Basic Pathological Mechanisms April 6-10 Flashcards
(104 cards)
1
Q
What are the causes of organ failure?
A
genetic predisposition, inflammation, infection, toxins, and trauma
2
Q
What organs are commonly transplanted?
A
kidney, liver, heart, pancreas, and lung
3
Q
What are potential barriers to transplantation?
A
genetic, immunological/inflammatory, physiological, psychological, surgical, social, financial, and ethical
4
Q
Describe the ABO blood group system.
A
Group A population has A antigens on red blood cells (and endothelial cells) and produces antibodies to B
Group O population expresses no antigens on red blood cells and produces both A and B antibodies
5
Q
What is the role of ABO antigens in transfusion medicine?
A
For a blood donor and recipient to be ABO-compatible for a transfusion, the recipient must not be able to produce Anti-A or Anti-B antibodies that correspond to the A or B antigens on the surface of the donor’s red blood cells
6
Q
What are major histocompatibility antigens?
A
class 1 and class 2 MHC
typically more potent inducers of rejection than are minor H antigens (disparities require more immunosuppression than minor H antigen disparities)
7
Q
In the HLA map, Class II MHC locus is closer to centromere or telomere? MHC class I?
A
centromere
telomere
8
Q
What is the clinical significance of HLA complexes?
A
solid organ & hematopoetic cell transplation; disease association; pharmocogenomics; paternity testing
9
Q
What is an autograft? How is this different from a xenograft?
A
a graft transplanted from one site to another site in the same individual; a xenograft is between individuals of different species
10
Q
How is a syngraft different from a allograft?
A
syngraft is between genetically identical individuals (monozygotic twins) and allograft is between genetically non-identical individuals with a species
11
Q
What is the fundamental immunogenetic principle?
A
Grafts that express histocompatibility antigens on donor cell surfaces that are not expressed by recipient cells
will be rejected.
12
Q
What is GVHD?
A
graft versus host disease following blood and marrow transplantation
With GVHD, the newly transplanted donor cells attack the transplant recipient’s body.
13
Q
How do recipient alloreactive T cells recognize donor HLA antigens?
A
direct recognition: donor HLA antigen (on donor cell) and donor peptide; occurs initially following allogeneic transplantation
indirect: recipient HLA antigen (on recipient cell) and donor HLA peptide; occurs later in transplantation
14
Q
What are minor H antigens?
A
Minor histocompatibility antigens are due to normal proteins that are in themselves polymorphic in a given population. Even when a transplant donor and recipient are identical with respect to their major histocompatibility complex genes, the amino acid differences in minor proteins can cause the grafted tissue to be slowly rejected.
15
Q
Describe hyperacute rejection.
A
(minutes to hours) preformed anti-donor antibodies and complement (type II hypersensitivity: neutrophils and lytic enzymes; C4d)
16
Q
What are pathological features of antibody-mediated rejection?
A
vasculitis, glomerulitis, and fibrinoid necrosis (chronic rejection)
17
Q
In kidney transplants what is the main target of cellular rejection?
A
renal tubule; neutrophils in peritubular capillaries
glomerulitis is not specific for rejection
18
Q
What are the forms of solid-organ graft rejection?
A
hyperacute: preformed antibodies (caused by previous blood transfusions, previous transplants, and pregnancy)
acute: T cell respone
acute vascular: de novo antibodies (immunoglobulins)
chronic: T and B cell response (fibroproliferative changes)
19
Q
How is histocompatibility tested?
A
HLA typing: microlymphoctotoxicy assay, flow cytometry, PCR with sequence-specific primers (SSP/SSO)
crossmatching
antibody screening
20
Q
What are approaches to eliminating graft rejection?
A
Minimization of genetic disparity between donor and recipient (HLA matching)
Pharmacologic immunosuppression: drugs and antibodies
Clonally-specific immunosuppression: blockade of co-stimulation
(to limit the effect of pathogens and prevention of neoplastic transformation)
21
Q
Describe microlymphocytotoxicity assay.
