Immunology Flashcards
1
Q
Liver Macrophage
A
Kupffer cell
2
Q
Kidney Macrophage
A
Mesangial cell
3
Q
Bone Macrophage
A
Osteoclast
4
Q
Spleen Macrophage
A
Sinusoidal lining cell
5
Q
Lung Macrophage
A
Alveolar macrophage
6
Q
Neural tissue Macrophage
A
Microglia
7
Q
Connective tissue Macrophage
A
Histiocyte
8
Q
Skin Macrophage
A
Langerhans cell
9
Q
Joint Macrophage
A
Macrophage like synoviocytes
10
Q
What produces superoxide and hydrogen peroxide?
A
NADPH oxidase complex converts oxygen into reactive oxygen species
11
Q
What enzyme catalyses production of hydrochlorous acid?
A
Myeloperoxidase, using hydrogen peroxide and chloride
12
Q
2 examples of bacteriocidal enzymes
A
Lysozyme and lactoferrin
13
Q
What is mediated by Toll like receptors which recognise pathogen associated molecular patterns?
A
Pathogen recognition
14
Q
What may be mediated by antibodies, complement components or acute phase proteins and facilitates phagocytosis
A
Opsonisation
15
Q
What describes killing mediated by reactive oxygen species generated by action of the NADPH oxidase comple
A
Oxidative killing
16
Q
What may be mediated by bacteriocidal enzymes such as lysozyme
A
Non-oxidative killing
17
Q
What do natural cytotoxicity receptors recognise and on which cell type are they?
A
Heparan sulphate proteoglycans by natural killer cells
18
Q
What receptor mediates migration of dendritic cells via lymphatics to lymph nodes?
A
CCR7
19
Q
What cells are derived from monocytes and resident in peripheral tissues?
A
Macrophages
20
Q
What are polymorphonuclear cells capable of phagocytosing pathogens and killing by oxidative and non-oxidative mechanisms?
A
Neutrophils
21
Q
What are lymphocytes that express inhibitory receptors capable of recognising HLA class I molecules and have cytotoxic capacity?
A
Natural killer cells
22
Q
What are immature cells are adapted for pathogen recognition and uptake whilst mature cells are adapted for antigen presentation to prime T cells?
A
Dendritic cells
23
Q
What are the primary lymphoid organs?
A
Those involved in lymphocyte development:
Bone marrow and Thymus
24
Q
What are the secondary lymphoid organs?
A
Anatomical sites of interaction between naive lymphocytes and microorganisms:
Spleen, Lymph nodes, Mucosal associated lymphoid tissue
25
What type of cell expresses CD3
T cell
26
MHC Class II receptor types
HLA-DP
HLA-DQ
HLA-DR
27
What CD4+ T cell subset develops in the presence of IL-12 and interferon gamma?
Th1 cells - these help CD8+ T cells and macrophages
28
What CD4+ T cell subset develops in the presence of IL-6 and TGF-beta?
Th17 cells - these help neutrophil recruitment and enhance the generation of autoantibodies
29
What CD4+ T cell subset develops in the presence of TGF-beta?
Treg cells - these express IL-10/TGF-beta and CD25+ Foxp3+
30
What CD4+ T cell subset develops in the presence of IL-6, IL-1-beta and TNF-alpha?
TFh - follicular helper T cells
31
What CD4+ T cell subset develops in the presence of IL-4 and IL-6?
Th2 cells - helper T cells
32
MHC Class I receptor types
HLA-A
HLA-B
HLA-C
33
What do Th1 cells secrete?
IL-2, IFN-gamma, TNF-alpha, IL-10
34
What do Th17 cells secrete?
IL-17, IL-21, IL-22
35
What do Treg cells secrete?
IL-10, Foxp3+, CD25+
36
What do TFh cells secrete?
IL-2, IL-10, IL-21
37
What do Th2 cells secrete?
IL-4, IL-5, IL-6, IL-10, IL-13
38
What cells express receptors that recognise peptides usually derived from intracellular proteins and expressed on HLA class I molecules?
CD8+ T cells
39
What subset of lymphocytes that express Foxp3 and CD25?
T regulartory cells
40
What subset of cells that express CD4 and secrete IFN gamma and IL-2?
Th1 cells
41
What cells play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells?
T follicular helper (TFh) cells
42
What cell surface receptors/ligands are required for CD4+ T cell / B cell interaction?
CD40L:CD40
43
What cell is dependent on the presence of CD4+ T cell help for generation?
IgG secreting plasma cells
44
Which cells are generated rapidly following antigen recognition and are not dependent on CD4+ T cell help?
IgM secreting plasma cells
45
What divalent antibody present within mucous which helps provide a constitutive barrier to infection?
IgA
46
What is the area within secondary lymphoid tissue where B cells proliferate and undergo affinity maturation and isotope switching?
Germinal centre
47
What include both the bone marrow and thymus; sites of B and T cell development?
Primary lymphoid organs
48
What carries lymphocytes from lymph nodes back to the blood circulation?
Thoracic duct
49
What is the site of deletion of T cells with inappropriately high or low affinity for HLA molecules and of maturation of T cells into CD4+ or CD8+ cells?
Thymus
50
What are the three pathways of complement activation?
Classical - C1q binding to antibody-antigen complexes, activating C4 + C2 = C4b2a C3 convertase.
Lectin - MBL binding to oligosaccharides on certain virions/infected cells, activating C4 + C2 = C4b2a C3 convertase.
Alternative - spontaneous breakdown of C3 in serum that then binds to bacterial cell wall components, involving factors B+I+P = C3bBbP C3 alternative convertase.
51
What is the major amplification step in the complement cascade?
Activation of C3. This then triggers the formation of the membrane attack complex C5-C9
52
Binding of immune complexes to this protein triggers the classical pathway of complement activation
C1
53
Cleavage of this protein may be triggered via the classical, MBL or alternative pathways
C3
54
What binds to microbial surface carbohydrates to activate the complement cascade in an immune complex independent manner?
MBL
55
Part of the final common pathway resulting in the generation of the membrane attack complex?
C5-C9
56
What are ligands for CCR7 and what are they important for?
CCL19 and CCL21 (Chemokines)
| Important for directing dendritic cell trafficking to lymph nodes
57
What clinical features to do with infection suggest immunodeficiency?
- 2 major or 1 major and recurrent minor infection in 1 year
- unusual organisms or sites
- unresponsive to oral antibiotics
- chronic infection
- early structural damage
58
What clinical features (other than infection) may be suggestive of a primary immune deficiency?
- Failure to thrive
- Skin rash (eczema)
- Chronic diarrhoea
- Mouth ulcerations
- Family history
59
Examples of secondary immunodeficiencies
- Infection (HIV, Measles, Mycobacteria)
- Biochemical disorders (Malnutrition, Diabetes, Renal insufficiency, mineral deficiencies (zinc, iron))
- Malignancy (Myeloma, Leukaemia, Lymphoma)
- Drugs (Corticosteroid, Anti-proliferative immunosuppressants, Cytotoxic agents)
60
IgA deficiency
- Complete affects 1:600 Caucasians
| - 30% associated with recurrent respiratory and gastrointestinal tract infection
61
Examples of organisms that rapidly colonise following depletion of commensal bacteria
Candida albicans
| Clostridium difficile
62
What causes failure of stem cells to differentiate along myeloid or lymphoid lineage?
Reticular dysgenesis - autosomal recessive severe SCID.
| Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
63
What is Kostmann syndrome?
Autosomal recessive severe congenital neutropenia.
| Classical form due to HCLS1-associated protein X-1 (HAX1) mutation
64
What is caused by a mutation in ELA-2?
Cyclic neutropenia - autosomal dominent episodic neutropenia every 4-6 weeks.
ELA-2 = neutrophil elastase.
65
What is Leukocyte adhesion deficiency?
Deficiency of CD18 (Beta-2 integrin subunit)
| Characterised by very high neutrophil counts in blood and the absence of pus formation
66
Deficiency of components of NADPH oxidase causes what disease?
Chronic granulomatous disease
- absent respiratory burst due to inability to generate oxygen free radicals leads to impaired killing of intracellular micro-organisms
- excessive inflammation due to persistent neutrophil/macrophage accumulation and failure to degrade antigens
- granuloma formation
- lymphadenopathy and hepatosplenomegaly
67
What tests are used to investigate chronic granulomatous disease?
- nitroblue tetrazolium (NBT) test - changes from yellow to blue in hydrogen peroxide produced
- dihydrorhodamine (DHR) flow cytometry test - when oxidised by hydrogen peroxide rhodamine is strongly florescent
Both are negative in chronic granulomatous disease
68
Which cytokines are important in defence against intracellular organisms (esp. mycobacteria)? Which cells produce them and what do they do?
- IL-12 and IFN-gamma
- infected macrophages produce IL-12
- IL-12 induces T cells to secrete IFN-gamma
- IFN-gamma activates NADPH oxidase in macrophages and neutrophils and stimulates them to produce TNF
- Any defect in cytokine or receptor production may cause susceptibility to mycobacterial infections
69
How are phagocyte deficiencies managed?
- infection prophylaxis with septrin (Abx) and intraconazole (anti-fungal)
- aggressive management of infections
- surgical drainage of abscesses
70
What definitive therapy is available for phagocyte deficiencies and what specifically chronic granuloumatous disease?
- Bone marrow transplantation.
| - Interferon gamma therapy for CGD
71
What are the immunodeficiencies involving phagocytes?
