5. Diseases of the Immune System, Neoplasia

Question 1

Cells, tissues, receptors and mediates of normal immune response

Answer 1

Lymphocytes
T-lymphocytes
B-lymphocytes
Natural killer (NK) cells
Antigen-presenting cells (APCs)
CD4+ helper T cells
CD8+ cytotoxic T lymphocytes
Antibodies

Question 2

Immune response

Answer 2

• The cells of the immune system are organized in tissues, some of which are the sites of production of mature lymphocytes (the generative lymphoid organs), the bone marrow, and thymus), and others are the sites of immune responses (the peripheral lymphoid organs, including lymph nodes, spleen, and mucosal lymphoid tissues).
• The early reaction to microbes is mediated by the innate immune system, which is ready to respond to microbes. Components of the innate immune system include epithelial barriers, phagocytes, NK cells, and plasma proteins, for example, of the complement system. Innate immune reactions are often manifested as inflammation. Innate immunity, unlike adaptive immunity, does not have fine antigen specificity or memory.
• 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 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., phagocytosed microbes and microbes in the cytoplasm of infected cells). Humoral immunity is mediated by antibodies and is effective against extracellular microbes (in the circulation and mucosal lumens).

Question 3

Lymphocytes

Answer 3

• Lymphocytes are the mediators of adaptive immunity and the only cells that produce specific and diverse receptors for antigens.
• T (thymus-derived) lymphocytes express antigen receptors called T-cell receptors (TCRs) that recognize peptide fragments of protein antigens that are displaced by MHC molecules on the surface of antigen-presenting cells.
• B (bone marrow-derived) lymphocytes express membrane-bound antibodies that recognize a wide variety of antigens. B cells are activated to become plasma cells, which secrete antibodies.

Question 4

NK cells and APCs

Answer 4

• Natural killer (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.
• Antigen-presenting cells (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 live in epithelia and most tissues.

Question 5

CD4+ and CD8+

Answer 5

• CD4+ helper T cells help B cells to make antibodies, activate macrophages to destroy ingested microbes, stimulate 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+ cytotoxic T lymphocytes kill cells that express antigens in the cytoplasm that are seen as foreign (e.g., virus-infected and tumor cells) and can also produce cytokines.

Question 6

Antibodies

Answer 6

Secreted by plasma cells neutralize microbes and block their infectivity, and promote phagocytosis and destruction of pathogens. Antibodies also confer passive immunity to neonates

Question 7

Immediate (type I) sensitivity

Answer 7

• Immediate (type I) sensitivity is also called an allergic reaction, or allergy.
• Type 1 hypersensitivity is induced by environmental antigens (allergens) that stimulate strong T(H)2 responses and IgE production in genetically susceptible individuals.
• IgE coasts mast cells by binding to the FceRI receptor; reexposure to the allergen leads to cross-linking of the IgE and FceRI, activation of mast cells, and release of mediators.
• Principle 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 form mildly annoying rhinitis to fatal anaphylaxis.

Question 8

Pathogenesis of diseases caused by antibodies and immune complexes

Answer 8

• Antibodies can coat (opsonize) cells, with or without complement proteins, and target these cells for phagocytosis by phagocytes (macrophages), which express receptors for the Fc tails and IgG 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 other essential molecules and cause functional derangements (either inhibition or unregulated activation) without cell injury.

Question 9

Mechanisms of T cell mediated hypersensitivity reactions

Answer 9

• Cytokine-mediated inflammation: CD4+ T cells are activated by exposure to a protein antigen and differentiate into T(H)1 and T(H)17 effector cells. Subsequent exposure to the antigen results in the secretion of cytokines. IFN-y activates macrophages to produce substances that cause tissue damage and promote fibrosis, and IL-17 and other cytokines recruit leukocytes, thus promoting inflammation.
• The classical T cell-mediated inflammatory reaction is delayed-type hypersensitivity. chronic T(H)1 reactions associated with macrophage activation often lead to granuloma formation.
• T cell-mediated cytotoxicity: CD8+ cytotoxic T lymphocytes (CTLs) specific for an antigen recognize cells expressing the target antigen and kill these cells. CD8+ T cells also secrete IFN-y.

Question 10

Immunologic tolerance and immunity

Answer 10

• Tolerance (unresponsiveness) to self antigens is a fundamental property of the immune system, and breakdown of tolerance is the basis of autoimmune diseases.
  
  • Central tolerance: immature T and B 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 to become functionally inactive (anergic), are suppressed by regulatory T lymphocytes, or die by apoptosis.

