Immunology Flashcards
Innate
‘Acute phase response’
induction: by monokines: TNF, IL1, IL6
function: acts on liver to release specific proteins
- fight infection eg. MBL, CRP
- prevent tissue destruction eg. a1-anti-trypsin
- promote tissue healing eg. fibrinogen
IL1 (macrophage/monocytes/DC): increase adhesion molecules, fever, haematopoiesis, IL6
IL6: acute phase proteins, osteoclasts, lymphocytes, fever, haematopoiesis
TNF (transmembranes): activates endothelium, increases vascular permeability, fever
Affinity maturation
- each cycle of B cell division in germinal centre causes selection of cells with highest Ag affinity
Alternative pathway
activation: directly by pathogen surgace with endotoxins on wall of gram negative bacteria
mechanism:
- C3 directly activated
Anaphylaxis
incidence: common, average age 2.4yrs
onset: 30 mins post exposure
- may be biphasic with reoccurence 1-8hrs after resolution
cause: 90% due to food
associations: 60% also have atopy
triggers: IgE sensitivity to food/bee stings/drugs/latex
- anaphylactoid: no necessarily IgE (direct mast cell degranulation assoc contract, opiates, aspirin, captopril)
clinical: skin, gut, airway, CVS
- anaphylaxis requires at least 1 of resp or CVS
diagnosis: serum tryptase <10ng/ml peak 1-2hrs
treatment: IM adrenaline 0.1ml of 1/10,000
Antibody function
1. Neutralisation
2. Complement activation: activates complement to bind to cell and cause apoptosis
3. Agglutination
4. Precipitation: complex too big, precipitates and eosinophil can phagocytose
APCs
APCs: macrophages, monocytes, dendritic cells, Langerhan’s cells, Kupffer cells (liver), B lymphocyte
receptors: all contain MHC class I and II
role: present Ag to T cells
Types:
Dendritic cells: from CD34 precursor, live in thymus, lymph, spleen, mucosa
Monocytes/Macrophages: express Fc gamma receptor, present Ag then release IL1 to activate T cells, cause phagocytosis, kill via oxidation/cytotoxins, live in circulation, tissues
B cells: Ag via Ig on surface, aid in endocytosis and Ag degradation, signal to T cells
Apoptosis
signals: Fas ligand and TNFR1
deficiency: ALPS (autoimmune lymphoproliferative syndrome)
- splenomegally, lymphadenopathy, AI cytopaenias
Asplenia protocol
Immunisations
Pneumococcal
- 13V at 2/4/6m, additional 23V at 5/10yrs
- if new diagnosis: given 2 doses 23V 5 years apart
Meningococcal
- 6wks-6mths: x2 doses MenC
- >12months: x2 doses 4 valent meningococcal 8 wks apart
- then ongoing 5 yrly 4V Men vaccines
Influenza: annually
AB prophylaxis: amoxycillin until 5 yrs or >1yr post splenectomy
Ataxia telangiectasia
genetic: AR, ATM gene defect Ch11q22-23
epidemiology: 2% carriers
diagnosis: mixed immune deficiency, low CD3/CD4/normal CD8, decreased response to mitogens, low IgA/IgG/IgE
clinical:
- onset <2yrs: ataxia, progressive loss of ambulation, extrapyramidal features, oculomotor apraxia, strabismus, nystagmus
- onset >5yrs: telangiectasia to nose, ears extremities
- sinopulmonary infections, pulmonary fibrosis, dysphagia
associations: lymphoma, leukaemia, brain tumours
diagnosis: high alphaFP/CEA, Ig, lymphocytes
management: symptomatic
prognosis: death by 25yrs
Atopic dermatitis
Eczema
mechanism: Th2 cell driven allergic inflammation causing hyperelastic epidermis, hyperkeratosis and water loss
incidence: 10-30% children, 50% by 1yr and 85% by 5yrs
- 40% resolve by adulthood
pathogenesis:
1) impaired epidermal barrier function
- disruption allows allergens to penetrate barrier and trigger immune cells
- hydration key to maintaining barrier
2) immune function disorder with inflammatory response to environment
- APC exhibit IgE molecules present to Th2
- marked perivenular T cell infiltrate and mast cell activation