- reticular dysgenesis
- kostmann syndrome
- leukocyte adhesion deficiency
- chronic granulomatous disease
- IL-12 / IFN-gamma cytokine or receptor deficiency
72
What causes recurrent infections with high neutrophil count on FBC but no abscess formation?
Lymphocyte adhesion deficiency
73
What causes recurrent infections with hepatosplenomegaly and abnormal dihydrorhodamine test?
Chronic granulomatous disease
74
What causes recurrent infections with no neutrophils on FBC?
Kostmann syndrome
75
What causes infection with atypical mycobacterium, normal FBC?
IL-12 / IFN-gamma cytokine or receptor deficiency
76
What is reticular dysgenesis?
- most severe form of SCID
- mutation in mitochondrial adenylate kinase 2 (AK2)
- failure of production of all granulocytes and decreased lymphocytes
- fatal in early life unless bone marrow transplant
77
What is the clinical phenotype of a child with SCID?
- unwell by 3 months (maternal IgG protects infant initially)
- multiple types of infection
- failure to thrive
- persistent diarrhoea
- unusual skin disease
- Fx of early infant death
78
What is the commonest form of SCID by what %?
X-link SCID - 45%
79
What is the mutation in X-linked SCID?
- Gamma chain of IL-2 receptor (that is also shared by multiple other cytokine receptors)
- causes an inability to respond to cytokines = early arrest of T + NK cells, immature B cells
80
In what condition is there thymic hypoplasia due to a developmental defect of 3rd/4th pharyngeal pouch?
DiGeorge syndrome
81
What are the clinical features of DiGeorge syndrome?
- congenital heart disease
- cleft palate, small mouth and jaw
- hypocalcaemia
- oesophageal atresia
- T cell lymphopenia
82
What chromosomal deletion causes DiGeorge syndrome?
22q11
83
What is the defect in bare lymphocyte syndrome?
Absent expression of either MHC Class I or II molecules (type I and II)
Type II leads to a similar presentation as SCID, profound deficiency of CD4+ cells, normal CD8+ and B cells, absent antibodies.
84
What are the immunodeficiencies involving T cells?
- Severe combined immunodeficiency
- DiGeorge syndrome
- Bare lymphocyte syndrome
- IL-12 / IFN-gamma cytokine or receptor deficiency
85
What causes severe recurrent infections from 3 months, CD4 and CD8 T cells absent, B cell present, IgM present, IgA and IgG absent?
X-linked SCID
86
What immunodeficiency causes a young adult to have a chronic infection with Mycobacterium marinum?
IL-12 / IFN-gamma cytokine or receptor deficiency
87
What causes recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG?
DiGeorge syndrome
88
6 month baby with two recent serious bacterial infections. T cells present – but only CD8+ population. B cells present. IgM present but IgG absent. What do they have?
Bare lymphocyte syndrome type II
89
What is the defect in Bruton's X-linked hypogammaglobulinaemia?
- absence of mature B cells caused by a defective B cell tyrosine kinase gene that leads to arrest of B cell development at pre B stage
- no circulating Ig after 3 months
90
How does selective IgA deficiency present?
- prevalence 1:600
- 2/3 asymptomatic
- 1/3 recurrent respiratory tract infections
91
What is the clinical phenotype of Hyper IgM syndrome (X-linked)?
- B cell maturation defect - only IgM antibodies
- boys present in first few years of life
- recurrent infections (Pneumocystis carini)
- failure to thrive
- autoimmune disease and malignancy
92
What cell counts and antibody titres are observed in hyper IgM syndrome?
- Normal B cells and T cells
- High serum IgM
- Undetectable IgA, IgE, IgG
- Also no germinal centre development
93
What is the underlying mutation in hyper IgM syndrome and which cell does it effect?
```
CD40 ligand (CD154) gene mutation - normally expressed on activated T cells and interacts with CD40 present on B cell surface
CANT CLASS SWITCH
```
94
How does common variable immune deficiency present?
- low IgG, IgA, IgE
- recurrent bacterial infections, often with severe end-organ damage
- autoimmune disease
- granulomatous disease
95
What are the B cell maturation immunodeficiencies?
- SCID
- Bruton's X-linked agammablobulinaemia
- X-linked hyper IgM syndrome
- Selective IgA deficiency
- Common variable immune deficiency
96
What immunodeficiency does an adult with bronchiectasis, recurrent sinusitis and development of atypical SLE have?
Common variable immune deficiency
97
What immunodeficiency does a child with recurrent bacterial infections, an episode of pneumocystis pneumonia, high IgM, absent IgA and IgG have?
X linked hyper IgM syndrome due to CD40ligand mutation
98
1 year old boy. Recurrent bacterial infections. CD4 and CD8 T cells present. B cells absent, IgG, IgA, IgM absent. What immunodeficiency does he have?
Bruton’s X linked hypogammaglobulinaemia
99
What immunodeficieny causes recurrent respiratory tract infections, absent IgA, normal IgM and IgG?
Selective IgA deficiency
100
What organisms are patients with complement deficiency at particular risk of being infected by?
Encapsulated bacteria
- Neisseria meningitides (Meningococcus)
- Streptococcus pneumoniae (Pneumococcus)
- Group B streptococcus
- Haemophilus influenza
101
Deficiency of components of which complement pathway are associated with SLE?
Early classical pathway - this is involved in clearance of apoptotic/necrotic cells - deficiencies result in increased load of self antigens and deposition of immune complexes
102
How do patients with C3 deficiency present?
- severe susceptibility to bacterial infections
| - increased risk of connective tissue disease
103
Deficiencies in components of the terminal complement pathway lead to a specific susceptibility to which organisms?
- Neisseria meningitis
- Streptococcus pneumonia
- Haemophilus influenza
104
How does active lupus cause complement deficiency?
Persistent production of immune complexes leads to consumption of complement causing a secondary functional complement deficiency.
105
In what condition is C1 inhibitor decrease?
Hereditary angiodema
106
What functional complement tests are there?
CH50 - classical pathway
| AP50 - alternative pathway
107
What are nephritic factors? What are they associated with?
Autoantibodies directed against components of complement pathway - stabilise C3 convertase leading to consumption. Associated with glomerulonephritis (classically membranoproliferative)
108
C3 deficiency with presence of a nephritic factor is associated with?
Membranoproliferative nephritis and bacterial infections
109
What is the cause of meningococcus meningitis with family history of sibling dying of same condition aged 6?
Terminal complement pathway component deficiency (C5-9)
110
Severe childhood onset SLE with normal levels of C3 and C4 may be due to what?
Early classical complement pathway component deficiency e.g. C1q, C2
111
Recurrent infections when receiving chemotherapy but previously well can be caused by?
MBL deficiency
| Mannose binding lectin
112
What are the complement immunodeficiencies?
```
Classical pathway deficiencies
MBL deficiency
Alternative pathway deficiencies
C3 deficiency
Terminal pathway deficiencies
```
113
What type of virus is HIV-1?
+ssRNA retrovirus with a diploid genome in an icosahedral virion
114
What receptor and co-receptor molecules does HIV-1 use to infect cells?
CD4 is the receptor, CCR5 and CXCR4 are co-receptor molecules
115
What antibodies are thought to be important in protective immunity against HIV?
Anti-gp120 and anti-gp41
Non-neutralising anti-p24 gag IgG also produced
HIV remain infectious even when coated with antibodies
116
3 important HIV-1 genes
env, gag, pol
117
What protein forms the HIV-1 capsid?
p24, encoded by gag gene
118
What protein forms the HIV-1 matrix?
p17, encoded by gag gene
119
What are the surface and transmembrane proteins in HIV-1?
gp120 (surface) and gp41 (transmembrane) encoded by env gene
120
What HIV-1 gene encodes reverse transcriptase?
pol
121
What other cell types are infected by HIV-1 other than CD4+ T cell?
Macrophages and dendritic cells
122
What key areas can HIV-1 interfere with an immune response?
- CD4+ helper T cells are killed or anergised
- this prevents activation of macrophages, dendritic cells, CD8+ T cells and B cells.
- T cell memory is lost
- APCs are killed leading to defective antigen presentation and memory cell activation
123
What are the 7 steps of HIV-1 replication?
```
1 - attachment/entry
2 - reverse transcription & DNA synthesis
3 - integration
4 - viral transcription
5 - viral protein synthesis
6 - assembly of virus & release
7 - maturation
```
124
What are the different classes of antivirals that target different phases of the viral replication cycle?
Attachment inhibitors and fusion inhibitors
Reverse transcription inhibitors
Integrase inhibitors
Protease inhibitors
125
What is the median time from HIV infection to AIDS development?
8-10 years
126
What tests are used to detect HIV infection?
Anti-HIV ELISA is a screening test, HIV antibody western blot if confirmatory.
Viral load PCR to detect viral RNA = most sensitive
127
What tests are used to monitor HIV disease progression?
- Viral load PCR (initial baseline plasma viral load good predictor of time to symptomatic disease)
- CD4+ T cell levels by flow cytometry (onset of AIDS correlates with CD4+ T cell count)
128
What two assays are used to measure HIV resistance to antiretrovirals?
Phenotypic assay - replication measured in cell cultures with increasing drug concentration
Genotypic assay - mutations sequenced
129
What does HAART stand for?
Highly active antiretroviral therapy
130
When should HAART be initiated and what regimen?
- in all symptomatic patients,
- when CD4+ < 200 cells/micro l
- ideally when CD4+ 200-350
- give 2 NRTIs + PI (or NNRTI)
131
What must an effective HIV vaccine elicit?
