Exam 2 Material Flashcards
(427 cards)
1
Q
what is the major mechanism by which the immune system kills both tumor cells and the cells of tissue transplants ?
A
CD8+ cells
2
Q
immune surveillance
A
immune system usually recognizes and eliminates neoplastic/malignant cells before they start proliferating
3
Q
why are tumors often able to survive and grow in otherwise immunocompetent individuals?
A
tumor immunity is often incapable of preventing tumor growth or is easily overwhelmed by rapidly growing tumors
4
Q
what evidence exists that tumor responses against tumors inhibit tumor growth?
A
lymphocytic infiltrates around some tumors and enlargement of draining lymph nodes correlate with better prognosis
5
Q
what evidence exists that tumor recognition shows features of adaptive immunity and is mediated by lymphocytes?
A
- tumor transplants are rejected by animals (and more rapidly if previously exposed)
- immunity to tumor transplants can be transferred by lymphocyte transfer
6
Q
what evidence exists that the immune system protects against tumor growth?
A
immunodeficient people have higher incidence of some tumors
7
Q
what evidence exists that tumors evade surveillance in part by activating inhibitory receptors on T cells?
A
theraputic blockade of inhibitory receptors (CTLA-4, PD-1) can lead to tumor remission
8
Q
5 features of immune response to tumors
A
- immune system protects against tumor growth
- tumor recognition shows features of adaptive immunity
- tumor recognition is mediated by lymphocytes
- tumor responses against tumors inhibit tumor growth
- tumors evade surveillance in part by activating inhibitory receptors on T cells
9
Q
what must a tumor do to be recognized by immune system?
A
must express antigens that are seen as non-self
10
Q
5 types of tumor antigens may be recognized by the immune system
A
- mutated self protein that does not contribute to tumorigenesis
- product of oncogene
- product of mutated tumor suppressor gene
- overexpressed/aberrantly expressed self-protein
- oncogenic virus
11
Q
examples of mutated self proteins that do not contribute to tumorigenesis
A
various mutant proteins in carcinogen or radiation-induced tumors
12
Q
examples of products of oncogenes
A
mutated Ras; Bcr/Abl fusion proteins
13
Q
examples of overexpressed/aberrantly expressed self-proteins
A
tyrosinase; gp100; cancer/testis antigens
14
Q
what are some examples of oncogenic viruses?
A
HPV E6; cervical carcinoma E7 proteins; EBV-induced lymphoma EBNA proteins
15
Q
driver mutations
A
products of mutated or translocated oncogenes or tumor suppressor genes that presumably are involved in the process of malignant transformation
16
Q
when can structurally normal self-proteins elicit immune responses?
A
when they are aberrantly expressed
17
Q
characteristic of majority of tumor antigens that elicit immune responses
A
endogenously-synthesized cytosolic or nuclear proteins displayed as Class I MHC-associated peptides
18
Q
how are cytotoxic T cell responses against tumors induced?
A
recognition of tumor antigens on APCs
19
Q
from what types of cells can tumors arise?
A
virtually any nucleated cell (b/c they express MHC I)
20
Q
3 phases of immune surveillance / tumor growth
A
- Elimination (immune surveillance)
- Equilibrium (immunoediting)
- Escape
21
Q
immunoediting
A
variant tumor cells arise that are more resistant to being killed; over time, a variety of tumor variants develop
22
Q
Clinical example of equilibrium phase?
A
woman treated for malignant melanoma 16 yrs before death; both kidneys donated to recipients who developed melanoma 1-2 years later (remember, transplant recipients are immunosuppressed)
23
Q
3 immunotherapy options for tumors
A
- passive immunity through transfer of tumor-specific T cells or antibodies
- active T cell immunity enhanced by vaccination with tumor antigen-pulsed dendritic cell
- active immunity enhanced by blocking inhibitory T cell receptors (CTLA-4, PD-1)
24
Q
immunodiagnostics
A
- Identification of cell of origin of an undifferentiated tumor
- Monitoring serum levels of cancer markers during treatment
25
cancer vaccine ideas
- heat shock proteins (clinical trials)
- genetic modifications of tumor cells
- creation of dendritic cell-tumor cell hybrid (hybridoma) -- do NOT have to know tumor Ag
- recombinant IFN-alpha (renal cell carcinoma, melanoma)
- IL-2 adoptive cellular therapy (didn't work)
26
cross-presentation
dendritic cell activates naive CD8+ T cell specific for antigens of a virus-infected or tumor cell that it has ingested by presenting the antigen to the T cell AND providing costimulation; also called cross-priming
27
problems with antibody-directed therapy
- tumor heterogeneity (some cells may not express the right antigen)
- low density of tumor antigen expression
- modulation of tumor antigen levels
- antibodies must bind to every tumor cell to kill it (no bystander killing)
28
ADEPT
antibody-directed enzyme/pro-drug therapy; monoclonal antibody-enzyme conjugate -- nontoxic pro-drug given and metabolized to active drug to produce high concentrations of cytotoxic drug localized at tumor site
29
why do immune responses often fail to check tumor growth?
tumors evolve in the host to evade immune recognition or resist immune effector mechanisms
30
6 mechanisms of tumor cell resistance to immune recognition and destruction
1. tumor stops expressing recognized antigen (antigen loss variants)
2. tumor stops expressing class I MHC
3. tumor secretes cytokines that suppress immune responses (ex: TGF-β)
4. tumor expresses ligands for T cell inhibitory receptors (ex: PD-1)
5. tumor induces regulatory T cells, which suppress CD4/CD8 effector
6. tumor induces low levels of B7 costimulators on APCs → preferential engagement of inhibitory receptor (CTLA-4) on T cells rather than stimulatory receptor (CD28)
31
major hallmark of cancer
ability to avoid destruction by the immune system
32
what activates NK cells?
lack of MHC class I expression
33
CTLA-4
up-regulated during T cell activation; high affinity for B7; inhibits activated T cells
34
main strategies/goals for cancer immunotherapy
- provide anti-tumor effectors (antibodies / T cells)
- actively immunize patients against their tumors
- stimulate patients’ own anti-tumor immune responses
35
problems with chemotherapy / radiation treatment of tumors
damage normal non-tumor tissues; associated with serious toxicities
36
antibody specific for CD20 used to treat...?
B cell tumors (usually along with chemotherapy); CD20 is not expressed by hematopoietic stem cells, so normal B cells are replenished after antibody treatment is stopped
37
dendreons provenge vaccine
for advanced prostate cancer; extended life expectancy ~4mos; few side effects; super expensive; company filed for bankruptcy
38
3 ways antibody treatment could generally help destroy a tumor
1. antibodies could bind to tumor antigens and either activate host effector mechanisms, such as phagocytes or the complement system, or deliver toxins to the tumor cells
2. antibodies could block growth factor signaling (ex: Her2/Neu in breast cancer)
3. antibodies could inhibit angiogenesis
39
adoptive cellular immunotherapy
T cells isolated from blood or tumor infiltrates of a patient, expanded with growth factors, and injected back into the same patient. The T cells presumably contain tumor-specific CTLs, which find the tumor and destroy it. (Variable results so far.)
40
example of mutated tumor suppressor gene
mutated p53
41
PD-1
inhibits T cells (like CTLA-4)
42
PD-L1/2
inhibitory ligand for PD-1
43
immune system "backup" for tumor cells that evade CD8+ cells?
NK cells -- especially important when tumor cells don't express MHC I
44
tumor microenvironment
disrupts CD3 signaling complex (zeta or epsilon chain)
45
TAM
tumor-associated macrophage; tumor promotes class-switching from M1 to M2, which induces angiogenesis
46
equilibrium phase of tumor cells
tumor cells that can evade the immune system arise and develop; Treg cells recruited
47
escape phase of tumor cells
tumor cell has successfully evaded immune system and begins to spread/proliferate
48
mice without gamma-delta T cells
develop skin cancer
49
mice without RAG and STAT1
increased incidence of gut and breast tumors
50
antibodies against CD20
can be used to kill B cell tumors
51
block CTLA-4 or PD-1
prevent T cell inactivation and hopefully kill tumor cell
52
what could kill a tumor that does not express MHC Class I?
