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Fall 2024 > Immunology Exam 4 > Flashcards

Immunology Exam 4 Flashcards

1
Q

Immune surveillance

A

Control and elimination of malignant cells
At times tumor immunity is incapable of preventing tumor growth or is overwhelmed by how fast tumors grow

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2
Q

How are tumor antigens expressed?

A

They are displayed by class I MHC to CTL’s which then kill tumor cells

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3
Q

Proof immune responses against tumors inhibit tumor growth

A

Lymphocytic infiltrates around some tumors and enlargement of draining lymph nodes correlate with better prognosis

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4
Q

Proof tumor rejection shows features of adaptive immunity and is mediated by lymphocytes?

A

Transplants of tumors between syngeneic animals are rejected, and more rapidly if the animals have been previously exposed to that tumor; immunity to tumor transplants can be transferred by lymphocytes from a tumor bearing animal

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5
Q

Proof the immune system protects against the growth of tumors

A

Immunodeficient individuals have an increase incidence of some types of tumors

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6
Q

Proof tumors evade immune surveillance in part by inhibiting T cells

A

Therapeutic blockade of T cell inhibitory receptors such as PD-1 and CTLA-4 leads to tumor remission

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7
Q

Types of tumor antigens that elicit immune responses

A

Neoantigens encoded by randomly mutated genes, Products of oncogenes or mutated tumor suppressor genes, Aberrantly expressed or overexpressed structurally normal proteins, and viral antigens

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8
Q

Neoantigens

A

Encoded by randomly mutated genes unrelated to tumorigenesis (passenger mutations)
Causes genetic instability of malignant cells
Neoantigens are the mutated proteins expressed from the passenger mutations
Not present in normal cells
Will not induce tolerance since they are not expressed in normal cells

Mutated protein antigens can be recognized by T cells if peptides take the mutated amino acid sequence and display it by an MHC molecule

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9
Q

Passenger mutations

A

Mutations that play no role in tumorigenesis
Expression of mutated proteins (neoantigens)

Number of these mutations determines the strength of the antitumor responses patients mount and the effectiveness of immunotherapies that enhance the responses

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10
Q

Products of oncogenes or mutated tumor suppressor genes

A

Caused by driver mutations
All of these mutations in the amino acids of these mutated proteins are all seen as foreign

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11
Q

Driver mutations

A

Mutations in genes that are involved in the process of malignant transformation

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12
Q

Aberrantly expressed or overexpressed structurally normal proteins

A

Protein expression that is dysregulated by tumor cells
Their expression could be enough to make them immunogenic
Self proteins expressed only in embryonic tissues may not induce tolerance but of the same proteins are expressed in tumors they may be recognized as foreign by the immune system

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13
Q

Viral antigens

A

Tumors caused by oncogenic viruses
The tumor antigens may be encoded by the viruses
Ex. Epstein-Barr virus (EBV), and human papillomavirus (HPV)

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14
Q

What is the role of CTLs in tumor rejected in animal models?

A

Tumors can be destroyed by transferring tumor-reactive CD8+ cells into tumor bearing animals
Abundant CTL infiltration predicts a more favorable clinical course compared with tumors with sparse CTLs

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15
Q

How can tumors of different cell types stimulate CTL responses?

A

Apoptosis tumor cells or proteins released from necrotic tumor cells or proteins released from necrotic tumor cells are ingested by hosts dendritic cell to undergo cross-presentation
DCs can also present ingested tumor peptides via class II MHC
Therefore CD4 and CD8 cells can recognize tumor antigens
Not known how APCs get costimulators to activate T cells

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16
Q

How are T cells activated with costimulators for tumor cells?

A

When tumor cells grow, they take up room and nutrients/blood from normal tissue
These healthy cells could be injured and therefore die
This would release DAMPs to activate the innate immune system
Therefore costimulators would be produced

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17
Q

Ways body kills tumor cells
(Think simple)

A

Antitumor CD4 cells, especially Th1 cells
Th1 cells activate macrophages.
Macrophages and NK cells are capable of killing tumor cells
Antitumor antibodies are also present in cancer patients

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18
Q

Ways tumors evade immune system

A
  1. Stop expressing class I MHC so peptides cannot be shown to CD8 cells
    Ex. Mutations in beta2-micro globulin which is part of MHC complex
  2. Can inhibit T cell activation by over-expressing proteins such as PD-1 or induce their expression.
    Can cause repeated stimulation of T cells to cause immune system to express PD-1. CD8 cells then experience exhaustion and do not attack antigen anymore.
  3. Can induce Tregs to inhibit DCs from doing their job
    Can also induce myeloid derived suppressor cells
    Will inhibit activation of Th1 and CD8
  4. Can secrete immunosuppressive cytokines like TGF-beta
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19
Q

