Immunology Flashcards
(201 cards)
1
Q
T helper (CD4+) cell differentiation
A
2
Q
What are the cells & molecules of the innate immune system?
A
Myeloid progenitor (except NK cells)
1. Phagocytes - neutrophils, monocytes, macrophages, dendritic cells
2. Mast cells
3. NK cells
Molecules of innate immunity
- Complement
- Coagulation proteins
- Acute phase reactants
- Cytokines & chemokines
3
Q
NK cells can only kill cells that have MHC expression. True or false
A
False
NK cells have inhibitory receptors that recognise MHC molecules on target cells -> this inhibits the NK cells.
Therefore, NK cells are only active against cells that have lost MHC expression. Viral infection and malignant transformation often result in loss of MHC expression
4
Q
CD8 + T cells target extracellular pathogens. True or false?
A
False.
Intracellular pathogens are degraded by Golgi, then expressed by MHC -1 to CD8 + T cells
Extracellular pathogens are phagocytosed, degraded & presented to CD4 T cells by MHC -2
5
Q
Where are the different toll-like receptors expressed?
A
Toll-like receptors are a type of pattern recognition receptor expressed on innate immune cells
- PAMPs and DAMPs bind to TLRs
- there are 9 types of TLRs - TLRs 1-9 - some expressed on cell surface & some intracellularly
- endosomal (intracellular) TLRs 3, 7, 8, 9 identify dsRNA & DNA -> identify intracellular viruses
6
Q
What cells express MHC 2?
A
Antigen presenting cells
Dendritic cells
B cells
Macrophages
7
Q
Molecules involved in migration of innate immune cells to site of infection / injury
A
- Rolling adhesion
-> S-LeX binds to E-selectin on the endothelium - Tight binding
-> Leucocyte function-associated antigen 1 (LFA1) binds to ICAM-1 (intracellular adhesion molecules [ICAM-1]) expressed on endothelial cells & APCs => tight binding
8
Q
Defects in MyD88 (myeloid differentiation primary response protein 88) and IRAK4 (interleukin 1 receptor associated kinase 4) cause?
A
Susceptibility to pyogenic bacterial infections
MyD88 adaptor protein involved in phagocyte function
TLR activation -> MyD88 adaptor protein -> downstream signalling -> NFkappaB activation -> transcription of inflammatory mediators
9
Q
Defects in UNC93B1, TLR3, toll/IL-1 receptor, TNF receptor associated factor 3 (TRAF), tank-binding kinase (TBK1) mutations
A
Susceptibility to HSV1 encephalitis, severe influenza pneumonia, encephalopathy, severe COVID19 infection
10
Q
Cytokines involved in innate immunity
A
IL-1, IL-6 and TNF alpha involved
- PAMPs / DAMPs bind to TLR
- release of pro-IL-1beta - cleaved caspase-1 => active IL-1 beta
- endothelial cells produce IL-6
IL-1 -> endothelial activation
IL-6 -> increase acute phase response
TNF alpha - drive Th1 differentiation, increase cell migration
Growth factors - GM-CSF, IL-12
Prostaglandins
Chemokines - CXCL8 / IL-8
Suppressive cytokines - TL-10, TGF beta
Liver produces acute phase reactants - CRP, MBL, ferritin, reduced albumin
11
Q
What cells express MHC 1?
A
All nucleated cells
12
Q
What immune defect underlies Familial Mediterranean syndrome (main type of periodic fever syndrome)?
A
Genetic defects in inflammasome production
13
Q
Mechanism of action of natalizumab
A
Binds VLA-4 (alpha 4 beta 1 integrin)
Blocks adhesion of active T cells to blood vessels / blocks crossing through BBB
MS
14
Q
Mechanism of action fingolimod
A
Blocks SIP-1 receptor -> normally allows T cells to leave lymph nodes & move into systemic circulation
Induces significant lymphopenia
15
Q
Complement pathway
A
16
Q
What is the role of natural killer cells?
A
Derived from a common NK / T cell progenitor
- important for killing virally infected cells & malignant cells
- only active against cells that have LOST MHC EXPRESSION (unlike CD8+ cytotoxic cells that can only kill cells that express MHC molecules)
NK cells express activating & inhibitory receptors
- Activating receptors - analogous to PRRs. Recognise changes associated with stress & viral infection
- Inhibitory receptors = killer inhibitory receptors (KIRs). KIRs recognise MHC class I molecules on target cells -> send negative signals to NK cells -> inhibition of activation
- negative NK receptors have the immunoreceptor tyrosine based inhibitory motif (ITIM)
Cells infected by viruses and malignant cells lose MHC expression
CD8+ cytotoxic T cells can only kill cells that have MHC expression
17
Q
Describe CD4+ T cell activation
A
Signal 1 - APC activated via TLRs. Extracellular pathogen phagocytosed -> presented via MHC class II. MHC -2 binds to TCR on CD4 T cell
Signal 2
CD40 on APC binds to CD40L on T cell
This induces expression of B7 (i.e. CD80/86) on APC -> which binds to CD28 on T cell
*CTLA-4 can bind to CD28 instead of B7, which prevents ongoing T cell activation
*Signal 3
Cytokines drive CD4 T helper cell differentiation
18
Q
Describe CD4 + T cell differentiation
A
- IL-12 drives TH1 differentiation. TH1 secrets IL-2, IFN gamma, LT. Activates macrophages / dendritic cells (esp via IFN gamma) & induces B cells to produce opsonising antibodies (IgG). Important for intracellular bacteria, fungi and viruses.
- IL-4 drives TH2 differentiation. TH2 produces IL-4, IL-13 and IL-5. Target cells are basophils and eosinophils. Also activates B cells to produce neutralising antibodies. Important for parasitic infections.
- IL-23, TGF beta, IL-6, IL-21 drive Th17 differentiation. Target cells are neutrophils. Important for extracellular bacteria & fungi
- IL-6 and IL-21 drive differentiation to Tfh cells
- IL-10 and TGF beta drive differentiation to T regulatory cells
19
Q
Mediators of adaptive immunity
A
IL-4, IL-5, IL-2, TGF beta
20
Q
Main role of TH1 CD4+ T cells?
A
TH1 cells activate macrophages (via IFN gamma, alongside CD40 / CD40L binding ) leading to macrophage activation & enhanced microbial killing
TH1 activate B cells (via IFN gamma) - leading to production of complement-binding & opsonising antibodies
TH1 activate neutrophils (via LT & TNF)
21
Q
Main role of TH2 CD4+ T cells?
A
- activates B cells via CD40/CD40L AND IL-4 to promite production of IgG and IgE. IgE drives mast cell degranulation
- activates eosinophils via IL-5
- activates alternative macrophage via IL4 and IL13, drives wound repair, tissue fibrosis, suppression of inflammation
22
Q
Key cytokines released by CD8 T cells to fight viral infections
A
CD8+ T cells create an anti-viral environment by secreting IL-2 and inteferon gamma
23
Q
What does CTLA4 bind to?
A
CTLA4 binds to CD80/86 (B7) with higher affinity than CD28 -> inhibits T cell activation
24
Q
What are the professional antigen presenting cells?
A
- Macrophages - lymphoid tissue, connective tissue (skin & mucosa); receptor mediated endocytosis, phagocytosis
- Dendritic cells - blood, lymphoid tissue, connective tissue. NOT phagocytes. Receptor mediated endocytosis, macropinocytosis.
- Activated B cells - blood, lymphoid tissue. Receptor (BCR) mediated endocytosis. Naive B cells do not express MHC II.
Above express MHC I and II
25
Molecules involved in adhesion of dendritic cell to naive T cell
ICAM1 on DC with LFA-1 on T cell
CD58 on DC with CD2 on T cell
DC-SIGN on DC with ICAM3 on T cell
26
Signals involved in activation of naive T cell via dendritic cell
Signal 1 - binding of MHC-II with TCR. Conformational change in LFA-1 allowing strong adhesion with T cell
Signal 2 - CD80/86 on DC binds to CD28 on T cell
Signal 3 - release of cytokines
TGF beta -> T regulatory cells
IL-12 -> TH1
IL -4 -> TH2
IL-6 -> Th17 and TFH
27
What is the main determinant of antibody diversity?