Potent antibodies and a cytotoxic T cell response
132
How do auto-inflammatory and auto-immune diseases differ?
Auto-inflammatory - local factors lead to inappropriate activation of innate immune cells resulting in tissue damage
Auto-immune - defective B and T cell responses in lymphoid organs leads to loss of tolerance and development of self-antigen reactivity
133
Where are abnormalities in monogenic auto-inflammatory disease?
In pathways associated with innate immune cell function, commonly in key cytokine pathways involving TNF and/or IL-1 - inflammasome complex
134
List of monogenic auto-inflammatory diseases
- Muckle Wells Syndrome (AD)
- Familial cold auto-inflammatory syndrome (AD)
- Chronic infantile neurological cutaneous articular syndrome (AD)
- TNF receptor associated periodic syndrome (AD)
- Hyper IgD with periodic fever syndrome (AR)
- Familial Mediterranean fever (AR)
135
Familial Mediterranean Fever
Autosomal recessive, MEFV mutation, pyrin-marenostrin fails to regulate cyropyrin.
Affects Sephardic>Ashkenazy Jews, Armenian, Turkish, Arabic.
Periodic 2-3 day fevers, abdo + chest pain, arthritis
Long term risk of amyloidosis, nephrotic syndrome, renal failure
136
What do you treat Familial Mediterranean fever with?
Colchicine 500 micro g BD
| Anakinra (IL-1R antagonist), Etanercept, Interferon
137
Where are abnormalities in monogenic auto-immune disease?
In pathways associated with adaptive immune cell function: tolerance, reg T cells, lymphocyte apoptosis
138
Autoimmune polyendocrine syndrome type 1
Autosomal recessive, defect in AIRE (auto-immune regulator) transcription factor.
produce antibodies against parathyroid, adrenal glands and cytokines (IL-17, IL-22) causing hypoparathyroidism, addisons and repeat candida infections
139
IPEX syndrome (immunodysregulation polyendocrinopathy enteropathy X-linked)
Foxp3 mutation, autoantibodies against pancreatic islet, thyroid, small bowel mucosa. Early age onset with diabetes, hypothyroidism, diarrhoea, eczematous dermatitis
140
Autoimmune lymphoproliferative syndrome (ALPS)
FAS pathway mutation, defect in lymphocyte apoptosis and failure of tolerance. Chronic non-malignant lymphoproliferation, autoimmune disease, and secondary cancers. Large spleen and lymph nodes
141
What reflects genetic abnormality affecting the innate immune system, often in a site-specific manner?
Auto-inflammatory disease
142
What condition is caused by a single gene mutation involving MEFV and affects the inflammasome complex, resulting in recurrent episodes of serositis?
Familial Mediterranean Fever
143
What describes damage resulting from the immune response to ongoing infection?
Immunopathology
144
What reflects genetic abnormality affecting the adaptive immune system and is often associated with presence of auto-antibodies?
Auto-immune disease
145
What condition is caused by a single gene mutation involving FOXp3 resulting in abnormality of T reg cells?
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X linked)
146
Examples of polygenic auto-inflammatory diseases?
Crohns disease, Ulcerative colitis, Osteiarthritis, Giant cell arteritis, Takayasu's arteritis.
In general these diseases are not characterised by presence of auto-antibodies and HLA associations are usually less strong.
147
What has been identified as IBD1 gene and what disease is associated with mutations of it?
NOD2 (CARD-15) mutations associated with Crohn's disease, present in 30% patients. Also found in patients with severe psoriasis and psoriatic arthritis
148
What does NOD2/CARD15 do?
Expressed by myeloid cells (macrophages, neutrophils, dendritic cells) recognises intracellular muramyl dipeptide (bacterial product), activates NFkB inducing pro-inflammatory cytokine expression - regulates innate immune response to intracellular bacterial products
149
What does inappropriate expression of pro-inflammatory cytokines/chemokines cause in Crohn's disease?
Leukocyte infiltration, focal inflammation in/around crypts, granuloma formation, and release of proteases, free radicals and PAF causing tissue damage with mucosal ulceration
150
Treatment for Crohn's?
Immunosupression with corticosteroids, azathioprine and TNF alpha antagonists.
151
What is the most common systemic vasculitis in the elderly?
Giant cell arteritis
152
What does a temporal artery biopsy show in giant cell arteritis?
Intimal proliferation, disrupted internal elastic lamina, and mononuclear cells throughout the vessel wall
153
What genetic polymorphisms are associated with giant cell arteritis?
Toll-like receptor 4, IL-6,8,10 gene promoter, ICAM-1, MMP 9, NO-synthase, MHC
154
Examples of mixed pattern immunological diseases?
Ankylosing spondylitis
Psoriatic arthritis
Behcet's syndrome
155
What HLA allele is strongly associated with ankylosing spondylitis?
HLA-B27
156
What genetic polymorphisms are associated with ankylosing spondylitis?
IL23R, ERAP1, ANTXR2, ILR2, HLA-B27
157
What sites are affected by inflammation in ankylosing spondylitis?
Specific sites where there are high tensile forces - entheses - sites of insertions of ligament or tendons to bone.
158
How do patients with ankylosing spondylitis present?
Low back pain and stiffness, worse after peroids or rest. Pain and swelling usually affecting hips and knees. Enthesitis, dactylitis, uveitis.
159
In what polygenic auto-inflammatory disease do ~30% patients have a mutation of CARD15 which may affect response of myeloid cells to bacteria?
Crohn's disease
160
What mixed pattern auto-inflammatory / auto-immune disease has >90% heritability that results in inflammation typically involving the sacro-iliac joints and responds to TNF alpha antagonists?
Ankylosing spondylitis
161
What polygenic auto-inflammatory disease results in a large vessel vasculitis and requires immediate treatment with high dose corticosteroids?
Giant cell arteritis
162
Examples of polygenic auto-immune diseases
Rheumatoid arthritis, myaesthenia gravis, pernicious anaemia, addions disease, systemic lupus erythematosus, primary biliary cirrhosis, graves disease, hashimoto's thyroiditis, diabetes mellitus, auto-immune haemolytic anaemia, goodpasture disease, sjogren's syndrome, systemic sclerosis, dermatomyositis, anca associated vasculitis...
163
What HLA allele is associated with Goodpasture disease?
HLA-DR15
| 10x risk
164
What HLA allele is associated with Graves disease?
HLA-DR3
| 4x risk
165
What HLA allele is associated with SLE?
HLA-DR3
| 6x risk
166
What HLA allele is associated with type 1 diabetes?
HLA-DR3/DR4
| 25x risk
167
What HLA alleles are associated with rheumatoid arthritis?
HLA-DR4 and HLA-DR1
| 4x risk
168
What polymorphism of PTPN-22 (Protein tyrosine phosphatase non-receptor 22) is associated with which diseases?
1858T allele increases susceptibility to;
| Rheumatoid arthritis, SLE, type-1 diabetes, vitaligo and Graves disease.
169
Allelic variants of CTLA4 are found in which diseases?
SLE, type-1 diabetes, auto-immune thyroid disease, coeliac disease and other auto-immune diseases
170
Tyrosine phosphatase expressed in lymphocytes associated with development of auto-immune disease including rheumatoid arthritis
PTPN22
171
MHC class II molecule that is associated with development of auto-immune disease including rheumatoid arthritis
HLA-DR4
172
Receptor for CD80/CD86, expressed on T cells, that influences T cell activation and is associated with auto-immune disease including diabetes and thyroid disease
CTLA4
173
Antigen presenting molecule that is strongly associated with development of Anti-GBM antibodies
HLA-DR15
174
What is PTPN-22?
Protein tyrosine phosphatase non-receptor 22, a lymphocyte specific tyrosine phosphatase which suppresses T cell activation.
175
What is CTLA4?
A receptor expressed by T cells that downregulates the immune system by transmitting inhibitory signals to control T cell activation.
176
What two main types of tolerance are there?
Central and peripheral.
| Central tolerance for T cells occurs in thymus, for B cells in bone marrow.
177
What are the major mechanisms of peripheral tolerance?
Anergy, regulatory cells and immune privilege.
These maintain the tolerant state of potentially auto-reactive cells and prevents their activation and proliferation in the periphery.
178
How does anergy work for T cells?
In the absence of costimulatory molecules (CD40-CD40L and CD80/86-CD28) T cells become 'anergised' and do not respond to subsequent challenge
179
A complete absence of CD25+ FoxP3+ CD4+ cells occurs in what condition?
IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome)
180
What are the different populations of regulatory T cells?
T reg cells (CD25+ FoxP3+ CD4+)
Tr1 cells (IL-10 secreting CD4+ T cells)
CD8+ regulatory T cells
181
Which sites in the body are immunologically privileged?
Eye, testes, placenta, fetus, CNS (may not be true) - they are able to tolerate the introduction of antigens without eliciting an inflammatory immune response
182
Which T cells express FoxP3 and CD25 and secrete cytokines IL-10, TGF beta to suppress activation of other T cells?
T reg cells
183
Within the thymus cells that bind with low affinity to HLA molecules die by neglect and those that bind with high affinity to HLA molecules are deleted - what is this process called?
Central tolerance of T cells
184
T cells that recognise HLA/peptide complexes on cells that do not express co-stimulatory molecules subsequently fail to respond to stimulation with antigen - what is this called?
T cell anergy
185
Cells that bind to polyvalent antigens in the bone marrow are deleted - what is this process called?
Central tolerance of B cells
186
What classification is used to classify the immune effector mechanisms resulting in tissue damage?
Gel and Coombs - however they are incomplete.