Current strategies for cancer immunotherapy

A

Use of specific antitumor antibodies,
Introduction of autologous T cells that recognize tumor antigens,
Enhancing existing host antitumor T cell immune responses by administering antibodies that block inhibitory molecules,
Vaccination with tumor antigens

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20
Q

Passive immunotherapy with monoclonal antibodies

A

Antibodies bind to antigens on the surface of the tumors and activate host effector mechanisms such as phagocytes, NK cells, and the complement system

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21
Q

Types of adoptive T cell therapy

A

Adoptive therapy with autologous tumor specific T cells, and Chimeric antigen receptor (CAR) expressing T cells

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22
Q

Adoptive therapy with autologous tumor specific T cells

A

T cells are isolated from patient
Expanded by culture with growth factors and injected into patient
They migrate to tumor and kill it
Also inject the cells with T cell stimulating cytokines like IL-2
With traditional chemo the results are inconsistent because perhaps the frequency of tumor specific T cells are too low. Might need to isolate TCRs and introducing the TCRs to autologous T cells before transfer

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23
Q

Chimeric antigen receptor (CAR) expressing T cells

A

Blood T cells from patient are transduced with viral vectors that encode a chimeric antigen receptor (CAR)
CAR on T cells recognizes a surface antigen on tumor cells and intracellular signaling domains from the TCR
Is able to recognize antigen and send signals to T cells to activate them.
Remarkable efficiency in treating and curing B cell derived leukemias and lymphomas. Does not work as well with solid tumors without injuring normal tissues and getting to the tumor sites is hard

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24
Q

Pros of CAR expressing T cells for tumor treatment

A

Avoids the limitations of MHC restriction of TCRs. Therefore can use same CAR for different patients regardless of HLA alleles

Tumors cannot evade CAR by down-regulating MHC I
Receptors provide antigen recognition from the extra cellular Ig domain and activating signals via the induced cytoplasmic domains

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25
Q

Cons of CAR expressing T cells

A

Cytokine release syndrome
Mediated by massive amounts of inflammatory cytokines
Can cause terrible inflammation but that can be treated by anti inflammatory drugs and anticytokine antibodies

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26
Q

What happens if CAR-T cells recognize a protein on tumor and healthy cells?

A

Will deplete normal B cells which will need antibody replacement therapy

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27
Q

Blocking inhibitory receptors on T cells for treating cancer

A

Removing checkpoints of the immune system
Using anti-CTLA-4 or anti-PD-1 to bind CTL-A and PD-1 which are usually unregulated in tumors
Reduces exhaustion of T cells and promotes differentiation of memory cells
Have increased chances of survival for patients with severe forms of cancer

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28
Q

Why might a tumor not respond to checkpoint blockade therapies?

A

The tumors may induce T cell expression of checkpoint molecules other than the ones being treated therapeutically

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29
Q

What is a sign a tumor will respond well to checkpoint blockade therapy?

A

If it has a high number of mutations
Means high number of neoantigens that T cells can respond to
If a patient has a deficiency in a repair enzyme and gets tons of mutations from it then they will respond more efficiently to this treatment

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30
Q

Who can you use anti-PD-1 therapy on for cancer?

A

Approved for recurrent or metastatic tumor with mismatch repair deficiencies, regardless of cell origin or histologic type of tumor

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31
Q

Is it beneficial to use combined use of different checkpoint inhibitors for checkpoint blockade for cancer?

A

Yes, it has higher rates of therapeutic success than just using one
CTLA-4 and PD-1 are treated together since they inhibit T cell activation in different ways

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32
Q

CTLA-4 inhibiting T cell activation

A

CTLA-4 on T cell binds B7 on dendritic cell so DCs are not able to bind CD28 which inhibits the T cell from activation

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33
Q

How does PD-1 inhibit T cell activation?