Junctional diversity is the greatest source of diversity.
- variations at sites of junction between V, D & J segments due to insertions & deletions performed by TdT (terminal deoxytransferase). Can accidentally cause frame shift or stop codons.
Combinatorial diversity - various combinations of light & heavy chain pairs
28
BCR gene re-arrangement
Each immunoglobulin has 2 light chains and 2 heavy chains
- each has a Fab domain (antigen binding site) and a Fc domain (mediator function)
- gene re-arrangement mediated by RAG enzymes
- heavy chain - V, D, J, constant
- light chain - V, J, constant
at pro-B cell stage - heavy chain is tested with surrogate light chain. If first heavy chain re-arrangement is sucessful, the other i snot re-arrangement
at pre-B cell stage - light chain is tested
immature B cell is then tested to ensure not self-reactive
29
Common pathogens that cause infection in patient's with antibody deficiency
Encapsulated organisms
Streptoccus pneumoniae
E.coli
Haemophilus influenzae
Giardia lambilia
30
Describe B cell development in the bone marrow
1. Multipotent progenitor cell / early lymphoid progenitor expresses Flt3 receptor, which binds to Flt3 ligand on stromal cells
2. Common lymphoid progenitor expresses IL-7 receptor. IL-7 binding drives differentiation to pro-B cell
3. Pro-B cell expresses cKit and binds stem cell factor (SCF) on a stromal cell. This drives heavy chain rearrangement.
4. IL-7 binds to IL-7 R on Pro-B cell, driving differentiation to Pre-B cell
5. IL-7 drives maturation from Pre-B cell to immature B cell
6. Bruton tyrosine kinase is important in B cell development, transduces signals from Pre-B and B cell receptors and regulates IL-7 responsiveness
31
What is the process responsible for affinity maturation for Abs?
Somatic hypermutation
- needed for affinity maturation
32
Describe Ig isotype switching including interleukins that drive certain isotypes. Describe role of different Ig
Involves activation induced deaminase
Isotype switching occurs in secondary lymphoid tissue after Ig encounters Ag.
Dependent on T cell help.
Irreversible gene recombination (cannot switch back to a constant region that has been cut out)
1st response - mostly IgM
Isotype switching allows specialised responses on later exposures
IgM -> IgG -> IgE -> IgA
- IgM - main role is complement activation
- IgG - IgG1, IgG3 (driven by interferon gamma) - opsonisation & phagocytosis, complement activation, neonatal immunity (placental transfer)
- IgE & IgG4 - driven by IL-4. Immunity against helminths & mast cell degranulation (immediate hypersensitivity)
- IgA - driven by TGF beta, APRIL, BAFF. Actively secreted into mucosal lumen by binding of Fc portions of IgA dimer to a polyIg receptor which triggers phagocytosis of IgA
Neutralisation - IgG, IgA
Opsonisation - IgG, some IgA
Antibody-dependent cellular cytotoxicity - IgG
IgG binds NK cell via Fc receptor -> cross linking of Fc receptor triggers NK cell killing
Degranulation - IgE
Complement activation - IgM, IgG
33
What antibody isotype is responsible for neonatal immunity?
IgG
Placental transfer
34
Monoclonal Abs targeting T helper cell pathways
35
Mediators of innate immunity
IL-6, IL-10, TNF, IFN alpha, IFN beta, IFN gamma, IL-12, IL-1
36
Stimulators of haematopoiesis
Stem cell factor
GM-CSF
IL-3
IL-7
37
What cytokines are involved in downregulation of the immune response?
IL-10
TGF beta
IL-35
38
How does C2 deficiency usually present?
Can present as SLE-like autoimmunity
Also recurrent sinopulmonary infections
39
What is the role of CRP in acute inflammation / innate immunity?
CRP binds to phosphocholine expressed on bacterial cell surfaces. This activates C1q (classical complement pathway) & promotes phagocytosis.
40
Positive & negative acute phase reactants
41
What are the cytokines responsible for suppression / release of positive / negative acute phase reactants?
IL-6 (major)
IL-1beta
TNF alpha
IFN - gamma
42
Allergy / hypersensitivity classification
43
What is the most common complement deficiency? How does it present? What is the basic management?
Type 1 C2 deficiency
Homozygous 28 base pair deletion
Treated with prophylactic penicillin (typical treatment for complement deficiency)
Vaccinated for meningococcus, haemophilus & pneumococcus
44
Describe pathophysiology of allergy
1. Sensitisation
- allergen exposure -> presented to T helper cells via MHC II on APCs -> Th2 cells release IL-4, IL-5, IL-13.
- IL-4 drives IgE class switching.
- IgE binds to Fc receptor on tissue mast cells -> mast cell degranulation
- IL-5 primes & recruits eosinophils -> non IgE mediated chronic immune response
2. Challenge
- subsequent exposure to same allergen -> allergen binds to IgE on mast cells -> rapid release of vasoactive amines -> immediate response of wheal & flare
- Histamine, heparin, tryptase, chymase
- Cytokines IL-4, IL-5, IL-13
- Prostaglandins
- 6-8 hours later, there is inflammatory cell infiltration -> oedema, heat
45
Describe the principles of allergy desensitisation
1. High dose exposure to antigen
2. Shift from TH2 response to TH1 and T regulatory cells
3. Subsequent exposure to allergen -> Th1 response -> release of IFN gamma -> IgG production -> inhibits IgE
T regulatory response -> IL-10 and TGF beta production -> shift from IgE to IgG and IgA production -> inhibits IgE
T regulatory cells inhibit TH2 cells
46
HLA associations with autoimmune disease
47
What is the inheritance pattern for SCID?
Largely X-linked and autosomal recessive
48
What type of primary immune deficiencies are most common?
Antibody defects
Combined T & B cell deficiencies
49
What is the most common cause of pneumonia in patient's with antibody deficiency?
Streptococcus pneumonia
50
Features of phagocyte defects (PID)
Bacterial infections - especially Staphylococcal. Other bacteria - serratia, pneumocytis, klebsiella, E.coli, Salmonella, proteus
Unusual infections - fungal (candida, aspergillus, nocardia)
Sites - deep seated skin infections, osteomyelitis, periodontal disease, lymph node, lung, liver
Delayed separation of cord (LAD - leucocyte adhesion deficiency)
Associated chronic granulomatous disease
51
How do defects of the early complement pathway typically present?
C1, C2, C4 deficiency usually presents as SLE-like autoimmunity (failure of tolerance to self antigens)
C2 deficiency can be associated with recurrent sinopulmonary infections
52
How do defects of the alternate complement pathway present?
Defects in the alternate pathway (factor B, D, properdin) result in Neisserial & bacterial infections
53
How does C3 deficiency manifest clinically?
Cannot be distinguished clinically from antibody deficiency - recurrent or severe infections
54
Defects in which part of the complement pathway will cause Neisseria meningitidis or gonococcal arthritis?
Late components
C5-C9
55
What prophylaxis should patients with defects in neutrophil function be on?
Phagocyte defects associated with bacterial (especially Staph) and fungal infections.
Prophylaxis with itraconazole and Bactrim
56
What features are suggestive of antibody or combined defect?
Recurrent sinopulmonary infections
Infections typically affect mucosal sites - e.g. sinuses, lung, GIT
Lung - Streptococcus pneumoniae, Haemophilus influenzae
GI - Giardia, enterovirus, campylobacter, salmonella, shigella
If Common Variable Immune Deficiency - can be associated with autoimmune cytopenias, chronic diarrhoea due to villous atrophy, exocrine pancreatic insufficiency, lymphocytic enterocolitis
57
What clinical syndromes are produced by CTLA4 deficiency?