- eosinophils secrete cytokines
chronic: lichenified AD is characterised by hyperplastic epidermis with hyperkeratosis and minimal spongiosis
- dysfunction of skin barrier causes water loss and dry skin
clinical: pruritus, excoriation, erythematous papules, scaling pupules, lichenifications, fibrotic papules
discoid eczema: unknown cause, not assoc atopy, low threshold for immunosuppresants, hypertrichosis post resolution
treatment: avoid triggers, skin moist, treat infection (mupirocin, bleach baths, empirical AB), topicol corticosteroids, systemic CS, topical immunosuppresants, systemic IS
Atopy
Ag presentation: Th2 activated
Early response
Th2 cytokines
- IL4: acts on R cells to produce Th2 and B cells to produce IgE switching
- IL5: attracts eosinophils
- IL13: promotes B Cell IgE switching
IgE production
- activates eosinophils/mast cells: release preformed mediators ie. histamine and leukotriene
Late response (steroid responsive)
- chemokines trigger production of further cytokines and inflammatory mediators
Autoimmune Polyendocrine Syndrome 1
(APS1)
defect: autosomal recessive defect in AIRE gene
pathophysiology: failure to delete autoreactive T-cells
clinical (triad):
- chronic mucocutaneous candiasis: Ab to Th17
- AI hypoparathyroidism
- AI Addison’s disease
X-linked Lymphoproliferative Disorder
incidence: 1:3,000,000 males
genetics: XLR trait, Xq25 defect in SLAP associated protein (SAP)
mechanism:
- SAP acts on T/NK/B cells causing defect in cellular and humoral immunity
increased cytogenic response to EBV:
- SAP controls apoptosis: uncontrolled T cell proliferation
- decreased T/NK cell ability to lyse EBV infected B cells
clinical:
- fulminant EBV infection, lymphomas (30%), acquired hypogammaglobulinaemia (30%)
diagnosis:
- low IgG, high IgM/IgA
- anaemia, thrombocytopaenia, abnormal LFTs
tx: manage EBV, MBT
prognosis: 70% die by 10 yrs, 100% by 40 yrs
B cell activation
BONE MARROW
- immature B cells: Pro-B, Pre-B and Immature B sent into blood
LYMPHOID TISSUE
germinal centre: naive B cell IgM/IgG (CD27-) in germinal centre and binds T cells to activate
- forms short lived plasmoblast (IgM) and GC B cell
cortex: plasmablast and Memory B cell (CD27+) forms
BLOOD
- long lived plasma cells sent into blood
B cell tests
Ab response to polysaccharide antigens
eg. Pneumococcal (T cell indep)
- best in infants >2yrs
- response measured by IgG levels
eg. Tetanus Ab
T cell dependent B cell activation
recognition: B cell MCH II binds Ag in Th cell TCR
costimulation: B cell CD40 binds T cell CD40L
effect: B cell isotype switching, affinity maturation, memory, polyclonal activation
Baked Egg and Milk
*>75% children tolerate these foods when baked
Basophils
cell type: granulocyte
structure: contain large cytoplasmic granules
- receptor on surface that binds Fc portion of IgE
role: phagocytosis and release histamine and heparin in allergy
C1 esterase inhibitor deficiency
(hereditary angioneurotic oedema)
pathophysiology:
- C1 esterase deficiency causing unchecked activation C2/C4
- increased kinin from C2
- post-cap venule constriction and oedema
inheritance: AD
clinical: onset young
- recurrent facial and limb swelling does not respond to steroid
- precipitated stress, exercise, menses, trauma
- associated recurrent abdominal pain
NO urticaria
diagnosis: C4/C2 low
treatment: danazol (attenuated androgen)
Cells of the innate
Macrophages (1st to engage pathogen):
- ingest pathogen non-specifically via surface receptor
- degrade with phagolysozyme/oxidative burst
- attract neutrophils to site
Neutrophils:
- die quickly to form pus
NK cells (large granular lymphocytes):
- develop in response IL 15
- express receptor for IgG and bind viral Ag
