Immunology Flashcards
1
Q
The most common type of Hyper IgM syndrome?
A
X-linked CD40 ligand deficiency
2
Q
Recurrent infections, FTT and steatorrhoea (due to pancreatic dysfunction), neutropenia - cause is?
A
Schwachman Diamond syndrome
3
Q
Presents at 6 months to 2 yrs
Low or absent B cells
IgA, IgM, IgG, IgD, IgE all low
A
X-linked agammaglobulinaemia:
Recurrent bacterial infections after 6 months when maternal immunoglobulins have gone
Unusual enterovirus infections (chronic meningoencephalitis)
Tonsils, adenoids, lymph nodes small or absent
Acquired infections with pyogenic organisms (e.g. Strep pneumo, Haemophilus influenza unless given Abs or IVIG)
Pneumocystis carinii rarely seen
4
Q
Recurrent infections, short stature and an erythematous photosensitive facial rash
A
Bloom syndrome:
Autosomal recessive
Increased risk of malignancy
Erythematous photosensitive rash in the first two years of life
5
Q
Features of the innate immune system
A
Rapid but non-speciifc.
Made up of acute phase proteins, cytokines, complement, neutrophils, macrophages, NK cells.
6
Q
Mechanism of PAMPs
A
Pathogen-associated molecular patterns
Neuts/NK cells/macrophages have receptors (pathogen-recognition receptors PRRs) that recognised PAMPs - produce cytokines - activate inflammation (CRP, complement)
Complement protein activates pathogen uptake by phagocytic cells.
7
Q
Features of the adaptive immune system
A
Slower, but antigen-specific and development of immunological memory.
B and T cells.
8
Q
Functions of antibodies (immunoglobulin)?
A
- Produced by B cells
- Neutralise toxins released by pathogens
- Opsonise pathogens to facilitate uptake by phagocytes
- Activate complement to cause cytolysis of pathogen
- Direct NK cells to kill infected cells by antibody-mediated cytotoxicity
9
Q
Function of T cells?
A
- Kill virus-infected cells and cancer cells
- Activate macrophages to kill intracellular organisms
- Help with B-cell antibody synthesis and memory B cell formation
10
Q
Antigen presenting cell types and role
A
Macrophages and dendritic cells are APCs that activate T cells and initiate adaptive immune response
11
Q
Dendritic cell role
A
Takes up pathogen at site of infection and becomes activated, migrates to peripheral lymphoid organs, presents antigens to naive T cells
12
Q
Types of phagocytes
A
Monocytes/macrophages
Neutrophils
Dendritic cells
13
Q
What is the process of B cell differentiation?
A
B cells develop in the bone marrow where assembly of pre-B cell and B-cell receptors by V(D)J (variable, diversity and joining) immunoglobulin gene rearrangement occurs. Immature B cells migrate to peripheral lymphoid organs where activation by antigens leads to proliferation and differentiation into antibody-producing plasma cells
14
Q
What is the process of T cell differentiation?
A
T cell precursors migrate from the bone marrow to the thymus where V(D)J recombination of T-cell receptors occurs, and T-cell precursors develop into naive CD4 and CD8 T cells. These naive cells emigrate from thymus into peripheral lymphoid organs where activation, clonal expansion, and differentiation into effector T cells occurs upon antigen encounter (priming).
15
Q
T-cell receptor excision circles
A
Surrogate marker of recent thymic output, indicator of normal T cell development.
Excision of the intervening gene segments during V(D)J recombination of TCR generates T-cell receptor excision circles.
Used as a marker for SCID in newborn screening
16
Q
Induction of self-tolerance
A
Occurs in the cortex of the thymus.
T cells that bind strongly to self cell-surface antigens are removed.
Cells that have low affinity are removed.
Only interactions with an intermediate affinity lead to CD4 or CD8 lineage commitment (positive selection) , followed by passage into the thymic medulla and exit into the periphery.
17
Q
3 important factors of innate immunity?
A
Recognition - PAMPs (pathogen-associated molecular patterns) recognised by PRR (pathogen-recognition receptors) on macrophages, neutrophils, dendritic cells
Acute inflammatory response - pathogens engulfed and killed, secretion cytokines and chemokines to recruit more effector cells to site of infection
Induction of adaptive immune response - activated antigen presenting cells migrate to lymphoid organs where antigens are presented to B and T cells
18
Q
Describe the complement pathway
A
Links innate and adaptive immunity.
Classical pathway: C1q, C1r, C1s, C4, C2, C3.
Lectin pathway: mannose-binding lectin (MBL), MASP 1 and 2, C4 and C2.
Alternative pathway: factor B, factor D, properdin (upregulating factor)
19
Q
Examples of cytokines
A
Interleukins, interferons, tumour necrosis factor (TNF).
