Diseases of Immunity Flashcards
(109 cards)
1
Q
Innate immunity
A
defense mechanisms present before infection
2
Q
Adaptive immunity
A
- develops after exposure to antigen
- mechanisms stimulated by infection/exposure
- lymphocytes (T-cells and B-cells)
3
Q
Two types of adaptive immunity
A
Cell mediated immunity Humoral immunity (antibody mediated)
4
Q
Cell mediated immunity definition
A
- defends against intracellular microbes
- mediated by T-lymphocytes (T-cells)
5
Q
Humoral immunity definition
A
- defends against extracellular microbes and toxins
- mediated by B-lymphocytes (B-cells) and their Ab’s
6
Q
Complement activation by the alternative pathway is considered a component of ________ immunity
A
innate
7
Q
T lymphocytes
A
Derived from precursors in thymus
Found in blood (60-70% of lymphocytes)
Found in spleen (PALS) and lymph nodes
T-cells recognize specific antigen with TCR
8
Q
T cell receptor recognizes antigen only when presented to the T cell in association with ____________
A
major histocompatibility complex
9
Q
Molecular analysis of _______ is used to determine ________ of T cell populations
A
T cell receptor (TCR); malignancy/ clonality (infiltrate of clonal T cells represent neoplastic population)
10
Q
Cluster differentiation molecule that is linked with the TCR and present on all T cells
A
CD3
11
Q
Cluster differentiation molecule present on helper T cells
A
CD4
12
Q
Cluster differentiation molecule present on cytotoxic T cells
A
CD8
13
Q
CD4+ T cells recognize antigen presented in association with ______ which is present on the surface of ________
A
MHC class II; antigen presenting cells
14
Q
CD8+ T cells recognize antigen presented in association with ______ which is present on the surface of __________
A
MCH class I; all nucleated cells
15
Q
What is different about T cells with gamma/delta TCR as compared to most T cells, which have alpha/Beta TCR?
A
T cells with gamma/delta TCR do NOT require MHC for antigen recognition and activation
16
Q
Describe the TWO signals needed for T cell activation
A
- Antigen/MHC (I or II) engages TCR/CD4or 8
- CD28 on T cell engages B7 CD80/CD86 on APC (co-stimulatory CD28 on T cell and activation CD80/86 on antigen presenting cell)
17
Q
What are the possible outcomes if a T cell is engaged with antigen/ MHC but does not receive co-stimulatory signal?
A
- fail to respond
- apoptosis
- anergy
co-stimulation is needed to prevent T cells from becoming responsive to self antigens
18
Q
Once activated, T cells produce _______ which induces proliferation of the activated T cell population
A
IL-2
19
Q
T cells differentiate into ______ cells and _____ cells.
A
Effector cells (act to clear the inciting antigen/infection); Memory cells (long lived, for antigen re-encounter)
20
Q
Th1 cells
A
secrete IL-2 and INF-ɣ (macrophage activation)
stimulate B cells to secrete opsonizing and complement-fixing antibodies (IgG)
mediate macrophage activation (Delayed Type Hypersensitivity)
21
Q
Th2 cells
A
secrete IL-4 (stimulate IgE synthesis from B cells) and IL-5 (activation of eosinophils)
22
Q
Th17 cells
A
secrete IL-17 (recruit neutrophils in acute inflammation)
23
Q
B lymophocytes
A
Develop from precursors in bone marrow
Found in blood (10-20% of circulating lymphocytes)
Found in lymph nodes, spleen, tonsils, GI tract
Arranged in aggregates called lymphoid follicles
24
Q
The antigen-binding component of the antigen receptor complex in B cells consists of ____________
A
immunoglobulin/ antibody
25
_____ and ____ are present on the surface of developing B cells and possess the unique antigen specificity for that B cell
IgM, IgD
26
Clonal B cell populations (B cell lymphoma) show ___ or _____ restriction, displaying only one type of light chain and thus clonality of a B cell population can be demonstrated by immunolabeling of the population.
Kappa or lambda
27
Plasma cells are differentiated B cells that secrete ____ and are the functional mediators of ______ immunity
antibodies (immunoglobulins); humoral
28
Do B cells require antigen to be presented with MHC on antigen presenting cells?