- kill virally infected cells w/o MHC expressed
- release IFN-g to trigger adaptive immunity
Chediak-Higashi
genetic: AR
pathophysiology: microtubule defect with abnormal neutrophil chemotaxis and degradation
clinical: partial albinism, recurrent infections, defective platelets, neutropathy, behavioural issues
diagnosis: large inclusion in all nucleated blood cells accentuated on peroxidase stain
managment: BMT, high dose ascorbic acid
Chronic granulomatous disease
incidence: 4/5,000,000, 1 is X linked (gp91), 3 are AR
pathophysiology:
- deficiency of subunits NADPH oxidate
- no H2O2 preventing production of free radicals/killing phagocytosed pathogens (esp Catalase +ve)
clinical (<5 years):
- pneumonia, lymphadenitis, hepatitis, abscess, OM
- catalase +ve infections (S.aureus, Serratia, Burkolderia, Aspergillus, Nocardia, Salmonella, fungi)
- sequelae: anaemia, FTT, HSM, dermatitis, CLD
treatment: BMT, AB prophylaxis, CS with granulomas, IFNg
diagnosis: granulomas (accumulated ingested material)
Chronic Mucocutaneous Candidiasis
age: childhood
genetics: STAT-1 gain of function causing Th1 development above Th17
defect: lack Th17 cells
clinical: candidiasis nails, skin, mucosa, oesophagus, lungs
Classic pathway
activation: Ab-Ag complex
mechanism:
- C1 (C1q,C1r,Cs) binds Ab-Ag complex
- C1q interacts Ab and causes ‘b’ binding to Ab and release of ‘a’
- C1 activates C4 to C4b
- C4b activates C2 to C2b
- C4b/C2b (C3 convertase) activate C3 to C3b
- C4b/C2b/C3b (C5 convertase) activates C5 to C5b
active components:
C3b: enhances phagocytosis by macrophages/neutrophils
- phagocytes have IgG and C3b receptors
- increases indirect opsonisation
C5b binds with C6/C7 to form C8/C9 (membrane attack complex)
- produces hole in bacterial wall causing cell lysis
- more effect on gram negative organisms due to thin cell wall
Complement cascade
3 pathways:
- classic: C1q activated by IgM/IgG/lipoteichoic acid/phosphocholine on organisms
- alternative: C3b binds foreign surface
- lectin: C4/C2 cleaved with activation by MBL and ficolins 1-3
function:
- cytolysis
- opsonisation
- inflammation
- immunse complex clearing
mechanism: cascade of proteins in plasma with sequential activation and release of complement fragments
products:
anaphylactoids: C3a/C5a
MAC complex: C5/6/7/8/9
Complement deficiencies
- many associated AI conditions
C3 deficiency
- no C5a, inefficient opsonisation, recurrent infection puogenic organisms (meningococcus, pneumococcus, minigitidis)
Deficiencies of control proteins
Factor I (regulates both pathways)
Factor H (assists dismantling alt p/w C3 convertase)
Properdin deficiency
- predisposed N.meningitidis meningitis
Membrane complement control proteins
CD59: prevents MAC development
CR1/CD46/DAF: prevents C3bBb
CVID
epidemiology: 1/10,000, 10% familial, assoc IgA def
age: 2 peaks 1-5yrs, 18-25yrs
mechanism: B cells can’t differentiate into plasma cells and secrete Ig
clinical: (late onset)
- enlarged LN, splenomegally (25%)
- recurrent infections: encapsulated, sinopulmonary, bronchiectasis
- AI disease: cytopaenias, alopecia, gastric atrophy, arthritis, dermatomyositis, vascultis, lupus
- other: malabsorption, benign lymphoproliferative disease, non-caseating granuloma
diagnosis: low IgG, normal IgM/IgA, normal T/B cells, impaired vaccination response
management: IVIg, antibiotics, chest physio, avoid steroids
Cyclic neutropaenia
definition: falling neutrophils in 4 week cycles
clinical: gingivostomatitis
diagnosis: twice weekly FBC for 2 months
treatment: supportive, GCSF
DiGeorge Syndrome
mechanism: thymic aplasia due to 3rd/4th pharyngeal pouch development defects
- low CD3 T cells, increased proportion B cells