NK cells
53
genes that contribute the most to the rejection of grafts
MHC genes
54
syngeneic grafts
from an identical member of a species
55
allogeneic grafts
from a different member of a species
56
xenogeneic grafts
from a different species
57
which grafts are always rejected by a recipient with a normal immune system?
allografts and xenografts
58
antigens of allografts that serve as principal targets of rejection?
proteins encoded in MHC
59
human MHC
HLA complex
60
MHC Class I corresponds to which HLAs?
HLA-A, -B, and -C
| *remember, Class I -- CD8!
61
MHC Class II corresponds to which HLAs?
HLA-DQ, -DP and -DR
| *remember, Class II -- CD4!
62
one of the strongest immune responses known?
response to MHC antigens on another individual’s cells
63
example of immunologic cross-reaction?
T cell recognition of allogeneic MHC molecules in allografts
64
why do T cells recognize allogeneic molecules?
- Allogeneic MHC molecules containing peptides derived from allogeneic cells may look like self-MHC molecules with bound foreign peptides
- a single allogeneic graft cell will express thousands of MHC molecules, every one of which may be recognized as foreign by a graft recipient’s T cells
- there is no mechanism for selectively eliminating T cells whose TCRs have a high affinity for allogeneic MHC molecules
65
how many T cells may react against an allogeneic molecule?
0.1% to 1% of all T cells (compared to 1 in 10^5 or 10^6 T cells that recognize any microbial antigen)
66
minor histocompatibility antigens
Non-MHC antigens that induce graft rejection (though usually not as strongly); most are allelic forms of normal cellular proteins that happen to differ between donor and recipient; important in blood transfusions and hematopoietic stem cell transplantation
67
direct allorecognition
T cells in the recipient recognize unprocessed donor allogeneic MHC molecules on graft dendritic cells; stimulates CTLs that attack graft
68
indirect allorecognition
graft cells (or alloantigens) are ingested by recipient dendritic cells; donor alloantigens are processed and presented by self-MHC molecules on recipient APCs to T cells; alloreactiv CD4+ cells (rather than CTLs) attack graft
69
CTLs attack graft in what kind of recognition?
direct allorecognition
70
CD4+ cells attack graft in what kind of recognition?
indirect allorecognition
71
mixed lymphocyte reaction
in vitro model of T cell recognition of alloantigens -- T cells from one individual are cultured with leukocytes of another individual, and T cell responses are assayed; magnitude of response is proportional to the extent of MHC differences btwn these individuals and is a rough predictor of the outcomes of grafts exchanged between these individuals
72
alloantibodies
also contribute to graft rejection; most are helper T cell–dependent high-affinity antibodies
73
alloantibody production
recipient B cells recognize donor alloantigens and then process and present peptides derived from these antigens to helper T cells (that may have been previously activated by recipient DCs presenting the same donor alloantigen), thus initiating antibody production. (This is a good example of indirect presentation of alloantigens)
74
hyperacute rejection
occurs w/i minutes of transplantation; characterized by thrombosis of graft vessels and ischemic necrosis of graft; mediated by antibodies that bind to antigens on the graft vascular endothelium and activate the complement and clotting systems, leading to injury to endothelium and thrombus formation; major barrier to xenotransplantation
75
acute rejection
occurs within days or weeks after transplantation; due to active immune response of host stimulated by alloantigens in graft; mediated by T cells (CD4+ or CD8+) and antibodies; the principal cause of early graft failure
76
chronic rejection
occurs over months or years, leading to progressive loss of graft function; may be manifested as graft fibrosis and graft arteriosclerosis; culprits believed to be T cells that react against graft alloantigens and secrete cytokines that stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells; alloantibodies also contribute
77
most common complication associated with organ transplant survivability?
chronic rejection
78
current immunosuppressive therapy designed primarily to prevent what?
acute rejection (activation of alloreactive T cells)
79
therapeutic monoclonal therapy with an anti-CD25 agent is most similar to which drug therapy?
Rapamycin
80
principal cause of graft failure?
chronic rejection
81
mainstay of preventing and treating the rejection of organ transplants?
immunosuppression, primarily of T cell activation and effector functions
82
cyclosporine / tacrolimus
block T cell cytokine production by inhibiting calcineurin activation of NFAT; very effective in preventing graft/transplant rejection (compared to Azathioprine)
83
rapamycin
blocks lymphocyte (T and B cell) proliferation by inhibiting mTOR and IL-2 signaling
84
mTOR
required for T cell responses to cytokine growth factors
85
major problem with immunosuppressive drugs?
nonspecific immunosuppression -- inhibit immune responses to more than just the graft
86
MHC matching
critical for the success of transplantation of some types of tissues (allogeneic bone marrow grafts) and improves survival of other types of organ grafts (renal allografts), BUT modern immunosuppression is so effective that HLA matching is not considered necessary for many types of organ transplants (heart), especially b/c # of donors is limited and recipients often are too sick to wait for well-matched organs to become available
87
long-term goal of transplant immunologists?
induce immunological tolerance specifically for the graft alloantigens -- will allow graft acceptance without shutting off other immune responses in the host
88
Xenotransplantation
possible solution for problem of shortage of suitable donor organs
89
frequent cause of xenotransplant loss?
hyperacute rejection b/c individuals often contain "natural" antibodies that react with cells from other species and the xenograft cells lack regulatory proteins that can inhibit human complement activation
90
natural antibodies
mediate hyperacute rejection of xenografts; production does not require prior exposure to the xenoantigens
91
transfusion
Transplantation of circulating blood cells, platelets, or plasma from one individual to another
92
major barrier to transfusion
presence of foreign blood group antigens, the prototypes of which are the ABO antigens
93
ABO antigens
carbohydrates on membrane glycoproteins or glycosphingolipids; contain a core glycan that may have an additional terminal sugar
94
transfusion reaction
Immunologic reaction against transfused blood products, usually mediated by preformed antibodies in the recipient that bind to donor blood cell antigens, such as ABO blood group antigens or histocompatibility antigens. Transfusion reactions can lead to intravascular lysis of red blood cells and, in severe cases, kidney damage, fever, shock, and disseminated intravascular coagulation.
95
Rh antigen
Rhesus factor; red cell membrane protein that can be the target of maternal antibodies that may attack a developing fetus when the fetus expresses paternal Rh and the mother lacks the protein
96
Blood type A
N-acetylgalactosamine terminal sugar; makes anti-B antibodies
97
Blood type B
galactose terminal sugar; makes anti-A antibodies
98
Blood type AB
N-acetylgalactosamine AND galactose terminal sugars; no antibodies
99
Blood type O
no terminal sugars -- only core glycan; makes both anti-A and anti-B antibodies
100
Hematopoietic stem cell transplantation
bone marrow cells or, more often, hematopoietic stem cells mobilized in a donor’s blood are injected into the circulation of a recipient, and the cells home to the marrow; used increasingly to correct hematopoietic defects, to restore bone marrow cells damaged by irradiation and chemotherapy for cancer, and to treat leukemias
101
Hematopoietic stem cell transplantation problems
- Before transplantation, some of the recipient's bone marrow has to be destroyed to create space to receive the transplanted stem cells, and this inevitably causes deficiency of blood cells, including immune cells
- The immune system reacts strongly against allogeneic hematopoietic stem cells, so successful transplantation requires careful HLA matching of donor and recipient
102
graft-vs-host disease
if mature allogeneic T cells are transplanted with the stem cells, these mature T cells can attack the recipient’s tissues and cause a systemic inflammatory reaction characterized by rashes, diarrhea, liver disease, eosinophilia, and enlarged lymph nodes
103
main factor dictating graft survival?