No, B cells can recognize soluble/ free antigen
29
Macrophages are activated by ______ which is produced by the ______ subset of T cells
IFN-y; Th1 helper T cells
30
Once antigen+ MHC II is presented to CD4+ cells by macrophages, the T cells differentiate into ______ and produce more ______ to activate more macrophages in a positive feedback loop
Th1 cells, IFN-y
31
List two types of dendritic cells
Interdigitating, follicular
32
Interdigitating dendritic cells
The most important APC for primary response
Located in epithelium/interstitium (antigen rich)
Called Langerhans cells when in the skin
Numerous fine processes to increase surface area
Express high levels of antigen trapping receptors and Class II MHC (for presentation to CD4+ T cells)
33
Follicular dendritic cells
Important APC for ongoing immune response
Located in germinal centers of lymphoid follicles, B cell rich regions in lymph nodes and spleen
Trap bound antigen with either Fc IgG pr C3b receptors
Present antigen to high affinity B cells; B cell activation→ follicular hyperplasia, lymphadenopathy, improve humoral response
34
NK cells are considered part of the ________ immune system and do not require prior sensitization
innate
35
List two ways NK cells recognize and target cells for lysis
- antibody dependent cell mediated cytotoxicity
| - monitoring class I MHC expression for abnormalities
36
Describe antibody dependent cell mediated cytotoxicity (ADCC)
- NK cells have CD16 (the Fc receptor for IgG)
| - abnormal or infected cells are coated with IgG, CD16 engages the opsonized cells and targets them for lysis
37
Explain how NK cells monitor class I MHC to target abnormal cells in continuous cellular surveillance
- NK cells have inhibitory receptors that bind MHC I on normal cells- normal amount and peptide MHC I is inhibitory
- altered or reduced expression of MHC I due to viral infection or neoplastic transformation results in lack of inhibitory signal and the cell is targeted for lysis
38
List five main functional classes of cytokines
1. Mediate Innate Immunity
2. Regulate Adaptive Immunity (lymphocytes)
3. Activate Inflammatory Cells
4. Affect Leukocyte Movement (Chemokines)
5. Stimulate Hematopoiesis
39
List some cytokines that mediate innate immunity
IL-1, IL-6, TNF→Acute-phase inflammatory response (recruit inflammatory cells, fever)
INF-ɣ→Activates macrophages
40
List some cytokines that regulate adaptive immunity (lymphocytes)
```
IL-2→ T-cell growth factor
IL-12→TH1 pathway
IL-4 →TH2 pathway (IgE and eosinophils)
IL-17→TH17 pathway (recruit neutrophils)
TGF-B downregulates immune response
```
41
List some cytokines that activate inflammatory cells
INF-ɣ→Activates macrophages
IL-5→Activates eosinophils
IL-17→Activates neutrophils
TNF→Acts on neutrophils/endothelial cells
42
List some cytokines that affect leukocyte movement
C-C (cys-cys) →Attracts monocytes/lymphocytes (NOT neutrophils)
C-X-C→Activation/chemotaxis of neutrophils
43
List some cytokines that stimulate hematopoiesis
CSF's- colony stimulating factor
44
List and describe three mechanisms of cytokines
1. Autocrine-act on same cell producing cytokine
Example: IL-2 production by activated T-cell
2 Paracrine-affect cells in same vicinity (local acting)
Example: INF-ɣ by TH1 cell activates macrophage
3. Endocrine-systemically affects many cells (distant)
Example: IL-1 and TNF systemic acute-phase response
45
Class III MHC genes encode _______ proteins
complement
46
MHC encoding genes are present on chromosome __
6
47
Class I MHC loci
HLA-A, HLA-B, HLA-C
48
Class I MHC heterodimer molecules consist of ...
polymorphic a chain linked to B2 microglobulin
49
Class I MHC molecules display peptides made where?
