Immunology Flashcards
1
Q
Type I hypersensitivity
- mediators
- examples of conditions
- Ix
- Tx
A
IgE mediated (anaphylaxis and atopic disease) Involves Mast cells
Ix - skin prick for specific IgE and RAST
Tx
- Antihistamines (decr vasc permeability and bronchoconstriction)
- Corticosteroids (decr inflammation)
- Adrenaline (helps vasoconstrict)
2
Q
Type II hypersensitivity
Mechanism
Examples of diseases
A
‘Cytotoxic’, tissue-specific
- Antibody mediated -> target cell damage
- Due to defective ‘central tolerance’
- Due to self-reactive B cells that produce IgM and IgG +/- C’ activation -> attacks healthy host tissue (binds to Ag on host cells) and comes Ag-Ab complex at tissue site
Examples:
- Goodpastures
- Graves
- MG
- Rheumatoid
- Autoimmune haemolytic anaemia
- Haemolytic disease of newborn
- ITP
- Transfusion reactions
3
Q
Central tolerance
A
Immune cells that are ‘self-reactive’ are destroyed in primary lymphoid organs (thymus for T cells and bone marrow for B cells)
4
Q
Type II hypersensitivity: give examples of each
- Complement system activation
- Opsonisation and phagocytosis
- Natural killer cell activation
- Physical presence of Ab at receptor binding site impairs physiologic function
A
- Goodpastures syndrome -> Ab, C’ activation against collagen in lung and kidneys
- Autoimmune haemolytic anaemia; ABO, Rh-hemolytic disease of newborn
- Pernicious anaemia, guillain barre, Rh fever
- Graves disease (activation of TSH receptor -> hyperthyroidism)
and Myasthaenia Gravis (inhibition of nicotinic Ach receptor )
5
Q
Type III hypersensitivity
Pathophys
Mediators involved
Examples of diseases
A
Immune complexes (Ag-Ab complexes) deposit in blood vessel walls causing inflammation and blood vessel damage through complement cascade activation (note C3 and C4 used in large amounts)
ex: SLE = vasculitis in kidneys (glomerulonephritis), joints (arthritis); other forms of glomerulonephritis ; Serum sickness; Farmers lung
6
Q
Type IV hypersensitivity
- Mediators
- Pathophys
- Examples
A
T cell mediated (no Ab involved): Reaction occurs in 24-72hrs
- > CD4 (Helper T cells): releases cytokines which attract other immune cells
- > CD8 (Cytotoxic or ‘Killer’ T cells): directly kills things, specific targets
- > Leads to inflammation and tissue damage
Dendritic cell presents Ag to CD4 naive T cell in LNs -> activation/ maturation into Th1 cell which releases cytokines -> attracts other immune cells which leads to local inflammation -> erythema, oedema, fever
CD4+ (helper T cell) mediated:
- Contact dermatitis - Poison ivy and nickel allergy
- Tuberculin skin test (reaction to Mycobacterium tuberculosis protein injection into dermis)
- Multiple sclerosis (myelin)
- IBD (lining of intensive)
- GVHD
CD8+ (Killer T cells) mediated
- Type 1 diabetes mellitus (pancreatic islet cells)
- Hashimotos thyroiditis (thyroid epithelial cells)
- GVHD
7
Q
Innate immune response
- Speed of response
- Memory?
- Specificity of response
What components?
A
Non-specific response (responds to molecular patterns ie PAMPs, DAMPs, rather than specific Ag)
Fast! Response in minutes to hours
No memory associated with this response (same reaction to Ag no matter how many times it is exposed)
- Mechanical (cilia, epithelial tight jxns)
- Chemical (ex low pH of stomach acid, enzymes, antibacterial peptides, defensives etc)
- Microbiome
- Cellular: monoctyes, macrophages, Neuts, eosinophils, basophils, mast cells
8
Q
Adaptive immune response
What cells are involved
Speed of response?
Specificity?
Memory?
A
Involves B and T cells and immunoglobulins
- Highly specific (generation of 10^23 different T cell receptors)
- Slower response (~2 weeks to peak)
- Generation of memory (enhanced second response)
Relies on cells being primed -> differentiate into the right cell to fight that specific pathogen
Takes a few weeks
Immunologic memory -> clonal expansion of immune cells to fight the infection. on destruction of the pathogen, some of the clonal cells become plasma cells which on subsequent exposure undergo clonal expansions such that the immune response is much faster and stronger
9
Q
Myeloid progenitor cells
Where are they made?
What cells do they differentiate into?
A
Made in bone marrow
Granulocytes
- Neutrophils
- Eosinophils
- Basophils
- Mast cells
Dendritic cells
Macrophages
Monocytes
10
Q
Monocytes - function/role and what cells do they differentiate into?
A
Phagocytic/Ag presenting/produce cytokines
Differentiate into macrophages and dendritic cells
11
Q
Dendritic cells
- role/purpose
A
Phagocytic/Ag presenting/produce cytokines:
Present Ag to T cells
- This connects innate to adaptive immune systems
12
Q
Macrophages
A
Phagocytic (eat dead cells, invading pathogens)
and APC
-> Present Ag to T cells (This connects innate to adaptive immune systems)
13
Q
Neutrophils
A
-> degranulate to produce free radicals -> direct killing
14
Q
Eosinophils
A
-> degranulate to produce histamines and cytokines (allergy/parasites)
15
Q
Mast cells
A
-> involved in asthma and allergic responses
16
Q
Basophils
A
-> degranulate to produce histamine and cytokines (allergy)
17
Q
Lymphoid progenitor cells
A
Made in bone marrow
- NK cells
- T cells
- B cells
18
Q
NK cells
A
(innate)
Complete development in bone marrow.
Degranulate to produce cytotoxic molecules that directly kill the target cell via apoptosis
Specifically against viruses
19
Q
B cells
A
- Adaptive immunity
- Complete development in bone marrow
- Live in lymph nodes
- Bind to Ag -> present the Ag on their surface -> displays the Ag to T cells -> activates T cells which help the B cell turn into a plasma cell which can produce lots and lots of antibodies (IgM/G/E/A) against that particular Ag
- Those Abs circulate in the blood
- This process takes a few weeks
Can turn into memory B cells for subsequent exposure
20
Q
T cells
A
Adaptive immunity
- Completes development in thymus
- Naive T cells are presented an Antigen which leads it to become ‘primed’ and differentiate into
1. CD4 T cells = helper t cell, secretes cytokines that coordinate immune response against that Ag
2. CD8 T cells = cytotoxic (kill target cells)
Can turn into memory T cells for subsequent exposure
21
Q
Where to B and T cells develop?
A
Common lymphoid progenitor cell
- > becomes immature B cell in bone marrow, then travels to spleen to become mature plasma cell -> secrets B cell receptors
- > some travel to thymus to differentiate into T cells
22
Q
What part of the B cell receptor encodes the type of Ig it is?
A
The heavy chain genes encode this
23
Q
What are the five types of Ig and what is the main role of each class?
A
IgM - 1st response -> activates C’ pathway most effectively
and doesn’t require T cell help
IgG - memory
- opsonisation + classical C’ pathway
IgA - acts at mucosal sites to prevent pathogens entering body
opsonisation
IgE - allergy mediator, induced by IL4, triggers granulocytosis of mast cells, eosinophils, basophils
IgD- helps mature B cells leave bone marrow
24
Q
what is the main role of each class of Ig?
IgM
IgG
IgA
IgE
IgD
A
IgM - 1st response -> activates C’ pathway most effectively
and doesn’t require T cell help
IgG - memory
- opsonisation + classical C’ pathway
IgA - acts at mucosal sites to prevent pathogens entering body
opsonisation
IgE - allergy mediator, induced by IL4, triggers granulocytosis of mast cells, eosinophils, basophils
IgD- helps mature B cells leave bone marrow
25
Primary immunological response
B cells activated through interaction with dendritic cells (presents Ag to B cell) -\> B cell presents Ag to T cell -\> B cell switches from producing IgM to producing IgE/G/A etc and some become memory B cells
Ultimately you get lots of short lived effector cells and a few long-lived memory B cells
Effector cells die out after immune response ends/pathogen is eliminated
26
What is the life span of a memory B cell and where do they live?
Live up to 10 years in lymph node
27
What Ig classes don't memory B cells produce
IgM and IgD
28
What are the 2 types of memory T cells and how long do they live/where do they live?