Mediate signalling between immune cells (c.f. chemokines which attract and recruit neuts, monocytes to site of infection, eg CXCL, CCL).
20
Q
Neutrophils ingest…
A
Pyogenic bacteria and fungi
21
Q
Macrophages kill…
A
Intracellular organisms e.g. TB, toxo, legionella, salmonella
22
Q
NK cells control…
A
Cytotoxic activity against virus- infected cells and cancer cells
23
Q
Complement activation causes…
A
- Recruitment of inflamm cells and provoke inflamm response (C3a, C5a)
- Opsonisation of pathogens and removal of immune complexes (C3b, C4b)
- Killing by lysis of pathogens and cells (membrane attack complex: C5b, C6, C7, C8, C9)
24
Q
Adaptive immune system is divided into humoral and cellular responses. What are these?
A
Humoral immunity: production of specific antibody against an invading pathogen or vaccine antigen.
Cellular immunity: T-cell dependent macrophage activation, cytotoxic T cells (CD8)
25
CD8 T cells (cytotoxic T cells) work by...
Recognising viral peptides via MHC-I, triggers apoptosis, releases cytotoxic granules. Effector molecules: IF gamma, TNFa, perforin, granzymes
26
Naive CD4 T cells work by...
Recognising antigens presented by MHC-II, differentiate into Th1 and Th2 cells.
Th1: activate macrophages to kill engulfed intracellular pathogens via IF gamma, TNFa, GMCSF, CD40 ligand, Fas ligand. Cell-mediated immunity
Th2: coordinate humoral immune response with Th1 cells by inducing differentiation of naive B cells into antibody-producing plasma cells via IL 4,5,13, CD40 ligand
27
Immunoglobulin types and complement pathway activation
```
IgG - classical pathway
IgM - classical pathway
IgA - alternative pathway
IgD - none
IgE - none
```
28
Recurrent sinopulmonary infections with encapsulated bacteria suggest a defect in?
Antibody-mediated immunity (B-cells) because these pathogens evade phagocytosis
29
Chronic diarrhoea, failure to thrive, malabsorption and infections with opportunistic pathogens suggest...
T-cell immunodeficiency
30
Recurrent infections with less virulent organisms such as viral, fungal, or protozoal infections suggests...
T-cell or NK-cell deficiency
31
Deep-seated abscesses and infections with staph, serratia and aspergillus suggests...
A disorder of neutrophil function, such as CGD
32
Delayed separation of the umbilical cord (esp with omphalitis and later onset peridontal disease) in addition to poorly formed abscesses indicates...
Leucocyte adhesion deficiency
33
Neisserial infections or early onset autoimmunity suggests...
Complement defect
34
Timing of presentation of immunodeficiency disorders.
- First few months of life?
- >3 months of life?
- Older child?
- Neutrophil defects in first few months eg congenital neutropenia, leukocyte adhesion deficiency.
- Antibody defects and T-cell defects after first 3 months once maternal antibody levels have waned e.g. agammaglobulinaemia, SCID
- CVID in adolescents or young adulthood, although milder phenotype of primary immunodeficiency can present later
35
Immunodeficiency with congenital heart disease and hypocalcaemia?
DiGeorge syndrome, 22q11.2
36
Immunodeficiency with abnormal gait and telangectasia?
Ataxia-telangectasia
37
Immunodeficiency with atopic dermatitis?
Hyper-IgE syndrome, Omenn syndrome
38
Immunodeficiency with eczema, easy bruising or a bleeding disorder?
Wiskott-Aldrich syndrome
39
Absence of lymphoid tissue eg. tonsils suggests.... and increased size of lymphoid tissue suggests....
Absence - agammaglobulinaemia or SCID
| Increased - CVID, CGD, HIV
40
Immunodeficiency with eczema and IBD?
X-linked (IPEX) syndrome - immune regulation with polyendocrinopathy and enteropathy
41
Describe the classical features of B cell defects
- Recurrent pyogenic infections with encapsulated organisms e.g. strep pneumona, haemophilus, GAS
- Recurrent sinopulmonary infections
- Diarrhoea due to giardia
- Minimal growth retardation
- Survival to adulthood
42
What are the features of complement defects?
- Recurrent infections with encapsulated organisms e.g. strep pneumona, haemophilus, GAS
- Recurrent Neisseria infections
- Increase autoimmune disease
- Severe recurrent skin or resp tract infections
43
What are the features of T cell defects?
- Recurrent infections less virulent organisms e.g. viruses, protozoa, fungal
- Growth retardation, malabsorption, diarrhoea, FTT
- Susceptible to GvHD from non irradiated blood
- Fatal reactions from live vaccines
- Increased incidence malignancy
- Poor survival beyond infancy or early childhood
44
What types of infections are associated with neutrophil defects?