MHC compatibility
104
Maternal Tolerance to Fetal Tissues
fetus expresses paternal alloantigens but is not rejected by mother; trophoblast and placenta play key role in tolerance but mechanisms unclear
105
Graft-vs-Leukemia Effect
mature T cells can kill leukemia cells
106
mycophenolate mofetil
blocks lymphocyte proliferation by inhibiting guanine nucleotide (DNA) synthesis in lymphocytes
107
corticosteroids
reduce inflammation; adverse effects include fluid retention, weight gain, diabetes, bone loss, skin thinning
108
antithyomcyte globulin
binds to and depletes T cells by promoting phagocytosis or complement-mediated lysis; used to treat acute rejection
109
anti-IL-2 (CD25) receptor antibody
inhibits T cell proliferation by blocking IL-2 binding; may also opsonize and help eliminate activated T cells that express IL-2R
110
CTLA-4-Ig (belatacept)
inhibits T cell activation by blocking B7 costimulator binding to CD28
111
anti-CD52 (alemtuzumab)
depletes lymphocytes by complement-mediated lysis
112
antibody-directed immunotherapy
inject monoclonal antibodies against tumor antigens or against signaling molecules (i.e. T cell inactivators); can combine with a toxin or radioactive molecule to try to directly kill tumor
113
antibody-directed enzyme/pro-drug therapy (ADEPT)
antibody conjugated with enzyme; antibody-enzyme complex binds target cell; nontoxic pro-drug given, which antibody-enzyme complex cleaves into active form at the tumor site
114
CSF1/CSF1R Blockade
Reprograms Tumor-Infiltrating Macrophages and Improves Response to T Cell Checkpoint Immunotherapy in Pancreatic Cancer Models
115
ways to improve efficacy of anti-tumor antibodies
1. Humanize antibodies-make mouse Abs more human
2. Smaller Abs
3. Make bi-functional antibodies or fusion proteins
116
-Omab
fully mouse antibody
117
-Ximab
chimeric antibody
118
-Zumab
humanized antibody
119
-Umab
fully human antibody
120
Ipilimumab
human antibody directed against CTLA-4; used for metastatic melanomas; very expensive but very effective (pts survive avg 6-9mos, sometimes longer); tumor cells remain in equilibrium phase
121
existing cancer vaccine?
HPV-16; does not eliminate established tumors but can prevent infection
122
generating specific anti-tumor T cells
Adoptive T cell immunotherapy; viral vector used to recombine T cell alpha and beta chain genes with specific vector DNA; viral particles infect other T cells and cause them to express these genes; T cells become specific for tumor and attack it
123
Chimeric Antigen Receptor (CAR)–Modified T Cells
anti-CD19/CD137 (costimulatory receptor) / CD3zeta (signal transduction) CAR–modified T cells re-infused into a patient expanded 1000 fold; chimeric T cells still detectable 6 months after infusion; regression of axillary lymphadenopathy occurred within 1 month after infusion and was sustained; B cell lymphopenia is complication but can be managed
124
3 stages of tumor development
1. elimination / immune surveillance
2. equilibrium / immunoediting
3. escape
125
Adoptive T cell immunotherapy
infuses the patient's modified TCR (CAR) lymphocytes using CD3 antibody and IL-2; efficacy due to robust clonal expansion of infused cells, resulting in destruction of tumor and development of anti-tumor memory cell
126
most promising immunotherapy to combat already established tumors?
Generation of anti-tumor T cells
127
“Second Set” Graft
introducing 2nd graft from same donor to same recipient; can show that exposure to 1st graft created immunological memory
128
graft rejection requires what type of lymphocytes?
T cells -- depletion or inactivation of T cells leads to reduced graft rejection
129
graft rejection is mediated by what cells?
lymphocytes -- the ability to reject a graft rapidly can be transferred to a naive individual through lymphocytes from a sensitized individual
130
graft rejection shows which 2 cardinal features of adaptive immunity?
memory and specificity -- prior exposure to donor MHC molecules leads to accelerated graft rejection
131
how to mitigate cytotoxic effects of steroids?
lower doses of steroids + other immunosuppressive drugs
132
Anti-metabolites
originally used to treat cancer but now used in post-transplantation therapy; includes Azathioprine, Cyclophosphamide, Mycophenolate
133
Azathioprine
purine analog that interferes with DNA synthesis; cytotoxic to T & B cells
134
Cyclophosphamide
alkylating agent; used in chemical weapons (nitrogen mustard)
135
Immunosuppressors that interfere with T cell signaling
Cyclosporin/Tacrolimus, Rapamycin
136
why does matching HLA between donor and recipient not prevent organ rejection?
multiple minor histocompatibility loci differences
137
what kinds of transplants are most likely to cause graft-vs-host disease?
Hematopoietic stem cell transplants
138
Type I Hypersensitivity
immediate; Th2, IgE, mast cells, eosinophils; allergy/atopy
139
Hypersensitivity
excessive or aberrant immune response causing injury or pathology to tissues of the body; can be:
1) dysregulated / uncontrolled response to foreign antigen causing damage
2) aberrant response against self – “autoimmunity “
140
allergy
Disorder caused by an immediate hypersensitivity reaction, often referring to the type of antigen that elicits the disease, such as food allergy, bee sting allergy, and penicillin allergy. All these conditions are the result of antigen-induced TH2 generation and IgE production, and mast cell or basophil activation.
141
Hypersensitivity reaction classification
classified on the basis of the principal immunologic mechanism that is responsible for tissue injury and disease
142
atopy
Propensity of an individual to produce IgE antibodies in response to various environmental antigens and to develop strong immediate hypersensitivity (allergic) responses. People who have allergies to environmental antigens, such as pollen or house dust, are said to be atopic.
143
development of immediate hypersensitivity reaction
- Th2 cells activated, produce IL-4 and IL-13
- B cells stimulated to produce IgE
- IgE binds to FceRI on mast cells
- multiple receptors cross-linked
- mast cell degranulation
144
sensitization
“first exposure” to an allergen
145
2 phases of immediate hypersensitivity reaction
1) immediate phase
| 2) late phase
146
immediate phase of immediate hypersensitivity reactions
develops within minutes of exposure; characterized by the release of preformed granules from the mast cell, mainly proteases and vasoactive amines (histamine), which promote vasodilation and smooth mm contraction. Over a slightly longer period of time, prostaglandins and leukotrienes also produce vasodilation and smooth mm contraction
147
histamine
released by mast cells in immediate hypersensitivity reactions; promotes vasodilation, increase in vascular permeability, and smooth mm contraction; does NOT play a role in bronchial constriction / asthma
148
late phase of immediate hypersensitivity reactions
develops 2-24 hours after exposure; activation of cytokine genes such as TNF that promote the recruitment of neutrophils and eosinophils that liberate proteases; primarily responsible for the tissue damage seen with repeat exposures
149
major mediator of a type I hypersensitivity reaction
mast cell
150
Mast cell degranulation
activated by crosslinking of the FcεRI leading to release of the preformed mediators; responsible for type I hypersensitivity
151
How an antigen or allergen affects the body and the extent of the response it stimulates depends on?
where antigen contacts immune system
152
systemic anaphylaxis
- Type I hypersensitivity
- drugs, venom, food, serum
- intravenous entry
- edema, increased vascular permeability, laryngeal edema, circulatory collapse, death
153
acute urticaria (wheal-and-flare)
- Type I hypersensitivity
- animal hair, insect bites, allergy testing
- entry through skin or systemic
- local increase in vascular permeability & blood flow, edema
154
seasonal allergies
- Type I hypersensitivity
- pollens, dust mite feces
- entry through contact with conjunctiva of eye, nasal mucosa
- edema of conjunctiva and nasal mucosa, sneezing
155
asthma
- Type I hypersensitivity
- dander, pollen, dust mite feces
- inhalation leading to contact with mucosal lining of lower airways
- bronchial constriction, increased mucus production, airway inflammation
156
food allergy
- Type I hypersensitivity
- nuts, shellfish, milk, eggs, soy, wheat, etc
- oral entry
- vomiting, diarrhea, pruritis, urticaria, anaphylaxis
157
dendritic cells secrete what to promote Th2 differentiation?
IL-4, IL-5, IL-9, IL-13
158
Th2 cells secrete what to perform effector functions?
IL-4 (germinal center rxn), IL-5 (eosinophils), IL-13 (mucus production)
159
how could you inhibit allergic rxn?