Live 25 years
Central memory T cells
- remain in lymphoid tissue
- undergo clonal expansion when re-exposed to pathogen
Effector memory T cells
- circulate around body looking for pathogen
- responds as primary immune response (CD4 and CD8 T cell response) when exposed to pathogen
29
Skin healing mechanism
Primary intension
- ex: shallow epidermis cuts
- wound edges come together
- stem cells in epidermis are brought close together and can regenerate damaged tissue near surface (minimal scar)
Secondary intension
- ex: tooth socks, severe burns
- Wound edges far apart so wound replaced by connective tissue that grows from base of wound upwards
Tertiary intention
ex: dog bite injury
- Wound cleaned and left open due to increased potential for bacterial contamination (abscess/collection)
- After period of days they then heal by primary or secondary intention
30
Steps of wound healing
1. Haemostasis (vasoconstriction + blood clot forms to prevent further blood loss)
2. Inflammation
(damaged cells released chemokine and cytokines, incr vascular permeability so attracted neutrophils and macrophages can enter area and clear foreign material and destroy pathogens -\> scab formation)
3. Epithelialization
(Stem cells in epidermis proliferate and replace lost/damaged cells)
4. Fibroplasia = production of granulation tissue
[Fibroblasts in dermis proliferate and secrete collagen (fibroplasia)
a) Collagen forms bungles which provide tensile strength
b) Stimulates blood vessel growth (angiogenesis)]
5. Maturation = wound gets more support
a) collagen cross linking to incr tensile strength of wound
b) collagen remodelling and then contraction which pulls edges of wounds together
c) regimentation restores original pigmentation
31
BK virus
Transmission
What systems does it affect and what are its clinical effects
Ix for Diagnosis
Tx
Affects urinary system in immunocompromised hosts
- ex: HIV, tacrolimus (immunosuppressive medication used in transplants to suppress immune-mediated rejection)
Transmission via droplets and ingestion -\> travels in blood to kidneys, stays latent in immunocompetent hosts but if immunocompromised can become reactivated
ix- viral DNA in blood and urine
Clinical effects/tx:
- Haemmhoragic cystitis in BM transplant recipients -\> tx is hydration and clot evaluation (catheter + flush)
- Ureteral stenosis and retention (inflammation/fibrosis causing narrowing) -\> tx is balloon dilation or stent
- Nephropathy in kidney transplant recipients (secondary to inflammation -\> tissue damage) -\> tx is immunosuppression
32
MHC II - what cells are they found on?
Only on Ag presenting cells (monocytes, macrophages, dendritic cells, B cells)
33
MHC I - what cells are they found on?
On all nucleated cells throughout body
34
What do histocompatibility genes code for and what is their purpose
HLA (human leukocyte antigens) ie
MHCI and MHC II proteins which are expressed on our cells
Helps to differentiate self cells from non-self cells
35
How are transplant donors selected and why?
Transplant donors are selected to share as many HLA Ag with the host as possible to minimise rejection/chance of GVHD
Even with twins who are HLA
identical, minor histocompatibility Ags are recognised as foreign and can mount immune response
36
GVHD immunological mechanism
When can this be beneficial?
T-cell mediated transplant rejection
Donor T cells react against recipients MHC Ags which they see as 'foreign'
- \> CD4 recognise MHCII -\> recruitment immune response
- \> CD8 recognise MHCI -\> direct destruction of target tissue
Common targets - skin, liver, gut
NOTE - this is seen as beneficial in leukaemia as this response helps to ELIMINATE the leukaemia recipient's cancerous blood cell lines
37
IgE mediated Type I HS pathophys
- immediate and delayed reaction
1. Sensitisation = first exposure
2. Subsequent exposure
Pollen breathed in -\>
Dendritic cells/M cells in gut/APC bind to pollen (allergen=Ag)
-\> Migrates to lymph nodes and presents the Ag to T helper cells = 'priming'
-\> Differentiation of T helper cell into TH2 cell driven by IL 4,5,10 cytokines
-\> TH2 cells produce IL4 which gets B cells to switch to plasma cells producing Allergen-specific IgE.
-\> Also produces IL5 which induces production of eosinophils
-\> Allergen-specific IgE attach to Mast cell and basophil surface
Second exposure event to allergen
- \> IgE-Coated mast cells bind to Allergen -\> mast cell degranulation -\> pro-inflammatory mediators including:
- eosinophils
- histamine -\> bind to H1 receptors in bronchi -\> bronchoconstiction (asthma)
- histamine -\> cause vasodilation -\> airway oedema, urticaria, hypotension
Late phase reactions (8-12hrs later) induced by IL4,5,10 and leukotriene release by mast cells
- TH2 cells
- Basophils
- Eosinophils
38
Molecules involved in anaphylaxis
Histamine -\> blood vessel permeability, dilation and bronchoconstriction
Tryptase -\> tissue injury
Cytokines IL 4, IL13
Leukotrienes (LTB4 and C4) - attract inflammatory cells to the area hours later (can lead to biphasic reaction)
39
Ix for allergy
1. Skin Prick Tests
- panels of up to 40 allergens are pricked into skin
- wheal reaction
2. RAST = blood tests look for IgE Ab against certain allergens (serum-specific IgE)
40
Erythema multiforme
what is it
cause/triggers
mx
When immune cells attach epithelial cells
Affects skin and MM
Often triggered by infection (HSV) or medications (anticonvulsants, abx)
Ft: targetoid lesions (central necrosis with macules, papules, vesicles and bullae
with haemmhoragic crusting of lips
Dehydration secondary to oral mucosa involvement
Mx: self-limiting,
Treat underlying cause (infection or stop any medications)
if due to HSV, can use acyclovir or valaciclovir as prevention
41
Bullous Impetigo
Staph aureus skin infection ('impetigo') leading to formation of multiple Bullae that rupture easily, leaving erosions
Most often affect face trunk, perineum and extremities
Tx - cefalexin to treat staph aureus and prevent transfer of staph between household members. Vancomycin if not responding to cef.
42
Staph scalded skin syndrome
Bullous impetigo in immunocompromised individuals
Widespread bullae, erosion and systemic sx (fever, malaise). Develops rapidly.
Mx - supportive care with rehydration and antipyretics + IV abx
43
DRESS (drug reaction with eosinophils and systemic symptoms)
Rare life threatening condition caused by medications (2-6 weeks after initiation of medication) - allopurinol, anti epileptics, sulphonamides, minocycline, vancomycin
Skin eruption leading to diffuse confluent erythema involving \>50% BSA
Eosinophilia on bloods
Systemic sx: fever, malaise, lymphadenopathy with involvement of kidney, liver, lungs
mx - withdraw offending medications
- topical CS OR if severe systemic (IV) CS
44
Steven Johnson Syndrome
Life threatening skin reaction with systemic compromise due to autoimmune response to a medication (often anticonvulsants)
Epidermal sloughing of skin and mucous membranes involving \<10% BSA
- essentially a burns reaction (macule and vesicles leading to skin sloughing)
Less severe version of Toxic epidermal necrolysis (TEN \> 30% BSA)
Tx
- Admission to burns unit or ICU
- Cease triggering medicaitons
- Supportive tx (IV fluids, PN)
- Systemic immune modulators (antihistamines, IVIg, corticosteroid)
45
Risk factors for allergic rhinitis
Fam hx atopy
Elevated IgE by age 6
Heavy Smoking mother
Heavy Exposure to indoor allergens
46
Pathogenesis of allergic rhinitis
a. Exposure of an atopic host to an allergen -\> IgE production
b. Bridging of IgE molecules -\> mast cell activation + degranulation -\> release of pre-formed inflammatory mediators (histamine, prostaglandin, leukotrienes)
c. Late phase allergic response (4-8 hours) -\> eosinophils, neutrophils and mast cells infiltrate nasal mucosa -\> leukotrienes, eosinophil peroxidase, major basic protein + IL-3, IL-5, GCSF
47
Sx of allergic rhinitis
And classification
a. Acute – sneezing, itch, rhinorrhoea (due to histamine)
b. Delayed – nasal congestion (due to infiltration inflammatory cells)
Classification
a. Episodic - \<4 weeks
b. Persistent - \>4 weeks
c. Mild – nil below features
d. Moderate to severe – sleep disturbance, school interruption
48
Sx of allergic rhinitis
And classification
a. Acute – sneezing, itch, rhinorrhoea (due to histamine)
b. Delayed – nasal congestion (due to infiltration inflammatory cells)
Classification
a. Episodic - \<4 weeks
b. Persistent - \>4 weeks
c. Mild – nil below features
d. Moderate to severe – sleep disturbance, school interruption
49
Tx for allergic rhinitis
Allergen avoidance
Nasal irrigation
Topical inhaled corticosteroids
- 1st line for tx of allergic rhinitis (sneezing, eye sx)
- takes 2-4 weeks for max sx benefit; needs to be continued for 2-6 months
Antihistamines (for itchy/sneeze/eye sx)
Antihistamines for SHORT TERM USE only (\<3 days) in children \>6 yrs
- reduces nasal congestion
50
What type of reaction is eczema/atopic dermatitis
Type I hypersensitivity reaction to allergen -\> inflammation of skin tissue -\> leaky skin tissue allows water to escape -\> leads to dry skin (which is itchy ++)
51
Eczema - types of skin lesions and distribution
Types
a. Acute = erythematous papules
b. Subacute = erythematous, excoriated, scaling papules
c. Chronic = lichenification, fibrotic papules
Distribution
a. Infancy = face, scalp, extensor; diaper area spared
b. Older children = flexural folds
52
What syndromes is eczema a feature of?