Question 11

Factors that lead to a failure of self-tolerance and the development of autoimmunity

Answer 11

• inheritance of susceptibility genes that disrupt different tolerance pathways, and
• infections and tissue injury that expose self antigens and activate APCs and lymphocytes in the tissues.

Question 12

Systemic lupus erythematosus

Answer 12

• systemic autoimmune disease caused by autoantibodies produced against self antigens and the formation of immune complexes.
• The major autoantibodies, and the ones responsible for the formation of circulating immune complexes, are directed against nuclear antigens. Other autoantibodies react with red blood cells, platelets, and phospholipid-proteins complexes.
• Disease manifestations include nephritis, skin lesions, and arthritis (caused by the deposition of immune complexes), hematologic abnormalities (caused by antibodies against red cells, white cells and platelets) and neurologic abnormalities (caused by obscure mechanisms).
• The cause of the breakdown in self-tolerance is unknown; possibilities include excessive generation or persistence of nuclear antigens, in individuals with inherited susceptibility genes, and environmental triggers (e.g., UV irradiation, which results in cellular apoptosis and release of nuclear antigens).

Question 13

Sjorgen syndrome

Answer 13

• Sjogren syndrome is an inflammatory disease that primarily affects the salivary and lacrimal glands, causing dryness of the mouth and eyes.
• The disease is believed to be caused by an autoimmune T-cell reaction against an unknown self-antigen expressed in these glands, or immune reactions against the antigens of a virus that infects the tissues.

Question 14

Systemic sclerosis

Answer 14

• Systemic sclerosis (commonly called scleroderma) is characterized by progressive fibrosis involving the skin, gastrointestinal tract, and other tissues.
• Fibrosis may be the result of activation of fibroblasts by cytokines produced by T cells, but what triggers T cell responses is unknown.
• Endothelial injury and microvascular disease are commonly present in the lesions of systemic sclerosis, perhaps causing chronic ischemia, but the pathogenesis of vascular injury is not known.

Question 15

Recognition and rejection of transplants

Answer 15

• Rejection of solid organ transplants is initiated mainly by host T cells that recognize the foreign HLA antigens of the graft, either directly (on APCs in the graft) or directly (after uptake and presentation by host APCs).
• Treatment of graft rejection relies on immunosuppressive drugs, which inhibit immune responses against the graft.
• Transplantation of hematopoietic stem cells (HSCs) requires careful matching of donor and recipient and is often complicated by graft-vs-host disease (GVHD) and immune deficiency.

Question 16

Types and mechanisms of rejection of solid organ grafts

Answer 16

• Hyperacute rejection: preformed anti-donor antibodies that bind to graft endothelium immediately after translation, 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 antibody-mediated (humoral) rejection: Antibodies damage graft vasculature.
• Chronic rejection: Dominated by arteriosclerosis, this type is caused by T cell activation and antibodies. The T cells may secrete cytokines that induce proliferation of vascular smooth muscle cells, and the antibodies cause endothelial injury. The vascular lesions and T cell reactions cause parenchymal fibrosis.

Question 17

Primary (inherited) immune deficiency diseases

Answer 17

• These diseases are caused by inherited mutations in genes involved in lymphocyte maturation or function, or in innate immunity.
• Lymphocytes and adaptive immune responses
• Deficiencies in innate immunity include defects of leukocyte function, complement, and innate immune receptors.
• These diseases present clinically with increased susceptibility to infections in early life.

Question 18

Some of the more common disorders affecting lymphocytes and the adaptive immune responses

Answer 18

• X-SCID: Failure of T cell and B cell maturation; mutation in the common y chain of a cytokine receptor, leading to failure of IL-7 signaling and defective lymphopoiesis.
• Autosomal recessive SCID: Failure of T cell development; secondary defect in antibody responses; approximately 50% of cases caused by mutation in the gene encoding ADA, leading to accumulation of toxic metabolites during lymphocyte maturation and proliferation.
• X-linked agammaglobulinemia (XLA): Failure of B-cell maturation, absence of antibodies; caused by mutations in the BTK gene, which encodes B-cell tyrosine kinase, required for maturation signals from the pre-B-cell and B-cell receptors.
• Di George syndrome: Failure of development of thymus, with T cell deficiency.
• X-linked hyper-IgM syndrome: Failure to produce isotype switched high-affinity antibodies (IgG, IgA, IgE); mutations in genes encoding CD40L or activation-induced cytosine deaminase.
• Common variable immunodeficiency: Defects in antibody production; cause unknown in most cases.
• Selective IgA deficiency: Failure of IgA production; cause unknown.