Cytotoxic T lymphocyte antigen 4 (CTLA4) is expressed on T cells - important role in immune regulation and self tolerance
Heterozygous loss of function mutations in CTLA-4 causes CHAI - CTLA-4 haploinsufficiency with autoimmune infiltration. Characterised by multi-organ autoimmune disease
LRBA deficiency causes a secondary loss of CTLA4
LRBA is a chaperone molecule that enables CTLA4 to be transported to the cell surface
This produces LATAIE - LRBA deficiency with autoantibodies, regulatory T cell defects, autoimmune infiltration & enteropathy.
Above can be treated with Abatacept
Abatacept is a selective costimulation modulator. Inhibits T cell activation by binding to C80/86 expressed on APCs, preventing CD80/86 from interacting with CD28 on T cells
58
What are the features of CVID?
CVID = common variable immune deficiency
Most common clinically significant PID in Australia
Incidence 1: 10,000 - 1:15,000
Heterogenous
Variable age of presentation (typically <20 yrs but often later in life)
Diagnosis of exclusion
Key features
- hypogammaglobulinaemia (IgG severely reduced) +/- IgA +/- IgM
- Recurrent infections
- Absence of antibody production in response to vaccination
- Needs Ig replacement
- Associated with autoimmune conditions, malignancy, lymphoproliferative disorders
59
What syndrome is GATA2 deficiency associated with?
Mono Mac syndrome
Very frequent monocytopenias and disseminated mycobacterium avium infection
60
Toll-like receptors are an important component of the innate immune system. What infectious susceptibility does TLR3 deficiency cause?
Herpes Simplex Encephalitis
61
CARD9 is an adaptor protein that mediates signals from PRRs to regulate cytokine expression (part of the innate immune system). What specific infectious susceptibility if CARD9 deficiency associated with?
Invasive fungal infections
62
What underlying defects cause mendelian susceptibility to mycobacterial diseases?
Defects in IFN gamma / IL-12 pathway ( TH-1) pathway
- includes mutations in IL-12, IL-23 receptor beta 1, STAT1 deficiency, IFN gamma receptor, autoantibodies to IFN gamma
- Present with severe BCG or non-tuberculous mycobacterial infection
Also susceptible to other intracellular pathogens - Salmonella, certain fungi, viruses
63
Leucocyte adhesion deficiency (AR) is a phagocyte defect, which causes impaired adhesion of neutrophils to endothelium. Mutations in which genes cause AE?
CD18 or CD15
64
What is the triad caused by Wiskott - Aldrich syndrome?
X-linked rare disorder
WASP gene defect
Triad of eczema + thrombocytopenia + immune dysfunction
65
What is the diagnostic criteria for HLH?
HLH = haemophagocytic lymphohistiocytosis
- multi-system syndrome characterised by excessive immune activation & defective NK and T cell cytotoxicity
- especially common in infants & children
- triggered by viruses (especially CMV & EBV), rheumatologic diseases, malignancy
Common clinical features - fever, rash, lymphadenopathy, hepatosplenomegaly, neurologic symptoms
Common biochemical features - high ferritin, cytopenias, LFT abnormalities
Diagnostic criteria - needs 5 of the following
- fever
- splenomegaly
- cytopenias in 2 or more blood lineages
- hight trigs and/or low fibrinogen
- haemophagocytosis in bone marrow, spleen, lymph node, or liver
- ferritin > 500 ng/mL (typically a lot higher)
- low or absent NK cell activity
- elevated soluble CD25
- elevated chemokine 9
66
# ****
What syndrome is a defect in FOXP3 associated with?
Causes X-linked immune dysregulation polyendocrinopathy enteropathy (IPEX)
Disorder of T regulatory cells
FOXP3 is critical for development & function of regulatory T cells (CD4+, CD25+)
Severe and early autoimmune enteropathy, T1DM, eczema, hypothyroidism
67
What are the most common primary immunodeficiencies?
1. Antibody defects
2. Combined B & T cell defects (i.e. cellular & humoral immunity)
3. Phagocyte defects
4. Other well defined PIDs
5. Complement deficiencies
68
What test is used to assess classical complement pathway activity?
Functional screening assay - CH50
If a component of classical pathway missing - CH50 will be 0
If a component of classical pathway reduced - CH50 will be reduced
Assess ability of classical complement pathway to lyse RBCs that are already coated with anti-sheep antibodies
69
Which test is used to assess function of the alternate complement pathway?
AH50
70
What are the complement regulators?
C1 inhibitor
Factor H
Factor I
71
What are the tests to assess neutrophil function?
1. Neutrophil oxidative burst test
- checks for activity of NADPH oxidase. Required for production of ROS, oxygen-dependent intracellular killing of phagocytosed pathogens
Uses NBT reduction test - if NADPH oxidase is functional - slide turns blue
* NADPH deficiency is a key feature of chronic granulomatous disease
2. Flow based assay
- neutrophils are stimulated with potent mitogen
- can identify heterozygote female carriers for X linked chronic granulomatous disease (defect in NADPH oxidase)
72
What is the mode of inheritance for leucocyte adhesion deficiency?
Results in both lymphocyte & phagocyte dysfunction. Primarily disrupts ability of cells to migrate to site of infection / injury. Autosomal recessive inheritance.
Often mutations in ITGB2 gene
3 types of LAD
Type 1 - adhesion of leucoyte to endothelial surfaces defective due to mutations in CD18 gene resulting in defective beta 2 integrin
Type 2 - absence of Sialyl Lewis X of E-selectin
Type 3 - defect in beta integrins 1, 2 and 3.
73
What types of infections are associated with T cell deficiency / defects?
Loss of cellular immunity
Susceptibility to intracellular organisms
1. Viral - progressive infections ith ordinarily "benign" viruses. CMV, EBV, HSV or other herpes vruses.
2. Fungal - Candida (mucocutaneous) - Th17, pneumocystitis, cryptococcus
3. Listeria
4. Mycobacteria
74
What types of infections do NK cell defects present with?
NK cell defects are rare
Can cause haemophagohistiocytsois
Intracellular pathogens
Can present with severe & fulminant herpes virus infections
75
What types of infections do myeloid / phagocyte defects cause?
High grade bacterial infections & fungal infections
1. Catalse-positive organisms - especially Staph aureus
Recurrent invasive skin & soft tissue infections, especially focal abscesses requiring incision & drainage, osteomyelitis, periodontal disease
2. Gram negative bacteria - E.coli, Proteus, Serratia, Pseudomonas
3. Invasive fungal infections - invasive aspergillosis, systemic candidasis, nocardia
76
What complement factors are involved in the membrane attack complex? What types of infections does deficiency in these factors cause?
C5, 6, 7, 8, 9
Disseminated neisseria infections, sepsis, gonococcal arthritis
77
What is the most common complement deficiency?
Type 1 C2 deficiency secondary to homozygous 28 bp deletion
C2 deficiency typically manifests in a SLE-like autoimmunity (failure to clear self antigen) - but recurrent sinopulmonary / pyogenic infections are also seen in C2 deficiency
78
Complement deficiencies
79
What are the infections associated with immunodeficiency secondary to corticosteroids?
Increased risk of common bacterial, fungal, viral and parasitic infections.
Bacterial - Staph aureus
Fungal - Candida
Viral - Herpes especially.
Parasistic infections
80
Can patients on high dose steroids receive live vaccines?
In patients with 14 days or more of high dose steroids - avoid live vaccines. Wait 4 weeks after cessation of steroids to vaccinate.
Vaccine responses are preserved if on chronic low-mod doses for kidney, pulmonary or rheumatological diseases.
81
What are the effects of steroids on the immune system?