Hyper IgE syndrome (Job syndrome is autosomal dominant form)
Phenylketonuria
Wiskott-Aldrich syndrome
53
Wiskott-Aldrich syndrome
- cause
- triad of features
- what is the main risk?
- tx
X-linked (WASP protein deficiency - req in actin polymerisation and signalling of T cells)
CD4 T cell deficiency -\> impaired B cell fxn as no T cell help
Features ('TIME'):
Thrombocytopenia (petechiae, bloody stools)
Immunodeficiency (recurrent otitis media/'draining ears', recurrent viral infections initially, then bacterial infx more problematic over time)
Malignancy risk
Eczema
Main risk - Intracranial haemmhorage, severe infections
Definitive tx is HSCT
54
Eczema management
Identify/avoid triggers
- irritants (dryness, humidity, heat, excess sweating, soap fabrics etc), foods, aeroallergents, infections
- Keep finger nails short/stop scratching
Emollients - BD +/- wet dressings
Anti-inflammatory agents (use in bursts to clear eczema, then stop)
- Topical steroids
- -\> face: 1% hydrocortisone
- -\> body: 0.1% methylpred (advantan fatty ointment) or 0.1% mometasone furoate (elocon)
Systemic immunosupppression
- Azathioprine (inhibits purine synthesis)
- Pimecrolimus ointment (calcineurin inhibitor)
- Methotrexate (inhibits dihydrofolate reductase)
Treat infx
- Bleach bath
- Antibiotics/antivirals as indicated
55
What type of reaction is allergic contact dermatitis?
Type IV hypersensitivity reaction
56
What are the most common (super)infections to think of in eczema ?
1. Bacterial
- Staph aureus
2. Viral
- HSV most common
- Enterovirus
- Molluscum contagiosum
3. Fungal
- Tinea
57
MOA azathioprine
Immunosuppressive agent
Inhibits purine synthesis, thus decreasing production of DNA and RNA requiring for synthesis of WBC
58
Criteria for anaphylaxis
Note - some features are transient and resolve before arriving to medical care
1. Acute onset with typical skin features (urticarial rash or erythema/flushing or angioedmea)
PLUS
2. Resp/CV and/or persistent GI symptoms
- Note: CV sx in infants can include pale/floppy and resp sx can include persistent cough or hoarse voice/change in character of cry
OR
3. Acute onset hypotension or bronchospasm or upper airway obstruction (even in absence of typical skin features)
59
RF for fatal aasthma
a. Adolescence
b. Nut and shellfish allergy
c. Poorly controlled asthma
d. Delays to administration of adrenaline or emergency services
60
What is the role of tryptase blood test in anaphylaxis
No role in diagnosis (anaphylaxis is a CLINICAL diagnosis) unless the diagnosis is unclear (ie anaesthetic reaction)
- take it 15min-3hrs post anaphylaxis and a second level 24 hours post
- If level is \>11.4 or elevated by 20% above baseline – diagnosis confirmed
61
MOA adrenaline
Adrenergic receptor agonist
Alpha-1 receptor
o Vasoconstriction + increased BP
o Reduces mucosal edema
Beta-2 receptor
o Broncho dilatation
o Reduces mediator release (Stabilises mast cells)
Beta-1 receptor
o Increases HR
o Increases cardiac contraction force
62
Pathophys serum sickness
Type III hypersensitivity reaction caused by Ag-Ab complexes
- Small complexes – circulate harmlessly
- Large complexes – cleared by reticuloendothelial system
- Intermediate complexes = may deposit in blood vessel wall and tissues – trigger vascular (leukocystoclastic vasculitis) and tissue damage (activation of C’)
- C3a and C5a – promote chemotaxis and adherence of neutrophils
- Tissue injury from liberation of proteolytic enzymes and oxygen radicals
Typically in response to snake venom or insect bites (reaction to the serum proteins) OR antibiotics like cefalcor, pencilling, bactrim or anticonvulsants or like rituximab
63
Presentation of serum sickness
and treatment
1. Rash (urticaria, pruritus) - initially erythematous, evolving into dusky centre with round plaques. mucous membranes NOT involved.
2. Fever
3. Polyarthritis/arthralgia
Beings 1-3 weeks after drug exposure, resolves in ~2 weeks (but can last up to 4 months)
Treatment
- Supportive, withdraw offending agent
- Antihistamines, NSAIDs
+/- steroids
64
Serum sickness
what type of HS reaction?
Blood test finding for serum sickness
Type III immune-mediated hypersensitivity run
Low C3 + C4 (nadir day 10) + total haemolytic complement (CH50)
Thrombocytopenia, neutropenia
Elevated ESR and CRP
65
How to differentiate serum sickness from a serum sickness-like reaction?
Serum sickness
- low c3, c4.
- onset 1-2 weeks post exposure to offending agent.
- Can be assoc w systemic sx such as edema (i.e., of the hands, feet, and face), lymphadenopathy, headache or blurry vision, splenomegaly, anterior uveitis, peripheral neuropathy, nephropathy, and vasculitis, renal injury
SSLR
- normal c'.
- Onset 5-10d post exposure to causative agent.
- Systemic symptoms are less likely in serum sickness-like reaction, which is usually limited to fever, arthralgias, rash/urticaria, and pruritis.
66
Henoch Scholein Purpura clinical prsentation
Most common vasculitis of childhood
Affects ages 2-8 most commonly
Occurs after URTI (viral or group A strep/strep throat) in 50% patients
Features
- Purpura (palpable purpura, petechiae, ecchymoses)
- Arthritis/arthrlgia (large joints of lower limbs)
- Abdo pain (beware of complications of intussusception, GI haemorrhage, bowel ischaemia/necrosis/perforation)
- Nephritis with proteinuria/haematuria, HTN
67
Ix for HSP
Urinalysis -\> urinary protein-creatinine ratio, blood
Blood pressure
UEC
ALbumin
Consider the following if diagnosis unclear (ddx ITP, leukaemia, infx) or to identify potential complications of HSP
- FBE
- Blood culture/urine culture
- Abdo imaging
68
Mx of HSP
Note- sx generally self-resolve within 24-72 hours (rash is last to resolve)
Mild pain - sx relief (panadol, bed rest, +/- NSAIDS if no CI)
Mod-severe pain - consider steroids (oral pred or IV methylpred with wean once sx resolved) if abdo pain, joint pain as may reduce duration of sx
F/U
- regular follow up for the next 12 months monitoring urinalysis and BP for renal complications
- If there is no significant renal involvement and normal urinalysis at 12 months, no further follow-up is required
69
HIV pathology
Targets CD4+ cells (macrophages, dendritic cells, macrophages have this on their surface)
gp120 receptor on the HIV molecule attaches to the CD4+ molecule's coreceptor (CCR5 or CXCR4) -\> injects ssRNA retrovirus (uses reverse transcriptase to make complementary strand DNA) into target cell
Results in the transcribing and translating of viral DNA by the host cell -\> making lots of new viral particles
70
Tx HIV
Antiretroviral therapy (ART): combination of medications that work to slow HIV replication, allowing immune system time to recover and allowing it time to fight off other inhx
71
What defines AIDs
T cells \<200 they now have AIDS
- Persistent fever, fatigue, LOW, diarrhoea
AIDS defining illnesses (PJP, recurrent bacterial pneumonia, fungal infections, certain tumours)
72
HIV natural history
Presentation with flu-like sx in acute infective period (with incr in HIV in blood, decr in T cells) until host immune system mounts counter attack (by 12 weeks, with decr in HIV viral load to almost undetectable and incr in T cells)
Then enters into latent/chronic phase
- however virus load gradually increasing though and T cells gradually decreasing
- opportunistic infections more common/severe
When body's T cells reach as low as 200-500 immune system is severely compromised
- lymphadenopathy, minor infections become severe (oral candidiasis, hairy leukoplakia)
73
Transmission HIV
Enters body most commonly via sex (75%; M-\>M but also M-\>F in developing nations)
- IV drug abuse
- Mo -\> fetus
CD4+ Immune cells in the peripheries take up the virus and travel to lymph nodes -\> more infection of other immune cells -\> spike in viral load
74
X-linked agammaglobulinaemia
Inheritance
Pathology
Presentation
Tx
X-linked recessive gene mutation featuring LACK of circulating B cells and antibodies of all classes (inherited and sporadic forms)
Mutation in BTK gene making Bruton's Tyrusine Kinase enzyme ineffective which is required for B cell maturation -\> no maturation occurs past pre-B cell stage so they do not leave bone marrow -\> no B cells or Ig in circulation -\> infections
Often presents at around 6-9 months (that's when maternal IgG runs out)
- no palpable LNs or tonsils on exam
- development of infections
Ix -
Plasma - IGs very low/absent with no or few circulating B cells
+/- BM (pre B cells)
+/- GI bx (no plasma cells)
Genetics - BTK mutation
Tx - lifelong IvIg infusions -\> boosts immune system and gives passive immunity
-\> treat infx immediately with abx
75
Infx with X-linked agammaglobulinaemia
Encapsulated bacteria (strep, HIB, mycoplasma)
- Sinopulmonary ix
- Septic arthritis
- OM
- Meningitis
Viral infections
- hepatitis
- enterovirus
- CNS infections with echovirus and coxsackie
- Echovirus associated myositis
- poliovirus -\> paralysis
Fungal and some parasitic infections (Giardia)
76
Ix findings for X-linked agammaglobulinaemia
FBE - Neutropenia at height of infection
Flow cytometry
i. Peripheral blood B lymphocytes \< 1% (demonstrated on flow cytometry), pre B cells present in bone marrow
ii. ↑ T cell percentage, normal T cell subset ratios, normal T cell function and thymus
Immunoglobulin levels
i. IgG, IgA, IgM, IgE \<95% centile for age and race
ii. \<100 mg/dL
iii. Isohaemagluttinins (natural Ab to type A and B polysaccharide antigens) absent
iv. Antibodies to vaccines absent
Intestinal biopsy : absence of plasma cells
Prenatal testing – can be performed on male fetuses
77
Common variable immunodeficiency (CVID)
What is it also known as?
