Immunology Exam 5 Flashcards
Most allergens are _______
Proteins
Most therapeutic antibodies used to treat cancer and other diseases are isolated from the blood of rabbits and domesticated animals such as horses and goats.
True/False
False
Hypersensitivity disorders may arise from recognition of self-antigens or environmental antigens.
True/False
True
The progression of HIV infection to AIDS is most directly due to which of the following?
A. A loss of CD4+ T cells to numbers insufficient to prevent infections
B. Reduction in CD8+ CTLs specific for HIV
C. Reduction in serum IgG levels to levels insufficient to prevent infections
A. A loss of CD4+ T cells to numbers insufficient to prevent infections
Many genes are associated with an individual’s chance of developing an autoimmune disease. Among the most important are ______ genes
human leukocyte antigen (HLA)
All of the following are effector mechanisms of antibody-mediated disease EXCEPT:
A. Complement- and Fc receptor–mediated inflammation and tissue injury
B. Antibody stimulation of cell surface receptors in the absence of the physiologic ligands
C. Death ligand-dependent apoptosis of cells
D. Opsonization and phagocytosis of cells
C. Death ligand-dependent apoptosis of cells
All of the following may result in an acquired immunodeficiency EXCEPT:
A. An inherited defect in B cell maturation
B. Malnutrition
C. Treatment with corticosteroids
A. An inherited defect in B cell maturation
Which of the following is a correct description of checkpoint blockade drugs used in tumor immunotherapy?
A. Soluble Ig-fusion proteins that contain the extracellular domains of T cell inhibitory molecules
B. Inhibitory monoclonal antibodies specific for T cell molecules that normally inhibit T cell activation
C. Inhibitory monoclonal antibodies specific for T cell molecules that normally enhance T cell activation
D. Small molecule inhibitors of JAK kinases involved in cytokine activation of T cells
B. Inhibitory monoclonal antibodies specific for T cell molecules that normally inhibit T cell activation
Histamine is a critical product of the late-phase reaction.
True/False
False
In comparison to individuals with a normal immune system, immunocompromised individuals are less likely to develop cancer.
True/False
False
Which of the following best describes the genetic basis of autoimmunity?
A. polymorphic only
B. polygenic and polymorphic
C. neither polygenic nor polymorphic
D. polygenic only
B. polygenic and polymorphic
Herceptin acts to inhibit HER2-positive breast cancer by ________
promoting antibody-dependent cellular cytotoxicity via NK cells
All of the following represent possible neoantigens (tumor-specific antigens) EXCEPT:
A. proteins coded for by tumor-causing viruses
B. amino acid substitutions in oncoproteins
C. low abundance proteins that are overexpressed
C. low abundance proteins that are overexpressed
Some cancer cells and some viruses evade the immune system by expressing IL-10 or IL-10-like proteins.
True/False
True
Which type of hypersensitivity reaction involves IgG and IgM antibodies targeting cell-surface or extracellular matrix (ECM) proteins?
Type 2
Active immunotherapies ______
are currently the primary focus of anti-cancer research and therapy
Which of the following statement describes leukocyte adhesion deficiency (LAD)?
A. LAD is a consequence of HIV infection.
B. LAD blocks the interaction of B cells and T cells.
C. LAD causes Type IV hypersensitivity.
D. LAD inhibits the crawling ability of certain innate immune cells
D. LAD inhibits the crawling ability of certain innate immune cells
All the following describe mRNA vaccines in regards to cancer EXCEPT:
A. The mRNA component of the vaccine codes for neoantigens.
B. Many clinical trials of mRNA vaccines are currently in progress.
C. These vaccines only can be used for prophylactic purposes.
C. These vaccines only can be used for prophylactic purposes.
People with allergies will generate immediate and late-phase reactions upon their first exposure to an allergen.
True/False
False
“Bystander activation” describes events associated with the ability of _____________
infection to induced activation of self-reactive T cells
Allergies represent an immune reaction to a foreign but non-pathogenic antigen
True/False
True
Mast cells, basophils, and eosinophils are components of the ______ immune system
Innate
Intestinal hypermotility has evolved to:
clear worms from gut
Autoimmune disease represent a type of hypersensitivity disorder.
True/False
True
A drug used to reduce the chance of transplant rejection might also be useful for the treatment of certain hypersensitivity disorders.
True/False
True
Onset of autoimmune disease is often associated with or proceeded by infection.