1. B cell function & antibody production largely preserved. Some reduction in IgG levels possible if high dose steroids or chronic use
2. Various T cell functions affected. Steroids cause T cell apoptosis. Impaired T cell migration & proliferation. T reg cells less affected than othe rsubsets
3. Leukocyte migration / trafficking affecting
4. Phagocytosis / neutrophil function largely preserved initially - but can be impaired with high dose steroids
5. Marked reduction in eosinophils
6. Impaired opsonisation & phagocytic function with high dose steroids
82
Indications for IVIG
Agammaglobulinaemia due to complete absence of B cells
Hypogammaglobulinaemia with impaired antibody responses
IVIG not required in any deficiency with normal antibody responses
83
Tests for a suspected antibody defect
1. Total Ig (assess IgG subclass if total Ig levels are normal)
2. Lymphocyte counts & subsets
3. Antibody function - assess response to a polysaccharide vaccine (Pneumovax) - normal response is Ig > 1g/L or 4 fold increase in Ig at four weeks post vaccination. Other vaccines - tetanus, haemophilus influenzae B, diphtheria vaccine
4. Exclude secondary causes of low Ig - renal / GIT losses (low IgG +/- IgA, but normal IgM) OR haematological malignancy.
84
Which immunoglobulin deficiency was associated with the recent H1N1 pandemic?
IgG2
Severe H1N1 infection is associated with IgG2 deficiency. Pregnancy-related reductions in IgG2 level may explain the increased severity of H1N1 infection in some, but not all pregnant patients.
85
Which immunoglobulin deficiency is associated with increased susceptibility to encapsulated organsims (e.g. Streptococcus pneumoniae or Haemophilus influenzae)?
IgG2 deficiency
86
What does specific antibody deficiency refer to?
Inadequate response to polysaccharide antigen in an individual with normal response to protein antigens, normal Ig levels and normal IgG subclass concentration
87
Defect in which molecule is most commonly associated with hyper IgM?
Most commonly due to deficiencies in CD40 or CD40 ligand
Heterogenous group of disorders characterised by abnormal class switch recombination (CSR)
Resulting in normal or increased levels of IgM, with low levels of IgG, IgA and IgE
Normal B cell counts
Associated with poor antibody response
Most commonly due to deficiency in CD40 ligand or CD40
Because CD40 - CD40L binding affects T cells -> this is a combined deficiency (whereas other forms of hyper IgM are humoral only
88
What infections are associated with immunoglobulin defects?
Recurrent sinopulmonary infections, GIT infections
Typically mucosal infections
Skin infections
Polysaccharide-encapsulated pyogenic organisms (Strep pneumoniae, haemophilus influenzae B, Strep pyogenes)
Staph aureus
Giardia or campylobacter
89
What is the inheritance pattern of primary agammaglobulinaemia?
Most commonly X linked
Also autosomal recessive inheritance pattern
90
Defects in which enzyme are responsible for primary agammaglobulinaemia?
Bruton tyrosine kinase - essential for B cell development
BTK genetic testing is the diagnostic test for primary agammaglobulinaemia
BTK transduces signals from pre-B cell and BCR. BTK is important for pre-B cell maturation by mediating IL-7 responsivesness, cell surface phenotype changes, activation of lamba light chain gene rearrangements
In mature B cells, BTK is essential for BCR mediated proliferation and survival
Absence / near absence of CD19 + B cells
Clinically absence or near absence of B-cell rich tonsils and adenoids
91
What drugs cause secondary IgA deficiency?
NSAIDs
Anticonvulsants
Sulfasalazine
Cyclosporin
92
Which cell lineages are affected in SCID?
SCID = severe combined immunodeficiency
Affects B cells +/- T cells +/- NK cells
93
What mutations underlie SCID?
There are 2 types of SCID
Typical SCID
- more severe
- most commonly caused by mutations in IL-2 receptor gamma chain (IL2RG)
Leaky SCID
-less severe than typical SCID
-most commonly caused by recombination activated gene 1 or 2 (RAG-1 or 2) mutations
94
How is SCID normally detected?
Typically diagnosed via newborn screening
Newborn screening test is T cell receptor excision circles (TRECs)
Low / absent T cell (CD3+) count in SCID
May not be detected as a newborn due to maternal IgG which provides some protection for the first few months
After this - increasing, severe infections including opportunistic infections (PJP, persistent mucocutaneous candidiasis, viruses - EBV, CMV, RSV, VZV, HSV, adenovirus), chronic diarrhoea, failure to thrive, fatal response to live vaccines due to dissemination
95
What is the most common cause of death in infants with SCID?
CMV is the most common cause of death in infants with SCID
96
What is the inheritance pattern of Wiskott-Aldrich syndrome?
X-linked disorder
Rare (1 in 100,000)
50% have the full WAS phenotype
50% have X linked thrombocytopenia (less severe & better prognosis than full WAS phenotype)
Due to mutation in WAS protein (WASp) expressed on X chromosome. Important for cytoskeletal function. Absence of WASp affects the formation of the immunological synapse - i.e. the site of interaction between T cells and APCs
97
What are the key features of WAS syndrome?
WAS = Wiskott-Aldrich Syndrome
WAS gene testing - 95% sensitive
X-linked -> therefore male patients
Triad present in 1/3 of patients of eczema, thrombocytopenia with small platelets and immunodeficiency (combined cellular & humoral)
Associated with autoimmune disease (haemolytic anaemia, vasculitis, arthritis, IBD, IgA nephropathy) & malignancy (lymphoma, leukaemia, brain tumours)
Immunodeficiency - combined cellular & humoral
- increased susceptibility to both bacterial & viral infections
- Low IgM, elevated IgA +/- IgE
Thrombocytopenia with small platelets
Mandatory criteria
Haemorrhage is the most common cause of death
Purpura, petechiae, haematomas
98
What enzyme deficiency is associated with hereditary angioedema?
C1 inhibitor deficiency
99
What complement factor deficiencies are associated with increased risk of SLE and why?
Early complement factors - C1q, C1r, C1s, C2, C4 deficiency associated with autoimmunity / SLE. Classical complement pathway is very important for clearance of immune complexes.
C1 deficiency 90% risk SLE
C2 deficiency 60% risk SLE
C4 80% risk SLE
C2 deficiency is most common
C1, C2, C4 deficiency can also cause immune complex mediated GN
100
Patients with complement deficiencies can receive live vaccines. True or false?
True
101
Which assay measures alternate complement pathway?
AH50
102
Which assay measures classical complement pathway?
CH50
* Measures the capacity of the patients serum (i.e. no cells) to lyse sheep erythrocyte coated with rabbit antibodies
For example, a CH50 of 200 units/mL means that a serum sample diluted 1:200 lysed 50 percent of the antibody-coated sheep erythrocytes (measured by haemoglobin release) in the test mixture
103
What is the most common complement deficiency? What is the mode of inheritance for genetic complement deficiencies?
C2 deficiency is the most frequent
Overall complement deficiencies are rare
All are autosomal recessive
104
What is the most common cause of complement deficiency?
Consumption
e.g. low C2, C3, C4 levels due to classical pathway activation in SLE
105
How does C3 deficiency manifest?
Major opsonin of complement system
Clincically cannot distinguish from antibody defect
Results in severe, recurrent infections with encapsulated organisms - begin shortly after birth
Pneumococcus most commonly
Less frequently - haemophilus influenzae, neisseria meningitidis
106
How do deficiencies in late complement factors manifest?
Deficiencies in C5-9 (terminal components) = inability to form membrane attack complex
Predisposes to disseminated neisserial infections, gonnococcal septic arthritis, sepsis
Eculizumab (C5 inhibitor) associated with 2000x increased risk for meningococcal infections
In terminal complement deficiency
- C3 and C4 will be normal
- CH50 and AH50 will be undetectable
107
PNH is caused by a mutation in which gene?
