Immunodeficiency Flashcards
1
Q
Secondary immunodeficiency diseases arise from
A
Infection with agents that deplete immune cells, malnutrition or treatments with immunosuppressive drugs.
2
Q
Antibody deficiency is due to…
A
B cell problems or facts in T cells affecting maturation of B cells
3
Q
Combined immunodeficiencies affect
A
Both B and T cells
4
Q
Phagocytes cell disorders affect
A
Granule yet and macrophages
5
Q
Complement deficiencies affect
A
Function or regulatory components of the complement system
6
Q
Immune regulation is when
A
Influencing mechanisms are designed to control autoimmune disease, apoptosis or immune pathology
7
Q
Primary immunodeficiency diseases arise from?
A
Intrinsic defects in cells and mediators of the innate and adaptive immune system
8
Q
The outcome of antibody deficiency is
A
Pus forming pyogenic infections. Incl. H. influenzae, S. pneumoniae, S. aureus
9
Q
Outcome of combined immunodeficiency is…
A
Infection by bacteria, viruses & opportunistic pathogens
10
Q
Neutrophil immunodeficiency leads to….
A
Bacterial and fungal infections
11
Q
Macrophage immunodeficiency leads to…
A
Mycobacterial diseases - they replicate in phagosomes of macrophages. There is an inability to clear mycobacterium when macrophages become affected
12
Q
Toll-like receptor immunodeficiency leads to
A
Infection with TLR specific pathogens
13
Q
Complement immunodeficiency leads to…
A
Pyogenic infections. Deficiencies can also increase susceptibility to autoimmune diseases (i.e. SLE) because, complement is a way of clearing apoptotic bodies from the blood stream. If complement doesn’t work, the DNA and his tones can cause links to systemic lupus.
14
Q
What does XLA stand for?
A
Congenital agammaglobulinamia (X-linked)
15
Q
What mutation causes XLA and what phenotype does it cause?
A
Mutation at the Bruntons tyrosine kinase (btk) gene that leads to a severe block in B cell development (at the pre-B to immature B cell stage)
16
Q
What other gene mutation gives rise to a similar phenotype?
A
Mutation in the adaptor protein BLNK but 80-90% of affected with XLA have mutations in BTK
17
Q
XLA children symptoms:
A
Lack IgA, M, D & E and have low IgG. Virtually no circulating B cells. No tonsils and tiny lymph nodes.
18
Q
Why do XLA children survive normally for the first 6 months?
A
Protection from maternal immunoglobulins
19
Q
How do you treat children with XLA?
A
Regular IgG injections
20
Q
How does IgA deficiency arise?
A
IgA secreting B cells are unable to differentiate
21
Q
Hyper IgM leads to…
A
No IgG, IgA, IgE
22
Q
Common Variable Immune Deficiency (CVID) has what effect on Ig secretion
A
Affects differentiation of most plasma cells but get IgM from immature B cells.
23
Q
What is the most common immunodeficiency?
A
CVID 1:10000
24
Q
A common pathology seen in hyper IgM syndrome is
A
Lymph node with no germinal centres
25
Patients with CVID are at high risk of
Autoimmune complications, granulatomous lesions, lymphoid hyperplasia, lymphoma
26
Giardia lamblia is a normally copable pathogen, when and where can it cause infection?
Infection in the GI tract due to a lack of IgA
27
What leads to hyper IgM syndrome?
CD40L deficiency. CD40L activates B cells (by T cells). This activation is required for class switch and formation of germinal centres where extensive B cell proliferation occurs.
28
Severe combined immunodeficiency (SCID) affects which immune cells
T cells
29
Adenosine deaminase and purine nucleoside phosphorylase affects what pathway that leads to SCID?
Thymocytes survival pathway
30
JAK3 and IL-7R genes when affected lead to what pathway being affected in SCID?
Lymphoid progenitor expansion
31
RAG1 or RAG2 genes affect what pathway in SCID?
Pre-T cell receptor
32
Pre-TCR signalling pathway is affected by which genes to lead to SCID?