- Recurrent skin infections with staph, pseudomonas, E.coli, aspergillus
- Abscesses in subcut, lymph nodes, lung, liver
- Abscess and pneumatoceles in lungs
- Bone and joint infections
- Delayed separation of umbilical cord
- Absence of pus at site of infection
- Poor wound healing
45
Describe a serum sickness-like reaction?
- Secondary to medications, usually cefaclor
- Not due to immune complex formation and deposition (like true serum sickness)
- Usually <6y
- Can occur days - weeks after exposure
- Fever, malaise, urticarial rash, facial swelling, joint pain and/or swelling, which is usually symmetrical
- The rash may also atypical and has been reported as being morbilliform, scarlatiniform and erythema multiforme-like
- Tx: stop medication, symptomatic relief
46
Nijmegen breakage syndrome (NBS)
- Severe microcephaly, IUGR
- Immunodeficiency with recurrent sinopulmonary infections
- Lymphoma susceptibility
- Radiation hypersensitivity is found in both lymphocytes and fibroblasts
47
CD40 ligand deficiency
- Also known as Hyper IgM
- Associated with cryptosporidium infection
- Risk of cholangiocarcinoma
- Susceptible to peripheral neuroectodermal tumours of the gastrointestinal tract
48
X-linked lymphoproliferative disease (XLP)
- Caused by mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein (SAP) gene
- T and NK cell defect and an uncontrolled cytotoxic T-cell immune response to EBV
- Fulminant infectious mononucleosis during the preschool years, fatal in 50%
- HLH with fever, HSM, lymphadenopathy, hepatic necrosis, cytopenia
- Can develop lymphoma, dysgammaglobulinaemia, aplastic anaemia
- Tx: immunosuppression, chemotherapy, HSCT
49
What are some immunodeficiency tests and what are we looking for?
- FBC - neutropenia, anaemia, lymphopenia, eosinophilia
- Serum immunoglobulin levels - low (normal age, immunodef), high (may indicate CGD, CF, HIV, autoimmune disease)
- Vaccine responses - conjugate and polysaccharide vaccine responses
- Skin prick tests - tests presence of antigen-specific T cells and functional APCs
- Lymphocyte phenotyping by flow cytometry - looking at T (CD3 and 4), B (CD19+20), NK cell subsets (CD56)
- Complement assays - CH50 test (classic pathway, C1-4), AH50 (alternative, C3, factor B, properdin). If both abnormal then likely defect in common pathway (C5-9)
- Neutrophil oxidative burst - NBT and DHR to look for oxygen radicals produced by activated neutrophils. In CGD, no blue stain (NBT) or fluorescence (DHR)
- Genetic testing - to confirm diagnosis e.g. 22q11 or ataxia-telangectasia
50
Diagnostic imaging in immunodeficiency?
Absence of a thymus on CXR suggests DiGeorge or other defects in T-cell development
51
Describe agammaglobulinaemia
- 85% X-linked (mutation BTK gene), rest AR (u heavy chain, BLNK)
- Onset 6-9m
- Arrest in B-cell differentiation at pre-B level
- Recurrent sinopulm infections by encapsulated bacteria
- Diarrhoea due to giardia
- Chronic enteroviral meningoencephalitis
- Absent tonsils and lymph nodes
- Decr IgG, IgA, IgM, absent vaccine response, CD19 B cells <2%
- Tx: immunoglobulin replacement (aim trough IgG >7-8), early treat infections
52
Describe CVID
- Majority sporadic, 10-25% AR or AD
- Adolescence or early adulthood
- Issue with differentiation at mature B-cell level
- Recurrent sinopulm infections by encapsulated bacteria
- Diarrhoea due to giardia and campylobacter
- Severe VZV, recurrent HSV
- Autoimmune disease: AIHA, ITP, SLE, graves, Chron's, granulomatous disease
- Splenomegaly, lymphadenopathy , normal or large tonsils
- Inc risk NH lymphoma, gastric cancers
- Decr 2 of IgG, IgA, IgM, poor vaccine response, CD19 B cells >1%
- Tx: immunoglobulin replacement, early treat infections
53
What is the age of development of different immunoglobulins?
IgM is detected by 1 week of age, reaches adult by 12m
IgA detected by 2 weeks of age, reaches adult by 7y
IgG reaches adult levels by 7-12y
54
Describe transient hypogammaglobulinaemia of infancy
- Temporary prolongation of physiological hypogammaglobulinaemia of infancy
- Accentuated nadir at 6m age, reaches normal levels by age 2-4 years
- Inc viral, sinopulmonary infections, usually mild
- Normal B and T cell numbers, normal vaccine responses
- Frequently in families with other immunodeficiencies
55
What are the causes of low immunoglobulins?