Mode of inheritance?
What is it?
Key Features
Key Ix findings
Mx
IE 'acquired hypogammaglobulinaemia'
Inheritance - AD or sporadic
Heterogenous group of cdtns characterised by hypogammaglobulinaemia with phenotypically NORMAL B cells (B cells \>1%)
Normal numbers of circulating lymphocytes - do not differentiate into Ig producing cells when stimulated
-\> later age of onset than XLA (late childhood/adulthood) and normal tonsils/LN
Features
- Low IgG +/- IgM, IgA (note IgM and IgA can be normal in some)
- Low (or normal) B cells
- T cell number and function normal
- Recurrent infx (HIB, pneumococcus, staphylococcus; sinopulmonary; bronchiectasis)
- Concurrent autoimmune disease (cytopaenias)
- Granulomatous disease
- Risk of malignancy (lymphoreticular)
- Chronic lung disease (COPD, bronchiectasis, interstitial pneumonia)
- Malabsorption syndromes (+ infx such a Giardia)
Ix
- Marked decr in levels of IgG, IgA +/- IgM
- NORMAL B cells (may be slightly reduced)
- Normal T cell numbers
Mx
- IVIG
- Abx (prophylaxis + tx)
- Resp PT
- Immunosuppression/modulation for autoimmune features
78
How long does maternal IgG persist for?
First 6-8 months of life
79
Transient hypogammaglobulinaemia of Infancy
What is it?
Features
Tx
Delayed synthesis of immunoglobulins until after maternal IgG catabolized
- low IgG levels
Features
- Normal Ab production to challenge (vaccination response)
- Normal growth patterns
- Lack of opportunistic infections – may have recurrent respiratory viral infections but generally not severe infx
- 60% in males
- Assoc w atopy
- Resolves spontaneously after 4 years (by definition)
Tx
- Consider Ab prophylaxis
- Rarely IvIG (3-6mo trial only)
- Monitor IgG, tends to incr w time
80
What is the most common immunodeficiency disorder?
Selective IgA deficiency
81
Causes of Selective IgA deficiency
Drugs
Congenital rubella or CMV
Other immunodeficiencies (DiGeorge, CVID)
--\> Genetic assocation (?AD defect w variable expressivity)
Pathogenesis unknown but 45% have Anti-IgA Abs
82
Associations with IgA deficiency
Autoimmune disease
- SLE/RA/Thyroiditis/Addisions
Allergic disease
Coeliac disease
Malignancy
CVID
IgG2 deficiency
83
Presentation and Tx of selective IgA deficiency
- Age \>4 (takes this long for IgA to reach 'normal' levels, variation younger than this)
- Often asymptomatic
- Infections (resp, GI, urological) as per other Ab deficiency syndroomes
- Giardiasis especially common
- Note hx autoimmune disease, atopy
84
In what Ig deficiency should IvIG NOT be given and why?
Selective IgA deficiency
due to risk of anaphylaxis as 45% of patients have antibodies to IgA and if IgE subtype can trigger fatal anaphylactic reaction following administration of blood products containing IgA
Note can transfuse IgG IVIG (\>99% concentration) if also IgG deficiency
85
What is Duncan disease also known as?
X-linked Lymphoproliferative Disease
86
X-linked Lymphoproliferative Disease
What is it
What causes it
What is the clinical picture
Prognosis/outcome
Rare severe dysregulation of immune system IN RESPONSE TO EBV
- \> defective immune response leads to excessive T cell proliferation to try and kill (but can’t) and persistence of EBV infected cells
- \> Genetic predisposition
3 types:
1. 60% Fulminant EBV infection and secondary HLH -\> often fatal
2. 30% Lymphoma (B cell lineage)
3. 20-30% Acquired hypogammaglobulinaemia/Dysgammaglobulinaemia
Poor prognosis
Often 70% die by 10 years, 100% by 40 years
87
SLE
What is it?
What causes it?
Pathophys?
Autoimmune disease
Type 3 hypersensitivity reaction
Combination of genetics + environmental triggers (UV radiation, cigarettes, virus, bacteria, certain meds, oestrogen)
Development of Ab against nuclear antigens (DNA, histones, other proteins) = anti ds-DNA
Forms Antigen-Ab complexes that can get into blood and deposit into vessels within kidneys, joints, heart, skin
Complexes initiates local inflammatory reaction via C' system activation -\> ultimately leads to cell apoptosis and tissue damage
88
Diagnostic criteria of SLE
4 or more of the following:
Skin
1. Malar Rash (butterfly rash on cheeks after sun exposure
2. Discoid rash (chronic)
3. Photosensitivity
Mucosa
4. Ulcers of mouth, nose
Serosa
5. Serositis (pleuritis, pericarditis/endocarditis/myocarditis)
Joints
6. Arthritis of 2+ joints
Kidneys
7. Renal disorders
Brain
8. Neuro disorders (seizures, psychosis)
Blood
9. Anaemia, thrombocytopaenia
89
Autoantibodies in SLE
Antinuclear Ab (very sensitive but not very specific as seen in lots of other Autoimmune disease
Anti-dsDNA (specific)
Anti-Sm (highly specific) Anti-phospholipid (sensitive, not very specific)
--\> can lead to antiphospholipid syndrome -\> hypercoagulable state
90
SLE treatment
Prevent - avoid triggers (sunlight etc)
Limit severity of flares
- Corticosteroids
- Immunosuppressants
91
Superantigen pathophys and exemples of conditions
- Class of antigen that results in excessive activation of the immune system
- Causes non-specific activation of large numbers of T cells (up to 20% vs normal activation is 0.01% against normal Ag) and subsequent massive cytokine release (TNF alpha, IL1, IL6, IFN gamma) that can lead to fever, shock, and death (multi-organ failure)
- - \>SAG is taken up by Ag presenting cells but skips Ag processing/presentation on MHCII molecule and instead binds outside of the MHC peptide binding groove and then also to the variable region of the TCR -\> activates huge numbers of polyclonal T cells
Examples
- Kawasaki disease
- Acute Rheumatic fever
- Scarlet fever (GAS)
- Strep toxic shock syndrome (GAS)
- Staph toxic shock syndrome
92
Clinical features of Wiskott Aldrich syndrome
What is the pathophys/cause of this
What is the age of presentation and prognosis
'TIME'
- Thrombocytopenia (due to small, defective platelets)
- Immunodeficiency
- Malignancy risk
- Eczema
X-linked disorder resulting in dysfunctional WASP protein
Results in impaired humeral responses to polysaccharide Antigens (Ab response)
Presents \<1 yo
Survival beyond teens is rare (infections, bleeding, EBV associated malignancies are major cause of death)
Mx - monthly IVIG (variable concentration of IgG, IgA, IgM)
93
What is the normal role of WASP protein and in what disorder is this disrupted
controls actin filaments required for micro vesicle formation downstream of protein kinase C and tyrosine kinase signalling
Wiskott Aldrich Syndrome (x-linked mutation in the gene coding for this protein)
94
What Ig are involved in the formation of immune complexes in the classic C' pthway?