CD3 and CD45
33
Positive selection of T cells is affected by what genes to cause SCID?
HLA class II & ZAP-70 (one of the early signalling molecules in T cell activation)
34
The calcium signalling pathway is affected by what genes to lead to SCID?
Stim 1 and Orai 1
35
Where is thymic epithelium derived from?
3rd and 4th pharyngeal pouches at 6 weeks gestation
36
What is the DiGeorge anomaly?
Congenital defects in organs derived from the 3rd and 4th pharyngeal pouches. Including the face and the heart.
37
What do Fas and FasL control?
Lymphocyte homeostasis
38
What disorders do defects in Fas and FasL give rise to?
Fas: Lpr mouse & ALPS type 1a in man FasL: Gld mouse & ALPS type 1b in man
39
FoxP3 is what to Treg cells?
A master gene
40
Where is the AIRE gene expressed and what does it control?
In the thymus and controls expression of self antigens. It leads to the deletion of self reactive cells.
41
What happens if AIRE is mutated?
Self reactive cells are able to leave the thymus leading to APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy.
42
Two diseases that arise due to defects in phagocytes are
Chronic granulatomous disease and leukocyte adhesion deficiency
43
What is the reaction for the breakdown of NADPH and the enzyme that carries out the reaction?
NADPH + 2O2 -\> NADP+ + 2O2- + H+ NADPH oxidase
44
Why is the oxidation of NADPH so important in phagocytes?
It produces superoxide anions which are antibacterial and this can generate hydrogen peroxide which combined are very important for control of infection in phagosomes of WBCs
45
What disease arises due to defective NADPH oxidaseB
CGD
46
Without NADPH oxidase, patients with CGD have an inability to........... Which leads to........ Children with CGD develop.........
1. Clear infection 2. Leads to granule a formation 3. Pneumonia, LN infections and abscesses in skin and live etc.
47
Type I LAD develops as a result of what?
CD18 defects which forms a major chain of a family of integrins including LFA-1 and CR3. Defects in CD18 prevents the cells from adhering to the vascular endothelial wall. Defects in CR3 also affects binding to opsonised bacteria via C4bi receptor.
48
Type II LAD occurs as a result of what?
Sialyl Lewis (sugar expressed on CD15) is dysfunctional because of a defect in a fucose transporter. SLX is required for leukocyte adhesion via E-selectin in the tethering stage of leukocyte adhesion.
49
What group of genetic complement deficiencies is autosomal dominant and what is it a deficiency in?
group II, causes angioedema by a C1 inhibitor deficiency
50
Why do Group I genetic complement deficiencies cause immune complex disease and what factors cause the effects? What type of genetic disease are they?
C1q, C1s (or C1r and C1s), C2, C4 These all reduce the size of an immune complex. Autosomal recessive.
51
Recurrent pyogenic infections occur in group III genetic complement disorders, what factors and involved and why do they have this effect?
C3, factor H, factor I. These factors cause pyogenic infections because, all are early triggers in both the classical and alternative complement pathways (C3 is the first trigger in both pathways). They promotes bacterial opsonisation and take up of bacteria by neutrophils and phagocytes.
52
Deficiencies in C9 complement causes what type of defect?
Asymptomatic
53
Are genes and mutations involved in secondary immunodeficiencies?
No.
54
How do infection and malnutrition affect each other?
They interrelate and promote each other. Malnutrition = depletion of protein-energy reserves and decreased immunity. Infection = decreased absorption, increased catabolism, decreased intake via anorexia, nausea and vomiting and increased nutrient from urine and faeces.
55
When are immunosuppressive drugs likely to be given?
For long periods after solid organ or bone marrow transplant
56
What are glucocorticoids used for?
To treat allergy symptoms and autoimmune conditions.
57
What interleukins do Glucocorticoids reduce?
IL-1, IL-6, IL-8 and IL-12 secretion
58
Glucocorticoids suppress:
Prostaglandin, COX2 synthesis and mast cell degranulation as well as, MHC II , CD80 & CD86 expression by APC's. This blunts the innate and adaptive immune responses.