- inhibit the CD-40 receptor or ligand necessary for B cell activation
- inhibit IL-4 or IL-13 which promote class switching to IgE
- inhibit transcription factor STAT6, which promotes differentiation of Th2 cells
160
unique features of mast cells that make them ideally suited to mediate allergic rxns
- location in epithelia -- can recruit pathogen-specific lymphocytes and nonspecific effectors to sites where pathogens most often enter body
- can promote mm contraction through lipid mediators
161
mast cells secrete what?
- enzymes (tryptase, chymase)
- toxic mediators (histamine, heparin)
- cytokines (IL-4, IL-13 [Th2]; IL-3, IL-5, GM-CSF [eosinophils]; TNF-alpha [inflammation])
- chemokines (CCL3 -- monocytes, macrophages, neutrophils)
- lipid mediators (prostaglandins, leukotrienes [smooth mm contraction, vascular permeability, bronchoconstriction]; platelet-activating factor [attract leukocytes, activate neutrophils/eosinophils])
162
eosinophils
extremely cytotoxic granules great for fighting parasites, but can also cause tissue damage; multiple levels of regulation; after initial exposure to cytokines, threshold for degranulation drops, leading to development of allergic rxns
163
eosinophil regulation
- bone marrow produces very few
- require eotaxins (2nd signal) to activate & allow entry into tissues
- FcεRI not expressed constitutively, but upregulated when eosinophil activated
164
chronic airway inflammation
can be caused by chronic Th2 activation / response
165
Airway remodeling
hypertrophy of smooth muscle cells leads to thickened airway walls --> fibrosis from chronic asthma
166
clinical pathological triad of chronic bronchial asthma
1) Intermittent airway obstruction
2) Chronic bronchial inflammation w/eosinophils
3) Bronchial muscle hyper-reactivity to bronchoconstrictors (cold air, exercise, viral infections, pollutants)
167
treatment of anaphylaxis
epinephrine -- vascular smooth mm contraction, increased cardiac output, bronchodilation, inhibition of mast cell degranulation
168
treatment of chronic bronchial asthma
corticosteroids, leukotriene antagonists, phosphodiesterase inhibitors -- reduce inflammation, relax bronchial smooth mm
169
allergic disease treatment
1) desensitization -- inject w/small doses of allergen over time to induce tolerance
2) anti-IgE antibody
3) antihistamines
4) cromolyn -- inhibit mast cell degranulation
170
role of histamine in airway constriction?
none -- no antihistamines for asthma treatment!
171
KDPI
Kidney Donor Profile Index -- Clinical formula incorporating 10 donor factors affecting estimated graft survival
172
EPTS
Estimated Post-Transplant Survival
173
solid organ transplants
```
Kidney
Pancreas
Heart
Lung
Liver
Small bowel
```
174
Quasi-tolerant state
the reality of organ transplantation; pharmacologically engineered; allows successful organ transplant, graft longevity, and enhanced quality of life for patients
175
treatment for acute rejection
```
High dose steroids
Thymoglobulin
Plasma exchange/IVIG
Rituximab
Bortezomib
```
176
treatment for chronic rejection
Adjust and /or change immunosuppression
Control any risk factors
Re-transplantation
177
Lymphoproliferative Disease
- EBV related- Primary vs reactivation (B cell)
- Related to intensity of immunosuppression
- Acute illness (infectious mononucleosis)
- Single or multiple tumors (LN, GI, CNS)
- Allograft dysfunction
- Fulminant disease
178
one of the most significant technological advances in immunology and medicine?
Monoclonal antibodies
179
Monoclonal antibodies
detect only one epitope on the antigen
180
Polyclonal antibodies
recognize multiple epitopes on any one antigen; serum will contain a heterogeneous complex mixture of antibodies of different affinity
181
Hemagglutination
a specific type of agglutination (clumping) that involves red blood cells exposed to their blood type antibody
182
monoclonal antibody drugs
block targeted molecule functions (e.g. prevent TNF-α from binding to its receptor in the treatment of rheumatoid arthritis), modulate signaling pathways, or induce apoptosis of targeted cells
183
how to make monoclonal antibodies in lab?
1. Inject mouse w/antigen you want antibody to be specific for
2. Mouse creates splenic B cells that produce antibody specific to antigen; cells isolated.
3. Fuse cells to an immortal myeloma cell line that can’t grow in the selection medium. The only cell that can survive are fusions btwn antibody-producing B cell and myeloma cells
4. Screen fusion cells for specific antibody you want to target by exposing them to antigen; expand cell line that is producing antibody you want
184
what Ig isotype are ABO blood groups?
IgM
185
Acute intravascular hemolytic transfusion
incorrect transfusion -- classical pathway of complement activated when IgM binds to ABO and causes hemolysis of the recipient’s RBCs
186
two blood tests that can check for antibodies that attack red blood cells?
Direct Coombs test and Indirect Coombs test
187
Direct Coombs test
used to detect presence of IgG antibodies/complement proteins bound to the surface of RBCs
- Patient’s blood sampled and serum washed away, leaving RBCs and bound antibody/complement proteins
- Anti-IgG and Anti-complement andibodies added, which bind to Fc region of IgG or to complement, causing agglutination
- Agglutination = positive test result
188
Indirect Coombs test
used to detect presence of anti-RBC antibodies in plasma
- Patient’s blood sampled and spun down to isolate serum
- Rh+ RBCs added to serum, which bind to anti-Rh antibody in serum and form antibody-antigen complexes.
- Anti-IgG antibodies added, which bind to Fc region of anti-Rh antibody.
- Agglutination = positive test result
189
ELISA
Enzyme-linked immunoabsorbant assay; used to measure specific antigen levels or antibody levels (titer) against a specific antigen
190
Direct ELISA
used to detect specific *antigens* bound to a well -- single enzyme-linked antibody bound to the antigen of interest
191
Indirect ELISA
used to determine the amount of *antibody* in a sample -- use of a primary AND secondary antibody for detection of an antibody of interest
192
ELISA acute values
antibody levels while body is fighting the disease process
193
ELISA convalescent values
antibody levels while body is recovering from the disease process
194
difference between acute and convalescent readings to indicate a recent exposure?
at least 4-fold difference
195
Acute ELISA is at least 4x higher than the Convalescent ELISA
This individual was previously exposed to the antigen and was recently exposed; his high acute response was due to the fast response by memory cells.
196
Convalescent ELISA is at least 4x higher than the Acute ELISA
This individual was initially naïve but was recently exposed to the antigen. High convalescent is due to the gradual accumulation of antibody.
197
Acute and Convalescent ELISA readings present but no significant difference
This individual was previously exposed but not exposed the second time. He has baseline antibody in his serum that was not elevated due to lack of new exposure to antigen.
198
Western Blot
HIV testing; used to detect the presence of specific proteins/antibody in a sample; not as good as ELISA at quantitating the amount of antibody in a sample, but is more specific and used to confirm ELISA results
199
Flow cytometry
uses lasers to count and sort cells in a sample by size, shape, and complexity; can also be used to detect presence of fluorescent molecules both on the cell surface and inside the cell; helps calculate relative levels or percentage of each cell type in a given sample, which is reported with a blood test with the absolute levels of
each cell type
200
FACS
Fluorescence-activated cell sorting; specific type of flow cytometry that helps sort samples into separate containers depending on the light scattering and fluorescent characteristics of each cell.
201
Lymphocyte proliferation assay
involves stimulating proliferation of lymphoblasts with a mitogen (e.g. pokeweed) and looking at how successfully they are able to proliferate; often done using flow cytometry; can be used to evaluate both T and B cell immunodeficiencies like SCID, DiGeorge Syndrome, Ataxia Telangietasia, etc. and to evaluate the effectiveness of T cell recovery after a transplant
202
what Ig isotype are Rh antibodies?
IgG
203
what test would you use to determine if Rh+ baby from Rh- mom?
direct coombs test
204
what test would you use to determine if Rh- mom producing Rh antibody?
indirect coombs test
205
what test would you use to detect HIV antibodies in serum?
indirect ELISA
206
what test would you use to detect HIV antigen in serum?
direct ELISA
207
Type II Hypersensitivity
leads to tissue injury by autoantibodies binding self-antigens, causing recruitment of complement factors and leukocytes (neutrophils!) to opsonize/destroy/phagocytose otherwise healthy, normal cells; occurs hours to a few days after initial challenge from antigen
208
Type III Hypersensitivity
antibodies bind persistent soluble antigens to form immune complexes that are deposited mainly in blood vessels and injured tissues; usually occurs about a week after initial exposure; complement activation!