187
Define hypersensitivity
An immune reaction which produces tissue damage on re-exposure to antigen.
188
Gel and Coombs classification of Hypersenitivity
Type I: Allergy - Immediate hypersensitivity which is IgE mediated
Type II: Cytotoxic, antibody dependent - Antibody reacts with cellular antigen
Type III: Immune complex disease - Antibody reacts with soluble antigen to form an immune complex
Type IV: Delayed type hypersensitivity…T-cell mediated response, antibody independent
189
What is the mechanism of a type I hypersensitivity reaction?
Rapid allergic reaction caused by antigen cross-linking Fc epsilon receptors on mast cells and basophils via pre-existing IgE causing degranulation.
190
What inflammatory mediators are released when mast cells and basophils degranulate?
Pre-formed histamine, serotonin and proteases released. Leukotrienes, prostaglandins, bradykinin and cytokines are synthesised and released.
191
What is the mechanism of a type II hypersensitivity reaction?
Autoantibodies bind to cellular or matrix associated antigen, then activate complement, NK cells or phagocytes to cause cell lysis, apoptosis or phagocytosis. Alternatively, autoantibodies can activate or block cell receptors e.g. Graves (sometimes considered Type V response)
192
Examples of type II hypersensitivity disease
Auto-immune haemolytic anaemia, Goodpasture disease, Pemphigus vulgaris, Graves disease, Myaesthenia gravis
193
What is the auto-antigen in auto-immune haemolytic anaemia?
Rhesus blood group antigen I, leads to destruction of RBCs causing anaemia
194
What is the auto-antigen in Goodpasture disease?
Noncollagenous domain of basement collagen type IV, causes glomerulonephritis, pulmonary haemorrhage
195
What is the auto-antigen in pemphigus vulgaris?
Epidermal cadherin, causes blistering of the skin
196
What is the auto-antigen in Graves disease?
Thyroid stimulating hormone (TSH) receptor, causing hyperthyroidism
197
What is the auto-antigen in myaesthenia gravis?
Acetylcholine receptor, causing muscle weakness
198
What is the mechanism of a type III hypersensitivity reaction?
Immune complex formation and deposition in blood vessels causes complement activation and infiltration of macrophages and neutrophils leading to increased vascular permeability, inflammation and damage to vessels - cutaneous vasculitis, glomerulonephritis, arthritis
199
Examples of type III immune complex driven autoimmune diseases and their autoantigens
Cryoglobulinaemia - Fc region of IgG, Hep C antigens
SLE - DNA, Histones, RNP
Rheumatoid arthritis - Fc region of IgG
200
What is the mechanism of a type IV hypersensitivity reaction?
CD4+ helper T cells recognise antigen in a complex with MHC Class II. They secrete IL-2 and interferon gamma, inducing the release of other cytokines, thus mediating the immune response leading to inflammations and tissue damage. Activated CD8+ T cells also destroy cells displaying antigen via MHC Class I on contact.
201
Examples of type IV cell-mediated autoimmune diseases and their autoantigens
Insulin dependent DM - Pancreatic beta-cell antigen
Rheumatoid arthritis - unknown synovial joint antigen
Multiple Sclerosis - myelin basic protein
202
What type of hypersensitivity reaction is a T cell mediated reaction to antigen?
Type IV
203
What type of hypersensitivity reaction is caused by antibodies reacting with antigens to form immune complexes that deposit often causing vasculitic skin rash, glomerulonephritis and arthritis?
Type III
204
What type of hypersensitivity reaction is caused by antibodies reacting with tissue antigens resulting in damage to the tissue?
Type II
205
What type of hypersensitivity reaction is IgE mediated activation of mast cells leading to release of substances including histamine, leukotrienes and prostaglandins? Reaction is usually to foreign rather than self antigen.
Type I
206
What class of antibody is responsible for Graves disease?
IgG autoantibodies that stimulate the TSH receptor
207
What autoantibodies are associated with Hashimoto's thyroiditis? What type of hypersensitivity reaction is it?
Anti-thyroid peroxidase and anti-thyroglobulin antibodies.
| Type II and type IV
208
What % of women >65 have anti-thyroid antibodies and how many of have hypothyroidism?
25%, a minority of which have subclinical hypothyroidism, a very small proportion have overt hypothyroidism - hence few indication for testing thyroid antibodies, rather test TFTs
209
What autoantigens are recognised by which type of immune cell in type I diabetes?
Glutamic acid dehydrogenase (GAD 65) and/or islet antigen 2 (IA2) are recognised by CD8+ cytotoxic T cells - type IV hypersensitivity
210
What autoantibodies are involved in type I diabetes?
Anti-islet cell, anti-insulin, anti-GAD, anti-IA-2
211
What autoantibodies are involved in pernicious anaemia?
Anti-gastric parietal cells and/or anti-intrinsic factor
212
What abnormalities and symptoms can occur in pernicious anaemia?
Vit B12 deficiency, macrocytic anaemia, neurological features - subacute combined degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy
213
In myaesthenia gravis, what are autoantibodies directed against?
Postsynaptic acetylcholine receptors. These antibodies are present in ~75% patients
214
What diagnostic test can you use in myaesthenia gravis?
Tensilon test - inject edrophonium (anti-cholinesterase) to prolong acetylcholine and allow it to act on residual receptors
215
What does a positive Tensilion test indicate?
Myaesthenia gravis
216
A man with haemoptysis has a kidney biopsy that shows crescentic nephritis and linear IgG deposits along basement membrane - what is the diagnosis?
Goodpasture disease
217
What autoantibody is associated with Goodpasture disease?
Anti-basement membrane antibody
218
What condition is associated with PAD2 and PAD4 polymorphisms?
Rheumatoid arthritis
PAD = peptidylarginine deiminases, create citrulline from arginine, polymorphisms are associated with increased citrullination of proteins
219
What condition is asscoiated with increased citrullination? What risk factors are related to this?
Rheumatoid arthritis. Smoking is associated with increased citrullination and development of erosive disease. Gum infection with Porphyromonas gingivalis (only bacteria known to express PAD enzyme) also associated with RA
220
What autoantibody is ~95% specific for rheumatoid arthritis? How sensitive is it?
Anti-cyclic citrullinated peptide, 60-70% sensitive.
221
What is rheumatoid factor and how sensitive and specific is it for rheumatoid arthritis?
An antibody directed against the Fc region of human IgG. Usually IgM anti-IgG, sometimes IgA or IgG anti IgG. 60-70% specificity and sensitivity
222
What type of hypersensitivity responses are involved in rheumatoid arthritis?
Type II - antibodies binding to citrullinated protiens may activate complement, macrophages and NK cells
Type - III - RF and anti-CCP immune complex formation and deposition with complement activation
Type IV possible self peptide recognition by T cells
223
What pathological changes occur at joints in rheumatoid arthritis?
Inflamed synovial tissue forms a 'pannus' overlaying and invading articular cartilage and adjacent bone tissues, plus an increase in synovial fluid volume
224
Which disease is associated with anti-GAD antibody?
Diabetes mellitus type I
225
Which disease is associated with anti-thyroglobulin antibody?
Hashimotos thyroiditis
226
Which disease is associated with anti-basement membrane antibody?
Goodpasture disease
227
Which disease is associated with anti-intrinsic factor antibody?
Pernicious anaemia
228
Which disease is associated with anti-acetylcholine receptor antibody?
Myaesthenia gravis
229
Which disease is associated with anti-TSH receptor antibody?
Graves disease
230
What is expressed by synovial macrophages and is pivotal in the cytokine cascade that leads to inflammation and damage in rheumatoid arthritis?
TNF-alpha
231
What describes the region of HLA DR beta chain that predisposes to development of rheumatoid arthritis?
Shared epitope
232
Which organism expresses PAD enzymes capable of deiminating arginine to form citrullinated proteins?
Porphyromonas gingivalis
233
Which antibody binds to citrullinated proteins and has ~95% specificity for development of rheumatoid arthritis?
Anti-CCP (cyclic citrullinated peptide) antibody or ACPA (Anti-citrullinated protein antibodies)
234
What antibody binds to Fc region of IgG?
Rheumatoid factor
235
What is the frequency of SLE?
1:2000, female preponderance. Most commonly presents in 2nd and 3rd decades
236
What cellular abnormalities are present in SLE?
Abnormalities in clearance of apoptotic cells, in immune cellular activation, B cell hyperactivity and loss of tolerance, and antibodies directed particularly at intracellular proteins
237
Examples of intracellular antigens that antibodies are directed against in SLE
DNA, histones, snRNP, ribosomes, scRNP
238
Which cytokine is important in stimulation of CRP production ?
IL-6
239
You request an anti nuclear antibody test on two patients with joint pain;
Patient A’s result is 1:640
Patient B’s result is 1:80
Based on this information, which has the “strongest” (i.e most positive) antibody?
Patient A as antibodies are measured by titre - the minimal dilution at which the antibody can be detected
240
What type of anti-nuclear antibodies are ~95% specific for SLE?
Anti-DNA antibodies - they are useful in disease monitoring as high titres are often associated with more severe disease, including renal or CNS involvement. Show homogenous staining of nuclei.
241
Speckled staining of nuclei is associated with...?
antibodies to extractable nuclear antigens (ENA) 4 - Ro, La, Sm, RNP (ribonucleoproteins)
242
Which ANAs may occur in diffuse cutaneous systemic sclerosis?
Anti- Scl70 (topoisomerase), RNA polymerase, fibrillarin
243
Which ANAs may occur in limited cutaneous systemic sclerosis?