Question 19

Human Immunodeficiency Virus life cycle and pathogenesis of AIDS

Answer 19

• Virus entry into cells: requires CD4 and receptors for chemokines; involves binding of viral gp120 and fusion with the cell mediated by viral gp41 protein; main cellular targets: CD4+ helper T cells, macrophages, DCs.
• Viral replication: integration of provirus genome into host cell DNA; triggering of viral gene expression by stimuli that activate infected cells (e.g., infectious microbes, cytokines produced during normal immune responses).
• Progression of infection: acute infection of mucosal T cells and DCs; viremia with dissemination of virus; latent infection of cells in lymphoid tissue; continuing viral replication and progressive loss of CD4+ T cells.

Question 20

Mechanisms of immune deficiency

Answer 20

• Loss of CD4+ T cells: T cell death during viral replication and budding (similar to other cytopathic infections); apoptosis occurring as a result of chronic stimulation; decreased thymic output; functional defects.
• Defective macrophage and DC functions.
• Destruction of architecture of lymphoid tissues (late)

Question 21

Progression of disease: HIV infection progresses through phases.

Answer 21

• Acute HIV infection: Manifestations of acute viral illness.
• Chronic (latent) phase: Dissemination of virus, host immune response, progressive destruction of immune cells.
• AIDS: Severe immune deficiency.

Question 22

Clinical features: Full blown AIDS manifests with several complications, mostly resulting from immune deficiency

Answer 22

• Opportunistic infections
• Tumors, especially tumors caused by oncogenic viruses
• Neurologic complications of unknown pathogenesis
• Antiretroviral therapy has greatly decreased the incidence of opportunistic infections and tumors but also has numerous complications.

Question 23

Amyloidosis

Answer 23

• Amyloidosis is a disorder characterized by the extracellular deposits of proteins that are prone to aggregate and form insoluble fibrils.
• The deposition of these proteins may result from: excessive production of proteins that are prone to aggregation; mutations that produce proteins that cannot fold properly and tend to aggregate; 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 B-cell proliferations (in which the amyloid deposits consists of immunoglobulin light chains); chronic inflammatory diseases such as rheumatoid arthritis (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 mutated proteins (e.g., transthyretin in familial amyloid polyneuropathies); and hemodialysis (deposits of B-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.

Question 24

Characteristics of benign and malignant tumors

Answer 24

• Benign and malignant tumors can be distinguished from one another based on the degree of differentiation, rate of growth, local invasiveness, and distant spread.
• Benign tumors resemble the tissue of origin and are well differentiated; malignant tumors are poorly or completely undifferentiated (anaplastic).
• Benign tumors tend to be slow growing, whereas malignant tumors generally grow faster.
• Benign tumors are well circumscribed and have a capsule; malignant tumors are poorly circumscribed and invade the surrounding normal tissues.
• Benign tumors remain localized to the site of origin, whereas malignant tumors are locally invasive and metastasize to distant sites.

Question 25

Epidemiology of cancer

Answer 25

• The incidence of cancer varies with age, geographic factors, and genetic background. The geographic variation in cancer incidence results mostly from different environmental exposures. Cancer can occur at any age, but is most common in older adults.
• Environmental factors implicated in carcinogenesis include infectious agents, smoking, alcohol, diet, obesity, reproductive history, and exposure to carcinogens.
• Cancer risk rises in certain tissues in the setting of increased cellular proliferation caused by chronic inflammation or hormonal stimulation.
• Epithelial cell linings may develop morphologic changes that signify an increased risk for developing cancer; such lesions are referred to as precursor lesions.
• The risk for developing cancer is modified by interactions between environmental exposures and genetic variants.

Question 26

Genetic lesions in cancer

Answer 26

• Mutations in cancer cells fall into two major classes, driver (pathogenic) mutations and passenger (neutral) mutations.
• Passenger mutations may become driver mutations if selective pressure on the tumor changes, for example, in the setting of treatment with an effective therapeutic drug.
• Tumor cells may acquire driver mutations through several means, including point mutations and nonrandom chromosomal abnormalities that contribute to malignancy; these include gene rearrangements, deletions, and amplifications.
• Gene rearrangements (usually caused by translocations, but sometimes by inversions of other more complex events) contribute to carcinogenesis by overexpression of oncogenes or generation of novel fusion proteins with altered signaling capacity.
• Deletions frequently affect tumor suppressor genes, whereas gene amplficiation increases the expression of oncogenes.
• Overexpression of miRNAs can contribute to carcinogenesis by reducing the expression of tumor suppressors, while deletion or loss of expression of miRNAs can lead to overexpression of proto-oncogenes.
• Tumor suppressor genes and DNA repair genes also may be silenced by epigenetic changes, which involve reversible, heritable changes in gene expression that occur not my mutation but my methylation of the promoter.