209
Type IV Hypersensitivity
mediated by T cells; called “delayed reactions” since it takes a while (24-48 hours) for effective T cell recruitment to the site of inflammation
210
ACID
```
mnemonic for the types of hypersensitivity rxns
A - Allergy
C - Cytotoxic/antibody-mediated
I - Immune complex deposition
D - Delayed
```
211
Autoimmune Hemolytic Anemia
Antibodies to own RBCs cause lysis of heme-containing erythrocytes, leading to anemia. (Type II hypersensitivity) Erythrocytes lost via:
1. Phagocytosis from macrophages
2. Lysis via complement MACs
212
Hemolytic Disease of the Newborn (Erythroblastic Fetalis)
mother is Rh-negative (does not have Rh antigen on RBCs) but baby is Rh-positive (has Rh antigen thanks to dad); When baby’s blood gets into the mother’s circulation, she begins to produce IgG antibodies against Rh-positive erythrocytes; 1st baby is fine since he’s already born by the time mom’s antibodies are produced, but if there is 2nd pregnancy w/Rh-positive child, those antibodies can cross placenta and cause hemolysis
213
RhoGAM
Pregnant Rh- mothers given prophylactic RhoGAM during and immediately following pregnancy to bind up all Rh+ erythrocytes and prevent mother’s sensitization
214
Goodpasteure’s Syndrome
type II reaction involving linear deposition of IgG on glomerular basement membrane and lung; IgG binds a subunit of collagen type IV and can quickly lead to massive kidney and lung damage; treatment options include immunosuppressive steroids and plasmapheresis
215
Graves Disease
example of non-cytotoxic type II rxn; Autoantibodies bind TSHr (thyroid stimulating hormone receptor) and mimic action of pituitary-produced TSH, constantly stimulating thyroid to produce hormones -- hyperthyroidism
216
autoantibodies
can either destroy self-antigens, or change the function of self-antigens
217
2 examples of non-cytotoxic type II rxns
Graves Disease; Myasthenia Gravis
218
Myasthenia Gravis
example of non-cytotoxic type II rxn; An autoantibody to skeletal muscle Ach receptors causes internalization and inactivation; fewer Ach receptors leads to muscle weakness and paralysis
219
immune complexes
antibody-antigen complexes
220
examples of Type III hypersensitivity reactions
- systemic lupus erythematosus
- polyarteritis nodosa
- post-streptococcal glomerulonephritis
- serum sickness
- arthus reaction
221
Precipitin Reaction
a solution containing antibody had antigen added to it until there was equivalence; centrifugation led to all antibody-bound antigens found in precipitant. If even more antigen was added until there was an excess, antigens were not completely coated by antibodies, but were rather bound by only a few antibodies and thus were in the supernatant after centrifugation because those complexes are so small. Small complexes are not cleared very well, and can force their way into glomeruli, blood vessel walls, and joint spaces, where they activate complement leading to basophil and neutrophil degranulation.
222
antigen excess
there is way too much antigen and it's usually very widespread, and the immune complexes that form are very small and tend to get deposited in all the wrong place. To clear it all out, we need a ton of antibodies, and those antibodies can overstimulate the complement and mast cell system to cause an overreaction
223
Serum Sickness
Disease caused by injection of large doses of a protein antigen into the blood and characterized by the deposition of antigen-antibody (immune) complexes in blood vessel walls, especially in the kidneys and joints (Type III hypersensitivity). Immune complex deposition leads to complement fixation and leukocyte recruitment and subsequently to glomerulonephritis and arthritis. Was originally described as a disorder that occurred in patients receiving injections of serum containing antitoxin antibodies to prevent diphtheria.
224
Arthus Reaction
Localized form of experimental immune complex–mediated vasculitis induced by injection of an antigen subcutaneously into a previously immunized animal or into an animal that has been given intravenous antibody specific for the antigen. Circulating antibodies bind to the injected antigen and form immune complexes that are deposited in the walls of small arteries at the injection site and give rise to a local cutaneous vasculitis with necrosis.
225
Subacute Bacterial Endocarditis
Really slimy bacteria can adhere to the heart valves and become really tough to get rid of. The body mounts an antibody response but still can’t really clean up the heart valves effectively. Type III reaction, complement activation...eventually these patients need a massive dose of peniciilin to get back to normal function
226
PPD test
determines whether you are sensitive to the tuberculosis-causing pathogen; Type IV hypersensitivity (T cell-mediated)
227
Allergic Contact Dermatitis
type IV hypersensitivity; small molecules called haptens from an organism like poison ivy can infiltrate the skin and bind self-proteins. This modifies the molecular structure of the protein, and new antigenic determinant is recognized by immune system as foreign when presented in MHC complexes
228
sensitization phase of Allergic Contact Dermatitis
first exposure -- occurs as a normal immune response with no pathologic consequences, with APC migration to lymph node, T cell migration to skin, and then silence since the uptake and presentation is complete
229
elicitation phase of Allergic Contact Dermatitis
subsequent exposure to antigen -- Inflammatory mediators secreted by TH1 cells and keratinocytes recruit macrophages and PMNs to the site of exposure where the typical rash erupts and remains for a few days. (The element nickel is actually able to elicit this response without formation of a protein-hapten complex, solely via binding of TLR4, so stay away from cheap jewelry dealers.)
230
Celiac Disease
immune overreaction to gluten; chronic, lifelong condition which, if untreated, can lead to irreversible intestinal villi damage; Acute episodes hallmarked by large inflammatory response, malabsorption, and diarrhea; avoidance of gluten-containing food products is enough to prevent symptoms
231
celiac disease genetic expression
95% of patients with celiac disease have the HLA-DQ2 gene and phenotype (on MHC Class II), though not everyone who expresses HLA-DQ2 has celiac
232
tissue transglutaminase (tTG)
```
modifies gluten (and several other) peptides so they can bind MHC class II receptors after absorption through the gut epithelium; celiacs produce IgA antibodies against tTG
that cause an immune response anytime gluten is ingested
```
233
most specific and sensitive way to diagnose celiac disease short of a biopsy?