True/False
True
Following delivery to the patient, which of these active immunotherapies is the most direct means to kill cancer cells?
A. checkpoint blockade
B. phophylactic vaccination
C. cellular vaccination with DCs
D. adoptive T cell transfer
D. adoptive T cell transfer
In contributing to autoimmune disorders, polymorphisms in HLA genes are typically located in and around the antigen cleft while polymorphisms in non-HLA genes are typically located in genes are typically located in gene regulatory regions that control protein expression.
True/False
True
Passive immunotherapy utilizes mAbs that recognize proteins expressed by normal cells.
True/False
False
Which approach is more likely to induce cancer cells able to resist treatment?
Passive immunotherapy
Shortly before infusion of T cells, patients may be treated with chemotherapy drugs to ________.
reduce the T cell population to make “room” for the new T cells
Which of the following is NOT a mechanism for cancer cells to evade the immune system?
A. increased expression of soluble stress ligands
B. decreased expression of cell-surface stress ligands
C. reduced expression of MHC Class 1 proteins
D. increased expression of neoantigens
D. increased expression of neoantigens
The ability to recruit and activate Treg cells would help cancer cells evade the immune system
True/False
True
Which of the following statements about mAbs is FALSE?
A. A given mAb is able to recognize several different epitopes
B. For therapeutic use, mAbs are typically generated in mice
C. mAbs are proteins
D. Polyclonal Abs are simple a mixture of various mAbs against the same antigen
A. A given mAb is able to recognize several different epitopes
The ability to evade the immune system generally occurs _____ in the development of cancer
Late
Tumor cells present cancer antigens via _____ proteins
MHC Class 1
How does the immune system detect cancer cells as foreign?
- Cancer cells express novel peptide sequences (neoantigens or tumor-specific antigens (TSAs))
- Cancer cell may also overexpress normally rare
proteins or proteins that otherwise failed to elicit
complete tolerance (Tumor-Associated Antigens)
Characteristics of cancer cell-specific antigens
- Increase as cancer develops and cancer cell genome becomes increasingly instable
- Consist of both passenger mutations (most) and driver mutations
- Presented by Class I MHC molecules on tumor cells
- May be ingested by DCs and presented by Class II MHC or cross-presented by Class I MHC
Steps in CTL response against tumors
- Dendritic cell grabs phagocytosed tumor antigen and migrates to lymph node
- Activation of tumor antigen-specific CD8+ T cell through cross-presentation
- Migration of tumor-specific CTL to tumor
- CTL killing of tumor cell
Other than CTLs, what are other responses against tumors?
- Anti-tumor antibodies have been found in blood of cancer patients but impact unclear
- Tumor antigen-specific CD4+ T cells (Th1 cells) support CTLs and macrophages via cytokines
- Activated macrophages can kill tumor cells via NO (nitric oxide)
- Activated NK cells can kill tumor cells that express stress ligands
What sources of chronic inflammation promote tumors?
Hepatitis B and C
H. pylori
Asbestos
Obesity
Strategies cancer uses to evade the immune system
- hide identity
- hide stress
- inactivate immunocytes
- avoid apoptosis
- induce immunocyte apoptosis
- neutralize intracellular toxins
- neutralize complement
- recruit Treg cells which inhibit Th and Tc cells
- up-regulate CD47 signal (don’t eat me)
Hide identity: mechanism and agent being evaded
- Repress tumor antigen (TATA/TSTA)
- Repress MHC class 1 proteins (not transcribed/not delivered to PM) (breast cancer does this)
- CTLs
Hide stress: mechanism and agent being evaded
- repress NKG2D ligands (MICA)
- NK cells (they have receptors that recognize cells expressing stress ligands)
Inactivate immunocytes: mechanism and agent being evaded
- Secrete stress ligands into environment to “distract” immunocytes
=> soluble ligand binds to receptor on immunocyte:
1. inhibits binding to stress ligand on cancer cell, or
2. induces endocytosis and degradation of receptor - NK cells, CTLs, and variety of immunocytes
Avoid apoptosis: mechanism
- inhibit capase cascade by increasing IAPs
- acquire resistance to FasL-mediated apoptosis
*Hallmark of cancer
Induce immunocyte apoptosis: mechanism and agent being evaded
- release soluble FasL
- release cytokines (IL-10/TGF-beta) (Epstein-Barr virus codes for modified IL-10)
- CTLs, dendritic cells, macrophages
Neutralize intracellular toxins: mechanism and agent being evaded
- enzymatic detoxification of H2O2
- macrophages, NK cells
Neutralize complement: mechanism and agent being evaded
- over-express mCRPs (membrane-bound complement regulatory proteins)
- complement system
Passive vs Active immunotherapy
Passive => use mAbs against neoantigens as drugs
Active => stimulate patient’s immune system to attack cancer
Example of passive immunotherapy
Herceptin/Trastuzumab = monoclonal antibody against HER2 (epidermal growth factor receptor)
Mechanisms of Herceptin action:
1. Promotes antibody-dependent cellular cytotoxicity via NK cells
2. Suppresses cell survival pathways by inducing HER2 endocytosis and degradation
Nomenclature of therapeutic monoclonal antibodies
Prefix + Substem A + Substem B + mab
Which mAbs are used to activate the immune system?