Inside the cell, as in viral and tumor antigens
50
Class II MHC loci
HLA-DP, HLA-DQ, HLA-DR
51
Class II MHC molecules consist of
polymorphic a and B chains, both of which are involved in antigen binding
52
Class II MHC is presented on which types of cells?
antigen presenting cells
| ex macrophages, B lymphocytes, dendritic cells
53
Class II MHC molecules display peptides made where?
exogenously, peptides that were phagocytosed and cleaved for presentation
54
HLA association: Ankylosing spondylitis andpostinfectious arthropathies
HLA-B27 (strong association)
55
HLA association: autoimmune diseases
HLA-DR
DR3-Sjögren syndrome/chronic active hepatitis
DR4-Rheumatoid Arthritis
DR3/4-Type I Diabetes
56
HLA association: inherited disorders of metabolism
```
HLA-A and B
Hereditary Hemochromatosis (Inherited with HLA-A)
21-hydroxylase deficiency (Inherited with HLA-Bw47)
```
57
Four broad types of immune disorder
1. hypersensitivity
2. autoimmune
3. immune deficiency
4. amyloidosis
58
Type I hypersensitivity
Immediate Hypersensitivity
- classic allergy, anaphylaxis, asthma
- IgE mediated antibody production, mast cell degranulation, release of mediators
- early: vasodilation, bronchoconstriction
- late: cellular inflammatory reaction
- Th2 mediated
59
Mast cell degratulation
- First exposure: APCs present antigen + MHC II to T cells which differentiate into Th2 cells and produce IL-4 that causes isotype class switching- production of IgE from B cells and IL-5 that activates eosinophils.
- circulating IgE binds Fc receptor on mast cells, priming them for subsequent activation
60
Anaphylaxis
Manifestation of type I hypersensitivity
vascular shock with widespread edema and difficulty breathing
treat immediately with epinephrine to counteract effects of histamine on smooth muscle
61
Mast cell activators
```
cross linking IgE
complement anaphylotoxins C5a and C3a
cytokines like IL-8
some drugs like codeine, morphine, adenosine
mellitin (bee venom)
stimuli like heat, cold, sunlight
```
62
Antibody classes (MADGE)
IgM: large pentamer present on immature B cells as a surface receptor, seen in early response to infection, can activate complement
IgA: mucosal antibody secreted by MALT, found in breast milk and saliva, may be secreted in dimeric form
IgD: found only on surface of developing B cells as an antigen receptor
IgG: only antibody that crosses placenta, can activate complement, primary antibody in humoral response
IgE: associated with eosinophils in response to allergy, asthma, parasites
63
Type II hypersensitivity
Antibody Mediated Hypersensitivity
- plasma cells are mediators, secrete antibody
- complement proteins and phagocytic cells are effectors
- four mechanisms: opsonization and phagocytosis, antibody-dependent cellular cytotoxicity, complement and Fc receptor mediated inflammation, antibody mediated cellular dysfunction
64
Opsonization and phagocytosis (Type II hypersensitivity)
- IgG and C3b are opsonizing molecules
- phagocytic cells have Fc receptor for IgG and C3b
- opsonized cells are phagocytosed
- ex erythroblastosis fetalis
65
Antibody dependent cellular cytotoxicity (type II hypersensitivity)
- effector cells (primarily NK cells) kill target cells with IgG on their surface; does NOT involve phagocytosis or complement
- lysis based on recognition of abnormal MHC I by NK cells
- effector cells: NK cells, eosinophils. NOT cytotoxic CD8+ T cells
- ex transfusion reactions
66
Complement and Fc receptor mediated inflammation (type II hypersensitivity)
- antibodies are deposited within tissues
- IgG or IgM activate complement cascade
- anaphylotoxins C3a and C5a increase vascular permeability and recruit inflammatory cells to site of antibody deposition
- ex: Goodpasture syndrome- antibody response against basement membranes
67
Antibody mediated cellular dysfunction (type II hypersensitivity)
- antibodies directed against cell surface protein receptors result in dysregulation of cellular function WITHOUT inflammatory or direct cellular injury
- may be stimulatory or inhibitory
- ex Graves disease, myasthenia gravis
68
Type III hypersensitivity
Immune Complex Mediated
Antigen combines with antibody in circulation forming circulating immune complex
Antigen-Antibody complexes deposited in blood vessels/tissue