Question 27

Self-sufficiency in growth signals

Answer 27

• Proto-oncogenes: normal cellular genes whose products promote cell proliferation.
• Oncogenes: mutant or overexpressed versions of proto-oncogenes that function autonomously without a requirement for normal growth-promoting signals.
• Oncoproteins promote uncontrolled cell proliferation
• Complexes of cyclins with CDKs drive the cell cycle by phosphorylating various substrates and normally are controlled by CDK inhibitors. Mutations in genes encoding cyclins, CDKs and CDK inhibitors result in uncontrolled cell cycle progression and are found in a wide variety of cancers including melanomas and brain, lung, and pancreatic cancers.

Question 28

Oncoproteins promote uncontrolled cell proliferation by several mechanisms:

Answer 28

• Stimulus-independent expression of growth factor and its receptor, setting up an autocrine loop of cell proliferation (e.g., PDGF-PDGF receptor in brain tumors).
• Mutations in genes encoding growth factor receptors or tyrosine kinases leading to constitutive signaling.
• Amplification of EGF receptor family genes such as HER2 in breast cancer.
• Fusion of portions of the ABL tyrosine kinase gene and the BCR protein gene, creating a BCR-ABL fusion gene encoding a constitutively active tyrosine kinase, in certain leukemias.
• Mutations in genes encoding signaling molecules.
• RAS commonly is mutated in human cancers and normally flips between resting GDP-bound state and active GTP-bound state; mutations block hydrolysis of GTP to GDP, leading to unchecked signaling.
• Overproduction or unregulated activity of transcription factors.
• Translocation of MYC in some lymphomas leads to overexpression and unregulated expression of its target genes controlling cell cycling and survival.
• Mutations that activate cyclin genes or inactivate negative regulators of cyclins and cyclin-dependent kinases.

Question 29

RB: governor of the cell cycle

Answer 29

• Like other tumor suppressor genes, both copies of RB must be dysfunctional for tumor development to occur.
• In cases of familial retinoblastoma, one defective copy of the RB gene is present in the germ line, so that only one additional somatic mutation is needed to completely eliminate RB function.
• RB exerts anti-proliferative effects by controlling the G1-to-S transition of the cell cycle. In its active form, RB is hypophosphorylated and binds to E2F transcription factors. This interaction prevents transcription of genes like cyclin E that are needed for DNA replication, and so the cells are arrested in G1.
• Growth factor signaling leads to cyclin D expression, activation of cyclin D-CDK4/6 complexes, inactivation of RB by phosphorylation, and thus release of E2F.
• Loss of cell cycle control is fundamental to malignant transformation. Almost all cancers have a disabled G1 checkpoint due to mutation of either RB or genes that affect RB function, such as cyclin D, CDK4, and CDK1s.
• Many oncogenic DNA viruses, like HPV, encode proteins (e.g., E7) that binding RB and render it nonfunctional.

Question 30

TP53: Guardian of the genome

Answer 30

• encodes p53, the central monitor of stress, which can be activated by anoxia, inappropriate oncogene signaling, or DNA damage. Activated p53 controls the expression and activity of genes involved in cell cycle arrest, DNA repair, cellular senescence, and apoptosis.
• DNA damage leads to activation of p53 by phosphorylation. Activated p53 drives transcription of CDKNIA (p21), which prevents RB phosphorylation, thereby causing a G1-S block in the cell cycle. This pause allows the cells to repair DNA damage.
• If DNA damage cannot be repaired, p53 induces cellular senescence or apoptosis.
• Of tumors, 70% demonstrate biallelic mutations in TP53. Patients with the rare Li-Fraumeni syndrome inherit one defective copy of TP53 in the germ line, such that only one additional mutation is required to lose normal p53 function. Li-Fraumeni syndrome patients are prone to develop tumors.
• As with RB, p53 can be incapacitated when bound by proteins encoded by oncogenic DNA viruses such as HPV.