IgM, IgG
95
What T cells and cytokines drive the allergic response/igE etc?
TH2 cells
Driven by: IL4
Produces: IL4,5,13
Function: stimulates IgE, mast and eosinophils and allergic disease
96
What cytokines/T cells activate macrophages?
TH1
Driven by IL12, IFN gamma
Produces: IFN gamma (amplifies response)
Function: activate macrophages
97
What cytokines/t cells are involved in neutrophil recruitment?
Th17 cells
Driven by IL1, IL6, TGFbeta
Produces IL17, IL22, IL21
Recruits leucocytes, mainly neutrophils, to sites of infection -\> defence of extracellular bacteria, fungal
98
Recurrent sinopulmonary infx -\> bronchiectasis
Hb, strep pneum, pyogenic bacteria, enterovirus
What immune defect?
B cell
99
```
Neisseria
Pyogenic bacteria (strep, HIB)
```
What immune defect?
C' defect
100
Gingivitis
what immune defect?
Neutrophil defect
101
PJP/other fungal infx are red flag for what immune defect?
What is prophylaxis for this?
T cell defect
Bactrim
102
What type of immune cells are removed from the graft prior to giving HSCT to limit GVHD?
T cells as aGVHD is T-cell mediated
103
What medications must be withheld prior to SPT?
Antihistamines for 1 week
Topical CS - avoid skin area
104
Chronic mucocutaneous candiadias
Cause/genetics
Clinical picture
Associated condition(s)
\< 5yo
Chronic severe candida skin and mucous membrane infx (absence of systemic infections)
- T cell defect
- mutation in AIRE (AR) or STAT1 (dominant) gene
- often assoc w endocrinopathies
- diagnosis based on skin scrapings, diagnostic testing
105
SCID
Clinical picture
and ix
Presents early (0-6mo)
- Severe infections
- Persistent mucocutaneous candiadisis (thrush), PJP, EBV
- Chronic diarrhoea
- FTT
Ix
- Lymphopenia (low CD3, 4 and 8)
- Absent T lymphocytes
- Low Ig levels (IgG lowest)
106
Physiology of contrast allergy
No single pathogenic mechanism has been defined, but it is likely that mast cell activation accounts for the majority of these reactions. Complement activation has also been described.
107
Cause of recurrent angioedema without wheals /urticaria/pruritis
C1 esterase deficiency
= hereditary angioedema
108
Job syndrome
Alternative name?
Pathophys
Sx
What differentiates this condition from severe atopic dermatitis?
= hyper IgE syndrome
Pathophys
- Impaired Th17 differentiation/function -\> decreased IL 17.
- T cell dysfunction and extremely high levels of serum IgE and eosinophils.
- Results in decr protection against extracellular pathogens inc staph and aspergillus
Features: FATED
- Face - coarse features
- Abscesses (staph Aureus, aspergillus; abscesses differentiates it from atopic dermatitis)
- Teeth retention (primary teeth)
- Eosinophilia
- Derm (eczema)
109
HLH
What is it?
Causes
Criteria for diagnosis
Tx
Excessive macrophage activity -\> elevated IGN-g and other cytokine levels -\> excessive inflammation and tissue destruction
```
Primary (genetic)
vs secondary (secondary to infection, lymphoid malignancy, systemic onset JIA)
```
Fever
Splenomegaly
Cytopenia of at least 2 lineages
High ferritin in \> 2000
Low fibrinogen (activated macrophages consume this)
High CD25
Tx - steroids +/- cox, but
110
Features of Ig deficiency disorders (general)
Sinopulmonary infx
Encapsulated bacterial infx - septicaemia
Predisposition to bronchiectasis if immunoglobulin untreated
Incr (CVID) or absent lymphoid tissue (XLA)
111
Initial ix for Ab deficiencies
IgG, IgA, IgM, IgE
Test of Ab FUNCTION
- response to vaccines (measure Ab levels right after vaccination and 4 weeks post)
--\>tetanus, diphtheria, HIB, pneumococcal Ab
--\>Isoagglutinins, ASOT
```
IgG subclasses
B cell enumeration (class switching etc)
```
112
Rituximab
MOA
Pre-mx Ix
Anti CD20 (B cell killer)
Pre-mx Ix
- IgG/A/M
- B cell enumeration
113
Severe Combined immuno deficiency (SCID)
X linked or AR
Severe and fatal if not recognised and treated early
Absence of adaptive immune response (T cells-defective which impacts B cell function and Ab production)
Born well at birth but FTT over first few months
Present 4-6mo w resp infx, chronic diarrhoea, chronic nappy area thrush
Bacterial infx less common due to maternal IgG up to 6mo
OE
No lymphoid tissue
Wasted but preserved HC
Resp sx
Abdo distension
Persistent diarrhoea (incl diarrhoea from rotavirus vaccine)
Oral/Nappy area thrush
Ix
Persistent lymphopaenia
-\> Low T +/- B cells
Hypogammaglobuliaemia (except maternal IgG)
Thin mediastinum on CXR due to no thymus
114
Causes of secondary Ab deficiency
Protein loss
- PLE
- Chlothorax
- Nephrotic syndrome
Drugs
- Steroid
- Rituximab
115
Infant with Rash - progressive, resistant to tx
Lose hair, eyebrows
FTT
Irritable++
Lymphadenopathy, hepatosplenomegaly
Severe, recurrent infx (resp)
Eosinophilia and high IgE with lymphocytosis
Omenn syndrome (RAG1, RAG2 gene mutations)
Form of SCID
Presents in infany
116
initial ix for SCID
TREC (screening)
FBE (lymphocyte count - low absolute count; abnormal lymphocyte subpopulations)
CXR (?mediastinum thin)
Flow cytometry for lymphocyte subsets (T, B and NK cell numbers) and naive T cells
Ig G/A/M/E
117
Most common genetic cause of scid
Common gamma chain SCID
- mutation in CGC of IL2 receptor
X-linked
118
Genetic mutations that can present as SCID
Common gamma chain mutation of IL2R
V(D)J recombination -\> at TCR and BCR gene loci
ADA (adenine deaminase deficiency) -\> premature death of lymphocyte precursors -\> progressive loss of T/B cells
- also neurological involvement
PNP deficiency (same pathway as above)
MHCII deficiency
22q11 (complete DiGeorge)
ZAP-70 kinase deficiency (signalling molecule downstream from T cell receptor)
119
Treatment of SCID
Supportive care
Tx of infections
HSCT
Gene therapy (up and coming)
Thymic transplant for complete Di George
120
DiGeorge syndrome
22q11 (de novo mutation or AD)
KEY: Affects Thymic development (and thus reduction in mature T cells/deficiency in T cell mediated immunity)
'Complete' Di George = Complete absence of thymus
Features;
- Lymphopaenia (specifically CD3, CD4 \> CD8)
- Low PHA response (=t cell response)
- Ig levels usually normal
- Variation in immune function (from near normal to SCID)
- Cardiac defects
- Characteristic facies
cleft palate
- Behaviour difficulties
Mild
- prophylactic Ab +/- Ig replacement
- SCID: thymic transplant is curative
121
CHARGE syndrome
Impacts thymic development -\> variable range in immune development (SCID to mild ID)
Features include
- coloboma
- heart anomolies
- choanal atresia
- retardation
- genital anomalies
- ear anomalies
122
Ataxia telangiectasia
AR mutation in ATM -\> DNA repair defect
First presents with progressive cerebellar ataxia ~toddler
Ocululomotor apraxia
Telangiectasia appears age 5-8
Variable immunological phenotype (Ab deficiency +/- impaired T cell immunity)
Progressive lymphopaenia with Ab decency
Malignancy risk (p53) -\> early death
123
HyperIgm
- what is the most common form
- presentation
- ix
- mx
```
CD40L deficiency (expressed on activated CD4+ T lymphocytes)
X-linked
```
```
Pathophys:
- due to defective CD40 ligand on T cells, B cells are unable to class switch from IgM to other iG classes so unable to produce longer lasting immunity
```
Presentation
- presents mostly before age of 1
- Sinopulmonary bacterial infections (humeral immune deficiency)
- Opportunistic infections (T cell immunity) - PCP is a big one, CMV, cryptosporidiosis, sclerosing cholangitis
- Autoimmunity
- Malignancy (HCC)
ix
- reduced IgG, igE, IgA production
- 50% - elevated IgM at presentation
- CD40 ligand flow cytometry
- Memory B cells absent or severely reduce in number
Mx - HSCT
124
Job's syndrome - what gene mutation causes this?