A

PD-1 on T cell binds PD-L1 on tumor cell which inhibits T cell activation

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34
Q

Tumor vaccines

A

Way to stimulate an immune response to tumors inside the patient
There has been little success
There are ones against neoantigens which uses the DNA of the patients tumor but it needs to be customized to the patient which would be expensive
Also the clones may overgrow and lose their MHCs and neoantigens

Can do vaccine with adjuvants and take the patients dendritic cells out and try to mimic cross presentation in the body
This is promising

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35
Q

Ways to avoid tumors caused by oncogenes viruses:

A

Get vaccinated against the virus
Ex: human papilloma virus, and hepatitis B

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36
Q

Genes that contribute to rejection of grafts

A

MHC genes

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37
Q

Syngeneic

A

Grafts that are identical to one another

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38
Q

Allogeneic

A

Grafts of same species that are different from one another

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39
Q

Xenogeneic

A

Grafts of different species

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40
Q

Allogeneic grafts

A

Allografts

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41
Q

Xenogeneic grafts

A

Xenografts

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42
Q

Antigens that serve as the targets of rejection

A

Alloantigens and xenoantigens

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43
Q

Antibodies and T cells that react with alloantigens and xenoantigens

A

Alloreactive/xenoreactive

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44
Q

What are transplants usually in a clinical setting? Xenografts or allografts?

A

Allografts

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45
Q

Proof for this:
Graft rejection shows memory and specificity
Adaptive immunity

A

Prior exposure to donor MHC leads to accelerated graft rejection

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46
Q

How do we know graft rejection is mediated by T lymphocytes?

A

The ability to reject a graft rapidly and be transferred to a naive individual by lymphocytes from a sensitized person

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47
Q

How do we know graft rejection requires T cells?

A

Depletion or inactivation of T cells using medicine or antibodies causes reduced graft rejection

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48
Q

Principal targets of rejection are antigens encoded?

A

Antigens of allografts are encoded in the MHC

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49
Q

The reaction to allogeneic MHC antigens on another persons cells is of the the strongest immune responses known?

A

Yes!
Memory and T cells are specific for foreign peptides will cross react with any allogeneic MHC molecule

Process of negative selection in the thymus eliminates cells that strongly recognize self MHC but not foreign MHC since they are not in the thymus during development of T cells
Therefore a single allogeneic graft with thousands of MHCs will cause the frequency of all reactive T cells to be 1000 fold greater than the frequency of T cells that recognize a microbial antigen

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50
Q

Do non-MHC proteins induce graft rejection?

A

Yes!
They are called minor histocompatibility antigens and are normal cellular proteins that differ in sequence between donor and recipient
They are peptides present on donors MHC molecules which trigger a T cell response
Reactions are not as strong as T cells against a foreign MHC

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51
Q

Direct allorecognition

A

DCs of graft transport to secondary lymphoid organs and display allogeneic MHC molecules by taking in MHC graft complex
Display them to CD8 cells of host which causes CD8 cells to recognize and kill graft cells

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52
Q

Indirect allorecognition

A

DCs of graft transport to secondary lymphoid organs and display allogeneic MHC molecules by taking in MHC graft complex
Display them to CD4 cells of host

CD4 cells can then:

Recognize donor MHC bound to recipient macrophage in graft which causes inflammation

Can also be activated by B cells ingesting a donor MHC and cause antibody mediated injury to graft cells

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53
Q

Where do costimulators come from during graft rejection

A

Possibly from donor cells undergoing necrosis as the organ is being transplanted
This would activate the innate immune system which would secrete cytokines

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54
Q

Mixed lymphocyte reaction (MLR)

A

In vitro T cell recognition of antigens
T cells of recipient are cultured with donor T cells to see if there would be a reaction if a transplant was to occur between them

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55
Q

Types of graft rejections

A

Hyperacute, chronic, and acute

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56
Q

Hyperacute rejection

A

Occurs within minutes of transplantation
Thrombosis of graft vessels and necrosis of graft
Mediated by antibodies that are specific for antigens on graft or IgM specific for blood group antigens (happens from past exposure to allogeneic cells from blood transfusions, pregnancy and prior organ transplants)
Antibodies bind antigens on graft which activates complement and clotting systems leads to injury of endothelium and thrombosis

57
Q

Acute rejection

A

Mediated by T cells and antibodies (specific for alloantigens on the graft)
Happens days or weeks after transplantation
CTLs may directly kill cells to CD4 cells will secrete cytokines and cause inflammation
Result in vascular damage
Antibodies contribute and cause complement classical pathway

58
Q

How is acute rejection currently prevented?

A

Immunosuppressive therapy in blocking the activation of alloreactive T cells

59
Q

Chronic rejection

A

Develops over months or years
Graft arteriosclerosis
T cells reactive to graft alloantigens make cytokines that induce inflammation and proliferation of smooth muscle cells leading to luminal occlusion

60
Q

What is the primary cause of graft failure?