- Yervoy/Ipilimumab
- Opdivo/Nivolumab
- Keytruda/Pembrolizumab
- Tecentriq/Atezolizumab
- Imfinzi/Durvalumab
- all are anti-CTLA-4/PD-1 which promotes costimulation/inhibit immune checkpoints
Types of active immunotherapies for cancer
- checkpoint blockade
- cancer vaccines
- adoptive T cell transfer
What prophylactic cancer vaccines are in use for humans?
HPV (human-papillomavirus) and HBV (hepatitis B virus)
~ focuses on viral-induced cancers
How do cellular cancer vaccines utilize TSA-loaded DCs?
- Isolate DCs from patient
- Expand Dcs in culture
- Activate DCs by exposure to TSAs from cancer
- Return activated DCs to patient
- DCs induce generation of CTLs that recognize TSAs
How does adoptive T-cell transfer work?
- Isolate T cells from patient
- Expand in culture
- Incubate with tumor cells or TSA-loaded APCs
- Infuse activated, cancer-specific T cells
How does chimeric antigen receptor (CAR) T cell therapy work?
- Identify neoantigen on patient’s cancer cells
- Raise antibody against this antigen
- Use rDNA to create CAR
- Introduce CAR gene into T cells
- Infuse CAR-T cells into patient
~works best with blood cancers
Why is CAR T cell therapy considered a “double-edged sword”?
The therapy eliminates the need for APCs and MHC/antigen displaying and signaling, but it can induce a cytokine storm.
What are autoimmune disorders associated with?
- loss of self tolerance
- abnormal display of self antigens
- inflammation/innate imune response
Mechanisms of loss of self tolerance
- Failure to delete or inactivate self-reactive lymphocytes, and/or
- Activation of APCs so self-antigens are presented in immunogenic manner
Mechanisms of abnormal display of self antigens
- Increased expression or persistence of self antigens, or
- Structural changes in self antigens due to stress/injury (neoantigens)
How does self tolerance fail?
- genetic susceptibility
- epigenetic changes
How are self reactive lymphocytes activated?
- environmental triggers recruit & activate self-reactive lymphocytes that may alter self-antigen display
- microbiome changes
Role of infection in autoimmunity
- Bystander activation: microbes activate APCs to express co-stimulators, which can activate self-reactive T cells
- Molecular mimicry: peptide similarity between microbial antigen and self antigen activates T/B cells that recognize self antigen.
What are hypersensitivity disorders a results of?
Result from tissue damage due to unchecked or inappropriate immune responses
What are the specific antigens the initiated hypersensitivity disorders?
- Self antigens => lead to autoimmune diseases
- Microbial antigens from persistent infections => antibody- or T cell-dependent damage
- Non-microbial environmental antigens => allergic disorders
What is the classification of hypersensitivity disorders?
Based on type of immune response and main damage-inducing effector mechanism
- Type 1: immediate
- Type 2: antibody-mediated
- Type 3: immune complex-mediated
- Type 4: T cell-mediated
What is immediate (type 1) hypersensitivity?
- allergies
- caused by antibodies specific for environmental antigens
What is antibody-mediated (type 2) hypersensitivity?
- Due to IgM and IgG specific for cell surface or ECM antigens (organ-specific)
- Effector mechanisms
1. Opsonization and phagocytosis kills host cells
2. Complement- and Fc receptor-mediated inflammation and injury
3. Inhibition of cell / tissue functions without injury (e.g., NT receptor)
What is immune complex-mediated (type 3) hypersensitivity?
