Immunology Final Exam (Part 3) - Immunodeficiency, Cancer, & Immunotherapy

What are the two basic types of immunodeficiency?

1) Primary/Congenital (inherited deficiency)

2) Acquired/Secondary (infection, immunosuppression (organ transplant, chemo, prolonged steroid use), malnutrition, disease, age)

What are the three components of adaptive immune system? Innate?

Adaptive = Cellular (T cells), Humoral (B cells), Combined B & T cells

Innate = Phagocytic; Complement

What are the 3 types of phagocytic cell?

Macrophages

Neutrophils

AP Dendritic cells

T/F: Congenital/Primary deficiencies are always severe, and can involve innate or adaptive

FALSE

can be mild or severe

(still can be either innate or adaptive)

How do congenital/primary deficiency arise?

Genetic defects

- single gene mutation leading to weakened immune function

What condition is a gene mutation that affects the formation and function of the thymus and would result in no T cell maturation?

DiGeorge syndrome

In Congenital/Primary deficiency, what would antibody disorders make someone susceptible to? (2) Does this make someone more susceptible to autoimmune diseases?

Sinupulmonary

Gastrointestinal

-- YES: autoimmune disease (autoantibodies; inflammatory bowel disease)

In Congenital/Primary deficiency, what would Cell-mediated immunity (T cell) disorder make someone susceptible to? (3) Does this make someone more susceptible to autoimmune diseases?

Pneumonia

GI

Mycoses of skin

NO

In Congenital/Primary deficiency, what would Complement disorder make someone susceptible to? (2) Does this make someone more susceptible to autoimmune diseases?

Sepsis, blood-borne infections

YES -- Autoimmune diseases

In Congenital/Primary deficiency, what would Phagocytosis disorder make someone susceptible to? (2) Does this make someone more susceptible to autoimmune diseases?

Skin abscesses

Reticuloendothelial infections

In Congenital/Primary deficiency, does Regulatory T cells make someone more susceptible to autoimmune diseases?

Autoimmune disease

What is a defect in a protein that is needed to make BCRs and TCRs caused by defective cytokine signaling, VDJ segment rearrangement resulting in no functioning B cells or T cells, and can now be treated with bone marrow transplants and in some cases gene therapy?

Severe Immunodeficiency Syndrome (SCIDS)

-- David Vetter

What is a MHC class I deficiency that is a primary immunodeficiency in which both innate and adaptive immune systems are compromised because of the effects of absent MHC class I on CD8+ T-cell and natural killer (NK) cell development and function, with the most frequent cause is loss of TAP1 or TAP2 proteins

Bare Lymphocyte Syndrome Type I

What congenital/primary condition is a nonfunctional CD40 (B cell) or CD40L (Th cell) which results in B cells unable to class switch and would secrete IgM, with T cells that don't activate APCs and B cells (T-dependent antigen response lacking, T-independent antigen response active)?

Hyper IgM Syndrome (X-linked)

What is an inherited immune disorder caused by an inability to produce B cells or antibodies, with a mutated gene for protein Bruton tyrosine kinase (BTK), with bacterial infections that can be treated with antibiotics and passive antibodies?

X-linked Agammaglobulinemia (XLA)

- Bruton type agammaglobulinemia, X-linked infantile agammaglobulinemia, congenital agammaglobulinemia

What is a defect in integrin adhesion molecules, with WBC recruitment inhibited, and bacterial and fungal infections common?

Leukocyte adhesion deficiency (LAD)

What molecules involved in stopping of WBCs? Rolling?

ICAM/Integrin = stop

Selectin/SLIG = rolling

What deficiency can happen in the Classical Complement pathway (and lectin pathway) that is the most common deficiency with recurrent infections, Upper respiratory tract, frequent ear infections, and colds, and is slightly higher in SLE patients?

C2 deficiency

What deficiency can happen in the Lectin Complement Pathway that is not a primary immunodeficiency, but is common (5-30%) of individuals, and increased susceptibility to bacterial infection?

Mannose Binding Lectin Deficiency

What three deficiencies can happen in the Alternate Complement Pathway?

1) Factor D

2) Factor B

3) Properdin deficiency: X-linked (susceptibility to Neisseria meningitis; family history of males dying form Neisseria infections)

What Acquired/Secondary immunodeficiency has its major cause from a virus, targets CD4+ Th cells, and mortality typically is due to opportunistic infections (Pneumocystis carinii; Kaposi sarcoma)?