A
A blood specimen from the patient is processed
to separate the lymphocytes from other cellular
blood components (separation of T and B lymphocytes)
antibody directed against a known MHC antigen is added to a well (then lymphocytes are added): during this incubation, if the lymphocyte possesses
the antigen that is the target of the antibody, the antibody will coat the cell.
complement proteins are added: During this incubation,
complement will attach to any cell that is coated with
antibody
22
Q
In regards to MHC complexes, which allele has the highest variability? least?
A
DRB1; DRA
23
Q
What are passenger leukocytes?
A
professional APCs: simulate immune response against the allograft (dendritic cells, B cells, macrophages, and monocytes)
24
Q
What is the result of a second transplantation following an initial rejection?
A
second rejection is more rapid and more potent (result of immunized T cells to the MHC complexes exhibited on the allograft)
25
Which is better: treatment of antibody-mediated rejection or T-cell mediated rejection?
T cell
26
How long can a donor organ be out of the body before incurring damage? Why?
at most two days; ROS from ischemia-reperfusion injury
27
What is the source of antigens that cause hypersensitivity reactions?
xenoimmune; alloimmune (transplant rejection and GVHD); autoimmune
28
What are effectors of hypersensitivity reactions?
humoral: antibody and/or complement
cell mediated: T cells and perhaps other leukocytes
mixed
29
Describe type 1 hypersensitivity
anaphylaxis
recognized by IgE bound to the surface of leukocytes (Two or more IgE must be able to bind to the antigen and bring the two IgE immunoglobulins together (requirement for cross-linking of two Fc regions of IgE; ITAM signaling))
effector cells are basophils and mast cells (histamine, heparin, leukotrienes (LTD4 and LTE4), and PGD2); have receptor for constant region of IgE or constant heavy 2 (Fc)); PLC signaling (calcium mobilization and DAG)
effects: degranulation, histamine, leukotrienes and PGD2 stimulate tetanic muscle contraction, vasoconstriction, and postcapillary venule relaxation (inflammation)
symptoms: wheezing, diarrhea, runny nose, and teary eyes
duration: minutes to hours
30
Describe type 2 hypersensitivity
recognized by circulating IgG or IgA (cross-linking required); localized immune response resulting in cell necrosis
effectors cells are monocytes, NK cells, neutrophils, and platelets
Neutrophils and platelets release superoxide, hydrogen peroxide, hydroxyls, nitric oxide, and myeloperoxidase (cathepsins and granzymes)
Monocytes and natural killer cells release perforin and death domain receptor agonists
leukocytes release cytokines and chemokines
duration: many hours to 1-2 days
examples: autoimmune thyroiditis, rheumatic mitral valve myocarditis and pericarditis
31
How is complement-mediated cytotoxicity different from other type 2 hypersensitivity? examples?
recognized by IgG or IgM
Membrane attack complex, sub-lethal metabolic change; chemotaxis, leukocyte activation, and phagocytosis
attack of squamal epidermis and blistering
32
Describe type 3 hypersensitivity.
recognized by circulating IgG, IgA, or IgM; cell death is not necessary and the complexes are diffusely expressed in the organism
effector cells are granulocytes (including platelets) and target cells via complement
glomerular nephritis, vasculits
33
Describe type 4 hypersensitivity.
recognized by T cell antigen receptor (TCR)
effector cells are factor-producing T cells
de novo synthesis of cytokines and chemokines
Methicillin can bind class II MHC molecules and cause T helper cells to stimulate cytokine production
duration: 2-4 days
34
How is cell-mediated cytotoxicity type 4 hypersensitivity different from factor-producing?
effector cells are cytotoxic T cells (lytic enzymes including granzymes, cathepsins,and perforin; TNF and lymphotoxin; FasL; chemokines and cytokines
Transitional metals can bind class I MHC molecules and cause a cytotoxic T cell response (also occurs with elastics)
multiple sclerosis
35
Describe type 5 hypersensitivity
Chaperone antibody: IgG, IgA, IgM; blocks the physiological interaction of natural ligand; myasthenia gravis)
imposter antibody: mimics the physiologic agonist; Grave's disease
handcuff antibody: antibody prevents a ligand-receptor complex from dissociating; C3 nephritic factor (membranoproliferative glomerulonephritis type II from constitutive activation of C3 convertase)
36
What are immunologically privileged sites?
brain, eye, testis, uterus (fetus)
Tissue grafts placed on these sites often last indefinitely, and antigen placed in these sites do not elicit destructive immune responses.