A

Chronic rejection

61
Q

Transplantation testing

A

Class I and II: type donor and recipient lymphocytes
* Lymphotoxicity test
* Lymphocytes isolated and added to micro-wells containing different abs to MHC
antigens
* Incubate, add complement (complement activated when ag-ab complexes are present)
* Add trypan blue, stains “dead” cells blue

Class I and II: simulate an in vivo reaction
* Mixed lymphocyte reaction
* Donor and recipient lymphocytes mixed and incubated together for 5 days with titrated
radio-labeled thymidine
* Centrifuge and decant supernatant, read in scintillation counter
* High radioactivity=incompatibility; low radioactivity=compatibility

62
Q

Process for donor transplantation

A
  • ABO and lymphotoxicity tests performed on recipient
  • Test family members first (if applicable)
  • If no match, recipient’s tissue and blood type registered with the
    National Organ Registry
  • ABO and lymphotoxicity tests performed on donated cadaver organs,
    and also registered with National Organ Registry
  • If organ and recipient are matched, cadaver organs transplanted into
    compatible recipient within 24 hours
  • Mixed lymphocyte reaction test initiated, but transplant occurs before
    results
63
Q

Different types of immunosupression

A

Immunosuppression
* Steroids- decrease activity of neutrophils,
MPs, lymphocytes
* Cytotoxic drugs-interfere with DNA replication
* T cell inhibition- blocks signal transduction in antigen bound T cells, cytokines not produced
* Monoclonal antibodies- abs blocking IL-2
receptor, T cells can’t undergo clonal
expansion

64
Q

Factors of blood transfusion

A
  • ABO/ Rh compatibility
  • Naturally occurring anti-A and
    anti-B antibodies
  • Antibodies IgM-will bind target ags
    (if present), resulting in
    transfusion reaction
65
Q

Types of hypersensitivity reactions

A

Type I, II, III, IV
Classified based on the immunologic mechanism responsible for tissue injury and disease

66
Q

Type I hypersensitivity Rxn

A

Immediate hypersensitivity
Allergy (atopy) therefore IgE and mast cell activation
Rapid vascular leakage, excessive mucosal secretions, contraction of bronchial and intestinal smooth muscle and inflammation
Ex. Hay fever, food allergies, asthma, anaphylaxis

67
Q

Sequence of events in Type I hypersensitivity Reaction

A
  1. Th2 and Tfh cells are activated
  2. These T cells activate B cells and promote class switching to IgE
  3. IgE is made and is bound by its Fc receptors on mast cells
  4. Repeated exposure involves cross-linking of IgE bound to mast cells which causes mast cell activation
  5. This activation cause increase in vascular permeability and smooth muscle contraction. Cytokines are also produced to recruit neutrophils and eosinophils
68
Q

Type II hypersensitivity Reaction

A

Antibody mediated diseases
Involves antibodies (IgG), complement and neutrophils

69
Q

Steps of Type II hypersensitivity

A
  1. Antibodies specific for cell an tissue antigens deposit in tissue
  2. This causes local inflammation, phagocytosis and destruction of the antibody-coated cells
    Is often auto-antibodies
70
Q

How to treat type II hypersensitivity

A
  1. Steroids can be used to reduce inflammation since steroids decrease activity of neutrophils, MPs and lymphocytes
  2. Plasmapheresis- Removal of antibodies from circulation
  3. Splenectomy- Treatment specific for hemolytic anemia
71
Q

Type III Hypersensitivity Reaction

A

Immune complex mediated
Can be short term (acute) or long term (chronic)
IgG cause disease by forming immune complexes that deposit in blood vessels
These immune complexes are not effectively removed by neutrophils and deposit in the kidneys and joints
Complement activated by immune complexes which results in widespread inflammation
Ex: Systemic Lupus Erythematosus

72
Q

Systemic Lupus Erythemtosus

A

Antibodies to DNA, nucleoproteins
Causes nephritis (kidney inflammation), vasculitis, and arthritis
Images: Malar (butterfly) rash on face is a characteristic of SLE
Panniculitis (inflammation of subcutaneous fat-shown on legs)

73
Q

Type IV Hypersensitivity Reaction Causes

A

Diseases caused by T lymphocytes (also called delayed hypersensitivity)
- Autoimmunity and exaggerated/persistent immune responses to microbial or environmental antigens
- Autoimmune responses are localized
- Response to environmental antigens- contact sensitivity to
chemicals
– Examples: therapeutic drugs, poison ivy, nickel
– Chemicals bind and modify self-proteins, immune response ensues
- Mechanism- inflammatory, T-cell mediated cytotoxicity
- Concept behind PPD test for tuberculosis

74
Q

Treatment of type IV hypersensitivity

A

Steroids to reduce inflammation
Targeted therapies with monoclonal antibodies
Inhibit T cell activation