Anti-centromere
244
Which ANAs may occur in idiopathic inflammatory myopathies?
- Anti-aminoacyl transfer RNA synthetase antibody eg Jo-1 (cytoplasmic) (DM)
- Anti-signal recognition peptide (SRP) antibody (nuclear and cytoplasmic) (PM)
- Anti-Mi2 (nuclear) (DM>PM)
245
Which ANAs are characteristically found in Sjogren's syndrome?
Anti-Ro and La
246
What complement component levels can act as a surrogate marker of SLE disease activity?
Unactivated C3 and C4 levels - the more depleted, the more active the disease.
247
Normal levels of C3 but low levels of C4 indicates what in context of SLE?
Active disease
248
Low levels of both C3 and C4 indicates what in context of SLE?
Severe active disease
249
Normal levels of C3 and C4 indicates what in context of SLE?
Inactive disease
250
What three tests are there for anti-phospholipid antibodies?
- Anti-cardiolipin antibodies (target phospholipids)
- Anti-beta-2-glycoprotein-1 antibody
- Lupus anti-coagulant (prolongation of phospholipid-dependent coagulation tests due to presence of antibodies directed against phospholipids)
251
In systemic sclerosis, which T cell subsets dominate?
Th17 and Th2
252
What effects do cytokines have in systemic sclerosis?
They lead to activation of fibroblasts, development of fibrosis, activation of endothelial cells and contribute to microvascular disease.
There is also a loss of B cell tolerance to nuclear antigens.
253
What involvement is there in limited cutaneous systemic sclerosis?
Skin involvement does not progress beyond forearms, but may involve peri-oral skin, CREST = Calcinosis, Raynauds, Oesophageal dysmotility, Sclerodactyly, Telangectasia, and Primary pulmonary hypertension.
254
What involvement is there in diffuse cutaneous systemic sclerosis?
Skin involvement does progress beyond forearms, CREST = Calcinosis, Raynauds, Oesophageal dysmotility, Sclerodactyly, Telangectasia, and Primary pulmonary hypertension.
There is more extensive GI disease, interstitial pulmonary disease and scleroderma renal crisis
255
What is the immunopathological mechanism in dermatomyositis?
Within muscle, perivascular infiltration of CD4+ T cells and B cells, immune complex mediated vasculitis - type III response
256
What is the immunopathological mechanism in polymyositis?
Within muscle, CD8+ T cells surround HLA Class I expressing myofibres and kill them via perforin / granzymes - type IV response
257
What is the clinical presentation of idiopathic inflammatory myositis (dermatomyositis and polymyositis)?
- progressive and symmetrical weakness, prodominantly proximal muscle groups but may involve pharyngeal or respiratory muscles
- periorbital oedema with heliotrope rash on eye lids
- scaley red rash on extensor surfaces
- Gottron's papules
- may be associated with interstitial lung disease, fevers, arthritis, raynauds
- strong association with presence of underlying malignacy
258
Which antibody is associated specifically with limited cutaneous form of systemic sclerosis?
Anti-centromere
259
What is used as a screening test for a connective tissue disease?
Presence of ANA
260
What antibody is associated specifically with diffuse cutaneous form of systemic sclerosis?
Anti-Scl70, Anti- RNA polymerase or Anti-fibrillarin
261
What antibody may be positive in SLE or in Sjogren’s syndrome but not usually in systemic sclerosis?
Anti-Ro or La
262
Which antibody is highly specific for diagnosis of SLE and is present in ~70% patients?
Anti-dsDNA
263
Which antibody is sometimes positive in patients with immune mediated myositis particularly if they have interstitial lung disease?
Anti-Jo-1 (t-RNA synthetase)
264
What small vessel vasculitides are associated with anti-neutrophil cytoplasmic antibodies?
- Microscopic polyangiitis / polyarteritis (MPA)
- Granulomatosis with polyangiitis (GPA) / Wegener's granulomatosis
- Eosinophilic granulomatosis with polyangiitis (eGPA) / Churg-Strauss syndrome
265
What do ANCA target?
Antigens located in primary granules within cytoplasm of neutrophils. Inflammation may lead to expression of these antigens on cell surface and antibody engagement may lead to neutrophil activation (type II hypersensitivity)
266
Which antibodies are associated with cANCA?
Cytoplasmic fluorescence associated with antibodies to proteinase 3.
267
Which antibodies are associated with pANCA?
Perinuclear fluorescence associated with antibodies to myeloperoxidase.
268
With which disease is cANCA strongly associated with?
Occurs in > 90% of patients with Wegener's granulomatosis with renal involvement
269
With which diseases is pANCA associated with?
Microscopic polyarteritis and Churg-Strauss vasculitis, but is less sensitive and specific than cANCA
270
Which antibody may be found in patients with microscopic polyangiitis (MPA)?
P-ANCA - Perinuclear ANCA - Myeloperoxidase specific
271
Which antibody may be found in patients with granulomatosis and polyangiitis (Wegener’s, GPA)?
C-ANCA - Cytoplasmic ANCA - Proteinase 3 specific
272
What antibody may be positive in a subset of small vessel vasculitides including MPA, GPA and eGPA?
ANCA - Anti-neutrophil cytoplasmic antibody
273
What indications are there for a bone marrow transplant?
- Life-threatening primary immunodeficiency e.g. SCID, leukocyte adhesion defect
- Haematological malignancy
274
What indications are there for antibody replacement therapy?
- Primary antibody deficiency - X-linked agammaglobulinaemia, X-linked hyper-IgM syndrome, Common variable immune deficiency
- Secondary antibody deficiency - Haematological malignancies (CLL, multiple myeloma) and after bone marrow transplant
275
Examples of diseases where specific human immunoglobulin is sometimes used for post-exposure prophylaxis (passive immunisation)?
Hep B, Tetanus, Rabies, Varicella Zoster
276
What immune replacement options are there for immunosuppressed patients who are failing to control infection with persistent viruses e.g. CMV, EBV..?
- autologous T cell expanded in vitro then reinfused
- donor (HLA matched) T cells expanded and infused
- 'Banks' or FLA matched, virus specific T cell are being developed
277
In what conditions is recombinant interferon alpha used?
Hep C, Hep B, Kaposi's sarcome, Hairy cell leukaemia, CML, multiple myeloma
278
In what condition was recombinant interferon beta used?
Relapsing MS
279
In what condition is recombinant interferon gamma used?
Chronic granulomatous disease
280
What treatment could be used to 'boost' the immune response in post-transplant lymphoproliferative disorder?
EBV-specific CD8 T cells
281
What treatment could be used to 'boost' the immune response as part of the treatment of Hepatitis C?
IFN alpha
282
What treatment could be used to 'boost' the immune response in X linked hyper IgM syndrome?
Human normal immunoglobulin
283
What treatment could be used to 'boost' the immune response in X-linked SCID?
Bone marrow transplantation
284
What treatment could be used to 'boost' the immune response in chronic granulomatous disease?
TFN-gamma
285
What treatment could be used to 'boost' the immune response in an immunosuppressed seronegative individual after chicken pox exposure?
Varicella zoster immunoglobulin
286
What is the difference between prednisolone and prednisone?
Prednisone is metabolised by the liver into prednisolone. Prednisone used in USA, prednisolone used in Europe
287
What are the immune effect of corticosteroids?
- reduces prostaglandin synthesis
- inhibits phagocyte migration and function
- inhibits lymphocyte function and promotes apoptosis
288
How do corticosteroids reduce protaglandin synthesis?
They inhibit phospholipase A2, blocking arachidonic acid and hence prostaglandin formation and so reduces inflammation.
289
How do corticosteroids effect phagocytes?
- reduce expression of adhesion molecules on endothelium and block chemotactic signals thus reducing extravasation = transient increase in neutrophil counts
- decrease phagocytosis and release of proteolytic enzymes
290
How do corticosteroids effect lymphocytes?
- promotes sequestration in lymphoid tissue = lymphopenia
- blocks cytokine gene expression
- decreases antibody production
- promotes apoptosis
291
Examples of anti-proliferative immunosuppressant drugs
cyclophosphamide, mycophenolate, azathioprine, methotrexate
292
How does cyclophosphamide work as an immunosuppressant?
Alkylates guanine base of DNA, damaging it and preventing cell replication. Affects B > T cells
293
What are the major indications for use of cyclophosphamide?
- Multisystem connective tissue disease or vasculitis with severe end-organ involvement e.g. Wegener's, SLE
- Anti-cancer agent
294
What are the major side effects of cyclophosphamide?
Bone marrow depression, hair loss, sterility, haemorrhagic cystitis, bladder cancer, haematological malignancies, non-melanoma skin cancer, Pneumocystis Jiroveci infection
295
How does azathioprine work as an immunosuppressant?
Metabolised by liver to 6-mercaptopurine which blocks de novo puirine synthesis, preventing DNA replication. Preferentially inhibits T cell activation and proliferation.
296
What are the major indications for use of azathioprine?
- Transplantation
- Auto-immune disease
- Auto-inflammatory diseases e.g. IBD
297
What are the major side effects of azathioprine?
Bone marrow suppression, hepatotoxicity, infection (serious infection less common than with cyclophosphamide)
298
What should be checked if possible in patients before starting azathioprine therapy?
Thiopurine methyltransferase (TPMT) activity or gene variants - 1:300 individuals are unable to metabolise azathioprine thus extremely susceptible to bone marrow suppression. Always check FBC after starting therapy.
299
How does mycophenolate mofetil work as an immunosuppressant?