```
'Hyper IgE syndrome'
STAT3 mutation (AD or de novo) affects function of Th17 cells (neutrophil recruitment)
```
DOCK8 = AR form, assoc w molluscum contagiosum infx
Predisponisition to cutaneous fungal and bacterial infx
Presentation
- Delayed loss of primary teeth
- Poor vaccine resonse
- Bacterial infections (staph pneumonia w abscess)
- fungal infx (aspergillus lung infx)
- eczema
125
Chronic severe molluscum infection
- assoc w what immunodeficiency?
Job's syndrome/Hyper IgE syndrome, AR form caused by DOCK 8 mutation
126
Roles of complement pathway
Phagocytosis of microbe
Recruitment and activation of leukocytes -\> Destruction of microbes by leukocytosis
Formation of MAC complex -\> Osmotic lysis of microbe
127
What mediators of C' pathway recruit inflammatory cells
C3a
C5a
128
Complement pathways
- what are the three?
Where do they converge?
What happens after they converge?
* *1. Classic pathway** (IgM or IgG Ab-Ag complexes) - encapsulated pathogens (S pneumo, HIB)
- C1q binds Fc of IgG or IgM to form C1 complex. that cleaves C4-\> C4a/b which cleaves C2 to C2a/b
- C2a binds C4b, forms *C3 convertase* which goes to common pathway
**2. Lectin pathway** (serum lectin binds mannose on pathogens) - fungal, salmonella, listeria
- Ab independent (involves PAMPS and MBL)
**3. Alternative pathway** (amplification) - Neisseria meningititis
- Requires Factor B, D and properdin to form the *C3 convertase* that enters common pathway
**Common pathway**
C3 then cleaved by *C3 convertase* into C3 a and C3b
1. C3a -\> recruits inflammatory cells
2. C3b cleaves C5 to C5a/b
- \> amplification via alternative pathway
- \> triggers production of MAC (c6 to c9)
-\> MAC creates pore in pathogen cell membrane -\> apoptosis/lysis
129
Low C4 +/- Low C3 - within what C' pathway does the problem lie?
Classical
130
Low C3, normal C4 - within what C' pathway does the problem lie?
Alternative pathway problem
131
Classic pathway deficiencies - list 2
Deficiency in components (C1, C2, C4) predisposes to SLE
Deficiency in C1 esterase inhibitor leads to uncontrolled activation of pathway -\> Hereditary angioedema
132
Pathophys of hereditary angioedema
What is the key distinguishing feature from an Ig-E driven angioedmea?
Deficiency in C1 esterase inhibitor leads to uncontrolled activation of pathway -\> Hereditary angioedema
Incr activation of factor XII and production of bradykinins -\> incr vasc permeability and angioedema
133
What do alternative pathway deficiencies lead to?
Component deficiencies (Properdin, factor B, factor D) lead to susceptibility to encapsulated infections (Strep pneumonia, NEISSERIA, HIB, )
Control protein deficiencies lead to uncontrolled activation of alt pathway -\> atypical HUS
134
Presentation and treatment of hereditary angio-oedema
Presentation:
'Attacks' - skin/GI/airway, bradykinin driven by overacrtivation of Classic C' pathway
NO urticarial rash as not mast cell driven. May have a rash called erythema marginatum, but looks different and is NOT itchy.
Mx - must carry action plan
a) Mild/cutaneous: tranexamic acid, Danazol
b) Severe: C1 esterase inhibitor (IV) concentrate, FFP or bradykinin antagonist
135
Ix for C' function
C3, C4
- If C3 low with normal C4, think alternative pathway
- If C4 low with normal C3, think classic pathway
Complement function
- CH50 (if 0, think classic pathway deficiency)
- AP50 (if 0, think alternative pathway deficiency)
- If CH50 and AP50 0 - think MAC complex deficiency
For hereditary angioedema
- C1 esterase inhibitor level
136
Functions of neutrophils
1. Interaction with pathogen
- direct
- indirect (opsonisation of microbes via FcR or C' R)
2. Phagosome formation via fusion of neutrophil granules
3. Product 'NETS' (neutrophil extracellular traps)
137
Chronic granulomatous disease
Genetics
Pathophys
Presentation
Mx
X-linked OR AR forms
Defects in genes that encode the phagocyte NADPH oxide enzyme complex
-\> inability for neutrophils to destroy the pathogens they have phagocytosed
Presentation:
- Bacterial, fungal infx
- Granuloma formation
- Classically present with SUPPURATIVE ADENITIS OR ABSCESSES
- \*Classically Liver abscess-\> CGD until proven otherwise\*)
Problems with catalase positive organisms (Staph, Mould/aspergillus, Nocardia, Burkholderia)
Ix - Respiratory burst studies
Mx
- Bacterial and fungal prophylaxis (bactrim and itraconazole)
- Aggressive mx of infections
- Monitor for disease complications (IBD)
- HSCT is curative (survival to middle ages without this, AR\>X-linked)
138
Leukocyte adhesion deficiency
What is it/inheritance
Clinical features
Mx
AR inheritance
- 3 forms with different mutations in different components involved in leukocyte trafficking
Clinical features
- Absent pus formation and POOR WOUND HEALING
- DELAYED cord separation
- Peripheral leucocytosis with associated neutrophilia
- Recurrent bacterial infection (staph, pseudomonas, gram negative infections)
Mx
- Aggressive tx of infx
- HSCT is curative
139
Innate immune system
- What cells are involved
- What molecules are involved
Involves myeloid progenitor cell offspring
- Neutrophils
- Monocytes
- Macrophages
- Mast cells
- NK cells
Molecules
- Cytokines
- Chemokines
- Complement
- Coagulation proteins
140
What is the role of TLRs?
Recognise conserved microbial molecules
Both inside and outside cells
-\> TLR 1-9
-\> Signal infection presence, not specific
-\> activate inflammatory cytokines (IL1, IL6, TNF alpha)
-\> vasodilation, incr vasc permeability (=heat, swelling, redness) and inflammatory cells migrate into tissues, releasing mediators (pain)
Important role in activating adaptive immune system if innate doesn't get job done.
141
Outcomes of acute innate response activation : SIRS response
Liver: CRP, mannan-binding lectin
Bone marrow: Neut mobilisation -\> phagocytosis
Hypothalamus: Mount fever
Fat, muscle: protein and energy mobilisation
B and T lymphocytes: incr activation
142
How do leukocytes know where to go?
Follow chemokines (small molecules that attract leukocytes, guide migration around body)
Other molecules within tissues further guide migration
Selectins
Integrins
ICAM
143
C1 esterase inhibitor deficiency leads to what condition?
Hereditary angioedema (uncontrolled activation of classical C' pathway)
144
MHCI molecules are present on what cell type?
What do they process?
What cells are they found on?
Found on APCs
Process Viral/intracellular proteins
Bind to CD8+ T cells
145
MHCII molecules are present on what cell type? What do they process?
What cells are they found on?
Found on Ag presenting cells: DCs, B cells, macrophages
Bind to CD4+ T cells
Bacterial/extracellular proteins
146
Signals involved in activation of APCs and T cells essential for adaptive immune response
Signal 1: Dendritic cell is activated via TLR ligands, DAMPS, PRRs
Signal 2: Ag peptides are processed and presented by MHC molecule on APC
Signal 3: CD40, CD80 and CD86 bind their receptor on T cell
Signal 4: T cell subset differentiating cytokines (induced by PAMPs, DAMPs)
147
CD4+ T cells
Role
vs CD8+ T cells
Role
'Helper' T cells (4x2):
1. Recruit phagocytes (macrophages and neutrophils) to eat bacteria
2. Differentiate into Th1, Th2, Th17 adn Treg cells
---\> Th1 ( macrophage activation)
--\> Th2 (IgE, eosinophils, mast cell activation)
--\> Th17 (neutrophil recruitment)
- -\> T reg cells
3. Bind MHCII on APCs
'Cytotoxic' T cells (8x1):
1. Direct killing of targeted cells/microbes using performs, granzymes
2. Bind MHCI on APCs
148
Development of T and B cells
1. Common lymphoid progenitor
2. If it expresses a pre B or T cell receptor then it goes onto further maturation
3. Expresses Ag receptor
4. Proliferation
5. Positive and negative selection depends on strength of Ag receptor (if too strong -\> dies as predisposes to autoimmunity. If no response -\> also dies)
149
Humoral vs cellular immunity
Humoral: B cells and Abs
Cellular: T cells
150
What is the key factor that leads to diversity in lymphocytes
V(D)J recombination of B and T cell receptors
151
Which imune cell and cytokine(s) is involved in formation of germinal centre and class switching)
Follicular helper t cells (Driven by BCL 6 and IL21)
-\> Produces IL21 (important for B cell function -\> formation of germinal centre and class switching)
152
Regulatory T cells
What is their role and what cytokines do they produce?