PNH = paroxysmal nocturnal haemoglobinuria
Acquired mutation in multipotent haematopoietic stem cell (abnormal clone)
Mutation in PIGA gene
Unable to synthesise GPI anchor (glycosyl phosphatidylinositol). GPI anchor attaches proteins CD55 and CD99 to the RBC membrane
CD55 and CD99 are complement regulatory proteins
Lack of complement control proteins => cells regarded as foreign surface => increased activation of alternate complement pathway
Deficiency of complement-control => complement-mediated RBC lysis
108
What does flow cytometry show in PNH?
Absence of CD55 and CD99 on RBC membrane (GPI linked proteins)
109
Which complement pathway is involved in the pathophysiology of PNH?
Alternate pathway
110
What are the key clinical features of PNH?
Recurrent episodes of intravascular haemolysis
Chronic haemolytic anaemia
BM failure (pancytopenia)
Thrombosis due to platelet activation / free Hb in plasma - venous > arterial ; in atypical locations
Haemoglobinuria (25%)
Smooth muscle dystonia
111
What are the treatment options for paroxysmal nocturnal haemoglobinuria?
Anti-complement therapy
specificially anti-C5A therapy
1. Eculizumab - anti-C5 monoclonal Ab (prevents cleavage of C5 to C5a). Must have neisseria meningitidis vaccination before starting eculizumab
2. Avacopan - blocks C5a receptor. Can still produce MAC - no increased risk of N. meningitidis
3. Pegcetacoplan - pegylated peptide inhibitor of C3. Superior to eculizumab with respect to change in Hb, including control of intravascular & extravascular haemolysis
112
Atypical HUS is less likely to cause long-term complications e.g. severe hypertension or renal failure, compared to typical HUS. True or false
False
Unlike individuals with typical HUS, who usually recover from the life-threatening initial episode and usually respond well to supportive treatment, individuals with atypical HUS are much more likely to develop chronic serious complications such as severe high blood pressure (hypertension) and kidney (renal) failure.
113
Which complement pathway is involved in atypical HUS?
Atypical HUS = complement mediated HUS
Due to accelerated activation of alternative pathway
114
What are the causes of atypical HUS?
Inherited - main cause
5 principal complement genes implicated in CM-HUS are factor H, factor I, factor B, membrane co-factor protein (MCP) and C3
Most common is loss of factor H
Can have heterozygous mutations in factor H, I or CD46. Can also have gain of function mutations in C3 or B
Leads to accelerated activation of alternate complement pathway
Uncontrolled activation of complement on ell membranes including vascular endothelium & kidney cells
Can also have acquired atypical HUS - due to acquired autoantibody against factor H or I
115
What are the typical triggers for atypical HUS?
1. Infection - 80% children, 50% adults - esp URTI or gastro
2. Pregnancy - exclude placental abruption with DIC or severe pre-eclampsia
3. Surgery
4. Cancer / chemotherapy
5. Autoimmune disease flare
116
What are the clinical features of atypical HUS?
Sudden simultaneous occurence of thrombocytopenia, microangiopathic haemolytic anaemia and acute renal failure
ADAMTS13 negative (not TTP)
Shiga toxin negative (not typical HUS)
Not triggered by a drug - not drug induced TMA
Extra-renal manifestations
- CNS manifestations are the most common extra-renal finding
- cardiac ischaemic events
- pulmonary haemorrhage & failure
- Pancreatitis
- Hepatic cytolysis
- Intestinal bleeding
117
What does the blood film show in atypical HUS?
Schistocytes
118
What is the treatment for atypical HUS?
Supportive care
pRBC transfusions
Avoid platelet transfusions
Anti-complement therapy - eculizumab
Can also give PLEX to remove autoantibodies
Whilst awaiting ADAMST13 -> plasma exchange as empiric therapy for TTP
ADAMS13 deficiency seen in TTP
119
What ia donidalorsen?
Donidalorsen = new therapeutic for hereditary angioedema
- antisense oligonucletoide
- reduces prekallikrein expression
- reduces hereditary angioedema attack rate in recent RCT (NEJM 2024) - may have a role in prophylaxis in hereditary angioedema
120
Outline the management of hereditary angioedema
Acute management
- Icatibant - bradykinin 2 receptor antagonist
- C1 inhibitor concentrate - IV for severe life-threatening episodes
Long term management
- Education & trigger avoidance
- test family members
- prophylaxis prior to triggers
- pharmacological prophylaxis
Regular C1 inhibitor concentrate infusions
Danazol, TXA (limited by side effects)
Lanadelumab - monoclonal Ab against plasma kallikrein, subcut fortnightly
121
How to distinguish between hereditary and acquired angioedema based on blood tests?
Both will have decreased C1 esterase inhibitor level and function
Low C4 levels in hereditary angioedema
Low C1q levels in acquired angioedema, but normal in hereditary angioedema
122
What is the typical clinical presentation of hereditary angioedema?
Acute attacks t ypically last 3-5 days without treatment
3 types of manifestations - upper airway, cutaneous or GI
Upper airway attacks 50%
- laryngeal swelling
- hoarseness
- dysphagia
- itchy throat
GI attacks
- nausea or vomiting, diarrhoea, abdominal pain
- GI attacks are experienced by a majority of patients with HAE due to bowel wall oedema
Cutaneous attacks
NO URTICARIA
NO PRURITIS
Non-pitting, non-dependent
Hereditary - 90% symptomatic before age 20
Acquired - typically presents after 40 yrs.
123
What are the typical triggers for an acute attack of hereditary angioedema?
Mild trauma e.g. dental work or intubation
Drugs - oestrogen containing, ACE inhibitors, tamoxifen
Infections
Stress
Changes in sex hormones - menstruation, pregnancy, tamoxifen
Genital swelling
H.pylori infection - associated with increased frequency of attacks (improves with eradication)
124
What is the mode of inheritance for hereditary angioedema?
Autosomal dominant
Mutation in SERPING 1 gene which encodes C1 esterase inhhibitor
Type 1 - deficiency
Type 2 - dysfunction
125
Pathophysiology of hereditary angioedema?
C1 esterase inhibitor deficiency
- C1 inhibitor has roles in complement & fibrinolytic pathway. HAE is caused due to its role in fibrinolytic pathway.
- Kallikrein (serine protease) converts high molecular weight kininogen to bradykinin.
- C1 inhibitor normally inhibits the conversion of prekallikrein to kallikrein by coagulation factor XIIa. Inhibits conversion of high molecular weight kininogen to bradykinin by kallikrein. Also inhibits XIIf - > which can activate classical complement pathway (causing decrease in C4 levels)
126
Acquired C1 inibibitor deficiency is seen in which conditions?
Lymphoproliferative disorders - specifically B cell lymphoproliferative disorders (lymphoma / MGUS)
Autoimmune disease - can get autoantibodies against C1-INH
C1q levels are reduced in acquired angioedema, but are normal in hereditary angioedema
127
Which condition is associated with increased CD4- CD8 (double negative) alpha beta - T cells in the peripheral blood?
Autoimmune lymphoproliferative syndrome (ALPS)
- autosomal dominant
- lymphadenopathy, splenomegaly, haemolytic anaemia, thrombocytopenia, high risk for lymphomas
128
What mutation causes IPEX syndrome? What are the key features?
IPEX = immune dysregulation polyendocrinopathy enteropathy
- X linked
- caused by mutation in FOXP3 - critical for development & function of T regulatory cells
- presents with severe & early onset autoimmune enteropathy, T1DM, eczema, hypothyroidism
129
What syndrome is an AIRE gene mutation associated with?
Autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (AKA autoimmune polyglandular syndrome)
AIRE gene = autoimmune regulator
- controls expression of self antigens in the thymus
Presents with hypoparathyroidism, Addison's disease, chronic mucocutaneous candidiasis, other autoantibodies
130
What is the pathophysiology of HLH? What are the commonly associated underlying conditions?