Immune complexes activate complement
Complement induces local inflammation→cell injury; inflammatory cells further activated through Fc-R
Platelet aggregation/Hageman factor activation
Planted antigens (antigen trapped in vessel wall) may combine with antibody to form in situ immune complexes
69
Major sites of immune complex deposition
- walls of small blood vessels- vasculitis, glomerulonephritis
- joints- arthritis
- organs where blood is filtered under pressure
70
Type IV hypersensitivity
Cell Mediated Hypersensitivity
- delayed type hypersensitivity (CD4+ T cells)
- cell mediated toxicity (CD8+ T cells)
71
Delayed type hypersensitivity
Type IV hypersensitivity
- mediated by CD4+ cells
- Th1 and Th17 subtypes mediate
TH1 –Activated macrophages dominate: IL-12→ TH1→INF-ɣ Macrophage activation
TH17-Significant neutrophil component: IL-23→TH17→IL-17 Neutrophil recruitment
72
Cell mediated cytotoxicity
Type IV hypersensitivity
Preformed mediators: Perforins and Granzymes contained in lysosome like granules in CTL cytoplasm
-Mediators released on contact with target cell
-Perforins perforate cell membranes of target cell, cause osmotic lysis of target cell
-Granzymes move into cell through perforin holes, activates caspases which induce apoptosis
73
Autoimmunity can be mediated by ________ immunity, by ________ immunity, or both
cell-mediated (T cells); humoral (autoantibodies)
74
Three requirements for autoimmune disease
1. presence of autoimmune reaction
2. reaction is not secondary to tissue damage
3. absence of other defined causes of disease
75
The underlying mechanism of autoimmunity is loss of _________
self tolerance
76
immunologic tolerance
immune response is not mounted against a specific antigen
77
self tolerance
an immune response is not mounted against an individuals own antigens
78
AIRE protein
autoimmune regulator protein, in thymus, stimulates expression of self antigens on thymic APCs
mutation in AIRE--> autoimmune polyendocrinopathy
79
Four mechanisms of peripheral tolerance
1. anergy
2. supression by regulatory T cells
3. clonal deletion by activation induced cell death
4. antigen sequestration
80
Anergy
"resting" antigen presenting cells with self antigen have low expression of co-stimulatory molecules; without co-stimulation, T cell gets a negative signal and causes irreversible inactivation of that T cell
Similar in B cells but caused by only partial activation of the B cell with the absence of cytokines from specific CD4+ helper cells
81
Suppression by regulatory T cells
Regulatory T cells express CD25 and act locally to suppress autoreactive T cells by secretion of inhibitory cytokines IL-10, TGF-B
Development of regulatory T cells requires activation of transcription factor Foxp3
82
Foxp3
Transcription factor needed for development of regulatory T cells
Mutation--> IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X linked)
83
Clonal deletion by activation induced cell death
1. Pro-apoptotic gene Bim triggers apoptosis in autoreactive T-cells by mitochondrial pathway
2. Fas-Fas ligand system triggers apoptosis in auto- reactive T and B cells by Death Receptor Pathway
- Persistent activation of autoreactive T and B cells by self antigens results in persistent expression of FasL. Fas-FasL engagement induces apoptosis
84
Antigen sequestration
- Testis, eye and brain are immune privileged sites
-Antigens in these sites hidden from immune system but may be released by trauma or infection
-Immune response to “neo antigens” →inflammation
Examples: Post-traumatic orchitis and Uveitis
85
Gene most frequently implicated in autoimmunity
PTPN-22
encodes for tyrosine phosphatase, mutation causes excessive uncontrolled lymphocytic activity and autoimmune disease
associated with RA, Type I DM, others
others:
- AIRE→ autoimmune polyendocrinopathy
- Foxp3→IPEX
- Fas→Autoimmune Lymphoproliferative Syndrome
86
Explain two mechanisms by which infection can lead to induction of autoimmune disease
1. up-regulation of co-stimulatory molecules: cytokines produced during infection induce expression of costimulators, allowing T cells to become activated upon Ag presentation, normal peripheral tolerance mechanisms are bypassed/ineffective