Serum testing for anti-tTG antibodies
234
Uticaria
hives -- histamine release triggered by engagement of FcyRIII on mast cells
235
wheat allergy vs celiac disease
wheat allergy = type I hypersensitivity
| celiac = type IV hypersensitivity
236
Silent celiac disease
Fulfill the definition of CD but patients have no symptoms
237
Potential celiac disease
patients have specific antibodies characteristic of CD; May or may not have symptoms consistent with CD; Lack evidence of autoimmune insult to intestinal mucosa
238
Latent celiac disease
Potential patients who have had a gluten-dependent enteropathy at some point in their life specific antibodies characteristic of CD; May or may not have symptoms consistent with CD; May or may not have auto-antibodies; These patients are rare as they would have had to be previously diagnosed as having CD but despite being on gluten, have a completely normal intestinal mucosa
239
Congenital/primary immunodeficiency
caused by genetic defects that lead to blocks in the maturation or functions of different components of the immune system; usually onset in childhood
240
acquired/secondary immunodeficiency
can result from a variety of causes; onset at any age
241
immunodeficiency symptoms
infections, malignancies, autoimmune diseases, systemic symptoms
242
opportunistic infections
only contract if you are immunocompromised
243
Aspergillosis
common mold that people breathe in on a daily basis; immunocompromised people highly susceptible to health issues caused by this fungus
244
B cell deficiency
absent/reduced follicles and germinal centers in lymphoid organs; reduced serum IgG; pyogenic and enteric bacterial and viral infections
245
T cell deficiency
reduced T cell zones in lymphoid organs; reduced DTH rxns to common antigens; defective T cell proliferative responses to mitogens in vitro; viral and other intracellular microbial infections, plus virus-associated malignancies
246
innate immune deficiency
symptoms variable depending on defective component; pyogenic bacterial and viral infections
247
immunodeficiency diseases
Disorders caused by defective immunity
248
examples of acquired/secondary immunodeficiency
HIV/AIDS
249
examples of congenital/primary immunodeficiency
SCID
250
SCID
Disorders manifesting as defects in both the B cell and T cell arms of the adaptive immune system
251
X-linked SCID
deficiencies: markedly decreased T cells, normal/increased B cells, reduced serum Ig
mechanism: cytokine receptor common gamma chain gene mutations, defective T cell maturation due to lack of IL-7
252
Autosomal recessive SCID due to ADA, PNP deficiency
deficiencies: progressive decrease in T (mainly) & B cells, reduced serum Ig (ADA); normal B cells & serum Ig (PNP)
mechanism: accumulation of toxic metabolites in lymphocytes
253
Autosomal recessive SCID due to other causes
deficiencies: decreased T & B cells, reduced serum Ig
mechanism: defective maturation of T & B cells; may be mutations in RAG genes and other genes involved in VDJ recomb/IL-7R signaling
254
X-linked agammaglobulinemia
B cell immunodeficiency
deficiencies: decrease in all serum Ig isotypes; reduced B cells; often meningitis
mechanism: block in maturation beyond pro-B cells due to mutation in Bruton tyrosine kinase (BTK)
255
Bruton tyrosine kinase
mutation causes X-linked agammaglobulinemia (B cell immunodeficiency)
256
Ig heavy chain deletions
B cell immunodeficiency
deficiencies: IgG1, IgG2, or IgG4 absent, sometimes IgA or IgE absent
mechanism: chromosomal deletion at 14q32
257
DiGeorge Syndrome
T cell immunodeficiency
deficiencies: decreased T cells, normal B cells, normal/decreased serum Ig
mechanism: anomalous development of 3rd & 4th branchial pouches leading to thymic hypoplasia; 22q11.2 deletion
258
cytokine receptor common gamma chain (Υc) gene
mutations cause more than 99% of cases of X-linked SCID
259
IL-7
defects affect T cell maturation
260
adenosine deaminase (ADA)
mutations cause about half of the cases of autosomal SCID -- accumulation of toxic metabolites in proliferating cells causes greater deficiency in T cells than B cells
261
purine nucleotide phosphorylase (PNP)
causes autosomal SCID -- accumulation of toxic metabolites in proliferating cells causes greater deficiency in T cells than B cells
262
RAG1 / RAG2 genes
encode the VDJ recombinase that is required for Ig and T cell receptor gene recombination and lymphocyte maturation; mutations cause rare cases of autosomal SCID
263
most common clinical syndrome caused by a block in B cell maturation?
X-linked / Bruton's agammaglobulinemia
264
most widely used treatment for SCID?
hematopoietic stem cell transplantation
265
treatment for X-linked agammaglobulinemia?
Ig replacement therapy
266
X-linked hyper-IgM syndrome
defects in helper T cell-dependent B cell and macrophage activation caused by mutations in CD40 ligand
267
mutations in CD40 ligand
cause X-linked hyper-IgM syndrome (defects in helper T cell-dependent B cell and macrophage activation)
268
common variable immunodeficiency (CVID)
mutations in receptor for B cell growth factors, costimulators, cause reduced/no production of select Ig isotypes; can cause recurrent infections, autoimmune disease, and lymphomas
269
Bare Lymphocyte Syndrome
mutations in genes encoding TFs for MHC Class II expression cause lack of MHC II expression and impaired CD4+ T cell activation, leading to defective cell-mediated immunity and T-cell dependent humoral immunity
270
Defects in T cell receptor complex expression/signaling
mutations/deletions in genes encoding CD3 proteins or ZAP-70; rare; cause decreased T cells or abnormal ratios of CD4+/CD8+ subsets, leading to decreased cell-mediated immunity
271
Defects in Th1 responses
mutations in genes encoding IL-2 receptors or IFN-gamma; rare; cause decreased T cell-mediated macrophage activation and susceptibility to intracellular microbial infection
272
Defects in Th17 responses
mutations in genes encoding STAT3, IL-17, IL-17R; rare; cause decreased T cell-mediated inflammatory responses and susceptibility to infections with pyogenic bacteria and mucocutaneous candidiasis
273
X-linked lymphoproliferative syndrome
mutations in SAP cause uncontrolled EBV-induced B cell proliferation, uncontrolled macrophage and CTL activation, defective NK cell and CTL function
274
Pneumocystis jiroveci
a fungus that survives within phagocytes in the absence of T cell help; boys with X-linked hyper-IgM syndrome are susceptible
275
Chronic granulomatous disease
mutations in genes encoding subunits of phagocyte oxidase cause inability to kill phagocytosed microbes; immune system calls in more macrophages and activates T cells, which recruit more phagocytes -- leads to collections of phagocytes around infections (granulomas)
276
Leukocyte adhesion deficiency
caused by mutations in genes encoding integrins, molecules required for expression of ligands for selectins, or signaling molecules activated by chemokine receptors required to activate integrins; blood leukocytes do not bind firmly to vascular endothelium and are not recruited normally to sites of infection
277
Complement C3 Deficiency
mutations in C3 gene cause defects in complement activation; usually fatal
278
Complement C2/C4 Deficiency
mutations in C2/C4 genes cause deficient activation of classical pathway
279
Chediak-Higashi Syndrome
mutation in gene encoding lysosomal trafficking regulatory protein causes defective lysosomal function in neutrophils/macrophages/DCs and defective granule function in NK cells
280
Herpes Simplex 1 encephalitis
mutations in gene encoding TLR3 cause defective antiviral immunity in CNS
281
recurrent bacterial pneumonia
mutations in gene encoding MyD88 cause defective innate immune responses to pyogenic bacteria
282
Wiskott-Aldrich syndrome
X-linked disease characterized by eczema, thrombocytopenia (reduced platelets), and immunodeficiency manifested as susceptibility to bacterial infections; defective gene encodes a cytosolic protein involved in signaling cascades and regulation of the actin cytoskeleton
283
Ataxia-telangiectasia
characterized by gait abnormalities (ataxia), vascular malformations (telangiectasia), and immunodeficiency; caused by mutations in a gene whose product is involved in DNA repair; defects in this protein lead to abnormal DNA repair (e.g., during recombination of antigen receptor gene segments), resulting in defective lymphocyte maturation.
284
HIV attacks what?
CD4+ cells
285
irradiation and chemotherapy treatments for cancer cause what problem?
decreased bone marrow precursors for all leukocytes
286
immunosuppression for graft rejection and inflammatory diseases causes what problem?
depletion or functional impairment of lymphocytes
287
involvement of bone marrow by cancers causes what problem?
reduced site of leukocyte development
288
protein-calorie malnutrition causes what problem?
metabolic derangements that inhibit lymphocyte maturation and function
289
spleen removal causes what problem?
decreased phagocytosis of microbes
290
AIDS
caused by HIV infection; defined by a CD4+ count of less than 200 cells/mm3 or an AIDS-defining illness
291
HIV
retrovirus that infects and destroys cells of the immune system, mainly CD4+ T lymphocytes; infects via major envelope glycoprotein (gp120)
292
HIV life cycle
- infection of cells
- production of viral DNA
- integration of viral DNA into host genome
- production of viral particles
293
gp120
major envelope glycoprotein of HIV; binds to CD4 and particular chemokine receptors -- mainly CXCR4 on T cells and CCR5 on macrophages
294
provirus
viral DNA integrated into host DNA
295
HIV virion binds to what?
CD4 and chemokine receptors on T cells -- gp120 binds to CD4, then after conformational change, binds CCR5/CXCR4
296
Most cases of AIDS are caused by?