59
What are the 5 evolved components of natural immunity
Physical barriers, phagocytosis, lectins, enzymes, NK cells
60
What are the 5 factors of acquired immunity?
Antibodies, lymphocytes, antibody receptors, lymph nodes, regulation
61
Immunoglobulins and TCRs equip mammals with the capacity for...
Acquired immunity to antigens
62
What enzyme adds bases to the J region as antibodies are generated?
Terminal nucleotide transferase
63
What is immunological tolerance?
There is central tolerance and peripheral tolerance as well as self-tolerance ( a number of mechanisms that protect the individual from self reactive lymphocytes).
64
What is the difference in affinity maturation of B and T cells?
T cells do not undergo somatic hypermutation in the TCR genes.
65
When T cells enter the thymus they have no TCR or CD4 or CD8, what is this called in terms of CD molecules?
Double negative
66
What is the pre-Talpha
A molecule that mimics the TCR alpha chain and binds the beta chain. It selects for a beta chain that will bind and fold correctly. Once a beta chain has been selected for the TCR alpha chain can be selected.
67
What does the pre-Talpha chain signal?
Allelic exclusion where beta chain expression from one chromosome prevents beta chain expression off of the other chromosome. This is not the case for the the alpha chain, meaning you can get two alpha chains being expressed.
68
Why do 98% of all thy oxygen die by apoptosis?
Because firstly they do not have a TCR that is able to interact with MHC or because of negative selection and their MHC receptor has high affinity for self MHC or (self MHC + self antigen) on an APC such as a macrophage or a DC. Also if there are cells with higher affinity the T cells are not selected.
69
Where does negative selection occur?
Mainly on the medullary dendritic cells and macrophages.
70
What is positive selection and where does it occur?
Selection of cells whose receptor (TCR) binds MHC molecules on cortisol epithelial cells in the thymus.
71
If a TCR does not have a good enough for with the MHC, what happens?
It does not get positive signals for selection.
72
Define epitope...
An epitope, also known as an antigenic determinant, is the part of an antigen that is recognised by the immune system, specifically by antibodies, B cells or T cells.
73
What is an example, function and action location of the protein that is recognised as a self antigen in Multiple Sclerosis?
Myelin basic protein which forms part of the myelin sheath is made and expressed in the thymus.
74
Pro B cells receive signals of what from where to c-kit?
Signals from stem cell factor expressed on bone marrow stromal cells
75
What is IL-7 to a pro B cell?
A growth factor, it causes proliferation to pre- B cells
76
What proteins are the surrogate light chain made up of?
VpreB and lambda5 associate non covalently.
77
How many divisions does a B cell undergo before the correct light chain is produced?
6-8
78
How specific is the surrogate chain?
Non specific
79
What stops heavy chain rearrangement before the light chain is rearranged and is the same mechanism in place for the light chain?
Allelic exclusion and no, this does not occur for the light chains, the 2 light chains can rearrange one after the other from each allele.
80
What happens if a developing B cell receptor links strongly with a self antigen?
Cell development is arrested (less Ig production). However, there is continued expression of RAG genes and this allow further light chain rearrangement (from the second allele). The new light chain couples with the existing heavy chain to give a new receptor. If the new receptor does not interact strongly with self-antigen the immature B cell migrates to the periphery and matures. If the new light chain is still self reactive, the B cell undergoes apoptosis.
81
What enzyme is used to prove receptor editing?
Hen egg white lysozyme
82
How was it shown that receptor editing occurs?
Transgenic mouse expressing HEL as self antigen x transgenic mouse expressing anti-HEL on B cells. F1 mouse expresses HEL as a self antigen and possesses B cells specific for HEL. B cells negative for HEL are negatively selected in the marrow: most B cells auto reactive with HEL are deleted. Some undergo receptor editing, this is shown by B cells being released that are not auto reactive with HEL.