- Primary antibody deficiencies (XLA, CVID, THI, hyper IgM, IgA def)
- Prematurity <36/40
- Excessive losses (protein losing enteropathy, nephrotic syndrome)
- Drug-induced (anti-malarials, captopril, carbemazapine, phenytoin)
- Infections (EBV, HIV, congenital CMV and toxo)
- Others (malignancy, SLE)
56
What are the types of class-switch recombination defects?
- Defective CD40 ligand (X-linked, account for 70%) and CD40 (AR) interactions: opportunistic infections
- Defect in CD-40 mediated NF-KB activation: anhidrotic ectodermal dysplasia with immunodeficiency (NEMO gene): increased susceptibility esp meningitis and atypical mycobacteria
- AID and UNG defects (no opportunistic infections)
57
Describe HyperIgM syndrome
- Most due to CD40 ligand deficiency = X-linked
- Decr ability to switch from IgM to IgG, A, E
- Recurrent sinopulm infections, opportunistic PCP (40%) and crypto, recurrent viral HSV, CMV, parvovirus
- Cryptosporidium enteritis and sclerosing cholangitis, liver failure
- Haematological and liver malignancy
- Autoimmune: ITP, IBD, arthritis
- Neutropenia - ulcers and gingivitis
- Normal B and T cell numbers (c.f. SCID), absent CD40 ligand on flow cytometry. Reduced vaccine response.
- Tx: Immunoglobulin, cotrimoxazole for PCP prophylaxis, may need stem cell transplant
58
What is the most common form of SCID?
X-linked SCID caused by IL-2 gamma chain deficiency due to mutation on Chr Xq13.1, JAK3 (all remaining forms are autosomal recessive). T cell defect due to defect in IL-7 receptor and NK cells due to IL-15 receptor
59
What causes lymphopenia and hypogammaglobulinaemia?
SCID. Lymphocyte count <2.5 is abnormal in infants and indicates likely SCID
60
Describe SCID
- Defect in T cell development, may have absent or present B cells, however cannot work without T cell interaction (can be T-B+ or T-B-)
- Most common is X-linked
- Severe infections first few months of life
- Resp infections, opportunistic eg. PCP, chronic oral and perineal candidiasis, BCG-related abscess, chronic diarrhoea and FTT, disseminated viral infections, eczema-like skin rash from maternofetal engraftment, absent lymphoid tissue
- Lymphopenia <2.5, low IgG, A, M (may have maternal IgG)
- Need to rule out HIV
- Tx: prophylaxis, treat infections, Ig replacement, HSCT
61
Describe DiGeorge Syndrome
- 22q11.2 deletion (detect via FISH)
- CATCH 22 (cardiac abnormalities, abnormal facies, thymic hypoplasia, cleft palate, hypocalcaemia)
- Hypocalcaemia, absent thymus, parathyroid hypoplasia, conotruncal abnormalities
- Usually partial T-cell defect, improves with age, 1% have complete aplasia with SCID phenotype
- Increased autoimmune diseases (cytopenia, arthritis, endocrinopathies)
- May need prophylaxis, Ig replacement, thymic transplant, don't respond well to HSCT
62
Describe the different antibody types
IgM - pentomeric, first immunoglobulin produced in infection, intravascular
IgG - crosses placenta, 80% of antibodies, goes to site of infection
IgA - 2nd most abundant, is secreted in breast milk, tears, saliva, mucous
IgE - low levels, involved in type 1 hypersensitivity reactions
IgD - minimal role except early B cell receptor
63
Describe Omenn Syndrome
- Type of SCID
- Exaggerated inflammatory response caused by oligoclonal T-cell populations, often autoreactive in nature
- Generalised erythroderma with alopecia, loss of eyebrows/lashes
- Chronic diarrhoea, lymphadenopathy, hepatosplenomegaly
- May have lymphocytosis rather than lymphopenia because of clonal T-cell expansion, raised IgE and eosinophils
- Often due to RAG1 or 2 deficiency, T-B-
64
Describe Wiskott-Aldrich Syndrome
- X-linked disorder, Xp11.22, abnormal expression WASP protein
- Thrombocytopenia, eczema, combined immunodeficiency
- High IgE and IgA, decr IgM, small and decr platelets, poor vaccine responses, waning T cell function and numbers over time
- Opportunistic infections, sinopulmonary, viral eg CMV
- Bleeding - can be fatal in 1/3rd due to ICH
- Autoimmune: AIHA, neutropenia, nephropathy, arthritis/vasculitis
- Tx: prophylaxis, treat infections, IVIG or steroids for plts, Ig replacement, HSCT (better outcomes if <5yo)
65
Describe Ataxia Telangectasia
- Mutation in ATM gene on 11q22.3, DNA-repair defect, AR
- Onset age 2-5 years
- Recurrent OM, pneumonia, meningitis with encapsulated organisms
- Cutaneous and conjunctival telangectasia over age 2, progressive cerebellar ataxia (early onset), choreoathetosis.