HIV-1
297
During the course of HIV infection, the major source of infectious viral particles is?
activated CD4+ cells
298
what cells serve as reservoirs of infection in HIV?
dendritic cells and macrophages
299
depletion of CD4+ T cells after HIV infection is caused by?
cytopathic effect of the virus, resulting from production of viral particles in infected cells, as well as death of uninfected cells
300
clinical features of HIV infection
- early mild acute illness which subsides within a few days
- clinical latency w/progressive loss of CD4+ T cells in lymph tissues and destruction of architecture of lymph tissues
- blood CD4+ count begins to decline
- AIDS when CD4+ count <200 cells/mm^3
301
clinicopathologic manifestations of full-blown AIDS are primarily the result of?
increased susceptibility to infections and some cancers, as a consequence of immune deficiency
302
Pneumocystis jiroveci
aka PCP pneumonia; AIDS patients particularly susceptible, so often take prophylactic bactrim
303
bactrim
prophylactic against PCP pneumonia; recommended daily for AIDS patients
304
how does AIDS affect CD8+ cells?
Patients with AIDS show defective CTL responses to viruses, even though HIV does not infect CD8+ T cells, probably because CD4+ helper T cells are required for full CD8+ CTL responses against many viral antigens
305
two most common types of cancers caused by oncogenic viruses in AIDS patients?
B cell lymphomas, caused by the Epstein-Barr virus, and a tumor of small blood vessels called Kaposi’s sarcoma, caused by a herpesvirus
306
Epstein-Barr virus
causes B cell lymphomas
307
Kaposi’s sarcoma
tumor of small blood vessels caused by a herpesvirus
308
immune responses to HIV
Infected patients produce antibodies and CTLs against viral antigens, and the responses help to limit the early, acute HIV syndrome, but these immune responses usually do not prevent progression of the disease
309
why are CTLs often ineffective in killing HIV-infected cells?
the virus inhibits the expression of class I MHC molecules by the infected cells
310
elite controllers
A small fraction of patients control HIV infection without therapy
311
HLA-B57 and HLA-B27
presence of these molecules seems to be protective against HIV, perhaps because they are particularly efficient at presenting HIV peptides to CD8+ T cells.
312
current treatment for AIDS is aimed at?
controlling replication of HIV and the infectious complications of the disease
313
highly active antiretroviral therapy (HAART) / combination antiretroviral therapy (ART)
Combinations of drugs that block the activity of the HIV viral reverse transcriptase, protease, and integrase enzymes administered early in the course of the infection
314
wasting syndrome
significant loss of body mass, caused by altered metabolism and reduced caloric intake
315
AIDS dementia
likely caused by infection of macrophages (microglial cells) in the brain
316
Fc portions of Ig molecules
made up of the heavy-chain constant regions; contain the binding sites for Fc receptors on phagocytes and for complement proteins
317
Fc regions
antibodies use these to activate diverse effector mechanisms that eliminate microbes and toxins
318
Fab regions
antibodies uses these to bind to and block the harmful effects of microbes and toxins
319
IgG
- neutralization of microbes & toxins
- opsonization of antigens
- activation of classical complement
- ADCC mediated by NK cells
- neonatal immunity
- feedback inhibition of B cell activation
320
IgM
activation of classical complement
321
J chain important for which Ig isotypes?
IgA, IgM
| JAM!
322
which Ig isotypes activate classical complement?
IgG, IgM
| GM makes classic cars
323
IgA
- mucosal immunity
- secretion into lumens of GI, respiratory tracts
- neutralization of microbes, toxins
324
IgE
- mast cell degranulation (allergic rxn)
| - defense against helminths
325
22q11.2 deletion
causes DiGeorge Syndrome (T cell deficiency)
326
DiGeorge Syndrome classic triad of symptoms
1. cardiac anomalies
2. hypoplastic thymus w/immunodeficiency
3. hypoplastic parathyroid w/hypocalcemia
327
Δ32 CCR5 mutations
protective against HIV since this is how HIV virions bind macrophage CD4 receptors; also increase susceptibility to plague and west nile virus
328
which 3 drugs are HIV patients usually on?
1. reverse transcriptase inhibitor
2. integrase inhibitor
3. protease inhibitor
329
4 steps of HIV clinical course
1. Primary infection
2. acute infection
3. clinical latency
4. AIDS
330
B cell deficiencies generally cause what?
- Recurrent pyogenic bacterial infection (particularly encapsulated bacteria)
- Enteric bacterial and viral infections
331
T cell deficiencies generally cause what?
- Viral infections
- Opportunistic infections (esp. intracellular microbial infections)
- Virus-associated malignancies
332
Examples of Defects in Lymphocyte Maturation
- Severe combined immunodeficiency (SCID)
- X-linked (Bruton’s) agammaglobulinemia
- DiGeorge Syndrome
333
Examples of Defects in Lymphocyte Activation or Function
- Common Variable Immunodeficiency (CVID)
- X-linked hyper-IgM syndrome
- Bare lymphocyte syndrome
334
Examples of Defects in Innate Immunity
- Chronic Granulomatous Disease (CGD)
- Leukocyte Adhesion Deficiency
- Complement deficiencies
- Chédiak-Higashi Syndrome
335
how to diagnose SCID?
low T cells (absolute lymphocyte count OR maternal T cells -- CD45RO -- in circulation)
336
how to diagnose CVID?
- Markedly reduced serum IgG + low IgM/IgA
| - Poor or absent response to vaccines
337
how to diagnose X-linked hyper-IgM Syndrome?
- defective class-switch recombination
- normal/increased IgM
- deficient IgG, IgA, IgE
338
how to diagnose CGD?
Nitroblue tetrazolium test
339
how to diagnose C3 deficiency?
CH50 test
340
live attenuated vaccine
a living microbe that has been weakened in the laboratory so it does not cause disease; very immunogenic & long-lasting but contraindicated in immunocompromised pts and could mutate into more virulent strain
341
most immunogenic type of vaccine?
live attenuated
342
immunogenic
stimulates immune response
343
types of live attenuated vaccines
```
Oral polio
MMR
varicella
oral typhoid
smallpox
yellow fever
BCG
zoster
```
344
what type of cell is important for immune response to live attenuated vaccines?
CD8+ (viral/intracellular pathogen defense)
345
inactivated vaccine
microbes that have been killed by chemicals, heat, or radiation; induce T cell-dependent B cell response but less immunogenic than live attenuated and more side effects
346
types of inactivated vaccines
Inactivated polio
hepatitis A
rabies
347
toxoid vaccines
Made from formalin-inactivated toxins
348
types of toxoid vaccines
tetanus
| diptheria
349
Subunit Vaccines
Contain only antigens which best stimulate the immune system, extracted from whole organisms or produced through recombinant DNA technology; induce T cell-dependent B cell response but less immunogenic than live attenuated and inactivated vaccines
350
types of whole organism subunit vaccines
```
Acellular pertussis
influenza
pneumococcus
meningococcus
IM typhoid
```
351
types of recombinant subunit vaccines
HBV
| HPV
352
Conjugate Vaccines
Linking polysaccharide antigens to proteins to better stimulate the immune system, and allow the antigens to be recognized by T cells
353
Types of Conjugate Vaccines
HiB
pneumococcus
meningococcus
354
Polysaccharide Vaccines
type of subunit vaccine that do not induce long-lasting immunity because T cells only recognize peptide-MHC complexes, and in order for a B cell to develop into a memory B cell it must have the help of a CD4+ T cell during the germinal center reaction; generates T-independent B cell response w/lower affinity antibodies; no germinal center reaction; no memory B cells; no "booster" effect w/2nd vaccination
355
which type of vaccine is not effective in children under age 2, gives the least robust response, and does not prevent colonization?
polysaccharide vaccines
356
vaccine trade-offs
immunogenicity of vaccine vs potential increased risk to patient by using that type of vaccine
357
recent resurgence of pertussis due to?
substitution of the whole cell with acellular pertussis in the 1990s (less immunogenic, but fewer side effects)
358
Adjuvants
substances added to a vaccine to increase immune system stimulation but not cause too much damage; allows use of less of actual antigen in vaccine to get same immune response
359
types of adjuvants
- Aluminum salts (most common)
- Oil in water
- TLR agonists
- Liposomes
360
routes of vaccine administration
- intramuscular
- subcutaneous
- intradermal
- oral
- intranasal
361
which type of vaccine administration best with adjuvants?
intramuscular (DTaP)
362
which type of vaccine administration best for live attenuated?
subcutaneous (MMR)
363
which type of vaccine administration best for dose-sparing?
intradermal - more dendritic cells just under skin (BCG)
364
which type of vaccine administration best for inducing mucosal immunity?
oral (polio) or intranasal (influenza)
365
3 main considerations for timing of vaccination
1) Age at administration
2) Spacing between doses
3) Co-administration of multiple vaccines
366
The age at which a vaccine is administered depends on?