It blocks de novo nucleotide synthesis, thus prevents DNA replication. Inhibits T>B cell proliferation, also inhibits macrohpages + dendritic cells
300
What are the major indications for use of mycophenolate mofetil?
- Alternative to azathioprine in transplantation
| - Autoimmune diseases and vasculitis as alternative to cyclophosphamide
301
What are the major side effects of mycophenolate mofetil?
- Bone marrow suppression (leukocytes and platelets)
| - Infection (herpes virus reactivation, progressive multifocal leukoencephalopathy - JC virus)
302
How does plasmapheresis work and what are the problems with it?
Patients blood passed through cell separator then own cellular constituents reinfused. Plasma treated to remove immunoglobulins then reinfused too or replaced with albumin in 'plasma exchange'.
Rebound antibody production limits efficacy, thus often combined with anti-proliferative agent.
303
What are the major indications for plasmapheresis?
Severe antibody-mediated disease e.g. Goodpastures syndrome, severe acute myasthenia gravis, severe vascular rejection (anti-HLA antibodies to donor)
304
Examples of calcineurin inhibitors?
Cyclosporin, tacrolimus
305
How does cyclosporin work?
Inhibits calcineurin thus blocking cytokine (IL-2) transcription, which prevents lymphocyte proliferation and effector functions
306
What are the major side effects of cyclosporin?
- Nephrotoxicity
- Hypertension
- Neurotoxicity
- Diabetogenicity
- Dysmorphism (gingival hyperplasia, hirsutism)
307
Which immunosuppressive agent is most likely to cause osteoporosis as a side-effect?
Corticosteroids e.g. prednisolone
308
Which immunosuppressive agent is most likely to cause infertility as a side-effect?
Cyclophosphamide
309
Which immunosuppressive agent is most likely to cause progressive multifocal leukoencephalopathy as a side-effect?
Mycophenolate mofetil, from JC virus infection
310
Which immunosuppressive agent is most likely to cause neutropenia as a side-effect, particularly if TPMT is low?
Azathioprine
311
Which immunosuppressive agent is most likely to cause hypertension as a side-effect?
Cyclosporin
312
What does Basiliximab target?
CD25 (IL-2R alpha chain)
313
What does Abatacept target?
CD80 (B7-1) > CD86 (B7-2) = co-stimulatiors on APCs
314
What does Rituximab target?
CD20
315
What does Natalizumab target?
Alpha-4 integrin
316
What does Tocilizumab target?
IL-6 receptor
317
What are the indications for rabbit anti-thymocyte globulin use?
Prevention and treatment of acute rejection in organ transplantation (renal, heart) and therapy of aplastic anemia.
318
What are the main complications of anti-thymocyte globulin use?
- Infusion reactions (cytokine release syndrome)
- Leukopenia
- Infection
- Malignancy
319
Which antibody targets CD25 and what is its action?
Basiliximab inhibits T cell proliferation by blocking IL-2 receptor. It is used for prophylasxis and prevention of allograft rejection.
320
Which antibody targets CD80 (B7-1) and what is its action?
Abatacept is a fusion protein of the Fc region of IgG1 fused to the extracellular domain of CTLA-4. It reduces T cell activation by binding to co-stimulatiors CD80 (B7-1) and CD86 (B7-2) on APCs preventing CTLA-4 and CD28 interaction. Used for rheumatoid arthritis.
321
What are the clinical features of a cytokine storm?
Fevers, myalgia
Increased vascular permeability: pulmonary and cerebral oedema, cardiovascular collapse, poor peripheral perfusion and shock.
322
Which antibody targets CD20 and what is its action?
Rituximab targets and depletes mature B cells. It is used to treat lymphoma, rheumatoid arthritis, SLE and ANCA+ vasculitis. Side effects include infusion reactions, infections (PML) and exacerbation of CV disease.
323
Which antibody targets alpha-4 integrin and what is its action?
Natalizumab inhibits T cell migration by blocking cell adhesion preventing extravasaion into tissues. It is used for highly active relapsing-remitting MS and Crohn's disease. Hepatotoxic.
324
Which antibody targets CD11a and what is its action?
Efalizumab inhibits T cell migration by binding to LFA1 and was used to treat psoriasis but was withdrawn following fatal cases of PML
325
Which antibody targets IL-6 receptor and what is its action?
Tocilizumab reduces macrophage, T cell, B cell and neutrophil activation by inhibiting IL-6 action. Indicated for Castleman's disease and rheumatoid arthritis. Hepatotoxic and elevates lipids.
326
Which antibody targets CD128 and what is its action?
TGN1412 was in clinical trials but caused non-regulatory T cells to proliferate and secrete pro-inflammatory cytokines resulting in cardiovascular collapse requiring ITU care - stimulated CD28
327
Which monoclonal antibody inhibits T cell migration but may only be used in highly active remitting/relapsing MS?
Natalizumab (Anti-alpha-4 integrin)
328
Which monoclonal antibody inhibits T cell activation and is effective in rheumatoid arthritis?
Abatacept (CTLA4-Ig fusion protein)
329
Which monoclonal antibody depletes B cells and is effective in treatment of B cell lymphomas and rheumatoid arthritis?
Rituximab (Anti-CD20)
330
Which monoclonal antibody inhibits function of lymphoid and myeloid cells and used in management of rheumatoid arthritis?
Tocilizumab (Anti-IL6 receptor)
331
Which monoclonal antibody is specific for CD25 that inhibits T cell activation and is used to prevent rejection?
Basiliximab (Anti-IL2 receptor)
332
What does Infliximab target?
TNF-alpha
333
What does Adalimumab target?
TNF-alpha
334
What does Certolizumab target?
TNF-alpha
335
What does Golimumab target?
TNF-alpha
336
What does Etanercept target?
TNF-alpha and beta - acts as a antagonist - false receptor
337
What does Ustekinumab target?
IL-12 and IL-23
338
What does Denosumab target?
RANK ligand
339
Which antibodys targets TNF-alpha and what are their action and uses?
Infliximab, Adalimumab, Certolizumab and Golimumab all directly bind to TNF-alpha, inhibiting its action. Used for inflammatory conditions e.g. rheumatoid arthritis, ankylosing spondylitis, IBS, psoriasis and psoriatic arthritis. Aditional risks of lupus-like conditions and demyelination.
Etanercept also - TNF receptor p75-IgG fusion protein - TNF antagonist.
340
Which antibody targets IL-12 and IL-23 and what is its action and uses?
Ustekinumab binds to p40 subunit of IL-12 and IL-23, inhibiting their action. Indicated for treatment of Psoriasis. Increased risk of TB infection.
341
Which antibody targets RANK ligand and what is its action and uses?
Denosumab inhibits RANK mediated osteoclast differentiation and function thus reduces bone resorption. Used to treat osteoporosis. Risk of avascular necrosis of jaw.
342
What potential side-effects are there with all monoclonal antibody treatments?
- Injection site reactions (peak at ~48 hours, cellular infiltrates)
- Infusion reactions (urticaria, hypotension, tachycardia, wheeae - IgE, headaches, fevers, myalgias, cytokine storm)
- Infection (acute and chronic)
- Malignancy (Lymphoma, non-melanoma skin cancers, melanoma)
- Auto-immunity
343
Examples of common vaccines which cannot be used in immunosuppressed patients?
Measles, BCG, Yellow fever and oral polio vaccine (injected ok) - all contain live pathogen
344
What is allergen desensitisation useful for?
Reducing clinical symptoms in monoallergic disorders e.g. reactions to bee and wasp venom, grass pollen, house dust mite
345
What are the advantages and disadvantages of allergen immunotherapy?
Advantages - Unequivocal evidence of efficacy in some patients and the only available allergy therapy that alters the natural course of disease.
Disadvantages - Risk of severe adverse reaction and death, very costly and laborious.
346
Define atopy and allergic disease
Atopy: The production of specific IgE responses to common environmental antigens.
Allergic disease: The development of type I hypersensitivity responses to environmental allergens.
Atopy and allergic disease are not synonymous
347
Which allergic diseases typically present in infancy?
Atopic dermatitis and food allergy (e.g. milk, egg, nuts)
348
Which allergic diseases typically present in childhood?
Asthma and allergic rhinitis (hayfever)
349
Which allergic diseases typically present in adulthood?
Drug allergy, bee allergy, oral allergy syndrome and occupational allergy
350
What is the classical clinical history of an IgE allergic response?
- Occurs within minutes or up to 2 hours post exposure to allergen
- Consistent, predictable responses (angioedema, urticaria, rhinoconjunctivitis, wheeze, diarrhoea, vomiting, anaphylaxis)
- At least 2 organ systems involved
- May be triggered by cofactors (exercise, alcohol, infection)
351
What is the classical clinical history of a non-IgE allergic response?
E.g. food intolerance
- Recurrent episodes of abdominal pain, diarrhoea
- Fatigue
- migraine
- hyperactivity
- depression
- confusion
352
Which tests can be done to investigate allergic disease?
- Skin prick tests (Gold standard)
- Quantitate specific IgE to putative allergen
- Component-resolved diagnostics
- Challenge test (supervised exposure to allergen)
353
What investigation is useful during a suspected acute allergic episode?
Serum mast cell tryptase level to indicate systemic mast cell degranulation. Peak concentration 1-2 hours, returns to baseline by 6 hours.
354
What controls are used during skin prick testing?
Histamine is used as a positive control, a dilutent is used as a negative control.
355
What response indicates a positive skin prick test result?
A wheal ≥ 2mm greater than the negative control. Steroids do not influence results but anti-histamines should be stopped 48 hours beforehand.