However damage to an immunologically privileged site can induce an autoimmune response.
37
How autoimmunity induced?
cross-reaction between self/non-self (the GAD 65/Coxsackie virus P2-C paradigm)
drug-conjugated to self protein; foreign protein with sequence similarity to self protein; and cross-reaction
38
Describe X-linked (Bruton's) Agammaglobulinemia.
characterized by the failure of B-cell precursors (pro-B cells and pre-B cells) to develop into mature B cells
defect in a src family tyrosine kinase (btk) required for signal transduction in the B cell lineage (associated with the Ig receptor; light chains are not produced) pre-B cells cannot mature to express IgM on the surface
X-linked: more common in males
low immunoglobulin of all classes (A, G, E, M), no circulating B cells, preB cells in bone marrow in normal number; absence of plasma cells
normal cell-mediated immunity
Germinal centers of lymph nodes, Peyer's pathches, the appendix, and tonsil are underdeveloped
39
Describe hyper-IgM syndrome
defect in CD154, also known as gp39 or CD40L, a T cell surface molecule that stimulates Ig class switching/affinity maturation in B cells (X-linked); OR AID mutation
high serum titers of IgM without IgG, IgA, and IgE
normal B- and T-cell numbers
susceptible to extracellular bacteria infections
40
Describe Common Variable Immunodeficiency.
B-cell maturation defect and hypogammaglobulinemia (low levels of immunoglobulins; sometimes only IgG)
in contrast to X-linked agammaglobulinemia, most individuals with common variable immunodeficiency have normal or near-normal numbers of B cells in blood and lymphoid tissues (not able to differentiate into plasma cells)
the clinical manifestations are caused by antibody deficiency (resemble X-linked agammaglobulinemia)
affects both sexes equally
hyperplastic lymphoid follicles in nodes, spleen, and gut (B cells can proliferate in response to antigen but do not produce antibodies)
41
Describe Severe Combined Immunodeficiency (SCID).
complete functional B- and T-cell deficiency (defects in both humoral and cell-mediated immune responses)
X-linked: defects in common gamma chain of IL-2 (cytokine) receptor; T cell numbers are greatly reduced, and antibody synthesis is impaired (also have NK deficiency)
autosomal recessive:
adenosine deaminase deficiency (toxic to rapidly dividing immature lymphocytes, especially those of the T-cell lineage);
other causes: RAG somatic gene rearrangement machinery; purine
nucleoside phosphorylase deficiency; JAK3 mutation
histology: small thymus devoid of lymphoid cells
opportunistic infections with fungus, viruses, and parasites
42
Describe DiGeorge Syndrome (Thymic hypoplasia)
selective T-cell deficiency that results from failure of development of the third and fourth pharyngeal pouches (which gives rise to the thymus); hypoplasia or lack of the thymus
normal or variably reduced Ig levels; specific antibody often poor, mostly IgM; normal numbers of B cells
TBX1 mutation
reduced numbers of circulating T cells (poor defense against certain fungal and viral infections)
43
Descirbe ataxia-telangiectasia
autosomal-recessive disorder characterized by abnormal gait (ataxia), vascular malformations (telangiectases), neurologic deficits, increased incidence of tumors, and immunodeficiency
combined partial B- and T-cell deficiency (selective absence of IgA, low IgE): the most prominent humoral immune abnormalities are defective production of isotype switched antibodies, mainly IgA and IgG2
normal B cells
reduced CD4+ cells; poor T cell proliferation; no Hassall's corpuscles (thymic hypoplasia)
defect in kinase involved in cell cycle (ATM; structurally related to PI3K)
44
Describe Nezelof Syndrome.