HIV/AIDS

(virus = HIV-1; human immunodeficiency virus 1)

How is it that viral entry into cells occur with HIV/AIDS?

Gains access via rectal or vaginal mucosa & infects Th cells in the area (CD4 receptor)

-- virus hijacks cellular machinery to reproduce

-- CTLs stimulated trying to destroy the infected cell

Why is HIV-1 able to (in many cases) defeat the immune system?

Nature of virus

- slow replicating lentivirus (RNA retrovirus) that uses enzyme reverse transcriptase to make DNA (from its RNA) and insert into host DNA where it can stay in a latent state undetected for years (occurs 5-10 days from exposure to virus)

- high mutation rate allows virus to evade the immune system

What are the three phases of HIV infection?

1) Acute phase (Low CD4T, High HIV viral load)

2) Asymptomatic phase (Low HIV viral load, CD4T initially increase, as progress will slowly decrease)

3) AIDS (CD4T <200 & drops, HIV viral load spikes

What are the 3 criteria for AIDS?

1) Evidence of infection w/ HIV-1

2) <200 CD4+ T cells/microL of blood

3) Occurrence of opportunistic infections

What 5 things does Therapeutic agents block?

1) Receptors

2) Fusion

3) Reverse transcriptase

4) Integrase

5) Protease

What is the most effective HIV/AIDS treatment including Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), Protease inhibitors (PIs), & integrase inhibitors (using all three together)

Highly Active Anti-Retroviral Treatment (HAART)

What is the number 2 cause of death behind heart disease?

Cancer

What are 5 contributing causes to cancer?

1) Lifestyle (smoking & drinking)

2) Environmental pollutants

3) Genetics (aging & mutations)

4) Impaired immune surveillance

5) Viruses

Immunosuppression is associated with most tumors, with increased incidence of lymphoma and virus associated cancer.

HHV8 (Herpes Virus) in AIDS is associated with __________

HPV is associated with __________

Hepatitis B is associated with __________

Epstein-Barr is associated with ________

HTLV (human T-lymphotropic virus) is associated with __________

Karposi sarcoma

Cervical cancer

Liver cancer

Burkitt's lymphoma

Leukemia

Viral infections contribute to ______% of all human cancers?

12-20

What are the top 3 cancers by rate?

1) Female breast

2) Prostate

3) Lung/Bronchus

What are the top 3 cancers by death?

1) Lung/Bronchus

2) Female Breast

3) Prostate

What is a non blood cell (solid tumor) that is most common, and of epithelial origins?

Carcinomas

What is a non blood cell (solid tumor) that is the least common in bone, fat, and cartilage?

Sarcomas

What is a blood cell cancer that arises form early lymphoid or myeloid cells?

Leukemias

What is a blood cell cancer that spreads to lymphatic system with swollen lymph nodes?

Lymphomas

What is a blood cell cancer that arises form B cells?

Myelomas

What classification of cancer is the most common, resulting from exposure over time, and often has an environmental link such as chemicals, radition (UV & ionizing), diet, or normal metabolism?

Spontaneous

T/F: Cancer is most commonly an inherited disease

FALSE

-- generally not inherited

-- usually changes in DNA of cell during lifetime of the affected individual-genetic or epigenetic

T/F: Cancer can result from a single mutation, causing cells to proliferate, producing malignant tumors that invade healthy tissue-invasion.

FALSE

-- Results from an accumulation of multiple events; not single

What is it called when cancer spreads to other areas of the body and establishes secondary tumors?

Metastisis

T/F: Cancer is extremely rare at the cellular level

TRUE

-- actually a multiple loss of balance between division, differentiation, and cell death; NOT single cell

What are 5 properties of cancer cells?

1) No response to inhibitory influences

2) Loss of cell signaling/cell cycle

3) Anchorage independent growth

4) Grow in absence of stimulatory growth signals

5) Seem immortal

What encodes proteins that have various functions int he cell's normal activities?

Proto-oncogene

What is a mutated version of proto-oncogene, encoding proteins that promote the loss of growth control and the conversion of a cell to the malignant state-act dominantly (Ras)?