- Lymphopenia, antibody deficiency, decr IgA and IgE, incr AFP, variably depressed T cell function
- Very sensitive to radiation, risk leukaemia and lymphoma
- Tx: antibiotics, Ig replacement
66
Type 1 reactions
- Allergic reactions
- IgE antibodies bind to mast cells and cause degranulation
- e.g. asthma, food allergies, anaphylaxis hayfever
67
Type 2 reactions
- Cytotoxic antibody-dependant reactions
- IgM (type 2) or IgG (complement)
- AIHA, ABO incompatibility, thrombocytopenia, Goodpasture's, Grave's, myasthenia gravis
68
Type 3 reactions
- Antigen-antibody complexes, 1-3w post exposure
- Antibody-antigen immune complexes are deposited in tissues which triggers complement activation causing causing tissue damage
- e.g. RA, SLE, serum sickness (cefaclor, penicillin, cotrimoxazole- fever, arthralgias, LAM, erythema multiforme, decr C3+C4)
69
Type 4 reactions
- Delayed-type hypersensitivity reactions. 2-7d post exposure
- Cell mediated reaction involving CD8+ cytotoxic T cells and CD4+ helper T cells
- e.g. contact dermatitis, type 1 DM, Steven Johnson's, Mantoux test, chronic transplant rejection, GvHD
70
High IgE, eosinophilia, eczema, recurrent skin and pulmonary infections
Hyper-IgE syndrome
71
Describe Hyper-IgE syndrome
- Markedly elevated IgE levels (>1000), atopic dermatitis, eosinophilis (>0.8) and staph abscesses of skin, lung, joints, viscera
- Sinopulm infections, candidia and aspergillus
- Associated coarse facial features, joint laxity, fractures, pneumatoceles, retained primary teeth, newborn pustular rash
- Normal IgG, IgA, IgM. Poor vaccine response
- Most are AD (Jon syndrome, STAT3 mutation), rest AR (TYK2 and DOCK8 mutation)
- Tx: staph and fungal prophylaxis
72
Describe chronic mucocutaneous candidiasis
- Extensive candida infections of skin, nails, mucous membranes
- Related to defects of dendritic cells or impaired Th1 and Th17 immune response
- Tx fungal prophylaxis
- May be associated with autoimmune endocrinopathies (APECED)
73
What are suggestive signs of a neutrophil disorder?
Gingivitis, abscesses in skin and viscera, absence of pus, poor wound healing, delayed separation of umbilical cord, lymphadenitis
74
How do neutrophils kill ingested pathogens?
Using granular enzymes or by activation of oxygen radicals
75
Describe congenital neutropenia
- Multiple syndromes, most severe is Kostmann Syndrome
- Maturational arrest at promyelocyte stage. May have monocytosis
- Presents 1st year life
- Cellulitis, abscesses, osteomyelitis, colitis, sepsis, meningitis
- Neutropenia <0.5 for over 3 months
- Tx: aggressively treat infections. GCSF.
- Long term risk leukaemia and myelodysplastic syndromes
- May requires HSCT
76
What is the gene defect in Kostmann Syndrome?
Autosomal recessive
Mutation in HAX-1 gene
Severe congenital neutropenia
77
Schwachman-Diamond Syndrome
```
Autosomal recessive
Pancreatic exocrine insufficiency, skeletal abnormalities, short stature, recurrent infections lung/bone/skin.
Neutropenia, 25% have panyctopenia.
Inc risk leukaemia, myelodyspasia.
HSCT may be curative.
```
78
Cyclical neutropenia
Neutropenia for 3-6 days every 21 days, associated with stomatitis, oral ulcers, bacterial infections, severe debilitating bone pain when neutropenic.
AD, linkes to ELA2 and ELANE elastase genes
Can use GCSF when neutrophils are low
79
Leukocyte adhesion deficiency (LAD)
Neutrophils cannot bind to and migrate therefore lack of pus at sites of infection.
Paradoxical high neutrophil count in blood.
LAD1 most common, AR, ITGB2 (defect in common beta chain of beat 2 integrin), decreased CD18 and CD11
Failure separation umbilical cord, omphalitis, sepsis.
Severe orogenital infections, gingivitis, fungal
Absent pus
Tx: treat infection, prophylaxis, HSCT
80
Chronic granulomatous disease (CGD)
- Defect in intracellular killing as unable to activate respiratory burst. Hyperinflammatory state.
- 2/3rds X-linked, more severe, gp91 phox deficiency. 1/3rd AR, p47,22,67,40 phox deficiencies (inc AR in Maori)
- FTT, severe bacterial infections, abscesses, osteo
- Staph, pseudomonas, nocardia, aspergillus, burkholderia
- Granulomas, IBD, lymphadenopathy, hypergammaglobulinaemia, chronic dermatitis
- Use NBT or DHR tests, flow cytometry
- Treat with antifungal + Ab prophylaxis, steroids, interferon gamma infusions, HSCT, maybe gene therapy in future
81
Lack of pus at a site of infection usually indicates what/
Neutrophil migration defect
82
LAD 2 additional features?