83
A self reactive cell can escape the thymus by sequestration, what is sequestration?
Antigen hidden physically (barrier) or functionally (lack of APC) from immune system.
84
A self reactive cell can escape the thymus via homeostasis, explain how
The T lymphocyte pool size is controlled by growth factors and apoptosis.
85
What are the four ways a self reactive cell can escape the thymus?
Sequestration, privileged site, homeostasis, immune regulation.
86
tTrred and FoxP3 cells can be induced in vivo by...
TCR stimulation in the presence of TGFbeta
87
Why are tTreg cells and induced Treg cells anergic?
They fail to secrete inflammatory cytokines such as IL-2 and suppress the activation of neighbouring T cells.
88
Scurfy mice defect is mapped to....
The forkhead/winged helix transcription factor, FoxP3
89
In what cells is FoxP3 expressed at high levels?
CD25++ Treg cells
90
What do FoxP3 Treg cells secrete?
IL-10 and TGFbeta as well as other suppressive cytokines
91
As most Treg cells express high levels of CD25 what does this mean for IL-2?
CD25 is a high affinity IL-2 receptor and therefore Treg cells compete with other cells for IL-2.
92
How might a Treg cell function (4 possibilities)
1. Granzyme B 2. TGFbeta 3. CTLA-4 (induces IDO) 4. CD25 (to compete for growth factor)
93
FoxP3 Treg cells limit activation of self reactive T cells this is predominantly clear after
Infection or environmental stress.
94
When do autoimmune diseases arise?
When the immune system responds to self antigens and triggers antibody production against and/or inflammation in the target organ
95
Type I diabetes sufferers are often predisposed with what HLA allele?
DR3 & 4
96
Multiple sclerosis affects how many people and they are likely to be predisposed to which HLA allele?
1/1000 and DR2
97
What are the factors that contribute to an autoimmune disease?
Polygenic, environment, a relationship between susceptibility and resistance genes, an infectious agent, MHC is a major contributor to all autoimmune diseases
98
If you have to DR2 allele how much more likely are you to develop MS?
5 fold
99
Why are AID much more common in women?
Potentially due to women having stronger immune systems in order to allow them to deal with infection when carrying child etc.
100
Rheumatic heart disease is caused by what infectious agent and how
Group A streptococci and molecular mimicry
101
Multiple sclerosis is said to be made to relapse by what infectious agent?
URTI - strong correlation
102
What do the causative infections have that enable them to cause AID and the various relapses?
Molecular mimicry of self carbohydrates, but there is no evidence that a single infection causes any single AID.
103
As the incidence of infectious diseases decreased from 1950-2000, the incidence of immune disorders...
Increases
104
Graves' disease leads to
Hyperthyroidism
105
Rheumatoid arthritis in terms of autoimmunity is...
Auto reactive T cells vs thyroid antigens leader to HYPOTHYROIDISM
106
TID in terms of autoimmunity is
T cells vs islet antigens that leads to islet beta cell destruction
107
Multiple sclerosis in terms of autoimmunity is
T cells vs brain antigens which leads to destruction of the myelin sheath and loss of nerve axons
108
SLE in terms of autoimmunity is...
Antibodies to DNA, chromatin, proteins and ribonucleoprotein antigens causing glomerulonephritis, vascular is and rash
109
Sjorgren's syndrome in terms of autoimmunity is
Antibodies and T cells vs ribonucleoprotein antigens giving lymphocyte infiltration leading to exocrine gland dysfunction.
110
Hashimoto's disease is organ specific hypothyroid disease it leads to
Destruction of thyroid gland and produces reduced amount of thyroxin and other thyroid hormones
111
Goodpasture's syndrome has what pathology?
Linear deposits of auto-antibody along the basement membrane of the kidney, targeting the alpha3 chain of type IV collagen
112
Autoimmune diseases come in 3 classes...
1. Organ specific 2. Diseases caused by stimulating or blocking antibodies 3. Systemic autoimmune diseases
113
Ratio of SLE in female to males is
10:1
114
Symptoms of SLE ARE...
