If this threshold is not reached, the T cell may enter into an inactive state known as anergy. On any given APC, less than 1% of the MHC molecules display the same peptide.
- Which one of the following cell types would be most potent at activating naive T cells?
- Kupffer cells
- B cells
- Follicular dendritic cells
- Langerhans cells
Antigen-presenting cells (APCs) are responsible for presenting peptide-MHC complexes and costimulatory molecules to naive T cells; this leads to activation of the T cells. The most potent APCs are the dendritic cells, because they constitutively express high levels of costimulatory molecules. Langerhans cells are dendritic cells found in epidermis. Other APCs include macrophages and B cells. Kupffer cells are a type of macrophage found in the liver. Neither neutrophils nor follicular dendritic cells (FDCs) are involved in antigen presentation to T cells. FDCs are unrelated to dendritic cells and are found within the germinal centers of lymph nodes.
- Which one of the following descriptions of cytokine interleukin-2 is NOT true?
- Expression of its gene requires multiple transcription factors, such as Fos, Jun, and NFAT.
- It acts as an autocrine growth factor for T cells.
- It binds to CD25 on the cell membrane of T cells.
- It is only involved in the proliferation of helper T cells and not CTLs.
- It promotes susceptibility of T cells to apoptosis.
IL-2 is involved in the proliferation of both CD4+ and CD8+ T cells. Activation of the naive T cell results in signals transduced via the TCR (signal 1) and CD28 (signal 2). This signaling results in the activation of transcription factors, such as Fos, Jun, and NFAT, which increase transcription of the IL-2 gene. IL-2 is then secreted and acts as both a paracrine and autocrine growth factor for T cells by binding to the IL-2 receptor (one component of which is CD25). In addition to its growth factor activity, IL-2 also “primes” T cells for apoptotic death, and this role for IL-2 is important in homeostasis of the immune system.
- Which one of the following statements about T cells involved in an immune response is NOT true?
- Activated T cells receive survival signals from antigen during an infection.
- Activated T cells contribute to the activation of antigen-presenting cells via CD40 ligand.
- Memory T cells generated during a primary immune response express high levels of interleukin-2 receptors and actively proliferate long after the primary response is completed.
- The major effector function of helper T cells is to activate macrophages and other cells by releasing cytokines.
- When an infection is eliminated, activated T cells die by apoptosis.
Memory T cells are not actively proliferating and do not express high levels of IL-2 receptors. Instead, these cells are functionally quiescent and are not performing effector functions after a primary immune response. Effector T cells continue to survive in the periphery via proliferative signals from MHC-antigen binding to the TCR. Effector helper T cells can then activate macrophages and other lymphocytes via release of cytokines such as IFN-g, as well as through CD40 ligand on the cell surface. On elimination of the infection, the effector T cells die by apoptosis.
- Which one of the following statements about the molecules B7-1 and B7-2 is NOT true?
- B7-1 and B7-2 expression on antigen-presenting cells (APCs) is upregulated by the presence of “danger” signals, such as lipopolysaccharide, as well as cytokines, such as interferon (IFN)-g.
- B7-1 and B7-2 are expressed at low levels on some resting APCs.
- Induction of B7-1 usually occurs before the induction of B7-2 in an immune response.
- B7-1 and B7-2 bind to CD28 on T cells and provide “second signals” for naive T cell activation.
- Activated helper T cells can induce expression of B7-1 and B7-2 on APCs via CD40L binding to CD40.
The temporal patterns of B7-1 and B7-2 expression differ. B7-2 is expressed constitutively at low levels and induced early after activation of antigen-presenting cells (APCs), whereas B7-1 is not expressed constitutively and is induced hours or days later. The expression of B7-1 and B7-2 on APCs is induced by “danger signals” of infection. These signals are mediated by binding of lipopolysaccharide (LPS), unmethylated CpG DNA, and other ligands of Toll-like receptors. Signals mediated through cytokines, such as interferon (IFN)-g, as well as through CD40 ligand, can also up-regulate B7-1 and B7-2 expression on APCs. Both B7-1 and B7-2 bind to CD28 on naive T cells, thus providing the second signal needed for activation of T cells.
- In patients with hyper IgM syndrome, there is a genetically based deficiency in expression of CD40 ligand. In addition to defects in antibody isotype switching, these patients have defects in T cell–mediated immune responses and become infected with intracellular parasites. Which one of the following normal functions of CD40 ligand is important in T cell–mediated immunity?
- CD40-dependent isotype switching is required to produce antibody isotypes that activate T cells.
- CD40 ligand is required for CTL killing of CD40-expressing infected cells.
- CD40 ligand is required for maturation of CD4+T cells in the thymus.