Defective NK cells +/- cytotoxic T cells fail to eliminate activated macrophages. Resulting in excessive macrophage and CD8 + T cell activation with highly elevated interferom gamma & other cytokines
Multiorgan dysfunction
Underlying conditions
- haematologic malignancy 60%
- infections - especially viral (EBV & CMV) 25-40%
- rheumatologic / autoimmune disease 8-20%
131
What are the common signs & symptoms of HLH?
Fever 95%
Splenomegaly 70%
Hepatomegaly 67%
Neurology 30% - encephalopathy, seizures, ataxia
Respiratory failure
Circulatory collapse
Acute renal failure
132
What blood tests are suggestive of HLH?
Severe bicytopenias (92%) - anaemia, thrombocytopenia - can be extreme (plat <10, Hb < 50)
Hepatitis
Coagulopathy
High ferritin
High triglycerides
**Elevated soluble CD25 - soluble IL-2 receptor > 2400 U / mL 97% **
High CXCL9 (chemokine 9)
NK cell dysfunction
Bone marrow aspirate - haemophagocytosis - especially phagocytosis of multiple nucleated cells
133
What is the treatment of HLH?
Do not wait for CD25 or histology to come back before initiating treatment in acutely unwell patients
- dexamethasome
- etoposide (topoisomerise II inhibitor)
- intrathecal hydrocortisone & methotrexate for CNS involvement
- consider allogeneic HCT
134
What are the live vaccines?
BCG
VZV / Zoster
MMR
Japanese encephalitis
Yellow fever
Rotavirus
Oral typhoid
Risk of vaccine-related disease especially high with BCG, MMR or VZV
135
What are the inactivated vaccines that are routinely recommended for immunocompromised patients?
1. COVID 19
2. Influenza
3. Meningococcal
4. Pneumococcus
5. HPV
6. Hepatitis B - higher doses or additional doses of hepatitis B vaccine recommended in dialysis patients, HIV, post HSCT
136
Who should not receive live viral or bacterial vaccines?
1. Malignancy
- active lymphoma or leukaemia
- other generalised malignancy
- receiving chemo or radiotherapy
2. Transplant patients
< 2 yrs post solid organ transplant
<2 yrs post HSCT
Graft vs host disease
3. Immunosuppressive medications
- bMARDs, dMARDs
- high dose corticosteroids - > 20 mg pred daily or equivalent
Immunise 1 month prior
Short course <2 weeks - immunise anytime after cessation
Long course > 2 weeks - need to wait 1 month
4. Aplastic anaemia
5. Primary immunodeficiency
6. Pregnancy
7. HIV (depending on CD4 count)
137
Terminology hypersensitivity / allergy
138
Age distribution of atopic diseases
139
What is atopy?
Immunological reactivity & predisposition to IgE production in response to ordinary exposure & common allergens
140
Gold standard for food allergy diagnosis?
Oral food challenge
Use if both SPT & specific IgE are negative
Skin prick testing is the preferred first line test for suspected IgE mediated food allergy
141
What is the sensitivity / specificity / PPV / NPV of skin prick testing?
High sensivity 90%, low specificity 50%
Detects presence of allergen specific IgE to wide variety of allergens (food, aeroallergens, antibiotics, latex, some venoms). Antigen binds to IgE bound to cutaneous mast cells producing a wheel & flare - positive result if > 3mm.
2 methods - skin prick / puncture - most appropriate 1st step, can stop here if positive. If negative, proceed with intradermal testing - 100-1000 fold more sensitive. However, higher rate of false positives. Higher risk of systemic allergic reaction - NOT done for food allergy
Positive skin prick test indicates sensitisation i.e. presence of specific IgE, but does not necessarily correlate with allergy.
Diagnosis of allergy requires both evidence of sensitisation and clinical history
PPV < 50%
NPV > 95% - can eliminate the diagnosis of IgE mediated food allergy.
142
Contraindications / risks of skin prick testing
Risk of anaphylaxis 0.02% - higher risk of systemic allergic reactions with intradermal testing compared to skin prick / puncture.
Stop anthistamines 2-3 days prior
TCAs 7-14 days prior
H2 antagonists - 24 hours
Neuroleptics - variable
Cannot perform in unstable asthma, severe eczema
Cannot perform after massive mast cell degranulation events i.e. have to wait 4 weeks post anaphylaxis (can get false negatives if done too early), also cannot perform in patients at high risk of anaphyalxis.
Pregnancy - relative CI
143
Is RAST testing sensitive for IgE mediated allergy?
Detects free antigen specific IgE in serum
Less range of standardised antigens available
LESS sensitive & specific than skin prick testing
NPV for IgE mediated food allergy is good - > 90%
Poor performance for most allergens e.g. penicillins but acceptable for some e.g. latex, chlorhexidine, some venom
Helpful if SPT contraindicated & can be initiated by GP
Difficult to interpret if patient has very high levels of total IgE (> 1000 KU/L) e.g. in severe eczema
144
Risk factors for allergic rhinitis
Family history of atopy
IgE > 100 IU / ml before age 6
Exposure to maternal smoking within first year of life
Birth during pollen season
Firstborn status
Early use of antibiotics
Male sex
Presence of allergen-specific IgE
Exposure to indoor allergens e.g. dust mite allergen
145
Comorbid conditions with allergic rhinitis
60% patients also have allergic rhinitis
50% have comorbid asthma
Sinusitis
Eczema
Food allergy
146
Management of allergic rhinitis
Allergen avoidance
- HDM covers - no evidence
- remove carpets, wash linen in > 55C once weekly - for HDM
- for grass pollens - stay indoors, mask, long sleeves
Sublingual immunotherapy
efficacious in
Rhinoconjunctivitis to aeroallergens (HDM, pollens, animal dander)
Mild asthma
Preventative effect - new sensitisation & onset of asthma
Comparable efficacy for grass pollens and HDM
147
Monoclonal antibody approved for the treatment of atopic dermatitis
Dupilumab is approved for severe atopic dermatitis
Monoclonal Ab against IL-4 & IL-13
148
What gene is often involved in the pathogenesis of atopic dermatitis?
FLG gene (on chromosome 1q21). Encodes filaggrin. Filaggrin mutations result in epidermal barrier dysfunction which is a hallmark of eczema.
- Epidermal barrier dysfunction is caused by filaggrin deficiency
- Filaggrin is a key component of natural moisturing factor (NMF) alongside Na / Cl ions, urea, lactate
Other features of pathophysiology
- imbalance b/w stratum corneum protease & antiprotease activity
- tight junction abnormalities
- altered composition & lamellar organisation of epidermal lipids
- decrease in microbial diversity (reduced Strep, corynebacterium, propionibacterium genera) and increase in Staph aureus
149
What are the cardinal features of atopic dermatitis in adults?
Dry skin
Intense pruritis
Distribution in flexural surfaces & skin creases (antecubittal fossa, popilteal fossa, neck, front of ankles, periorbital area)
Uncommon to have lesions in axilla, gluteal or groin region - consider alternative diagnosis
150
What is the strongest risk factor for eczema?
Positive family history
70% patients will have a positive family history
151
What food allergies are likely to resolve by adulthood?
80% of egg & milk allergies resolve by 5 years
Only 20% of nut allergies resolve into adulthood
152
Cross-reactive food allergens
Walnuts & pecans
Pistachios & cashews
Peanut & lupin
Birch pollen & apple
Latex & kiwi / avocado
153
Is desensitisation or immunotherapy routinely used in Australia for the treatment of food allergies?
Immunotherapy for peanuts, mild and egg allergy currently under trial. Is being used overseas but not yet in Australia
154
Specific IgE against which antigen is associated with mammalian meat allergy?
Allergy against non-primate meats - beef, pork, lamb especially. Rarely can include allergy to cetuximab & gelatin.
IgE mediated food allergy, however, reaction usually delayed by several hours (gut Sx, urticaria, angioedema, anaphylaxis)
Likely mechanism - possible exposure to galactose alpha 1,3 galactose (alpha - gal) present on cells & tissues of all non-primate mammals - via tick bites
155
Specific IgE against which antigen is associated with wheat - dependent, exercise-induced anaphylaxis?