2. Molecular mimicry: infecting microbes express antigens similar to self antigen, causing generation of self-reacting lymphocytes ex rheumatic heart disease
87
Define epitope spreading
autoimmune disease persists and evolves following infection- release and damage of self antigens causes new and altered epitopes to be exposed, continued activation of new lymphocytes specific for the new self epitopes allows for progression of autoimmune disease
88
Anti-nulcear antibody types
Antibodies to DNA
Antibodies to histones
Antibodies to non-histone proteins bound to RNA
Antibodies to nucleolar antigens
89
Describe how the pattern of anti-nuclear antibody staining indicates the antigen type targeted by the antibody
Homogenous/ diffuse= chromatin, histones
Rim/ peripheral= dsDNA
Speckled pattern= common and least specific
Nucleolar pattern with few discrete spots= RNA
90
autophosphlipid antibodies
- relatively common in SLE patients
- target plasma proteins, epitopes revealed when protein binds to phospholipid
- antibodies also bind to cardiolipin which is used in screening for syphilis so lupus patients might have false positive syphilis screening
- antiphospholipid antibodies also interfere with clotting tests- falsely indicating impaired clotting mechanisms when actually patients have hypercoagulable state
91
In immunoflourescence of the skin in a patient with SLE, there will be deposition of ___________ along the _____________
IgG and complement; dermal-epidermal junction
92
Pathology of CNS manifestations of SLE
Seizure or psychosis, must be in absence of drugs or metabolic disorders
- Ascribed to vascular injury in central nervous system
- Antiphospholipid antibodies damage endothelium
- Intimal proliferation results in small vessel occlusion
- Focal ischemia in CNS results in neurologic disorder
93
Pathology of skin manifestations of SLE
Malar (facial butterfly) rash characteristic (50%)
- Sunlight exposure induces or accentuates the rash
- Edema, inflammation and vasculitis in the dermis
- Deposition of IgG and complement along the DEJ
94
What type of endocarditis is typical of SLE?
Libman Sacks endocarditis- non- bacterial, verrucous endocarditis consistiong of nodular fibroinflammitory deposits on BOTH valve surfaces
95
Differentiate the form of endocarditis associated with SLE from other forms of endocarditis
1. Rheumatic Heart Disease- Row of small vegetations.
2. Infective Endocarditis- Bulky, destructive vegetations
3. Non-Bacterial Thrombotic Endocarditis- Sterile, bland lesions on the leaflets without inflammation or tissue destruction
4. Libman-Sacks Endocarditis- Vegetations on both surfaces
96
Antibody: ANA
Antigen: many nuclear antigens
Diseases: SLE, drug induced LE, systemic sclerosis/ CREST, Sjogren
97
Antibody: anti-dsDNA
Antigen: native DNA
Disease: very specific for SLE
98
Antibody: anti-histone
Antigen: histones
Diseases: drug induced LE, SLE
99
Antibody: anti-Sm
Antigen: RNP Smith antigen
Diseases: very specific to SLE
100
Antibody: nuclear RNP
Antigen: ribonuclearprotein U1RNP
Diseases: SLE, mixed connective tissue disease (MCTD)
101
Antibody: SS- A (Ro) and SS-B (La)
Antigen: RNP
Diseases: Sjogren (common), SLE (less common)
102
Antibody: Anti Scl-70
Antigen: DNA topoisomerase I
Disease: systemic sclerosis, CREST
103
Antiboyd: anti-centromere
Antigen: centromeric proteins
Disease: CREST (common)
104
Antibody: Anti Jo-1
Antigen: histidyl-t-RNA synthase
Disease: inflammatory myopathies
105
List four categories of immune-mediated vasculitis
1. immune complex mediated (SLE, RA, drug induced)
2. direct antibody attack mediated (Goodpasture, Kawasaki)
3. cell mediated (allograft rejection)
4. antineutrophil cytoplasmic antibody (ANCA) mediated (Wegeners, Churg Strauss, microscopic polyangiitis)
106
List three major etiologic classifications of vasculitis
1. direct infection
2. immune mediated
3. unknown
107
Anti- Neutrophil Cytoplasmic Antibodies (ANCA)
Heterogeneous group of auto-antibodies against enzymes mainly found within the primary granules in neutrophils and in lysosomes of monocytes and in endothelial cells.
108
List vasculitis associated with pANCA
Churg- Strauss syndrome, microscopic polyangiitis
109
List vasculitis associated with cANCA
Wegener's granulomatosis