75
Q

Immunohematology

A

The study of the immunology of blood cells, particularly red blood cells
Is essential for proper diagnosis and blood incompatibilities during pregnancy, and to ensure safe blood transfusions

76
Q

Blood groups

A

ABO blood groups - ABH antigens
Antigens are found on RBCs and tissue cells
ABH antigens are glycolipids, consisting of lipids anchored to the cell membrane, and a terminal polysaccharide providing antigenic specificity

77
Q

Inheritance patterns of blood groups

A

2 sets of genes involved: H genes and ABO tri-allelic system

78
Q

H Genes

A

Mendelian inheritance
A precursor glycolipid on the cells contains terminal galactose
HH, Hh codes for L-fructosyltransferase which transfer fucose to terminal galactose on the glycolipid
This becomes the H antigen
hh - no enzyme produced, no H antigen. The precursor glycolipid is retained, and the phenotype is known as Bombay

79
Q

ABO tri-allelic system

A

AB codominant, O recessive
A and B code for glycosyl transferases
AA or AO codes for N-acetyl galactosamine transferase which adds N-acetyl galactosamine to galactose
BB or BO codes for galactose transferase, adding galactose to galactose
H becomes A or B.
If OO, then no transferase is made and H is retained. Phenotype is called O, even though the antigen is H

80
Q

AA, AO

A

Group A with A and H antigen

81
Q

BB, BO

A

Group B with B and H antigen

82
Q

AB

A

Group AB with less H antigen
Is the universal acceptor

83
Q

OO

A

Group O with H antigen
Is the universal donor

84
Q

Rh system

A

Blood group
DCE antigens, found on RBCs
Coded for by 3 pairs of allelic genes
Dd, Cc, Ee

85
Q

DD or Dd

A

Codes for D antigen
D antigen is known as Rh

86
Q

dd

A

Does not code for anything
There is no d antigen
With O is O- and is the universal donor

87
Q

CC or Cc

A

Codes for C antigen

88
Q

cc

A

Codes for c antigen

89
Q

EE or Ed

A

Codes for E antigen

90
Q

ee

A

codes for e antigen

91
Q

D

A

It is a mosaic antigen
4 separate peptides

92
Q

Weak D

A

Du
Mutation arises where person has 1,2, or 3 peptides
Another variation exists called D null

93
Q

What type of blood for people with incomplete D antigens get?

A

D-negative blood products

94
Q

Which antigens are tested for cross-matching

A

ABH and D because of the strength
Are the only antigens routinely tested for cross-matching

95
Q

Testing for RBC Groups

A

ABO, D simple agglutination (Forward/front typing)
Testing for A, B, and D antigens
No test for H antigen. If no A or B present, group is assumed to be O

96
Q

Forward/Front Typing steps

A

Use alloantigens IgM
Have three separate tubes: one with anti-A antibodies, one with B and another with D
Centrifuge them then watch for agglutination = positive
Agglutination in all tubes is AB+
No agglutination in all tubes is O-

97
Q

Why is alloantigen IgM used in Forward Typing

A

To span the zeta potential of the RBCs (25 nm)
IgM spans 35 nm and IgG spans 15 nm
Therefore IgM can bind RBCs and agglutinate them in spite of zeta potential

98
Q

Zeta potential

A

A charge associated for RBCs to repel one another due to high sialic acid level which carries a negative charge
A cloud of + charged cations surrounds to RBCs, causing separation of the RBCs by about 25nm

99
Q

ABO Antibodies

A

Bacteria have similar structure to B and A antigens
Therefore body has natural antibodies made by B1 cells without immunizations
Group A has B antibodies
Group B has A antibodies
Group AB have no A or B antibodies
Group O have A and B antibodies

100
Q

Testing for ABO antibodies

A

Back typing or reverse typing tests for IgM A and or B antibodies
Is double check on forward typing
Is performed on serum or plasma
Tube 1 has unknown serum/plasma with A reagent, tube 2 has unknown serum/plasma with B reagent
Tubes are centrifuged and are analyzed for agglutination
Person with A antigen in forward type should have B antibodies in back type
Person with B antigen in forward type should have A antibodies in back type

101
Q

Other antibodies other than naturally occurring Anti-A and Anti-B

A

IgG antibodies such as anti-D, anti-Kell, anti-Kidd, anti-Duffy
An immune response during or after a transfusion or during pregnancy
Are IgG antibodies and therefore cannot be tested the same as IgM’s