- CD40 ligand on activated T cells binds to CD40 on antigen-presenting cells (APCs), and this enhances the expression of B7-1, B7-2, and cytokines by the APCs.
- CD40 ligand on T cells binds to B7-1 and B7-2 on APCs, and this enhances the function of the APCs.
CD40 ligand, a membrane-bound protein in the tumor necrosis factor (TNF) family of proteins, is expressed after T cell activation. When it binds to its receptor CD40, a TNF-receptor family member expressed on macrophages, and other antigen-presenting cells, signals are transmitted that enhance costimulator and cytokine expression (as well as other functions of macrophages). This serves to amplify the T cell response and enhance the killing of microbes ingested by macrophages. Antibodies are not required to activate T cells. CD40 does not transduce pro-apoptotic signals. CD40 ligand is not involved in T cell maturation and does not bind to B7-1 or B7-2.
- All of the following molecules act as transcription factors in T cell activation signaling EXCEPT:
All of these proteins are involved in the activation of T cells. However, Ras is not a transcription factor but a guanosine triphosphate (GTP)-binding protein present in the cytosol and in association with the plasma membrane. On exchange of guanosine diphosphate (GDP) for GTP, the Ras protein becomes functional and acts as an allosteric activator of MAP kinases, which leads the transcription of Fos.
- Which one of the following statements about the molecule Lck is NOT true?
- It is a member of the Src family of kinases.
- It binds to the cytoplasmic tails of T cell coreceptors CD4 or CD8.
- It phosphorylates ITAM motifs on the CD3 complex.
- It phosphorylates tyrosine residues on Zap-70 and activates it.
- It phosphorylates PIP2 to PIP3 and leads to the activation of Itk.
PI-3 kinase is responsible for the phosphorylation of PIP2 to PIP3, leading to the activation of Itk in T cells and Btk in B cells.
- A 7-month-old boy, the only child of second-degree cousins, saw a pediatrician for immunologic evaluation after developing Pneumocystis carinii pneumonia. Serum IgG, IgM, and IgA levels were normal. Blood cell count showed 10,600 leukocytes/mm3and 80% lymphocytes; 90% of the lymphocytes were TCR ab+ CD4+. In vitro lymphocyte-proliferative responses to PHA and anti-CD3 were absent, and the pattern of tyrosine-phosphorylated cytoplasmic proteins after anti-CD3 treatment of the T cells was distinctly abnormal. This boy most likely carries homozygous mutations in the gene encoding which one of the following proteins?
The patient shows signaling defects in TCR-mediated T cell activation, as well as defects in CD8+ T cell maturation. Zap-70 is a tyrosine kinase required for TCR-mediated T cell activation. Mutations in Zap-70 result in impaired TCR signaling, with abnormal tyrosine phosphorylation of downstream signaling molecules, and also a defect in CD8+ T cell maturation. It is not known why CD8+ maturation is selectively impaired in Zap-70 deficiency. VDJ recombination, and therefore RAG-1 function, must still be intact because TCR-expressing CD4+ T cells do mature. CD3, pre-Ta, and TCRa are also required for maturation of CD4+ T cells, and therefore these molecules must all be expressed by this patient.
- Which one of the following signaling molecules, if mutated, would affect B cell maturation and function primarily without affecting T cell function?
- PI-3 kinase
Btk is a Tec family protein tyrosine kinase that is particularly important in pre-B cell receptor complex signaling, and therefore in B cell maturation and activation. Mutations in Btk are responsible for X-linked agammaglobulinemia. Itk and Tec are other members of the Tec family that are important in T cells. PI-3 kinase is a phospholipid kinase involved in signaling in many cell types, including B and T cells, and Zap-70 is a protein tyrosine kinase particularly important in TCR signaling in T cells.
- All of the following are early T cell events that occur after antigen recognition by the TCR EXCEPT:
- Formation of the immunologic synapse
- Recruitment of signaling molecules, such as LAT, to glycolipid-enriched domains known as lipid rafts
- Enhanced adhesion between T cells and antigen-presenting cells (APCs) via T cell integrin LFA-1 and its ligand on the APC, ICAM-1, at the central zone of the immunologic synapse
- Clustering of the TCR and coreceptors leading to phosphorylation of ITAMs on CD3 by Lck
- Binding of CD28 with costimulators on APCs in the cSMAC, resulting in signal transduction activation
On binding of the TCR complex with MHC-associated peptides on an antigen-presenting cell (APC), several T cell surface proteins and intracellular signaling molecules are rapidly mobilized to the site of contact, known as the immunologic synapse. Molecules that are recruited to the central supramolecular activation cluster, or center of the synapse, include the TCR complex (TCR, CD3, and z chains), CD4 or CD8 coreceptors, and costimulatory molecules (CD28). The clustering of signaling molecules results in the phosphorylation of ITAMs on CD3 by CD4- or CD8-associated Lck. Integrins remain at the peripheral zone of the synapse and stabilize the binding of the T cell to the APC. LAT is a transmembrane adaptor molecule recruited to the synapse whose cytoplasmic tail forms part of a scaffold of signaling molecules.