Down-modulate immune response
Suppress CD4 and CD8 T cells, B cells and NK cells
Produce TGF beta, IL10
153
Mutation in ? can predispose children to early onset IBD and severe autoimmunity
Mutation in IL10 (foxp3) expressed by T reg cells
154
Kostmann syndome
What is it?
Genetics
What does it cause?
Presentation
Tx
='Severe Congenital Neutropaenia'
Causes arrest in myeloid maturation at the promyelocyte stage in the bone marrow -\> neutropenia +/- monocytosis, eosinophilia
Genetics: AD (ELANE mutation, 50-60% cases) and AR (HAX1) forms
Presents w severe neutropenia usually in first mo of life
- No dysmorphic features
- Propensity for infections (skin infx, pneumonia, perirectal accesses, oral ulcers, gingivitis)
Tx - GCSF, HSCT
155
What is PHA skin test response a marker of?
Screening test for cellular mediated (T Cell mediated) immunocompetence
156
Red man syndrome
What is it most often triggered by?
What is the pathophys?
Tx?
Vancomycin
This syndrome is caused by nonspecific histamine release and is most commonly described with administration of intravenous vancomycin.
It can be prevented by slowing the vancomycin infusion rate or by preadministration of H1-blockers
157
Insect bites
What is the tx for the following:
- local reaction
- large local reaction
- anaphylaxis
- local: remove stinger, cold compress
- large local: as above + oral pred + NSAID (pain) + antihistamine (itch)
- -\> 7% risk of anaphylaxis w future stings
- anaphylaxis: adrenaline etc
- -\> venom immunotherapy indicated for anphylaxis and generalised urticaria to bite
158
Gingivitis = problem with what part of immune system?
Neutrophil function
159
Diagnosis (ix) of chronic granulomatous disease
a flow cytometric dihydrorhodamine neutrophil respiratory burst assay is a quick and cost-effective way to evaluate NADPH oxidase function
160
what is role of C3b in c' pathway
opsonisation (coating of Ag with Ab and C')
161
what is role of C5a in c' pathway
Neutrophil chemotaxis
162
what is role of C5b-C9 in c' pathway
cytolysis (cell apoptosis) by MAC
163
Role of IFNs
Viral infections (alpha, beta, gamma)
164
Encapsulated organisms
Psudomonas
Strep pneumoniae
H influenzae B
N meningiditis
E coli
Salmonella
Klebsiella
165
ALL Ig subclasses are low
Very low or absent B cells
Recurrent bacterial infections (sinusitis, OM, pneumonia) after 6mo of age
Small or absent tonsils, adenoids
?diagnosis
?cause
X-linked agammaglobulinaemia
BTK gene mutation - necessary for successful B cell expansion and maturation
tx - IVIG infusions
166
Young adult with recurrent sinopulmonary and GI infections with enlarged tonsils or LN
Normal B cell counts
Low IgA, IgG, IgM
Diagnosis?
Cause?
Associations
Tx
Common variable immunodeficiency
B cells unable to differentiate into Ig producing plasma cells
Prone to resp infections (H influenzae, S pneumoniae, M catarrhalis, S aureus, PCP, M pneumoniae) and GI infections (giardiasis)
Can be associated w lymphoma and GI malignancies as well as autoimmune diseases (pernicious anaemia, haemolytic anaemia, thrombocytopenia, leucopenia)
tx - Ig replacement, cimetidine can help to incr IgG
167
Reduced or absent IgA +/- IgG levels
Increased IgM
Diagnosis?
Sx
Association
Seletive IgA deficiency
Intestinal giardiasis common - chronic diarrhoea
Recurrent respiratory infections
Recurrent urogenital infections
Note may be asymptomatic
Associated autoimmune disease
Transfusion reactions common - develop serum Ab to IgA in the blood and IgE can cause fatal anaphylaxis
168
what condition is associated with a high rate of anaphylaxis to blood products?
Selective IgA deficiency
-\> need 5x washed OR blood products from IgA deficient donors
169
7month ex-prem infant
Recurrent respiratory infections (none severe/life threatening)
Normal B and T cell numbers
Low IgG and IgA levels
Normal vaccine responses
?diagnosis and prognosis
- Transient Hypergammaglobulinaemia of Infancy
- defined in infants over 6 months of age whose IgG (+/- IgM, IgA) is significantly lower (less than 2 standard deviations) than 97% of infants at the same age.
- This most commonly is corrected by 24 months of age but may persist for a few more years.
- However the ability of these infants to make antibodies is frequently near normal and most of the patients are not unusually susceptible to infection.
- Have NORMAL vaccine response
170
What is the most common form of IgG subclass deficiency in children?
And what sort of infections does this predispose the child to?
What other immune deficiency is it associated with
Response to vaccines?
Treatment
IgG2
- \> predisposed to encapsulated bacterial infections (strep pneumoniae, HIB, meningococcus)
- \> often p/w recurrent sinopulm infections (don't make them that sick) +/- meningitis +/- bacteraemia
Normal total levels of IgG but low specific subclass (IG1-4)
Can be associated with IgA deficiency as well
Poor or partial responses to pneumococcal polysaccharide vaccines
Treatment - abx prophylaxis, IVIG for severe infections only
171
Severe infectious mononucleosis (EBV) infection leading to fulminant hepatitis and liver failure in a 5 year old male.
What is the diagnosis?
What else can happen? Acutely and chronically
Duncan disease or X-linked lymphoproliferative syndrome
Abnormal immune response to EBV infection leading to
Acutely
1. Liver necrosis and failure
2. Aplastic crisis
Chronic
3. B cell lymphomas (Burkitt lymphoma)
4. Acquired hypogammaglobulinaemia
Treatment
- IVIG
- Abx
- Stem cell transplant
172
What is the immunodeficiency associated with DiGeorge syndrome?
Infections associated?
Thymic hypoplasia
- \> Decr number and function of T cells (directly correlates with degree of thymic hypoplasia)
- \> Reduced PHA (measures proliferation of T cells)
- \> low absolute lymphocyte count
T cell defect -\> Fungi and PJP
173
Role of PHA
T cell proliferation
174
1 month old presents with FTT, recurrent viral respiratory infections, eczematous rash and chronic diarrhoea
She also has recurrent oral thrush
What is the diagnosis/immune defect?
What is treatment
SCID
- Impaired function of T cells and/or B cells FROM BIRTH (low #s of both)
- -\> even if normal B cell numbers, you don't have T cells to help B cells and enable class switching so don't produce Ig (hypogammaglobulinaemia)
- Will have absent thymus, adenoids, tonsils
- \*red flag is pneumocystis pneumonia\*
Treatment is stem cell transplant, ideally within first 3 months of life
175
Boy with history of refractory eczema cx by recurrent staph infections presents with skin abscess
He has coarse facial features and has retained his primary teeth
what is the diagnosis?
What is the inheritance?
What is the underlying immune defect?
Job /hyper IgE syndrome
Autosomal dominant
Immune defect: Very high levels of IgE (\>1000) and hypereosinophilia
T cell abnormalities and impaired neutrophil locomotion
Tx: penicillin prophylaxis, I&D abscess, gammaglobulin infusions if deficient
176
Boy with thrombocytopenia at birth
Severe eczema
Recurrent sinopulmonary infections/meningitis
What is the diagnosis/underlying immune deficiency
Whatare they predisposed to?
Wiskott-Aldrich syndrome (X-linked recessive)
- \> Progressive T lymphocyte deficiency
- \> Progressive Ab production (normal initially, then IgM is first to reduce)
Progression to encapsulated organisms, HSV, VZV, PCP
Predisposition to lymphoma/leukaemia and autoimmune diseases
177
Progressive ataxia first noticed when child starts to walk
Telangiectasia to sun exposed areas onset from 3 years of age
Recurent sinopulmonary infections
What is the diagnosis/immune defect?
Other associations?