Question 31

TGF-B, contact inhibition, and APC-B-catenin pathways

Answer 31

• TGF-B inhibits proliferation of many cell types by activation of growth-inhibiting genes such as CDKIs and suppression of growth-promoting genes such as MYC and those encoding cyclins.
• TGF-B function is compromised in many tumors by mutations in its receptors (colon, stomach, endometrium) or by mutational inactivation of SMAD genes that transduce TGF-B signaling (pancreas).
• E-cadherin maintains contact inhibition, which is lost in malignant cells.
• The APC gene exerts anti-proliferative actions by regulating the destruction of the cytoplasmic protein B-catenin. With a loss of APC, B-catenin is not destroyed, and it translocates to the nucleus, where it acts as a growth-promoting transcription factor.
• In familial adenomatous polyposis syndrome, inheritance of a germ line mutation in the APC gene and sporadic loss of the sole normal allele causes the development of hundreds of colonic polyps at a young age. Inevitably, one or more of these polyps evolves into a colonic cancer. Somatic loss of both alleles of the APC gene is seen in approximately 70% of the sporadic colon cancers.

Question 32

Altered cellular metabolism

Answer 32

• Warburg metabolism is a form of pro-growth metabolism favoring glycolysis over oxidative phosphorylation. It is induced in normal cells by exposure to growth factors and becomes fixed in cancer cells due to the action of certain driver mutations.
• Many oncoproteins (RAS, MYC, mutated growth factor receptors) induce or contribute to Warburg metabolism, and many tumor suppressors (PTEN, NFI, p53) oppose it.
• Stress may induce cells to consume their components in a process called autophagy. Cancer cells may accumulate mutations to avoid autophagy, or may corrupt the process to provide nutrients for continued growth and survival.
• Some oncoproteins such as mutated IDH act by causing the formation of high levels of oncometabolites that alter the epigenome, thereby leading to changes in gene expression that are oncogenic.

Question 33

Evasion of apoptosis

Answer 33

• Evasion of cell death by cancers mainly involves acquired abnormalities that interfere with the intrinsic (mitochondrial) pathway of apoptosis.
• The most common abnormalities involve loss of p53 function, either by way of TP53 mutations or overexpression of the p53 inhibitor MDM2.
• Other cancers evade cell death by overexpressing anti-apoptotic members of the BCL2 family, such as BCL2, BCL-XL, and MCLI, which protect cells from the action of BAX and BAK, the pro-apoptotic members of the BCL2 family.
• In a large majority of follicular B-cell lymphomas, BCL2 levels are high because of a (14;18) translocation that fuses the BCL2 gene with regulatory elements of the immunoglobulin heavy chain gene.
• Inhibitors of MDM2 (which activate p53) and inhibitors of BCL2 family members induce the death of cancer cells by stimulating the intrinsic pathway of apoptosis and are being developed as therapeutic agents.

Question 34

Limitless replicative potential (immortality)

Answer 34

• In normal cells, which lack expression of telomerase, the shortened telomeres generated by cell division eventually activate cell cycle checkpoints, leading to senescence and placing a limit on the number of divisions a cell may undergo.
• In cells that have disabled checkpoints, DNA repair pathways are inappropriately activated by shortened telomeres, leading to massive chromosomal instability and mitotic crisis.
• Tumor cells reactivate telomerase, thus staving off mitotic catastrophe and achieving immortality.

Question 35

Sustained angiogenesis

Answer 35

• Vascularization of tumors is essential for their growth and is controlled by the balance between angiogenic and anti-angiogenic factors that are produced by tumor and stromal cells.
• Hypoxia triggers angiogenesis through the actions of HIF-Ia on the transcription of the proangiogenic factor VEGF.
• Many other factors regulate angiogenesis; for example, p53 induces synthesis of the angiogenesis inhibitor thrombospondin-1, while RAS, MYC, and MAPK signaling all upregulate VEGF expression and stimulate angiogenesis.
• VEGF inhibitors are used to treat a number of advanced cancers and prolong the clinical course, but are not curative.

Question 36

Invasion and metastasis

Answer 36

• Ability to invade tissues, a hallmark of malignancy, occurs in four steps: loosening of cell-cell contacts, degradation of ECM, attachment to novel ECM components, and migration of tumor cells.
• Cell-cell contacts are lost by the inactivation of E-cadherin through a variety of pathways.
• Basement membrane and interstitial matrix degradation is mediated by proteolytic enzymes secreted by tumor cells and stromal cells, such as MMPs and cathepsins.
• Proteolytic enzymes also release growth factors sequestered in the ECM and generate chemotactic and angiogenic fragments from cleavage of ECM glycoproteins.
• The metastatic site of many tumors can be predicted by the location of the primary tumor. Many tumors arrest in the first capillary bed they encounter (lung and liver, most commonly).
• Some tumors show organ tropism, probably due to activation of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastatic site.