Oncogene

What encodes proteins that restrain cell growth and act recessively (p53) by providing internal safeguards such as preventing mutations, fixing damaged DNA, and can induce apoptosis if genetic damage severe?

Tumor suppressor genes

A mutation of what protein is commonly found in most tumors? What type of gene is this from?

p53

(Tumor suppressor protein coded by tumor suppressor gene)

What is the immune system actively monitoring, identifying, and elimination cancerous cells, eliminating pathogens (virus causing cancer) and reducing pro-tumor inflammation, but is very difficult to study in body?

Immunosurveillance

T/F: Acute inflammation is pro-tumor/pro-cancer

FALSE

-- acute is good, helping healing and promotes good things

-- CHRONIC inflammation is pro-tumor/cancer

What are the 3 immunosurveillance cells? (TQ) What immune systems are they a part of?

1) CTL (Tk) -- ADAPTIVE immune system

2) NK cells -- INNATE immune system

3) Macrophages -- INNATE immune system

T/F: CTL releases cytokines

FALSE

-- helper T does

-- CTL kills by perforin or FAS ligand

In spontaneous tumors, tumor cells will produce proteins that activate _____ & _______ which results in ________ being not as effective due to traffic pattern and lack of activation, causing conflict between self tolerance and surveillance?

CTLA-4 & PD-1

CTLs

What cell slows proliferation and induces apoptosis of our own CTL?

PD-1 (Programmed death 1 receptor)

What cell binds B7 w/ 1000x affinity than CD28, out competing CD28 and resulting in NO T cell activation?

CTLA-4

In cancerous blood cells, CTLs are ______ effective in fighting cancer, with traffic patterns intersecting (blood, lymph, lymph nodes), and some blood cell cancers produce high levels of _________?

MORE

High levels of B7 (co-stimulation)

In virus associated tumors, CTLs effectiveness is LIMITED to _____________?

Hiding viruses

T/F: Viruses which cause acute infection (typically) do not cause cancer

TRUE

CTL SUMMARY w/ effectiveness against cancer

1) Spontaneous = CTL LESS effective (lack of activation)

-- conflict of self tolerance and surveillance

2) Blood cells = CTL MORE effective (cancer produces B7)

3) Virus associated = CTL LESS effective (limited since virus hides)

Highly active __________ can provide protection against cancer, since they can secrete ______ which can kill certain types of cancers (attacks blood vessels feeding the tumors, leading to cell death/necrosis)?

Macrophages

TNF

What is a cancer therapy, that is also the tuberculosis vaccine, that is a potent innate immune stimulator as direct injection causes inflammation and macrophages to "attack" the tumor?

Bacille Calmette Guerin (BCG)

T/F: Both macrophages and NK cells need cytokines to become activated (acute inflammation) while chronic inflammation suppresses macrophages and NK cells, reducing their ability to fight cancers

TRUE

T/F: Macrophages are in the blood/lymph, so they must be "called in" to the tissue, making them slow to activate at first.

FALSE

-- macrophages EVERYWHERE (in the tissues), and is quick acting!!

What cells attack cells that express low levels MHC and abnormal proteins, that is quick acting and recognized diverse target structures, located in blood and must be "called in"?

NK cell

T/F: NK cells need to be activated by Th cells to kill

FALSE

-- NK cells do NOT need to be activated to kill

How are antibodies involved in the fight against cancer w/in the body?

IgM naturally produced against tumors

- recognize new antigens and modified "normal antigens"

- complement activation possible

How is antibodies being used in the latest cancer treatment?

Monoclonal antibodies can mark cancer cells so immune system better recognizes/destroys

- some bring T cells closet o cancer cells, helping them kill

What is the CAUTION acronym for picking up on cancer?

C = Change in bowel/bladder habits

A = A sore that does not heal

U = Unusual bleeding/discharge

T = Thickening or lump in your breast or elsewhere

I = Indigestion of difficulty swallowing

O = Obvious change in growth/mole

N = Nagging cough/hoarseness

Vaccines and Cancer SUMMARY

Hep B --> High rate of Liver Cancer

-- vaccine to minimize infection

HPV --> Connected to Cervical Cancer

-- contains two most common strains that cause cancer

-- Merck vaccine also contains two additional strains

Therapeutic cancer vaccines

-- designed to treat cancer directly

In the emerging field of immunotherapy, what two things is Monoclonal antibodies used for? What two things are T cells used for?