- An experiment is performed in which a point mutation is introduced randomly into the Zap-70 gene for a particular strain of mice. The mutant mice display a defect in T cell development. However, precursor T cells isolated from the thymus of these mice show normal expression levels of Zap-70 of the correct molecular weight. On further in vitro analysis, the mutant Zap-70 is found to bind to ITAM motifs in the cytoplasmic tail of the z chain, but only when the z chain is phosphorylated. No phosphorylated LAT is detected, however. Given these data, in which of the following protein domains is the mutation most likely to be present?
- Pleckstrin homology (PH) domain
- Proline-rich (PR) domain
- SH1 domain
- SH2 domain
- SH3 domain
In this experiment, the mutant Zap-70 can still bind to the phosphorylated z chains but cannot phosphorylate LAT. This suggests that the SH2 domains are normal but that the SH1 kinase domain has been mutated. Zap-70 does not contain a PH, PR, or SH3 domain. The PH domain allows proteins to localize to the membrane by binding to PIP3. PR domains mediate protein-protein interactions via binding to SH3 domains.
- Which one of the following accurately depicts the correct order of events in a TCR signal transduction pathway?
- TCR → Lck → Zap-70 → LAT → Grb-2 → SOS → Ras → Erk → Fos
- TCR → Lck → Zap-70 → LAT → SOS → Grb-2 → Ras → Erk → Fos
- TCR → Lck → ITK → LAT → Grb-2 → SOS → Ras → Erk → Fos
- TCR → Lck → Zap-70 → LAT → SOS → Grb-2 → Ras → Erk → Jun
- TCR → Lck → Zap-70 → LAT → PLCg → DAG → calcium release
Activated Zap-70 phosphorylates the transmembrane adapter protein LAT at tyrosine residues, which serve as docking sites for SH2 domains of other proteins. In one pathway, the SH2 domain of Grb-2 binds to phosphorylated LAT. Grb-2 is then able to recruit Sos to the membrane. Sos catalyzes GDP/GTP exchange on Ras, a G protein that is active when guanosine triphosphate (GTP) is bound and inactive when guanosine diphosphate (GDP) is bound. Active Ras functions as an allosteric activator of mitogen-activated protein kinases (MAPK), leading to downstream activation of Erk through phosphorylation. Activated Erk stimulates the transcription of Fos (through intermediate activation of a protein called Elk). In a second pathway, PLCg binds directly to activated LAT and is then phosphorylated by Zap-70. Activated PLCg leads to the cleavage of PIP2 to IP3 and DAG. Although DAG activates protein kinase C (PKC), it is IP3 that causes a release of calcium into the cytosol.
- Damage to neurons in patients with multiple sclerosis (MS) may be caused by autoreactive T cells that recognize peptides derived from myelin proteins presented by self MHC molecules. These autoreactive T cells secrete interferon (IFN)-g and promote inflammation, which damages the myelin sheath surrounding neurons. The exact immunodominant epitopes recognized by autoreactive T cells in MS patents have been identified. One potential method of therapy for patients with MS is to administer therapeutic peptides that differ from the immunodominant epitopes by one or two amino acids. Which one of the following statements best describes the basis for this therapeutic approach?
- The therapeutic peptides, called “altered peptide ligands,” could inactivate T cells specific for myelin proteins, or drive them to differentiate into T cells that do not produce IFN-g.
- The therapeutic peptides, called “altered peptide ligands,” could interfere with processing of the natural myelin proteins by the patient’s antigen-presenting cells.
- The therapeutic peptides could bind to the TCRs of myelin-specific T cells but not to the self MHC molecules, thereby blocking T cell activation.
- The therapeutic peptides could down-regulate MHC expression.
- The therapeutic peptides could replace the damaged myelin and restore neuronal function.
Altered peptide ligands are synthetic peptides in which the TCR contact residues have been changed, so that the peptide induces only partial responses by the responding T cell. These peptides still bind to the same MHC molecules as the original peptides, but they can cause T cell inactivation (anergy) or change in the cytokines the T cell produces. Altered peptide ligands do not interfere with processing of the natural proteins nor can they bind to TCRs without being presented by MHC molecules. There is no basis to say that peptides can down-regulate major MHC expression or replace damaged proteins in the myelin sheath.