1) Presence of maternal antibodies (will remain as long as breastfeeding)
2) maturity of immune system
3) risk of exposure to disease
367
spacing between doses of vaccine?
- 3 week minimum btwn primary doses
- 4 month minimum btwn primary and boosters
- NO max interval in terms of immune response
368
maximum interval between vaccine doses?
does not exist -- artificial "deadline" in the interest of getting patients protected as soon as possible
369
Co-administration of Multiple Vaccines
Live vaccines should either be given simultaneously or greater than or equal to one month apart b/c they tend to elicit a large-scale systemic response; no interference w/inactivated vaccines
370
Herd Immunity
the reduction of diseases in an unimmunized segment of the population in which a large portion of the population has been immunized
371
R0
basic reproduction number -- number of secondary cases generated by an infectious individual in a fully susceptible population; takes into account how crowded an area is.
372
which is better: a low or high R0?
low - this means there are fewer 2ndary cases generated by an infectious individual
373
(R0 – 1)/R0
threshold of proportion of immune individuals needed in a population. Over this number, the incidence of the infection will decrease. If the immunized proportion is equal to this number, the incidence of disease will remain the same.
374
types of pathogens that pose major challenges for vaccine development
- pathogens for which there is no natural immunity (HIV, CMV, HSV)
- pathogens that mutate rapidly (influenza, HIV)
- pathogens w/multiple serotypes (rhinovirus, group A strep, Dengue fever)
375
the only disease that has been fully eradicated through vaccination?
smallpox
376
1st Known Vaccination
1774 - cowpox experiment
377
vaccines not yet used commercially
DNA and Recombinant Vector Vaccines
378
TH1
Phagocytosis and complement!
- produce IFN-γ, IL-12
- TFs: STAT1, STAT4, T-bet
- activate phagocytes to eliminate ingested microbes
- stimulate production of opsonizing and complement-binding antibodies
379
TH2
Allergy and parasite defense!
- produce IL-4, IL-5, IL-13
- TFs: STAT3, GATA3
- stimulate IgE production
- activate M2 macrophages
- activate eosinophils, which function mainly in defense against helminths
380
TH17
Inflammation and infection!
- produce TGF-beta, IL-17, IL-22
- TFs: RORyT
- play a role in defense against extracellular bacterial and fungal infections
- implicated in several inflammatory diseases
381
CD8+ effector molecules
- Perforin & Granzymes
- FasL-Fas
- TNF-alpha & IFN-gamma
- NF-κB/Stat-1
382
IL-2
major growth factor for T cell proliferation and differentiation; also NK cell proliferation and activation; deficiency can cause autoimmunity
383
IFN-gamma
- activation of M1 macrophages
- TH1 differentiation
- B cells -- isotype switching to opsonizing and complement-fixing IgG subclasses
- increased expression of MHC Class I & II
- increased antigen processing & presentation to T cells
384
TNF-alpha
- activation of endothelial cells (inflammation)
| - activation of neutrophils
385
IL-3
induced maturation of all hematopoietic lineages
386
IL-4
B cells - isotype switching to IgE
TH2 differentiation
M2 macrophage activation
387
IL-5
activation and increased generation of eosinophils (TH2)
| B cells - IgA production
388
IL-6
B cells - proliferation of antibody-producing cells
389
IL-7
proliferation of early T and B cell progenitors; survival of naive and memory T cells
390
IL-9
produced by CD4+ cells; promotes survival & activation of mast cells, B cells, T cells, and tissue cells
391
IL-12
- TH1 differentiation
| - induces IFN-gamma synthesis, increased cytotoxic activity of NK cells and CD8+ cells
392
IL-13
produced by TH2 cells
- B cells - isotype switching to IgE
- increased mucus production
- increased collagen synthesis
- M2 macrophage activation
393
IL-17
produced by TH17 cells
- increased chemokine production by endothelial cells and macrophages
- increased GM-CSF production
394
Molecular mimicry
the postulated mechanism whereby immune responses to a microbe containing antigens that cross-react with self antigens may trigger an autoimmune response. This autoimmune response may then persist, even in the absence of the inciting microbe
395
T cell threshold of activation
In general, the TCR binds to peptide-MHC complexes with lower affinity than antigen-antibody interactions. This relatively low-affinity interaction occurs briefly; thus, a T cell may need multiple engagements with the antigen- presenting cell (APC) before a threshold of activation occurs. If this threshold is not reached, the T cell may become anergic
396
IL-21
produced by TH17 cells
- activation, proliferation, differentiation of B cells
- increased generation of TH17 cells
397
IL-10
produced by M2 macrophages, regulatory T cells
| - inhibition of IL-12, costimulators, and MHC Class II (anti-inflammatory)
398
IL-22
produced by TH17 cells
- production of defensins
- increased epithelial barrier function
- survival of hepatocytes
399
IL-1
produced by macrophages, DCs, etc
| - activation of endothelial cells (inflammation)
400
TGF-beta
produced by regulatory T cells
- inhibition of T cell proliferation and effector functions
- differentiation of TH17 and Treg
- inhibition of B cell proliferation
- IgA production
- inhibition of macrophage activation
401
examples of Type II hypersensitivity reactions
- Autoimmune Hemolytic Anemia
- Hemolytic Disease of the Newborn (Erythroblastic Fetalis)
- Goodpasteure's Syndrome
- Graves Disease
- Myasthenia Gravis
402
adhesion molecules in naive T cells
L-selectin
LFA-1
CCR7
403
adhesion molecules in activated T cells
E- and P-selectin Ligand
LFA-1 or VLA-4
CXCR3
404
CD28
a feature of naïve T cells which provides costimulation (with B7) during activation by dendritic cell
405
CD40L
upregulated after activation of a CD4+ T cell; provides costimulation for interactions between the helper T cell and the cells it is helping (B cells, macrophages)
406
which part of antibody determines function?
constant region of heavy chain
407
immature B cells express?
IgM
408
mature B cells express?
IgM and IgD
409
what kinds of recombination occur in B cell heavy and light chains?
- heavy: VDJ
| - light: VJ
410
germinal center reaction
B cell activation and proliferation due to interaction with
| antigen and helper T cell
411
somatic hypermutation
germinal center reaction generates high-affinity
| antibodies via changes in complementarity-determining region
412
affinity maturation
B cells produce antibodies with increased affinity for antigen during the course of an immune response; depends on somatic mutation of V genes
413
2 ways to activate B cell
1. T cell-dependent
| 2. T cell-independent
414
T cell-dependent B cell activation
activated CD4+ cell recognizes antigen on B cell and uses CD40L to bind to CD40 on B cell (2 signals)
415
T cell-independent B cell activation
B cell is exposed to antigen that also binds complement receptor CR2; this activates the B cell without T cell participation; This method is much faster than T cell-dependent activation but the B cell cannot do as much (no isotype switching); B cell recognizes antigen and activated complement bound to antigen (2 signals)
416
what does a B cell need to be able to switch Ig isotypes?
T cell activation!
417
Isotype switching
permanently alters the germline DNA to attach a new C region to the end of the Ig gene
418
AID enzyme
induces Somatic Hypermutation, Gene Conversion and Isotype Switching in activated B cells
419
APE1
the DNA repair enzyme that allows a new C region to be joined to the variable region of the Ig gene: class switching of isotypes
420
FcyRI
activation of phagocytes
421
FcyRIIA
phagocytosis
422
FcyRIIIA
ADCC (NK Cells)
423
FceRI
activation of mast cells, eosinophils
424
C50 test
determines if a patient has high or low complement activity
425
complement opsonizers
C3b, C4b
426
complement inflammatory stimulators
C3a, C5a
427
IFN-alpha
- activation of NK cells
- enhanced expression of MHC Class I molecules
- accelerated degradation of viral RNA