Monoclonal antibodies = autoimmune & cancer

T cells = adoptive cell transfer & CAR T cell therapy

What is the difference between a plasma B cell and a cancerous B cell?

Plasma = makes specific antibodies; dies after few days

Cancerous = NO antibodies made; lives long time ("immortal")

What is the hybrid B cell (merged from plasma & cancerous B cells) that does make antibodies, but lives long "immortal"? What are the antibodies produced by this called?

Hybridoma (Hybrid cell)

-- Monoclonal antibodies

T/F: Monoclonal antibodies are all identical and have the same antigen specificity

TRUE

T/F: Monoclonal antibodies are made in the body

FALSE

-- commercially made

(produced by combining B cell w/ cancer cell)

What are two possible functions of monoclonal antibodies?

1) Bring T cells close to cancer cells, helping kill cancer cells

2) Mark cancer cells so that the immune system will better recognize and destroy them

Inflammation associated with _________ is mainly caused by TNF (cytokine produced by macrophages) and infiltrates the joints with the help of self-reactive Th cells?

Rheumatoid Arthritis

Monoclonal antibodies are now the #1 treatment used w/ Rheumatoid Arthritis, with injections under the skin every two weeks, because it can block the action of what?

TNF

What is a drawback of monoclonal antibodies and Rheumatoid Arthritis (Enbrel & Humira)?

Immunocompromised

What are the thickened and scaly skin characteristic of psoriasis?

Skin plaques

What cytokine has a strong causation to skin plaques in psoriasis since it causes the keratinocytes to proliferate when they shouldn't?

IL-17

Monoclonal antibodies can block the interaction between ________ & _____________ in Psoriasis?

IL-17 and receptor on keratinocytes

What is the drawback of monoclonal antibodies being used for Psoriasis?

IL-17 (which is blocked) is the cytokine that helps to defend against fungal infections

What is a blood cell cancer arising when B cells have mutations that block maturation?

Non-Hodgkin Lymphoma

What protein is on the surface of immature B cells, specifically non-Hodgkin lymphoma cells, but not on the surface of mature B cells?

CD20

How does Monoclonal antibodies help with Non-Hodgkin Lymphoma?

Bind CD20 and tag for destruction, sparing blood stem cells & long-lived plasma B cells

About 25% of breast cancer patients have tumors that express large amounts of what growth factor receptor?

HER2

When ligated, HER2 can cause what to occur?

Cancer cells to proliferate and metastasize

How do monoclonal antibodies help with Breast Cancer?

Bind HER2 receptors and BLOCK growth signals

How do T cells ("natural" T cells) help to treat disease, aka how does T cell immunotherapy work?

Uses T cells that have been modified by genetic engineering to make them "better, faster, & stronger"

When surgeon removes tumors, they often find T cells, called ______________ in the tumor, which indicates that was occured?

Tumor infiltrating lymphocytes (TIL)

-- indicates T cells were trying to fight cancer, but there was not enough of them

What procedure is when immunologists take TIL cells form a tumor and growths them in a lab, testing them for tumor recognition, then increasing proliferation to produce about 100 billion tumor specific T cells, injecting them back into the patient to treat the cancer and is a promising treatment, especially for melanomas?

Adoptive Cell Transfer (ACT)

What T cell therapy is the use of genetic engineering to modify a patient's T cell so that they produce an "artificial" T cell receptor?

CAR (Chimeric Antigen Receptor) T Cell therapy

The _________ of the CAR T cell will identify the target, the _______ protein will send the TCR engaged signal, and the ________ domain will provide the co-stimulation, all in one chimeric protein.

Recognition domain

CD3

CD28

What are the two ways in which the chimeric protein in the CAR T cell is made?

1) Inserted into genome of lentivirus (modified so nonpathogen) and used to infect T cells from patient

2) Genes inserted directly into the T cell and incorporated into the genome

T/F: The CAR T cell therapy are grown in the lab to build up the numbers and infused back into the patient, and are customized to each individual patient as the chimeric receptor doesn't exist in nature.

TRUE

CAR T Cell Therapy targets one of two antigens on the B cell. What are these two antigens?

CD19 or BCMA