Anaphylaxis or urticaria 1-4 hours after ingestion of wheat followed by exercise
Possible increased intestinal permeability to wheat antigens e.g. omega 5 gliadin
Specific IgE to omega-5 gliadin
156
Risk factors for IgE mediated food allergy
Personal or family history of atopy (asthma, eczema, allergic rhinitis)
Known other IgE mediated food allergies
157
Common allergens in adult IgE mediated food allergy
Peanuts
Tree nuts
Shellfish
Fish
Milk
Egg
Wheat
Soy
Sesame
158
Classification of food allergy
IgE mediated food allergy - reactions <60 mins, typical GI, cutaneous, respiratory or cardiovascular symptoms
Allergy testing is not indicated
159
Non IgE mediated allergies
T cell mediated - contact dermatitis
IgG mediated allergic alveolitis
Eosinophil mediated gastroenteropathy
Non IgE mediated food allergy
FPIES = food protein induced enterocolitis
Non-IgE mediated cow's milk allergy
Other enteropathy
160
Non-IgE mediated causes of anaphylaxis
Blood products
Drugs
Immune aggregates
161
Mixed IgE / non-IgE mediated food allergy
Eosinophilic oesophagitis
Atopic dermatitis
162
Non-immune causes of anaphylaxis
Physical exercise
Cold temperature
Drugs
163
Classification of anaphylaxis
164
Diagnostic criteria for anaphylaxis
165
Role of serum tryptase testing in anaphylaxis
Tryptase is a serine protease produced & stored in mast cells & basophils
Precursor forms (pro-tryptases) are constantly released from resting mast cells
Alpha & beta tryptase detected by commercial assay - mainly beta tryptase released during anaphylaxis
Peaks within 30 - 90 mins ( 1 hour)
Repeat at 3-4 hours to check for delta change - reflects mast cell degranulation
Repeat at 24 hours to assess baseline tryptase - if remains elevated can be suggestive of underlying mast cell disorders e.g. mastocytosis
166
An identifiable trigger is found in most cases of anaphylaxis. True or false.
False.
In up to 50% cases, the cause of anaphylaxis remains unknown
167
Compare the temporal profile of action of histamine vs tryptase in anaphylaxis
168
When to start IV adrenaline infusion in anaphylaxis?
IM adrenaline is the preferred route for initial management of anaphylaxis
Dose is 0.01mg/kg to max of 0.5mg IM
If refractory hypotension despite 2-3 x IM adrenaline doses and IV fluids (max 50ml/kg in first 30 minutes) - start IV adrenal infusion (note risk of cardiac arrhythmia)
169
Role of adjunct therapies in anaphylaxis
IV promethazine contraindicated as can worsen hypotension and cause muscle necrosis
Consider glucagon for persistent hypotension e.g. in patients who are beta blocked
Bronchodilators should not be used as a 1st line medication for anaphylaxis as they do not prevent or relieve upper airway obstruction
Benefit of steroids in anaphylaxis is unproven
Antihistamine have no role in anaphylaxis.
Can use nebulised adrenaline for upper airway obstruction and bronchodilators for persistent wheeze.
170
Causes of urticaria
171
What are the clinical features of urticaria?
Central swelling, with or without erythema
Itching
Migratory
Fleeting time course - lasting 30 mins - 24 hours
Leaves behind normal skin
172
What type of hypersensitivity reaction is serum sickness?
Type III hypersensitivity
self-limiting allergic reaction following exposure to foreign antigens. Deposition of immune complexes consisting of patient's antibodies bound to foreign antigen deposit in blood vessels and stimulate the complement cascade & inflammatory cascade
Typically caused by murine or chimeric monoclonal Abs e.g. infliximab or rituximab
Other causes:
Snake anti-venom
Insect bites e.g. bees
Antiserum for rabies & tetanus
Equine & rabbit anti-thymocyte globulin (ATGAM) in transplant patients
173
What are the types of hypersensitivity reactions?
174
What is the clinical presentation of serum sickness? What blood tests suggest serum sickness?
Fevers > 38.5 C
Rash - pruritic, does NOT involve mucous membranes (helps to distinguish from SJS / TENS), lesions last longer than urticaria (days)
Arthralgias - pain out of keeping with clinical findings (minimal swelling), typically involves MCPs, knees, wrists, ankles, shoulders
Bloods show neutropenia with a reactive lymphocytosis
Low C3 / C4 (complement cascade activated)
Can have an AKI - Cr up to 2 x normal, mild proteinuira in 50%, overt GN rare
175
Types of hypersensitivity reactions
176
Patients with a latex allergy can cross react to what other allergens?
Latex is made of hevea which contains 60 polypeptides that can bind to IgE. 15 of tehse proteins have been named.
Some proteins e.g. Hev b 6 can cross-react with food allergens
Avocado, kiwi, white potato, tomato, banana, chestnut, papaya
Mainstay of management is latex avoidance
Immunotherapy and anti-Ig trials so far not promising
Use of synthetic non-Heavea based products or at least powder-free products is recommended
177
Latex allergy manifesting as a skin rash is an example of a type 4 hypersensitivity reaction. True or false
Latex can cause an IgE mediated contact urticaria that presents within 1 hour of exposure (wheal & flare)
but can also produce a T cell mediated delayed irritant contact dermatitis which occurs 1-4 days after direct skin contact
178
What type of drug allergy is most common?
Allergy only represents 5-10% of adverse drug reactions (majority of which are pharmacological 80%).
The majority of drug allergy is T cell mediated (maculopapular / morbilliform rash or severe cutaneous adverse reactions) as opposed to IgE mediated immediate hypersensitivity which represents the minority
179
For drug allergy, specific IgE testing is more sensitive but less specific than skin prick testing. True or false.
False.
For drug allergy, specific IgE is more specific but less sensitive than skin prick testing.
Skin prick testing is limited by lack of validated tests for majority of drugs.
Specific IgE really only available for some beta lactam antibiotics.
180
What are the most common causes of DRESS? and typical latency period?
DRESS = drug reaction with eosinophilia & systemic symptoms
Vanc > sulphonamides > beta lactam
Latency typically 2-8 weeks but can be shorted - especially beta lactam antibiotics & iodine contrast
1. Antiepileptics - carbamazepine, lamotrigine, phenytoin
2. Allopurinol
3. Sulphonamides e.g. Bactrim
4. Miinocycline
5. Antibiotics - beta lactams, vancomycin
181
What type of hypersensitivity reactions cause DRESS, SJS / TEN and AGEP?
DRESS - type 4b hypersensitivity (Th2 / eosinophil mediated)
SJS / TEN - type 4c hypersensitivity (CD8 + T cell mediated)
AGEP - type 4d hypersensitivity (neutrophil mediated)
182
What is the RegiSCAR criteria?
Diagnostic criteria for DRESS.
Potential cases require at least 3 of the following:
1. Hospitalisation
2. Reaction suspected to be drug related
3. Acute skin rash
4. Fever > 38 C
5. Enlarged lymph nodes at 2 sites
6. Involvement of at least one internal organ
7. Blood abnormalities e.g. raised eosinophils, abnormal lymphocyte count, low platelets
183
Key clinical & biochemical features of DRESS
1. Cutaneous
- typically > 50% BSA involved
- maculopapular rash, coalescing erythema, purpura, exfoliative dermatitis
2. Mucosal symptoms - 50% cases, milder compared to SJS / TENS
- Marked facial oedema in majority of cases
3. Systemic symptoms
- fevers > 38.5
- lymphadenopathy
- LFT derangements in 90%
Can be mild, but also up to 10 x ULN
Cholestatic > mixed > hepatocellular
- kidney failure - protienuria
- lungs - dry cough, dyspnoea
- cardiac - hypotension & tachycardia - poor prognostic factor
Biochemical features
Leucocytosis (95%)
- elevated eosinophils > 0.7 - 80-95%
- neutrophilia -80%
- monocytosis - 70%
- lymphocytosis - 50%
Blood film shows atypical lymphocytosis
184
Management of contrast allergy
Risk factors for contrast allergy - previous reaction, severe asthma, cardiac disease, use of beta blockers, women. Allergy to seafood not associated with contrast allergy.