356
What are the pros and cons of skin prick tests?
Pros: rapid, cheap, easy, more sensitive and specific than blood tests, visible response for patient
Cons: requires experience to interpret, 1 in 3000 anaphylaxis risk, limited value in patients with dermatographism or extensive eczema, commercial food extracts are often labile
357
What is a RAST test?
Radioallergosorbent test is a blood test used to determine to what substances a person is allergic to by quantitating serum IgE directed against a specific allergen. Useful to confirm allergy diagnosis, inform prognosis and monitor clinical response to anti-IgE treatment.
358
What are the indications for specific IgE testing?
- unable to stop anti-histamines
- dermatographism
- extensive eczema
- history of anaphylaxis
- borderline/equivocal skin prick test results
359
What is the gold standard for food and drug allergy testing?
Challenge test - increasing volumes of offending food/drug are ingested. Must take place under close clinical supervision hence very expensive.
360
Define anaphylaxis
A severe systemic allergic reaction i.e. causes respiratory difficulty and hypotension. Almost always involves skin (itch, erythema, urticaria, angioedema) and may also include nausea, vomiting, diarrhoea, uterine cramps, rhinitis and a 'sense of doom'
361
Examples of allergens which can cause non-IgE-mediated mast cell degranulation and anaphylaxis.
Aspiring, NSAIDs, i.v. contrast media, opioid analgesics, exercise
362
What reactions can mimic anaphylaxis?
- Histamine poisoning
- C1 inhibitor deficiency
- Systemic mastocytosis
- Carcinoid syndrome
- Phaechromocytoma
- Myocardial infarction
- Pulmonary embolism
- Vaso-vagal attack
- Anxiety or panic disorder
363
At what times post allergen exposure should serum tryptase be measured at?
1, 3 and 24 hours. The rise is inversely proportional to the drop in blood pressure during anaphylaxis
364
What is the emergency management of anaphylaxis?
- Lie down and elevate legs to boost venous return to the heart
- IM adrenaline 500ug
- Oxygen 100%
- Fluid replacement
- Chlorpheniramine 10mg IV
- Hydrocortisone 100mg IV
- Inhaled Bronchodilators
365
Defects in which structural protein are an important risk factor for atopic dermatitis, allergic airway disease and IgE sensitisation?
Filaggrin - a structural protein which maintains integrity of epithelial barrier and contributes to hydration of skin. Loss of function mutation is found in 10% of Europeans and 50% of patients with severe AD
366
Defects in which proteins predispose to Staph aureus superinfection in atopic dermatitis?
Beta-defensin and cathelicidin
367
What type of adverse reaction to food is Coeliac disease?
Cell-mediated food allergy.
368
What causes oral allergy syndrome?
Allergic reactions in the mouth in response to eating certain fresh fruits, nuts, and vegetables. Caused by cross-reactivity of IgE directed against pollen (birch) from respiratory exposure. Cooking usually denatures proteins thus avoids symptoms.
369
Major food allergies in adults.
Peanuts, tree nuts, fish, shellfish, sesame seed.
370
Major food allergies in children.
Cow's milk, egg, wheat, peanut, tree nut. First 3 usually resolve by age 8
371
How is allergic rhinitis classified?
Seasonal (tree or grass pollen, fungal spores)
Perennial (house dust mite, pets)
Occupational (Latex, lab animals)
372
What is the aetiology of acute urticaria?
Idiopathic in 50% of cases
IgE mediated reactions to food, drugs and latex
Viral infections and febrile illnesses
373
Define chronic urticaria
Persistent itchy wheals lasting more than 6 weeks. 50% last more than a year, 20% more than 20 years.
374
What is the aetiology of chronic urticaria?
Idiopathic
Autoimmune (IgG against FcER1 or IgG against IgE)
Physical (heat, cold, pressure, solar, exercise)
There may be underlying thyroid disease.
375
Which drugs can precipitate or exacerbate symptoms in patients with chonic urticaria?
Aspirin, NSAIDs, opiates
| ACE inhibitors in those with angioedema
376
What drug treatments are available to prevent chronic urticaria?
Antihistamines
Doxepin if unresponsive to anti-histamines
Ciclosporin for refractory cases.
377
Define auto- iso- allo- and xenografts?
Autografts - within the same individual
Isografts - between genetically identical individuals of the same species
Allografts - between different individuals of the same species = most transplants
Xenografts - between individuals of different species
Prosthetic graft (plastic, metal)
378
For a patient in end stage renal failure, what provides the best patient survival?
Kidney transplant. RR of death higher initially but lower in the long run. Also cheaper.
379
What mechanism is behind the majority of organ transplant failures?
Antibody-mediated rejection and nonadherence
380
What are the phases of immune response to a transplanted graft?
Phase 1: recognition of foreign antigens
Phase 2: activation of antigen-specific lymphocytes
Phase 3: effector phase of graft rejection
381
What are the most relevant protein variations between individuals in clinical transplantation?
1. ABO blood group - antigens on endothelial lining of blood vessels in transplanted organ as well as blood cells
2. HLA coded on chromosome 6 by MHC complex
382
What are the chances of HLA matching between parent and child, and siblings?
```
Parent to child: will share 3/6 alleles or more
Sibling to sibling:
25% full match 6/6
50% half match 3/6
25% no match 0/6
```
383
What are the most important HLA classes matched in transplantation?
HLA-A
HLA-B
HLA-DR
384
How many HLA alleles does a person express?
6
385
What can induce hyperacute rejection?
Naturally occurring anti-A or anti-B antibodies in the host
386
What is the difference between direct and indirect antigen presentation with respect to transplantation?
- Direct antigen presentation occurs when donor APCs activate host/recipient T cells = acute rejection
- Indirect antigen presentation occurs when host APCs present donor peptide to host T cells - normal immune mechanism/response = chronic rejection
387
Which mechanisms of T cell activation are mostly behind acute and chronic rejection?
```
Acute = direct antigen presentation
Chronic = indirect antigen presentation
```
388
How do cytotoxic lymphocytes kill cells?
Release of toxins to kill target cell - Granzyme B
Punch holes in target cells - Perforin
Apoptotic cell death - Fas-Ligand and Th1 cytokines
389
What are the symptoms of acute T-cell mediated rejection?
Deteriorating graft function
Pain and tenderness over graft
Fever
390
How could an individual have preformed antibodies against donor cells?
- Naturally occurring anti-ABO antibodies
- HLA antibodies arise through previous exposure e.g. transplantation, blood transfusion, pregnancy. class I antibodies particularly important
391
If a graft biopsy shows complement activation and deposition, what is this associated with?
Antibody mediated rejection seen in hyperacute rejection. Primary antibody target = endothelium thus deposition seen in peritubular capillaries, arteries, glomerular endotherlium etc.
392
What are the indications for a haematopoietic stem-cell transplant?
- haematological and lymphoid cancers
- autoimmune diseases leading to loss of marrow cells
- acquired (autoimmune) or inherited deficiencies in marrow cells such as errors of metabolism or immunodeficiencies
393
Example of a drug which can be used to eliminate a hosts immune system?
Cyclophosphamide
394
Examples of drugs used for GVHD prophylaxis?
Methotrexate
| Cyclosporine
395
What are the common symptoms of GVHD? How is it treated?
Skin: rash
Gut: nausea, vomiting, abdominal pain, diarrhoea, bloody stool
Liver: jaundice
Treatment with corticosteroids
396
For which organs is HLA matched transplant beneficial and which are not?
Essential for stem cell transplant
Clear benefit for kidney
Controversial for liver
Need for transplant outweighs match benefit for heart and lung transplants
397
What are the three main types of assay used to screen for anti-HLA antibodies prior to transplantation?
- Cytotoxicity assays: does the recipient serum kill the donor’s lymphocytes in the presence of complement? – detection of cell death using vital dyes
- Flow cytometry: does the recipient’s serum bind to the donor’s lymphocytes (bound antibody detected by fluorescently-labelled anti-human Ig)
- Solid phase assays: does the recipient’s serum bind to recombinent single HLA molecules attached to a solid support such as beads (bound antibody detected by fluorescently-labelled anti-human Ig)
398
What does eculizumab target?
Anti-complement - C5
399
What does Daclizumab taget?
CD25, the alpha subunit of the IL-2 receptor of T cells. Used to prevent transplant rejection, esp kidneys
400
How does Sirolimus work?
Binds to and inhibits mTOR which prevents activation of T cells and B cells by inhibiting their response to IL-2
401
How does Belatacept work?
Fusion protein of Fc fragment of IgG1 linked to CTLA-4 = selectively blocks the process of T-cell activation by interrupting co-stimulation
402
What are the commonest side-effects of immunosuppression post transplant?
- Infection (conventional and opportunistic)
- Viral associated malignancy x100 (Karposi's and lymphoproliferative disease)
- Skin cancer x20
- Other cancers x2-3
- Atherosclerosis, hypertension, hyperlipidaemia = x20 risk of death from MI
403
What different routes of vaccine administration are there and how do they effect the response?
- Subcutaneously – good. Uptake, processing and presentation to Langerhans cells in skin
- Intramuscular OK
- Intravenously Ag is taken to spleen
- Orally (gastrointestinal). Good general response and local response within gut tissue
- Intranasal (respiratory) OK, but may get allergic responses
404
What type of T helper cell response favours cell-mediated immune response?
Type 1 - Th1
405
What type of T helper cell response favours a humeral immune response?
Type 2 - Th2
406
What is the target for influenza infectivity-neutralising antibodies?