Fever, weakness, arthritis, skin rashes, pleurisy and kidney dysfunction
115
SLE forms antibodies to
DNA, histones, RBC, platelets, leukocytes, and clotting factors
116
In SLE where do immune complexes deposit?
The vascular endothelium and cause vasculitis as well as nephrons and cause nephritis
117
Type I hypersensitivity is caused by
Allergens
118
Allergen:
an antigen that gives rise to immediate hypersensitivity
119
What mediated type I hypersensitivity?
Ige
120
What cells are involved in TIHS and what do they contain?
Mast cells and basophils and they contain histamine, leukotrienes and cytokines, prostaglandins, serotonin
121
How is TIHS treated?
Antigen-specific immunotherapy
122
What causes TIIHS?
IgG, IgA & IgM antibodies against the cell surface or ECM
123
TIHS (or intermediate HS) causes what prototypic disorder
Anaphylaxis, allergies and asthma
124
TIHS has what pathogenic lesions?
Vascular dilation, odema, smooth muscle constrictions and mucus production
125
TIIHS has what prototypic disorder?
Autoimmune haemolytic anaemia
126
TIIHS has what pathologic lesions?
Phagocytosis and lysis of cells + inflammation
127
TIIIHS has what type of prototypic disorder?
Systemic lupus erythromatosus
128
TIIIHS has what pathologic lesions?
Necrotising vasculitis, inflammation
129
TIVHS has what type of prototype disorder?
Contact dermatitis and autoimmune diseases
130
TIVHS has what pathologic lesions?
Perivasclar cellular infiltrates, oedma, granuloma formation.
131
What is the PK test?
Praunitz & Kustner test. Inject person A's serum into a healthy person, then 24hrs later inject their suspected allergen into healthy person. If there is a response then A is allergic to the allergen.
132
What does IgE have?
An extra constant region domain, a different hinge region, high affinity and low affinity IgE receptors (FceRI and FceRII). FceRI is only on mast cells and basophils which are the only cells capable of secreting high levels of histamine.
133
Why do we need immediate hypersensitivity?
late phase reaction to helminths and insect larval infestation involving eosinophils
134
If an antigen is administered systemically when there is pre-formed IgE it leads to:
anaphylactic shock
135
Subcutaneous administration of antigen results in:
wheal and flare reaction
136
Activation of mast cells and basophils results in:
Exocytosis of granules containing histamine and serotonin, synthesis of lipid mediators such as prostaglandin D2 and leukotrienes. Secretion of cytokines IL-1, IL-4, IL-5, IL-6 TNF.
137
Susceptibility of allergy increases how much if mother OR father have it. Plus, mother AND father
OR: 30% AND: 50%
138
IgE antibodies:
IgE have a shorter serum half life than other immunoglobulins, it is primarily made in response to allergens and parasites, is bound to high affinity FceRI on mast cell. IgE synthesis by B cells is strictly T cell dependent.
139
In response to allergens, Th1 produces: Th2 produces:
Th1: IFN-gamma and IL-10 Th2: IL-4, IL-5, IL-13
140
IgG4 and IgE are both dependent on? and function how?
IL-4, IgG4 blocks the binding of IgE
141
A Th2 secrets IL-4 and IL-10 is also present what immunoglobulin is produced?
IgG4 NOT IgE
142
Why do children living in a house with a cat not become allergic?
Because they can make IgG4 antibodies for the FelD1 allergen that may not suffer from cat allergy due to IgE being blocked.
143
Allergens are derived from:
grass pollen, mite fecal matter and animal dander
144
Do allergens elute readily in aqueous solution?
YES
145
Basophils are recruited to local sites by?
cytokines from T cells or mast cells
146
What activates mast cells and basophils?
cross-linking of high affinity FceRI by allergen
147
What are direct triggers of mast cells?
Opiates, antibiotics, complement can cause IgE independent degranulation.