102
Q

Antibody IgG Screen Test

A

Tube 1 Unknown serum with known RBCs that have phenotypes corresponding to RBC antigens other than A or B. Reagent cells must be type O
They are centrifuged and cannot be tested for agglutination
Wash tube to get out unbound antibodies
Add enhancement and incubate at 37 degrees Celsius for 15-45 minutes
Centrifuge and look for agglutination. If it is present it is positive for abnormal RBC antibodies
If there is no agglutination, anti-human globulin is added which is anti-IgG. Agglutination will occur if IgG is present

103
Q

Hemolytic disease of the newborn

A

When mom is negative for a particular RBC antigen and fetus is positive for said antigen (Greatest concern are D, E, c, C, Kell
If there is a fall or impact during an accident mom and baby’s blood could mix. During delivery the blood also could mix.
Takes 1 mL of fetal RBCs to immunize the mom

104
Q

Positive antibody test means for mom

A

A positive antibody screen is a cause for immediate concern, as
this indicates that the mother has either received a blood transfusion in the past, reacted to incompatible fetal antigens in the past, or is mounting an immune reaction against the current developing baby’s antigens.

105
Q

What can mom’s IgG’s do to baby?

A

a) IgG produced against the fetal antigen travels across the placenta into the fetal circulation, binds the corresponding RBC antigens,
complement is activated, and the fetal RBCs are lysed.
b) Fetus can develop very serious anemia and suffer significant
inflammation due to the activity of C3a, C4a, and C5a.
c) Bilirubin production increases, but is transferred through the placenta to mom’s circulation, and is metabolized by her liver and excreted.
d) Intrauterine testing performed (amniocentesis or cordocentesis) to
determine if an intrauterine transfusion or blood exchange is needed, or if baby should be delivered early to receive extra-uterine treatment.
e) Bilirubin levels need to be closely monitored after birth, as the excess
bilirubin due to hemolysis cannot be processed by the newborn’s liver.
Dangerously high bilirubin levels can lead to kernicterus, a deposition
of bilirubin crystal in the newborn’s brain which can cause damage
resulting in the potential impairment of growth and development.
Babies that are determined to have a high bilirubin level are treated
with phototherapy to degrade the excess bilirubin

106
Q

Mom’s antibody screen test is negative

A

the mother is D-, she should receive a Rhogam, or RhIg (anti-D, IgG) injection around 28 weeks gestation, and again within 72 hours post-delivery, if the baby is D+. The Anti-D IgG in the Rhogam will bind any fetal RBCs that may be in
the mother’s circulation, and thus they will be lysed or removed by the
spleen before the mother’s immune system is able to recognize the
foreign antigens and mount an immune response. If baby types as D-, A second post-delivery dose of Rhogam is not necessary.

107
Q

ABO incompatibilities

A

ABO incompatibilities between the mother and fetus do exist, but do not
pose as significant of a risk for HDN, as ABO antibodies are primarily IgM
and do not cross the placenta

108
Q

Cross-matching blood

A

In order to ensure a safe transfusion, you must first forward type the patient’s RBCs (the “recipient”), and back-type the serum or plasma.
Next, an antibody screen is performed to rule out the presence of any
abnormal RBC antibodies. If the antibody screen is negative, testing proceeds with the crossmatch.
2) A crossmatch requires an in vitro mixing of recipient and donor blood, to serve as a simulation of what will occur in vivo upon transfusing the blood product. Group compatible blood is used for crossmatching. (A+ for an A+ patient, unless blood products are in short supply).
a) Tube 1- Mix patient/recipient’s serum or plasma with donor RBCs
b) Tube 2- Mix patient’s RBCs with patient serum or plasma (this is called
an “auto-control”)
c) Centrifuge tubes.
d) If agglutination is present in tube 1, it is likely that the donor has a blood type that is incompatible with the recipient (ABO discrepancy), which is usually attributed to human error. Occasionally, agglutination
can occur at this point due to the presence of a cold agglutinin (a phenomenon that can occur due to several causes that we won’t be discussing further in this class).
e) If agglutination is not present in tube 1, add enhancement media (LISS or albumin), incubate at 37 degrees Celsius for 15 to 45 minutes, re-centrifuge and observe for agglutination. If agglutination present, the
donor and recipient are incompatible due to an IgG antibody or some other unknown mechanism, and the donor unit is not suitable for this recipient.
f) If there is no agglutination after the incubation phase, add AHG, mix, and re-centrifuge. If agglutination occurs after this step, there is an incompatibility likely due to an abnormal IgG RBC antibody (and the antibody screen would likely also be positive in this case). This donor unit is unsuitable for this patient.
g) If there is agglutination in tube 2 after the immediate spin or any of the subsequent steps, this patient’s cells are coated with autoantibodies. Transfusion would be postponed until further testing and investigation as to the source of the autoantibodies takes place