normal levels of circulating Ig; poor antibody function
normal numbers of B cells, minor hypoplasia of follicles in lymph nodes
diminished numbers of circulating T cells; impaired T cell function
multiple defects in T cell activation, including CD3 subunits, ZAP-70
45
Antibodies are sufficient for immunity for what?
bacterial pathogens
46
What are T cells required for?
immunity to intracellular bacteria, many mycobacteria, fungi, yeasts & most eukaryotic pathogens
47
Are virus treated with antibodies alone? cell-mediated responses? both?
can be neutralized by antibody alone (acting in concert with innate immunity, the levels of antibody to achieve viral neutralization must be high; once viral infection is established, T cell responses become more important
48
How does most bacteria enter the body?
upper airways or gut
49
What are characteristics of antibody deficiency?
recurrent infection; treated with infusion of gammoglobulin from pooled donor serum
50
What stimulates basophil degranulation?
polyvalent antigen (a group of antibodies that have affinity for various antigens); multi-haptenated carrier (a small separable part of an antigen that reacts specifically with an antibody but is incapable of stimulating antibody production except in combination with an associated protein molecule); two antigen binding sites or FceR
51
What are anaphylaxtoins?
are fragments (C3a, C4a and C5a) that are produced as part of the activation of the complement system that activate leukocytes
52
Why is type 2 hypersensitiy slower than type 1?
IgG and IgA have much lower affinity for antigen than IgE (less efficient signal transduction)
53
How can bacteria cause disease?
some bacteria are always pathogenic; some bacteria are part of normal flora and acquire extra virulence factors making them pathogenic; some pathogenic bacteria are quarantined in the normal flora and cause disease if they gain access to deep tissues by trauma, surgery, etc; in immunocompromised many nonpathogenic bacteria become pathogenic
54
What is Koch's postulate?
the pathogen must be present in every case of disease; the pathogen must be isolated from the diseased host and grown in pure culture; the specific disease must be reproduced when a pure culture of the pathogen is inoculated into a healthy susceptible host; the pathogen must be recoverable from an experimentally infected host.
55
What is the iceberg concept of infectious disease?
In outbreaks of most disease in animal groups, both clinical cases (the tip of the iceberg) and subclinical cases (unobserved beneath the ocean surface) are present in the group. For many infectious agents, particularly those that are endemic, more of the infections in a group are subclinical (silent) than are clinical. For some exceptions, such as rabies, few if any subclinical infections occur and almost all if not all clinical infections end in death.
56
What is evidence for the clinical significance of a pathogen?
evidence of local inflammation or immune response; isolated in abundance, pure culture, on more than one occasion (may be isolated from deep tissues)
57
What is the function of normal flora?
can protect against infection by preventing pathogens colonising epithelial surfaces; removal of normal flora with antiboitics can cuase superinfection, usually with resistant microbes
58
Describe gram positive bacteria
purple, circular bacteria in clusters; thick peptidoglycan layer in the bacterial cell wall retains the stain after it is washed away from the rest of the sample, in the decolorization stage of the test.
Despite their thicker peptidoglycan layer, gram-positive bacteria are more receptive to antibiotics than gram-negative, due to the absence of the outer membrane.
Teichoic acids and lipoids are present, forming lipoteichoic acids, which serve as chelating agents, and also for certain types of adherence.
59
Describe gram negative bacteria.
Gram-negative bacteria cannot retain the violet stain after the decolorization step; alcohol used in this stage degrades the outer membrane of gram-negative cells making the cell wall more porous and incapable of retaining the crystal violet stain. Their peptidoglycan layer is much thinner and sandwiched between an inner cell membrane and a bacterial outer membrane, causing them to take up the counterstain (safranin or fuchsine) and appear red or pink.