Skin prick testing - high specificity but low sensitivity (opposite to normal)
No specific IgE validated
Use low-osmolar - non-ionic contrast - reduced risk of allergy
Pre-medication for suspected IgE mediated reactions - pred 50mg 13, 7 and 1 hour prior with 50mg diphenhydramide 1 hour prior
185
What is the difference between SJS and TEN?
SJS affects <10% BSA
TEN affects > 30% BSA
SJS / TEN overlap if 10-30%
186
What is the pathogenesis of SJS / TEN?
Type 4 c hypersensitivity - mediated by cytotoxic T lymphocytes (CD8+)
- metabolite peptides of drugs presented by MHC 1
- drug-specific cytototixc T cells kill keratinocytes directly & indirectly via soluble death mediators e.g. granulysin
Perforin & granzymes released by CD8 T cells cause cell lysis
IFN gamma and TNF alpha released from CD8 T cells -> extensive keratinocyte apoptosis
Erosion of skin & mucosa -> detachment at basement membrane and sloughing
187
What are the most common drug & infective causes of SJS / TEN? what is the latency period?
Beta lactams > sulfonamides
1. Allopurinol
2. Antiepileptic drugs - phenytoin, carbamazepine, lamotrigine
3. Antibacterial sulphonamdies - Bactrim, sulfasalazine. Does not cross-react with non-antibacterial sulphonamdies
4. Nevirapine (HIV drug)
5. NSAIDs / COX-2 inhibitors
6. CTX agents - thalidomide, capecitabine, tamoxifen, check point inhibitors
Infections that triggers SJS / TEN - mycoplasma pneumoniae, CMV
Risk of SJS / TEN limited to first 8 weeks of treatment - typically 4-28 days of continuous use of drug
188
What are the known risk factors for SJS / TEN?
1. HIV - associated with 100-fold increased risk of SJS / TEN
2. Malignancy - esp. haematologic. 30-60 x incidence compared to general population. Abx most common trigger in this population
3. Genetic factors - certain HLA haplotypes but very small effect size
HLA B15:02 - carbamazepine & other anticonvulsants. Prevalence 10% in Asian populations
4. High drug doses
5. SLE
6. Physical stimuli - UV light or radiation light
189
Causes of death in SJS / TEN?
What are the predictors of mortality in SJS / TEN?
Sepsis
ARDS
Multi-organ failure
25% mortality rate
Predictors of mortality
- age > 40 yrs
- presnece of malignancy
- hyperglycaemia - BSL > 14
- urea > 10
- bicarb <20
- tachycardia > 120 bom
- epidermal detachment > 30%
190
Management of SJS / TEN
1. Immediate cessation of culprit drug. Re-exposure contraindicated for life
2. Supportive care in ICU or burns unit
3. Wound care, IV fluids, analgesia, nutrition (NGT), antibiotic cover
4. MDT
5. Beyond supportive care, few established therapies
-> systemic glucocorticoids
-> IVIG for 3 days for extensive disease
-> immunosuppressants - TNF inhibitors, cyclosporine
191
What are the key features of SJS / TEN?
- drug exposure < 8 weeks, 4-28 days after continuous drug use, average 14 days
- prodromal febrile illness - fever, early flu like Sx, 1-3 days prior to mucocutaneous lesions
- painful, rapidly progressive rash
- erythematous macules progressing to vesicles & bullae -> necrosis and sloughing of the epidermis & mucosa
- lesions start on face & thorax spreading to other areas, symmetrically distributed
- scalp, palms & soles usually spared
- positive Nikolsky sign (sloughing of skin on gentle pressure due to epidermal detachment)
- majority of patients have mucosal involvement with oral, ocular & genital mucositis
- ocular involvement in 80% patients - most commonly severe conjunctivitis with purulent discharge
Acute phase for 8-12 days with persistent fever, raw painful areas of denuded skin
Re-epithelialisation may begin after several days but typically requires 2-4 weeks
192
What is this rash?
What are the most common causes?
What are the expected biopsy findings?
Hypersensitivity vasculitis (AKA cutaneous small vessel vasculitis, leukocytoclastic vasculitis)
- drugs acting as haptens -> Ab production -> immune complex deposition in small vessels
Common culprits
- Sulphonamides (frusemide, thiazide)
- Penicillins
- Cephalosporins
- Allopurinol
- Phenytoin
Certain infections - HCV, HBV, chronic bacteraemias, IE, infected shunts, HIV also associated with cutaneous small vessel vasculitis
Non-blanching, maculopapular rash with palpable petechiae & purpura that develops 7-10 days post drug exposure
Biopsy findings - neutrophilic infiltrate
Leukocytoclasia (nuclear dust)
evidence of tissue damage
fibrinoid necrosis
Expect resolution of rash within days to a few weeks post cessation of drug
193
What drugs can cause direct mast cell activation without IgE?
Opioids, codeine, vancomycin, NSAIDs, quinolones
194
In type 1 hypersensitivity to penicillins, what component of the antibiotic are antibodies attacking?
Antibodies against central beta lactam ring (shared b/w penicillins, cephalosporins & carbapenems) are associated with type 1 IgE hypersensitivity
Can also develop immediate hypersensitivity to side chains (R groups) -> this is the case in selective immediate hypersensitivity to aminopenicillins (i.e. amoxicillin & ampicillin) but able to tolerate other penicillins
195
Sensitisation to what component of cephalosporins is associated with cross-reactivity with penicillins and among cephalosporins?
Sensitisation to the R1 side chain
**Penicillins cross-react especially with 1st & 2nd generation cephalosporins**
196
What penicillin antibiotic should be avoided in a patient with anaphyalxis to cephalexin?
Cephalexin and amoxicillin / ampicillin share an R1 side chain group
197
Use of ceftriaxone is contraindicated in patients with cephazolin anaphylaxis.
Cephazolin is the most common cephalosporin to cause anaphylaxis in the US.
It has a unique R1 and R2 side chain and does not appear to cross-react with other cephalosporins apart from ceftezole
198
Work up of labelled penicillin allergy
- Reaction history poor predictor of positive SPT
- penicilloyl derivative (major determinant) used in SPT. Sensitivity 90% - if both major and minor determinant - sensitivity 100%. High negative predictive value.
- Specific IgE has high specificity (83 - 100%) and low sensitivity (0-25%)
-
199
What are the features and typical triggers for acute generalised erythematous pustulosis?
Latency 1-18 days - very short time to onset typically 24 hours
Causes - Vanc > amoxicillin; penicillins, macrolides
Red-studden small pustules
Superficial pustulres begin on face, disseminates within a few hours
Typically not unwell, quick resolution
200
Antibiotic cross-reactivity
Penicillin - cephalosporin <2%
Penicillin - carbapenems <1%
Penicillin - aztreonam - no cross-reactivity
Antibiotic sulphonamides (e.g. Bactrim) do not cross-react with non-antibiotic sulphonamides (e.g. frusemide)
201
A patient is commenced on cetuximab. They later develop this rash.
Acneiform rash (papules + pustules) affecting face + upper body is the most common cutaneous reaction to EGFR inhibitors.
Monoclonal Abs - cetuximab and panitumumab
Oral small molecule EGFR inhibitors - gefitinib, erlotinib, lapatinib
- occurs as a result of direct EGFR inhibition, not as an allergic reaction to the therapy
- Usually within the first 4 weeks of drug initiation
- in about 85% patients; more common with monoclonal Abs than small molecule inhibitors
- indicative that the drug is working