- Due to IgM and IgG specific for soluble antigens in blood (systemic)
- Antigen may be either self or foreign antigen
=> Occurs in individuals who receive therapeutic antibodies produced in animals - Complexes activate complement and recruit leukocytes via Fc receptors
- Leads to inflammation, thrombosis, and injury
What are the therapeutic interventions fro hypersensitivity diseases?
- Broadly acting anti-inflammatory agents ( corticosteroids, NSAIDs)
- Anti-cytokine therapies
- Depletion of certain immune cells and antibodies
- Specific biologic agents
- Tolerance-inducing therapies
What is T cell-mediated (type 4) hypersensitivity?
Cytokine-mediated inflammation via CD4+ helper T cells
=> cytokines recruit neutrophils and macrophages
* CTLs kill cells and damage tissue
What do broadly acting anti-inflammatory agents do?
inhibit cytokine secretion
What do anti-cytokine therapies do?
bind to and inhibit specific cytokines or cytokine receptor pathways
What does depletion of certain immune cells and antibodies do? (hypersensitivity)
- monoclonal Abs that deplete lymphoid cells, only B cells, or only T cells
- plasmapheresis can remove autoantibodies and immune complexes
What do specific biologic agents do? (hypersensitivity)
- CTLA-4-Ig blockade of the B7 co-stimulator pathway
- Anti-integrin Abs Inhibit leukocyte migration
What do tolerance-inducing therapies do?
- Deliver known antigen while inhibiting lymphocytes specific for the antigen
- Activate or infuse Tregs
Sequence of events in immediate hypersensitivity
- first exposure to allergens
- activation of Tfh cells and stimulation of IgE class switching in B cells
- production of IgE
- binding of IgE to FcR on mast cells (now sensitized)
- Repeat exposure to allergen
- activation of mast cell: release of mediators
7a. vasoactive amines, lipid mediators –> immediate hypersensitivity reaction
7b. cytokines –> late-phase reactions (2-4 hours after)
Steps in mast cell activation
- IgE-coated resting mast (high-affinity receptor)
- Antigen-cross-linked IgE-FcRI triggers signal cascade to activate mast cell
3a. Degranulation releases hydrolases, proteases, vasoactive amines (histamines), and lipid mediators.
4a. vascular and smooth muscle response: immediate reaction
3b. cytokines are synthesized
4b. inflammation: late phase reaction
What are the mediators of immediate hypersensitivity reaction?
Vasoactive amines (histamines)
- relaxation of vascular smooth muscle
- leakage between epithelial cells
Protease
- local tissue damage
Lipid mediators
- bronchoconstriction
- leukocytes (inflammation)
What are the mediators of late phase hypersensitivity reaction?
Cytokines
- inflammation
Eosinophils
- recruitment and activation
Primary vs secondary immunodeficiency
Primary
- congenital/genetic defect
- become apparent in infancy or early childhood
Secondary (more common)
- acquired/not inherited
- May result from malnutrition, some cancers, immunosuppressive drugs or infection of immune cells
What is leukocyte adhesion deficiency (LAD)?
- Innate immune immunodeficiency
- mutations in leukocyte or endothelial adhesion molecules (integrins/ligands)
- causes failure of leukocytes to move to the site of infection
What are severe combined immunodeficiencies (SCIDs)?
- Impaired T cell development
- May involve defects in B cell development
**if not humoral defects still occur bc of helper T cell failure - cause severe infections by various pathogens
Progression (phases) of untreated HIV infection
- Acute phase
- Transition phase
- Chronic (clinical latency) phase
- AIDS
Describe the acute phase of an HIV infection
- infection of activated CD4+ T cells in mucosal epithelia
- death of most local infected CD4+ T cells within two weeks
Describe the transition phase of an HIV infection
- Dissemination of virus via – - DCs to lymph nodes
- Transfer of virus to node CD4+ T cells
- Viral replication => “viremia”
- Spread of CD4+ cell infection throughout body
- Adaptive immunity response to virus => partial control
Describe the chronic phase of an HIV infection
- Infection and cell death limited to lymphoid tissues
- Immune system still able to control other infections
- CD4+ T cell numbers decline over years
Describe the AIDS phase of an HIV infection
- CD4+ T cell numbers drop below functional level
- Opportunistic infections
- Cancer
- Cachexia
- Organ failure
Main treatment for
Two different reverse transcriptase inhibitors + a protease inhibitor