109
Q

Immunodeficiency diseases

A

Disorders caused by defective immunity

110
Q

Primary or congenital immunodeficies

A

Result from mutations in single genes or two genes in which leads to impaired maturation or function of different components of the immune system
Exhibit an autosomal recessive inheritance
Can be inherited from parents or can be de novo

111
Q

Acquired or secondary immunodeficiencies

A

Defects in immunity as a result of infections, nutritional abnormalities, medical treatments that cause a loss or inadequate function of various components of the immune system

112
Q

Main causes if immunodeficiency

A

Abnormalities in two components of the immune system: phagocytes and the complement system
Examples: Chronic granulomatous disease, Leukocyte adhesion deficiency, Chédiak-Higashi syndrome, mutations in TLRs, deficiencies in complement proteins

113
Q

Chronic granulomatous disease

A

Defective production of ROS by phagocytes
Recurrent bacterial and fungal infections
Caused by mutations in genes encoding phagocyte oxidase complex (phlox-91) is mutated in X linked form
This enzyme catalyzes the production of microbicidal reactive oxygen species in lysosomes
Neutrophils and MPs are unable to kill microbes they phagocytose
Organisms that produce catalase that breaks down the microbicidal hydrogen peroxide that is produced by host cells from left over ROS. To counter this the immune system calls in more MPs and activates T cells which activates and recruits phagocytes. Collections of MPs accumulate around infections to try and contain them which causes collections of them. Look like granulomas

114
Q

Most common form of CGD

A

is X linked and are mutations in subunit of phagocyte oxidase that is encoded by PHOX91 gene of X chromosome

115
Q

Leukocyte adhesion deficiency

A

Type 1: Defective leukocyte adhesion to endothelial cells and migration into tissues linked to decreased or absent expression of beta2 integrins. Have recurrent infections of bacteria and fungi. Mutations in the gene encoding the beta chain (CD-18) of beta2 integrins
Type 2: defective leukocyte rolling on endothelium and migration to tissues because of decreased or absent expression of leukocyte ligands for endothelial P and T selectins. Recurrent bacterial and fungal infections. Mutations in gene encoding GDP-fucose trasporter-1 which is required for transport of fucose into the golgi

Essential integrin chain is a golgi transporter required for the expression of the ligand for selectins. Or mutations in signaling molecules activated by chemokine receptors that are required for activating integrins

116
Q

Deficiencies in complement proteins

A

C3 deficiency results in severe and fatal infections
C2 and C4 deficiency results in increased bacterial and viral infections (increased incidence of systemic lupus erythematosus
Deficiencies of complement regulatory proteins results in excessive complement activation

117
Q

Chediak-Higashi Syndrome

A

Mutations in gene encoding LYST which is a protein involved in fusion of vesicles (including lysosomes)
Defective vehicle fusion and lysosomal function in neutrophils, MPs, DCs, CTL, NK cells since these cells normally use proteins in specialized secretory lysosomes to kill other infected host cells
Recurrent infections with bacteria

118
Q

TLR signaling defects

A

Caused by mutations in genes encoding TLR3 (recurrent herpesvirus encephalitis and severe influenza) and MyD88 (severe bacterial infections, often pneumococcal) which compromises NK-kappaB activation and type I interferon production in response to microbes

119
Q

Severe combined immunodeficiency SCID

A

Defects in both T and B cells of the adaptive immune system
Defect in humoral immunity is a sign that helper T cells are not working properly

120
Q

X linked SCID

A

Caused by mutations in the common gamma chain signaling subunit of the receptors for several cytokines (IL-2,4,7,9,15,21)
When this chain is not functional, immature lymphocytes (esp pro-T cells) cannot proliferate in response to IL-7 which therefore results in reduced survival for these T cells. B development happens normally but will be affected by the lack of helper T cells.
NK cells are also affected since gamma c chain is part of the receptor for IL-15 which helps with proliferation and maturation of NK cells.