No teichoic acids or lipoteichoic acids are present (non-pili adhesins and pili + adherence proteins)
60
What are exotoxins?
bacterial proteins (virulence factors) that elicit features of a bacterial infection when injected as pure proteins
61
What are characteristics of virulence factors?
when the gene for the factor is deleted, the model system loses virulence; adding the gene back restores virulence
biochemical evidence of damaging potential
without virulence factors, bacteria are in commensal relationship with the host
62
What are the effects of glycopeptides and teichoic acid released during gram-positive infections?
following lysis of bacteria, binds to a circulating protein which then binds to the surface of macrophages
release of IL-1, IL-6, TNF-alpha and initiation of inflammation, complement, and coagulation
63
What is the action of lipopolysaccharide from the gram-negative cell wall?
following lysis of bacteria, binds to LPS-binding protein; complex binds to CD14 on macrophages (coactivation with TLR-4)
release of IL-1, IL-6, TNF-alpha and initiation of inflammation, complement, and coagulation
64
Describe bacteria transformation.
some substance needed to produce the capsule was passed from the dead bacteria (S strain) to the live ones (R strain)
DNA is the substance that causes bacterial transformation
65
What are S. pneumoniae virulence factors?
most important: capsule
choline binding proteinA, pneumolysin (pore-forming toxin), pyruvate oxidase, autolysin, pneumococcal surface proteinA, and neuraminidase A
66
Is S. pneumoniae gram positive or negative?
positive
67
What causes Strep throat?
Streptococcus pyogenes
68
What are virulence factors of S. pyogenes?
M protein (different types cause different disease states)
69
Describe S. aureus infections.
skin lesions (boils), pneumonia, meningitis, UTI, osteomyelitis, and endocarditis
causes food poisoning by releasing enterotoxins into food (targets gut)
causes toxic shock syndrome by release of superantigen TSST into the bloodstream
70
What are S. aureus virulence factors?
panton-valentine leukocidin: lyses polymorphonuclear leukocytes and macrophages (damages membrane of host defense cells)
surface proteins that promote colonization of host tissue; invasins that promote spread into tissues (leukocidin); capsule and protein A inhibit phagocytic engulfment
71
Can S. aureus be inherently resistant to antimicrobial agents? can resistance be acquired?
Yes; Yes
72
Which types of bacteria can cause Toxic-shock syndrome? What are the clinical features?
S. aureus and S. pyogenes; fever, hypotension, rash, vomiting, diarrhea, and eventually multiple organ failure
73
Describe Anthrax.
spore-forming, rod-shaped bacterium (Bacillus anthracis)
livestock disease (lies dormant in soil for years is eaten by a grazing animal causing spores to reproduce); return to soil and water
74
What are virulence factors of Anthrax?
protective antigens: forms a channel that permits edema factor and lethal factor to enter host cells
edema factor: causes fluid to accumulate (pleural effusion)
lethal factor: disrupts a key molecular switch that regulates the cell's functions
75
Is Anthrax more common in developed or developing countries?
developing
76
How can humans contract Anthrax?
cutaneous (enters a break in skin and causes ulcer), gastrointestinal, or through inhalation
77
At what stage of Anthrax infection does treatment become difficult?
when spores travel from the lungs to nearby lymph nodes, where they reproduce and secrete their toxins (causing severe breathing problems and shock)
78
How are immunodeficiencies clinically manifested?
by increased infections (either newly acquired or reactivation of latent infections)
79
What are complication in TLR signaling defects?
result in recurrent herpes simplex encephalitis and defects in MyD88 (downstream adaptor proteins) are associated with destructive bacterial pneumonias
80
T/F: T-cell defects almost always lead to impaired antibody synthesis?
T
81
Describe Wiskott-Aldrich Syndrome.
X-linked disease characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection
the thymus is morphologically normal
progressive loss of T lymphocytes in the peripheral blood and in the paracortical area (T-cell zones) of lymph nodes
response to protein antigens is poor
low IgM, but levels of IgG are usually normal (IgA and IgE are elevated)
mutation in WASP (links antigen receptors to cytoskeletal elements)
82
What is a concept associated to manifestation of hypersensitivity diseases?
Hypersensitivity usually results from an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses
The development of hypersensitivity diseases (both allergic and autoimmune) is often associated with the inheritance of particular susceptibility genes (HLA molecules)
83
What are the two phases of local immediate (type 1) hypersensitivity?