Impairment of neutrophil rolling.
Dysmorphism
Growth and mental retardation
83
LAD 3 additional features?
Defective neutrophil adhesion.
| Thrombocytopenia
84
Most common organisms in chronic granulomatous disease?
Staph, pseudomonas, nocardia, aspergillus, burkholderia
85
Name 5 T-cell immunosuppressant medications
Prednisolone, ciclosporin, tacrolimus, mycophenolate, azathioprine
86
Most common mutation associated with a positive Dihydrorhodamine 123 (DHR) test?
gp91phox mutation - positive in 70%, X-linked, rest are autosomal recessive (p47,22,67,40 phox)
87
Which immunodeficiency syndrome is associated with cryptosporidium?
CD40 ligand deficiency is also known as Hyper IgM and is known to be associated with cryptosporidium infection. Chronic infection and inflammation can lead to cholangiocarcinoma.
88
What are the lab findings in haemophagocytic lymphohistiocytosis?
```
Very raised ferritin, ESR, CRP.
Pancytopenia.
Hypoalbuminaemia and raised LFTs.
Low fibrinogen, raised D-dimer
Haemophagocytosis in the bone marrow
```
89
Describe the features of Chediak-Higashi Syndrome
- Lysosome-related organelle disorder, build up of giant granules in lymph/platelets/melanocytes.
- Immunodeficiency with recurrent staph and strep infections
- Neuro: weakness, ataxia, peripheral neuropathy
- Oculocutaneous albinism
- Accelerated phase driven by EBV - lymphoproliferative syndrome with haemophagocytosis, often fatal
- Treatment with HSCT
90
What does IPEX syndrome stand for?
Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome
91
Describe IPEX syndrome
Enteritis - diarrhoea, FTT, villous atrophy
T1DM, hypothyroidism
Eczematous skin rash
Infections - virus, fungi, bacteria. cytopenia, raised immunoglobulins
Eosinophilia, low albumin, mutation FOX-3 gene
Tx: immunosuppression, HSCT
92
Describe the classical complement pathway?
Antibody-dependant
Activated by antigen-antibody complexes or raised CRP
C1-C4
93
Describe the alternative complement pathway?
Antibody-independent
Activated by C3b from classical pathway, or by hydrolysis of C3 on microbial surfaces
C3, protein B + D, properdin
94
Describe the lectin pathway?
Antibody-independent
Activated by interaction of mannose binding lectin with microbial carbohydrate
C2-C4, mannose binding lectin
95
C5-C9 complement deficiency predisposes to...?
Recurrent meningococcal infections
96
C1, C2, C4 complement deficiency predisposes to...?
Encapsulated bacterial infections, SLE, glomerulonephritis
97
C1 inhibitor deficiency predisposes to...?
Hereditary angioedema
98
Factor D or properdin complement deficiency predisposes to...?
Recurrent neisseria infections
99
Final pathway of complement system creates?
Opsonin
Anaphylatoxin
Chemotactic factor
Membrane attack complexes
100
C3 complement deficiency predisposes to...?
Severe pyogenic infections, encapsulated organism infections
101
Tests for complement pathway deficiencies?
CH50 - classical
AH50 - alternative
If both abnormal, suggests issue with terminal common pathway (C5-C9). If just one abnormal, suggests issue with early portion of that pathway
102
Describe hereditary angioedema
AD, due to C1 esterase inhibitor deficiency
Recurrent episodes non pruritic angioedema affecting face, limbs, abdomen, airway. Can be life threatening.
Treatment with airway management, FFP or C1 esterase inhibitor concentrate, tranexamic acid or danazol prophylaxis. Antihistamines, corticosteroids not helpful. ACE inhibitors can trigger episodes
103
What are the transplant outcomes in SCID?
90% survival if MHC-identical, 60% if haploidentical. Early transplant before acquisition of infections improves outcomes.
104
Peripheral stem cells as a source for HSCT v cord blood stem cells
Peripheral - inc risk GvHD, can obtain large amount
| Cords - decr risk GvHD, only small amount available which limits use in older children and adults
105
Order of preference for allogenic transplants
Matched sibling > haploidentical parent > matched unrelated donor > unrelated cord blood units
106
Early complications of HSCT
Rejection
B-cell lymphoproliferative disorder if T-cell depletion used
GvHD - fever, skin rash, diarrhoea, HSM, raised LFTs
Infections (bacterial, fungal, viral eg EBV, adenovirus, CMV)
Organ complications related to toxicities of conditioning agents
107
Late complications of HSCT
```
Chronic GvHD (>100 days)
Incomplete immune reconstitution
Growth retardation
Endocrine issues
```
108
Risks of preconditioning prior to HSCT
Pancytopenia - leading to infection and bleeding
Pulmonary toxicity
Veno-occlusive disease of the liver (alkylating agents eg cisplatin)
Mucositis
Haemorrhagic cystitis (cyclophosphamide)
109
What percentage of sensitised patients (eg on RAST/SPT) are clinically allergic?