Tx
Ataxia Telangiectasia (AR, ATM mutation)
- \> impaired cell mediated immunity (T cell numbers and function) and impaired Ab production (IgA \> IgE and IgG)
- \> due to abnormal DNA repair
Assocations
- Lymphomas and adenocarcinomas
- Hypogonadism/incomplete sexual development
- Premature ageing
- Glucose intolerance/diabetes
Treatment
- Avoid exposure to radiation when possible (MRI for pulm monitoring; X-rays only in acute setting)
- Abx prophylaxis
- Vaccination if can generate Ab response
- IV gammaglobulin if hypogammaglobulinemia or impaired specific antibody production, or who do not tolerate or fail therapy with antibiotics
178
Recurrent respiratory infections with small tonsils and profound NEUTROPAENIA
Immunological ix reveal
- Low/absent IgG, IgA, IgE
- Normal/high IgM
- Normal T and B cells
What is the diagnosis and underlying immune deficiency?
X-linked hyper IgM
Immune defect - Impaired Ab formation due to absent CD40 ligand on T cells (B cells require this for isotope switching)
179
Infant with liver abscess and hepatomegaly presents
Staph aureus is cultured from the aspirate fluid
What is the diagnosis?
What is the immune defect?
What investigations do you order to make the diagnosis?
Treatment?
Chronic granulomatous disease
Caused by defective/absent NADPH oxidase enzyme which is involved in killing bacteria and fungi -\> results in chronic inflammation and granuloma formation
Ix: flow cytometric dihydrorhodamine (DHR) neutrophil respiratory burst assay as the gold standard
- or Nitroblue tetrazolium test
- Biopsy shows granuloma
- Hypogammaglobulinaemia
Tx: gamma- IFN, Abx (prophylaxis and acute tx), neutrophil transfusions.
CURE with HSCT
180
Recurrent staph skin infections + abscess
ALBINISM (skin and eyes)
Easy bleeding and bruising from plt malfunction
Diagnosis? Immune defect?
Tx?
Chediak-Higashi syndrome
Immune defect: neutropenia and defective neutrophil degranulation, defective granulocyte mobility and chemotaxis
Diagnosis: blood smear showing giant inclusions within leukocytes and/or by the identification of biallelic pathogenic variants in LYST on molecular genetic testing.
Tx: high dose ascorbic acid, abx, HSCT is curative
181
Short stature, steatthorea (pancreatic exocrine failure), cyclical neutropenia +/- anaemia and thrombocytopenia
diagnosis?
Tx?
Schwachman-Diamond syndrome
Tx - Pancreatic enzyme supplementation, GMCSF
182
Leukocytosis
Delayed cord separation
Recurrent gram positive and negative infections
Chronic ulcers
Diagnosis?
Ix?
Tx?
Diagnosis is LAD
-\> abnormal leucocyte adhesion
Have peripheral neutrophilia (\>12000) /leucocytosis
Ix - flow cytometry and neutrophil chemotaxis studies
Tx - BMT, abx prophylaxis
183
Neisseria infection
- what is the underlying immune deficiency
Complement lytic pathway (C5-9)
184
A child with recurrent infections, short stature and an erythematous photosensitive facial rash.
What is this condition and what population is it most common in?
What risk does it carry for future?
```
Bloom syndrome (mutation in BLM gene -\> defective DNA repair)
- photosensitive rash +/- cafe au lait spots and immunodeficiency and dysmorphic ft (incl polydactyly)
```
Common in Ashkenazi Jewish population
Risk of malignancy (leukaemias, lymphomas, GIT tumours) and insulin-resistant diabetes
185
A child with recurrent infections, short stature, presents with peri-orbital oedema, proteinuria and has low albumin
what is this condition?
Schimke immuneouseous dysplasia
- \> AR disorder
- \> presents with: short stature, spondyloepiphyseal dysplasia, immunodeficiency and progressive renal failure. Children may also have skin and eye abnormalities.
- \> develop nephrotic syndrome secondary to FSGS and will progress to ESRF
- \> prone to strokes (cerebral ischaemia +/- assoc Moyamoya) -\> common cause of death
186
When should women planning on getting pregnant get vaccinated w rubella and why?
- pregnancy is contraindication to rubella vaccine administration
- rubella vaccine virus may cross the placenta and infect fetus (1% chance)
- however, there have been NO cases of congenital rubella syndrome reported in women inadvertently vaccinated in early pregnancy
- given the theoretical risk, women are advised to avoid pregnancy for 28 days following vaccination
187
13mo child with recurrent sinopulmonary infections and an episode of HSV 1
Normal lymphocyte count but NEUTROPENIC during infection
Low IgG and IgA and normal IgM levels
Normal T and B cell levels and normal T cell proliferation response
No evidence of vaccine response however despite being fully vaccinated
What is the diagnosis?
What is the underlying pathophys?
Hyper-IgM
70% Cases X-lined (mutation in XHIM resulting in abnormal T helper cell CD40 ligand)
- \> normally, in the presence of cytokines, CD40 interacts with B cells and signals them to switch from producing IgM to producing IgA, IgG, or IgE).
- \> In X-linked hyper-IgM syndrome, T cells lack functional CD40 ligand and cannot signal B cells to switch.
- \> Thus, B cells produce only IgM; IgM levels may be normal or elevated.
- \> Patients with this form may have SEVERE NEUTROPENIA and often present during infancy with Pneumocystis jirovecii pneumonia (or other opportunistic infections).
- \> Otherwise, clinical presentation is similar to that of X-linked agammaglobulinemia and includes recurrent pyogenic bacterial sinopulmonary infections during the first 2 yrs of life.
188
The Apidae family (honey bees) and the Vespidae family (yellow jackets, yellow hornets, white-faced hornets, and paper wasps) belong to the order Hymenoptera and account for most of the stings that lead to anaphylactic reactions. The stings are usually painful.
1. What is the risk of recurrence following anaphylaxis to bee/wasp stings?
2. What reduces risk of recurrence and by how much?
3. Does family history impact risk of anaphylaxis?
4. What is the role of venom-specific IgE screening?
Children who have had a previous anaphylactic reaction have a 30% risk of recurrence.
-\> People with LOCAL reactions have a low risk of a future anaphylactic reaction.
Venom Immunothreapy is safe and highly effective – reducing to risk to 5%.
A family history does not put a child at increased risk – the risk of anaphylaxis is \<1%.
Venom specific IgE is not indicated because it is common to have a positive test but not to exhibit symptoms when exposed.
189
What is the most common immunodeficiency and what is the prevalence?
IgA deficiency
1:500; most are asymptomatic.
Symptoms can be seen at any age; typically sinopulmonary infections; increased risk of allergy, autoimmune disease, and anaphylaxis from blood products.
190
A child with eczema, recurrent infections and recombinase activating gene 1 (RAG1) defect.
?diagnosis?
Omenn syndrome is a variant of SCID (severe combined immunodeficiency).
Children present with recurrent infections, exudative erythroderma, lymphadenopathy, hepatosplenomegaly, chronic persistent diarrhoea, and failure to thrive.
191
A child with eczema, recurrent infections, raised serum immunoglobulin E (IgE) , allergies and trichorrhexis invaginat.
diagnosis? Mutation?
Netherton syndrome
Trichorrhexis invaginata of hair is also known as "bamboo hair" and is pathognomonic of Netherton syndrome.
Caused by SPINK5 mutation causing corneal
192
Which vaccines are live vaccines?
Varicella and MMR vaccines are live vaccines.
The later oral polio vaccine (Sabin) was a live-attenuated vaccine.
-\> The injectable polio vaccine (Salk) is the original inactivated (dead) poliovirus vaccine.
193
A four-year-old boy presents with a long history of recurrent febrile episodes associated with mouth ulcers, diarrhoea, fatigue and bleeding gums.
Diagnosis?
Ix for diagnosis
Cyclical neutropenia
- \> A rare autosomal dominant disorder in which neutrophil counts oscillate between 0.1 and 1.5 every 21 days.
- \> Neutropenic periods last 3-6 days accompanied by malaise, anorexia, fever, lymphadenopathy and mucosal ulceration (stomatitis, gingivitis, periodontitis).
Ix: Neutrophil counts twice weekly for a minimum of 6 weeks.
194
Most common food allergies
Which persist vs which do children grow out of?
1. Egg
2. Cow's milk
3. Peanuts
4. Tree nuts (e.g.cashews)
5. Then wheat, soy, fish, shellfish and sesame
**Nuts/seafood** – tends to persist; review every 5 years
--\> around 20 per cent of children outgrow their _peanut allergy_ by the time they are teenagers,
--\> 10 per cent will outgrow a _tree nut_ allergy
**Egg, wheat, milk** – vast majority outgrow their allergies; review 12-18 months