The immediate reaction is characterized by vasodilation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions (congestion and edema). These changes usually become evident within minutes after exposure to an allergen and tend to subside in a few hours.
late-phase reaction is characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells, as well as tissue destruction, typically in the form of mucosal epithelial cell damage.
84
Describe sequence of events in type 1 hypersensitivity.
The first step in the generation of T H 2 cells is the presentation of the antigen to naive CD4+ helper T cells (differentiation into TH2 cells)
IL-4 induces class-switching to IgE (IL-5 activates eosinophils)
85
What are mast cells?
Mast cells are bone marrow–derived cells that are widely distributed in the tissues. They are abundant near blood vessels and nerves and in subepithelial tissues
circulating counterpart = basophils
activated by cross-linking of high-affinity IgE Fc receptors (repeat exposure to antigen)
When a mast cell, armed with IgE antibodies previously produced in response to an antigen, is exposed to the same antigen, the cell is activated, leading eventually to the release of an arsenal of powerful mediators responsible for the clinical features of immediate hypersensitivity reactions.
activation of mast cells leads to degranulation (discharge of preformed granules and de novo granules)
release of histamine, (in addition to inflammatory response causes enhance mucus secretion)
phospholipase A2 mediated pathways: leukotrienes C4 and D4, prostaglandin D2 (bronchospasm), and platelet-activating factor
IL-1 and TNF-alpha cytokine secretion
86
What type of infectious molecules are sensitive to membrane attack complex response?
thin cell walls
87
Deposition of antibodies in fixed tissues (basement membrane and ECM) causes what type of injury?
inflammation through activation of complement system
glomerulonephritis and rejection of grafts
type 2 hypersensitivty
88
T/F: Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition?
T
89
T/F: immune complex-mediated diseases tend to be systemic?
T
occurs following administration of a foreign serum (other individuals and species)
glomeruli and joints tend to be most affected
systemic lupus erythematosus (SLE)
90
What are signs of immune complex-mediated diseases?
lymph node enlargement, fever, joint pains, and proteinuria
vasculitis (fibrinoid necrosis), glomerulonephritis, and arthritis
91
Is complement system activation a component of immune-complex mediated disease (type 3 sensitivity)?
in most cases yes
92
Which APC-secreted cytokines induce TH1 differentiation? TH17?
IL-12
IL-1, IL-6, and IL-23
93
T/F: The major antigenic differences between a donor and recipient that result in rejection of transplants are differences in HLA alleles?
T
94
What is the difference between indirect and direct pathways of graft injection?
direct: donor APC presents antigen; indirect: recipient APC presents antigen (only activated CD4+ cells)
95
T/F: T cell cytokine mediated mechanisms can lead to both acute and chronic rejection?
T (rejection is an inflammatory response)
96
What is the target of acute antibody-mediated rejection?
graft vasculature
97
HLA-matching is required for which type of grafting?
HSCs (other grafts may benefit from matching but, due to immunosuppressive therapies, is not required)
depletion of donor T cells before transfusion virtually eliminates the disease (increased risk of tumorigenesis)
98
What are features of bacterial virulence? How can bacteria that is not virulent become virulent?
Bacterial damage to host tissues depends on the ability of the bacteria to adhere to host cells, to invade cells and tissues, or to deliver toxins
Mobile genetic elements such as plasmids and bacteriophages can transmit functionally important genes to bacteria, including genes that influence pathogenicity and drug resistance
99
Biofilm formation is a characteristic of what type of bacterial infection?
endocarditis and artificial joint infections
100
What are pili?
filamentous proteins on the surface of bacteria that act as adhesins
101
What is a gram-negative bacteria endotoxin?
LPS
102
What are examples of gram-positive bacteria?
Strep, Staph, and enterococcus
103
What are the consequences of Staph infection?
respiratory infection, osteomyletis, skin infections, endocarditis, food poisoning, and toxic shock syndrome
104
Staph infection causes what type of lesions?
pyogenic (pus)