30%
110
What are the three most common food allergies in children?
Egg white
Peanut
Milk
111
Which patients are at high risk for anaphylaxis?
History of anaphylaxis
Poorly controlled asthma
Multiple food and drug allergies
112
Timing of IgE mediated food allergy?
Onset minutes - 2 hours (usually <1 hr).
| Resolves within 4-12 hours
113
What does a skin prick test tell you?
Measures mast cell reaction in the skin (i.e. sensitisation) but doesn't tell you anything about a systemic reaction - need to correlate with symptoms/history.
114
What does RAST testing tell you?
Measures free circulating IgE, not IgE loaded onto mast cells, therefore indicates sensitisation rather than allergy.
115
What is the purpose of a negative control on SPT?
Accounts for cutaneous dermatographism. Positive test must be >3mm above the saline control
116
How do you test for a non-IgE mediated food reaction?
Oral food challenge (only way)
117
Examples of non IgE mediated allergies?
FPIES
Food protein induced enteropathy
Protein induced proctocolitis
Eosinophilic oesophagitis
118
Describe the difference between
- FPIES
- Food protein induced enteropathy
- Food protein induced proctocolitis
FPIES - onset weeks-months. Starts after 2-4 hours, acutely unwell, vomiting, abdo distension, bloody diarrhoea, shock, FTT (delayed). Looks like sepsis but without fever. Characteristic = persistent retching.
Enteropathy - onset early infancy, unwell miserable baby, vomiting, diarrhoea, FTT, oedema
Proctocolitis - onset early infancy, well baby, bloody streaks in stools
119
FPIES most common triggers?
Cow's milk and soy milk > rice, oats, legumes, chicken
120
Symptoms of eosinophilic oesophagitis?
```
Regurgitation, vomiting
Slow eater, food refusal
FTT
Difficulty swallowing
Food impaction
Epigastric pain
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121
Triggers and treatment for eosinophilic oesophagitis?
Dairy, wheat, egg, soy most common.
Some respond to omeprazole alone. If not, then food avoidance, elimination diet, swallowed aerosolised corticosteroids + then re-scope
122
Possible modifiable risk factors for food allergy?
- Transcutaneous sensitisation - increased severity of eczema leads to increased prevalence of allergy
- Timing of allergen ingestion - early exposure to allergen e.g. peanut decreases risk of allergy
- Probiotics - probiotics from 3rd trimester - 6m age may decrease eczema but not other allergies
123
Management of allergic rhinitis?
```
Allergen avoidance/reduction measures
Oral antihistamines (ceterizine, loratidine)
Nasal corticosteroids (mometasone, fluticasone)
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124
What is the risk of having an allergic reaction to a cephalosporin in a child with a SPT positive to penicillin?
Less than 2%.
Risk higher with first generation cephalosporins (cefazolin, cefalexin), due to chemical similarity of side chains of beta-lactam rings.
125
Episodes of angioedema with NSAIDs/paracetamol (less common) can be due to?
COX-1 inhibiting properties of the drug - urticaria, bronchospasm, angioedema
126
What are the types of severe cutaneous drug reactions?
AGEP
SJS/TEN
DRESS
- Cannot test for these (RAST/SPT) and re-challenge s contraindicated
127
Describe DRESS syndrome
Onset 2-8w, itchy exanthem, erythroderma, non erosive mucositis, fever, eosinophilia, atypical lymphocytes, hepatitis
128
Describe SJS/TEN
Onset 4-28d, painful dusky erythema, erosive mucositis, Nikolsky sign, high fever, flu-like illness, full thickness epidermal necrosis
129
Describe AGEP (acute generalised erythematous pustulosis)
Onset <3d, pustules, high fever, oedema, neutrophilia, eosinophilia
130
Omalizumab is a ........ monoclonal antibody, and is used to treat?
Anti-IgE antibody
| Used in severe allergic asthma
131
How does rituximab work?
Anti CD20 - knocks out B cells
132
What percentage of DiGeorge syndrome have 22q11.2 deletion?
Up to 90%
133
Which cytokine causes T-cell proliferation?
IL-2
134
Difference between SCID and HIV?
HIV have normal immunoglob levels, low CD4
| SCID have low immunoglob + low CD4, 8
135
Deficiency of MHC-II causes?
Insufficient T cells functional for survival = recurrent infections. MHC-II are responsible for CD4 development in the thymus.