148
Why does a) wheal form and b) flare form and c) how long does this take?
a) Extravasion of serum from capillaries due to histamine b) erythromatous flare is a axonal reflex c) 5-15mins and persists for 30+ mins
149
On triggering of mast cells what is secreted and how long do they take to form?
Pre-formed granule mediators (5 mins) - histamine, tryptase & heparin Newly generated (5-30mins) - arachidonic acid, prostaglandin D2, leukotriene D4 Cytokines (hours) IL-4 and TNFalpha.
150
Mediators released in an inflammatory response in asthmatic bronchi?
Spasmogens: histamine, leukotrienes, prostglandins Chemotactic factors: TNF-alpha and IL-5
151
Final step of inflam response in asthmatic bronchi
inflammation and bronchiole hypersensitivity as well as cell infiltrate, increase mucus and increased muscle, chronic broncospasm
152
Treatment of allergy and asthma:
Corticosteroids, inhibit influx of eosinophils, basophils and lymphocytes, reduce IL-5 and TNF-a and reduce T cell activity
153
What is antigen specific immunotherapy to treat TIHS?
Increase blocking of IgG, decrease response oof lymphocyes to antigen, decrease late reaction. Adjuvants to promote Th1 response antibodies to IgE, soluble IL-4 receptors.
154
What does the graph look like for allergen conditioning? draw
DRAW. (then look if necessary) and DESCRIBE.
155
Write out the complement cascade:
check.
156
Three mechanisms that TIIHS can be stimulated?
1. Fc receptor mediates 2. complement lytic pathway 3. C3 receptor mediated.
157
Opsonization is:
Coating of antigen/cell with antibody, leading to complement activation and phagocytosis.
158
Phagocytes have which C3 receptors and what other receptor:
CR1, CR3, CR4 and FcR
159
Effector mechanisms that cause TIIHS
1. Neutrophil adhesion to the basement membrane via antibody or complement 2. The tissue is too large for the neutrophil to phagocytose so it becomes FRUSTRATED 3. Neutrophils undergo extracellular enzyme release where they exocytose their lysosomal content causing damage to surrounding cells.
160
TIIHS reactions that can occur due to red blood cells:
Incompatible blood transfusions, haemolytic disease of the newborn, autoimmune haemolytic anaemia.
161
How do different blood group antigens form? DRAW
D-NAG-GAL
162
What blood group are universal donors?
O group
163
ABO incompatibility with the newborn is:
usually not severe - mild anaemia and transient jaundice
164
RhD incompatibility can be severe:
neonatal jaundice, enlargement of the liver and spleen, hydrops fetalis and stillbirth
165
What does sensitizing T cells to RhD+ do?
helps anti-RhD cells resulting in class switching to IgG which can then cross the placenta in subsequent pregnancies causing erythrocyte destruction
166
How is RhD incompatibility prevented?
Mother is injected with antibodies to the RhD antigen immediately after the birth of the first RhD+ child, preventing sensitization
167
Autoimmune haemolytic anaemia occurs:
when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases.
168
Examples of autoimmune haemolytic anaemia include:
Warm-reactive antibodies bind antigen at 37c (mainly RhD spec) Cold reactive antibodies bind antigen at
169
Where are autoantibodies to platelets now seen and in what percentage of patients?
70% of idiopathic thrombocytopenia purpura patients
170
What is ITP accelerated by?
Removal of platelets by splenic macrophages and often triggered by infection
171
Autobodies to self antigens in goodpastures syndrome:
antibodies to collagen type IV resulting in necrosis of the glomerulus
172
Autobodies to self antigens in pemphigus are
antibodies to desmoglein 1 or 3 results in the blistering of the skin
173
Autobodies to self antigens in Myasthenia gravis:
Antibodies to acetylcholine receptors results in severe muscle weakening. Antibodies actually remove the entire ACh receptor so they are few in the postsynaptic folds. Antibody mediated endocytosis of antibody: ACh receptor complex.
174
Infection with agents that deplete immune cells, malnutrition or treatments with immunosuppressive drugs.
Secondary immunodeficiency diseases arise from