Haemagglutinin (HA) - the receptor-binding and membrane fusion glycoprotein
407
What is a positive Mantous test result?
Redness and an induration of at least 10 mm in diameter 48 to 72 hours after 0.1 ml of 5 tuberculin units of liquid tuberculin is injected intradermally
408
How long does influenza protection last in the general population post vaccination?
~6 months
409
How long does TB protection last in the general population post BCG vaccination in the UK?
10-15 years
410
What cell surface markers differentiate a naïve T cell from a memory T cell?
Naïve: CD45RA+ CD45RO-
| Memory: CD45RA- CD45RO+
411
What are the characteristics of an immune memory response?
- Subsequent exposure to a potential pathogen is more rapid and more aggressive
- Different pattern of expression of cell surface proteins involved in cell adhesion and chemotaxis which allows memory cells to access non-lymphoid tissues, the sites of microbial entry
- Longevity
412
What are the two subsets of memory T cells?
- Central memory T cells (TCM) CCR7+ CD62Lhigh
migrate efficiently to peripheral lymph nodes. Produce IL-2, no IFN-g, no perforin.
- Effector memory T cells (TEM) CCR7- CD62Llow
found in other sites, such as the liver and lungs. Little IL-2 but high IFN-g and perforin.
413
What does the linear development model of memory cell generation suggest?
Persistence of antigen results in a larger immune response and the generation of more memory cells.
414
Examples of live vaccines
Yellow fever, MMR, Typhoid, Tuberculosis (BCG), Polio (Sabin), Vaccinia (Smallpox vaccine)
415
Advantages of live vaccines
- Establishes infection, extremely weak symptoms if any
- Often confers lifelong immunity after one dose (no boosters). Likely due to proliferation of organism in host
- Activates all phases of immune system. Can get humoral IgG and local IgA
- Raises immune response to all protective antigens
- More durable immunity; more cross-reactive
416
Disadvantages of live vaccines
- Possible reversion to virulence (recombination, mutation). E.g. Vaccine associated paralytic poliomyelitis (VAPP, ca. 1:750,000 recipients)
- Storage problems (cold chain)
- Safety issues
Spread to contacts of vaccinee who have not consented to be vaccinated (could also be an advantage in communities where vaccination is not 100%)
Spread vaccine not standardized--may be back-mutated
- Problem in immunodeficiency disease (may spread to these patients)
417
Examples of inactivated vaccines
Influenza, Cholera, Bubonic plague, Polio (Salk), Hepatitis A, Pertussis, Rabies
418
Examples of conjugate vaccines
Haemophilus Influenzae B (Hib, polysaccharide + protein (Tetanus toxin or mutant Diphtheria toxin))
Meningococcus
Pneumococcus
419
Advantages of inactivated / component vaccines
- No mutation or reversion
- Can be used with immuno-deficient patients
- Can lead to elimination of wild type virus from the community
- Storage easier
- Lower cost
420
Disadvantages of inactivated / component vaccines
- Some components have poor immunogenicity
- May need multiple injections
- May require adjuvants
- Often do not follow normal route of infection i.e. injection in arm
421
How does a “depot” adjuvant work?
A depot adjuvant acts by slowing the release of antigen. When the mixture of adjuvant and antigen are injected the adjuvant provides a “steady stream” of antigen for the response helping to increase the immune response without altering its specificity.
422
What is the primary adjuvant used in human vaccines?
Alum (hydrated aluminum potassium sulfate) - get a mainly antibody mediated response
423
Which adjuvants act as immunostimulants?
Complete Freund's adjuvant
| Interleukin 2
424
How are CpG motifs recognised by the immune system?
CpG motifs are much more common in prokaryotes and are usually unmethylated whereas in eukaryotes most are methylated.
Pattern recognition receptor TLR-9 binds CpG motifs
425
Advantages of DNA vaccines
- get a situation which resembles a virally infected cell
| - induce good immunity and CTL responses (MHC Class I driven)
426
Disadvantages of DNA vaccines
- plasmid could integrate into host DNA with unknown consequences
- possible responses to DNA could lead to autoimmune diseases e.g. SLE
427
What is the efficacy of the influenza vaccine in young adults and the elderly?
70-90% in young adults
| 30-40% in elderly
428
Why doesn't vaccination work effectively in the elderly?
- Immune senescence (terminally differentiated memory T cells, reduced production of naive T cells)
- Poor nutrition (calories, trace elements and minerals)
429
What is the definition and mechanism of anaphylaxis?
A systemic hypersensitivity reaction in which the response is so overwhelming as to be life-threatening.
Type I hypersensitivity response (IgE cross-linking, mass cell degranulation)
430
What are the clinical features of anaphylaxis?
Urticaria and angioedema, upper airway oedema, breathlessness and wheezing, flushing, dizziness, syncope, hypotension, vomiting, diarrhoea, rhinitis, headache, chest pain, etc.
431
What is the immediate treatment of anaphylaxis?
- O2 (via mask but may require intubation / tracheostomy)
- Adrenalin IM 0.5mg for adult (can repeat)
- IV anti-histamines (10mg Chlorpheniramine)
- Nebulised bronchodilators (salbutamol)
- IV corticosteroids (200mg hydrocortisone)
- IV fluids
432
Why are IV steroids given in anaphylaxis?
They are a systemic anti-inflammatory agent and are important in preventing rebound anaphylaxis. Takes ~30 mins to start working, few hours to peak.
433
What is the link between banana and latex allergies?
Cross-reactivity between latex and chitinase containing foods e.g. Avocado, apricot, banana, chestnut, kiwi, passion fruit, papaya, pear, pineapple.
434
How can you confirm a diagnosis of severe latex allergy?
In vitro IgE test - to look for specific IgE to latex
| In vivo test - skin prick for type I hypersensitivity, patch test for type IV
435
For what allergens does desensitisation work?
Insect venom and some aero-allergens (e.g. grass pollen)
436
What disorders are associated with recurrent meningococcal meningitis?
```
Immunological
- complement deficiency
- antibody deficiency
Neurological
- any disruption of blood brain barrier e.g. Occult skull fracture, hydrocephalus
```
437
Which immunological investigations would you perform for someone with recurrent meningococcal septicaemia?
C3 and C4 levels, CH50, AP50
Serum IgG, IgA, IgM
Protein electrophoresis
438
A patient with normal C3 andC4 levels but absent CH50 and AP50 tests is likely to have what?
A deficiency of a component in the final common complement pathway C5-C9 membrane attack complex
439
What further tests should a patient with clinical signs of SLE and who is ANA +ve have to help confirm the diagnosis and assess disease severity?
ds-DNA, ENA and cytoplasmic antibodies
C3 and C4 levels
ESR
Anti-dsDNA titre
440
What is the predominant effector mechanism of lupus nephritis in terms of the Gel and Coombs classification?
Type III response - antibody complexes
441
What is the mechanism of serum sickness?
A drug e.g. Penicillin binds to cell surface proteins and acts as a neo-antigen stimulating very strong IgG antibody response. Individual becomes sensitised to the drug and subsequent exposure stimulates immune complex formation and more IgG production = small vessel vasculitis.
442
Other than immunological disorders, what other factors can cause a 3 year old to have too many respiratory infections?
Allergic rhinitis, sinusitis, asthma.
Cystic fibrosis, ciliary disorders, foreign body.
Overestimation of infections.
443
What genetic polymorphisms predispose to rheumatoid arthritis? And what do they suggest about the pathogenesis?
HLA-DR4 and DR1 - suggests HLA class II presentation involved
PAD 2 and 4 - increase load of citrullinated proteins
PTPN-22 (1858T) - suggests T cell activation involved
444
What is the first line treatment of rheumatoid arthritis?
Methotrexate
And/or sulphasalazine, hydroxychloroquine, leflunomide.
Further treatment = biologics
445
What risks must be considered before starting a patient on immunosuppressive agents (esp. biologics)?
```
Infection
- screen for TB, Hep B, Hep C, HIV
- vaccinations
Malignancy
- prior history
- educate re sun exposure
```
446
What HLA alleles are associated with coeliac disease?
HLA DQ2 and HLA DQ8
447
What peptide is important in the pathogenesis of coeliac disease?
Peptides from gliadin are deamidated by tissue transglutaminase and presented to CD4 T cells by APCs
448
Which cell type is responsible for damage in coeliac disease?
Gamma-delta TCR expressing intra-epithelial lymphocytes (IEL)
449
Why are anti-gliadin and anti-transglutaminase antibodies sometimes present in coeliac disease?
Because the T helper cells which recognise deamidated gliadin peptides and drive the cellular response also stimulate B cells specific to transglutaminase/gliadin complex (either part) to produce antibodies. Anti-endomyosial cell antibodies are also seen as the cells express surface transglutaminase.
450
What is the gold standard test for coeliac disease?
Duodenal biopsy - shows villous atrophy, crypt hyperplasia and increased intra-epithelial lymphocytes
451
What complications of coeliac disease are there?
```
Malabsorption
Osteomalacia and osteoporosis
Neurological disease (epilepsy, cerebral calcification)
Lymphoma
Hyposplenism
```
452
What other disorders and autoimmune diseases is coeliac disease associated with?
```
Dermatitis herpetiformis (100% have coeliac)
Type I diabetes (7%)
Autoimmune thyroid disease
Down's syndrome
Lots more autoimmune diseases..
```
453
What is Wiskott-Aldrich Syndrome?
X-linked disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). They have small platelets that do not function properly and are removed by the spleen. WASp gene mutation