136
Describe T-dependant vs. T-independant vaccine response
T-dependant (antibodies)= conjugate e.g. tetanus, diptheria, prevenar
T-independant (mainly IgM)= polysaccharide e.g. pneumovax 23
137
What are the big 5 infectious organisms in CGD?
```
Staph aureus
Aspergillus
Serratia
Burkholderia
Nocardia
```
138
Symptoms of CGD carriers
If superoxide production <20% then get CGD-related infections. Carriers get autoimmune diseases, regardless of superoxide production = discoid lupus rash, aphthous ulcers, photosensitivity. X-inactivation changes with time therefore implications for use of carrier (e.g. HLA-matched sister) as a donor as may then get recurrence disease in transplant.
139
At what age does the umbilical cord usually separate?
2 weeks
140
What are the differentials for invasive pneumococcal/encapsulated organism disease?
Asplenia (look for Howell Joly bodies)
Complement deficiencies
B cell disorders/deficiency
141
CRP production is stimulated by which cytokine?
IL-6
142
Toll-like receptor defects
Invasive pneumococcal infections, <2yo
Delayed onset, weak fever and inflammatory response due to impaired production of pro-inflammatory cytokines
Low CRP
High mortality, but survivors see improvement over time a >2y/o the adaptive immune system kicks in
143
Partial C4 complement deficiency
Common, up to 30% normal population, doesn't usually cause an issue
144
C3 deficiency causes...?
Severe, recurrent pyogenic infections
145
What does infliximab target?
TNF-a
146
What does rituximab target?
CD20 (B cells)
147
What is the half-life of immunoglobulins?
IgM has a half-life of 5-8 days.
IgA has a half-life of 5-8 days.
IgG has a half-life of 21 days.
148
What is the significance of satellite dyskeratosis?
Pathognomonic of transfusion related graft vs host disease
149
What condition is trichorrhexis invaginata associated with?
- Trichorrhexis invaginata of hair is also known as "bamboo hair" and is pathognomonic of Netherton syndrome. - Netherton syndrome is a severe disorder of cornification caused by (SPINK5) mutations
- Eczema, recurrent infections, raised IgE
150
Describe haemophagocytic lymphohistiocytosis
- Overwhelming activation of normal T lymphocytes and histiocytes (immune system)
- Primary (multiple mutations identified) or secondary (EBV most common infective trigger, other viral, blood cancer)
- Fever, splenomegaly, >2 cytopenias, rash, weight loss, high lipids, low fibrinogen, haemophagocytosis in liver/spleen/LN/BM, low/absent NK cell activity, raised ferritin (thousands), elevated CD25 (soluble IL2 receptors)
- May present as meningitis/ADEM-like
- Tx: primary - chemo, allogenic SCT. Secondary - tx underlying cause, etoposide
151
What are the four factors associated with intestinal failure?
- Critical reduction in intestinal mass (short gut, NEC, atresia)
- Poor tolerance of feeds (motility, gastroschisis, Hirschsprung's)
- Abnormal electrolyte function (microvillus inclusion disease, tufting enteropathy)
- Multi-system disease (IPEX, mitochondrial disorders)
152
What is the energy content of the 3 major food groups?
- Carb - 4cal/gram
- Protein - 4cal/gram
- Fat - 9cal/gram
153
IL-1 is primarily produced by which type of cell?
Macrophages
154
Which cells produce IL-1, what is the target, and what are the primary effects?
- Produced by: Monocytes, macrophages, epithelial cells, fibroblasts
- Target: T cells, B cells, hypothalamus, liver
- Effect: inflammation, fever, acute phase reactants
155
Which cells produce IL-2, what is the target, and what are the primary effects?
- Produced by: CD4+ T helper cells, NK cells
- Target: T cells, B cells, monocytes
- Effect: growth and activation, error results in SCID
156
Which cells produce IL-3, what is the target, and what are the primary effects?
- Produced by: T cells
- Target: bone marrow progenitors
- Effect: growth and differentiation
157
Which cells produce IL-4, what is the target, and what are the primary effects?
- Produced by: T cells
- Target: naive T cells, T cells, B cells
- Effect: differentiation into a T2 helper cell, growth, activation and growth, isotype switching to IgE
158
Which cytokines are acute phase reactants?
IL-1, IL-6, TNF-a
| Proinflammatory cytokine secretion
159
What is the role of TGF-beta cytokine?
Inhibits activation and growth, "brakes" of immune system
160
What is the role of GM-CSF?
Stimulates growth and proliferation of bone marrow progenitor cells
161
Which cells produce TNF-a, what is the target, and what are the primary effects?
- Produced by: T cells and macrophages
- Acts on: T and B cells, endothelial cells
- Effect: activation, inflammation, fever, acute phase reactant
162
What is the role of IL-10?
Inhibits APC activity and cytokine production. Works with TGF-beta to inhibit/control immune response