121
Q

Autosomal recessive SCID

A

Half of them are caused by mutations in adenosine deaminase (ADA) which is an enzyme that breaks down ADA. Therefore toxic purine metabolites are accumulated in cells actively synthesizing DNA (proliferating cells)
T lymphocytes are greatly affected by this since they undergo tremendous proliferation during their maturation. Get a block in T cell maturation more than B cell maturation

122
Q

Other causes of autosomal recessive SCID

A

Mutations in RAG1 or RAG2 gene
These encode the recombinase needed for Ig and TCR gene recombination and lymphocyte maturation
B and T cells fail to develop without the presence of the RAGs

Also mutations in the ARTEMIS gene which encodes an endonuclease involved with VDJ recombination results in failure of T and B cell development

123
Q

Example of a selective B cell deficiency

A

X-linked agammaglobulinemia

124
Q

X-linked agammaglobulinemia

A

Pre-B cells in bone marrow do not survive
Mutations in Bruton tyrosine kinase (BTK) which results in defective production of this enzyme
This enzyme is activated by the pre-B cell receptor and it delivers signals that promote survival, proliferation and maturation of the cells
It is located on the X chromosome therefore women are mostly carriers and men are affected with this disease
They develop arthritis as well with this disease
Get accumulation of auto reactive B cells since B cell receptor signaling is not working which is responsible for B cell tolerance. Defective BTK is not good!

125
Q

HIV retrovirus

A

Infects CD4 cells
Two RNA strands within a protein core, surrounded by a lipid envelope derived from infected host cells but containing viral proteins
The viral RNA encodes structural proteins, various enzymes, and proteins that regulate transcription of viral genes and the viral life cycle

126
Q

Life cycle of HIV

A

Infection of cell, production of a DNA copy of viral RNA and integration into the host genome, expression of viral genes, and production of viral particles

127
Q

How does HIV infect cells?

A

With major envelop glycoprotein gp120 which binds to CD4 and to chemokine receptors on human cells (CXCR4 and CCR5). Major cells with these receptors are obviously CD4 cells
MPs and dendritic cells can be infected during phagocytosis
After binding to cellular receptors the viral membrane fuses with the host cell membrane. The virus is unloaded and the RNA is released and has a DNA copy of it created by the cell via reverse transcriptase enzyme
The double stranded DNA is then integrated into the cells DNA by a viral integrate enzyme. This integrated virus is called a provirus

128
Q

What happens when infected cell with HIV is activated?

A

Is activated by other infectious microbes or cytokines
The cell begins expressing its own genes and releasing cytokines, however these cytokines may causes the expression of the integrated viral genes. These viral RNAs are then made into a protein which costs the viral RNA and goes to the cell membrane and gets a lipid envelope from the host and leaves the cell as a viral particle
The provirus may hide in immune cells for years until they are activated which means they are undetected for therapies

129
Q

What does viral production of HIV cause?

A

Death of infected and uninfected cells, immune deficiencies, and clinical AIDS

130
Q

How to does a patient get AIDS

A

You can get HIV from sexual intercourse, sharing of contaminated needles, trans placental transfer, or transfusions of infected blood

131
Q

Acute viremia

A

When the virus is detected in the blood after someone is first infected

132
Q

What does HIV primarily infect?

A

CD4 cells at sites of entry through mucosal epithelia

133
Q

Why do T cells die after being infected with HIV?

A

Active viral gene expression and protein production interferes with the synthetic machinery of the infected T cells
The T cells lost during the progression of AIDS appears to be greater than the number of infected cells

134
Q

Acute HIV syndrome

A

Early after infection patients have a fever and malaise
It ends after a few days and leads into the clinical latency period

135
Q

Latency

A

Few clinical problems but loss of CD4 cells in lymphoid tissues and destruction of the architecture of these tissues
CD4 blood count begins to decline and when the count goes below 200 cells/mm^3 (normal is ~1,500 cells/mm^3 the patient is susceptible to infections and is diagnosed with having AIDS

136
Q

Clinical AIDS

A

Increased susceptibility to infections and some cancers
Patients not given antiretroviral drugs are infected with microbes such as viruses and funguses
EBV that is normally kept in check by T cells is reactivated causing severe disease
CD8 cells are affected since they rely on being activated by CD4 cells
CTLs are not effective in killing cells since the virus prevents type I MHC expression

137
Q

How are people resistant to HIV?

A

Certain HLAs can present peptides that the viruses cannot afford to mutate without changing their survival to CD8 cells
People homozygous for 32bp depletion of the CCR5 chemokine receptor lacks a functional CCR5 receptor and is immune to HIV

138
Q

Treatments for HIV

A

Drugs that block reverse transcriptase
Inhibitors of viral entry and fusion (highly active or combination antiretroviral therapy (ART))
Highly effective antiretroviral drugs do not completely eradicate HIV infection since the virus is constantly mutating its genes which can make it resistant to the drugs used

139
Q

Vaccines for HIV

A

Have been shown to be disappointing and development of effective vaccines will be necessary for control of HIV infection worldwide

Fall 2024 (13 decks)

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