- no lymphocyte response to mitogens
clinical:
- variable depending on complete/partial aplasia
- in complete resembles SCID
diagnosis: PHA no response
tx: BMT, thymic tissue transplant
Eosinophils
type: granulocyte
stimulating factor: IL5
function: extracellular mediations
- kill big organisms too large to be phagocytosed
- degranulate and release enzymes in allergy
Food allergy
class I (90% child allergies): egg, milk, peanuts, tree nuts, fish, soy
class II: kiwi, apples, carrots, peaches (analogues pollen)
- all milk allergies develop by 12 months
- all egg allergies develop by 18 months
- median age for peanuts is 14 months
resolution:
- most outgrow milk/egg allergies (50% by 5 yrs)
- peanut, nut, seafood don’t resolve (90% for life)
Genetic risk of atopy
no parents= 20%
1 parents= 60%
2 parents= 80%
Genetics of atopy
inheritance: genetic/HLA association
risk: 60% twin concordance eczema/asthma
- no allergic parents: 20% risk
- 1 allergic parents 50% risk
- 2 allergic parents 66% risk
3 genes: atopy (IgE/eosinophils), barrier, innate (pattern recognition)
Granulocytes
Neutrophils/eosinophils/basophils
- bone marrow
- 70% of WBC in the circulation
- live 2-3 days only
Haemophagocytic Lymphohistiocytosis
HLH
age: birth to 18 months, M>F
pathogenesis: syndrome of excessive inflammaiton and tissue destruction due to lack of normal inhibition of activated macrophages/lymphocytes
- often defect in NK cells causing cell lysis
trigger: infection or altered immune state
clinical: fever
- hepatomegally 95%
- lymphadenopathy 33%
- neurological sx 33%
- rash 31%
diagnosis: cytopaenia, elevated ferritin/LFTs, hypertriglyceridaemia, abnormal coags
treatment: steriods, IVIG, chemotherapy, HSCT
prognosis: fatal if untreated
Hereditary angioedema
genetic: AD haptoinsufficiency causing deficiency C1 esterase inhibitor
- type 1: decreased C1 (30% normal conc)
- type 2: normal levels dysfunctional protein
pathogenesis: uncontrolled activation of C1 which activates C4/C2 producing kinin
- C3 normal
diagnosis: reduced C4
clinical: variable frequency of attacks
- recurrent oedema W/O urticaria
- recurrent abdominal pain due to GI wall oedema
precipitants: illness, stress, drugs, trauma, surgery
tx: adrenaline DOESNT WORK
- replace purified C1
- bradykinin 2 receptor antagonist or kallikrein inhib
HLA markers and disease
Hyper IgE syndrome
genetics: sporadic/AD
mechanism: defect in STAT3 (TF) causing lack of Th17 then IL17 causing susceptibility to fungal infections
clinical triad:
1) recurrent staph/candida infections: skin, joint, abscess
2) high IgE >10,000
3) eosinophilia
- course facies (broad nose/prominent upper lip), osteopaenia, hyperextensible, scoliosis, chronic eczema
associations: lymphoma
diagnosis: normal/elevated IgG/A/M, fewer memory T cells
treatment: antibiotics
Hyper IgM syndrome
incidence: 1:500,000 males
genetics
type 1 (X linked): CD40L deficiency
- onset 6 months
- symptoms: sinopulmonary infections (encapsulated), opportunistic infection, neutropenia, lymphadenopathy, HSM
investigations:
- normal B cells
- increased IgM, decreased IgA/IgG/IgE/memory cells
- flow cytometry CD40L
complications: malignancies (HCC, cholangiocarcinoma)
tx: BMT, IVIg monthly
Hypersensitivity reaction
-pseudoallergic-
pathophysiology: poorly understood non IgE reactions
causes:
- vancomycin
- contrast media
- aspirin
- dextran
Immune Cells
(IPEX)
Immune dysfunction
Polyendocrinopathy
Enteropathy
X linked
defect: Foxp3 gene
pathophysiology: defect in T cell regulation causing autoimmune and autoinflammation
clinical:
- fatal 1st few months
- AI endocrinopathy, enteropathy, haem anaemia, ITP, neutropaenia
- atopy: eczema, food allergy, eosinophilia
- LN, SM
Immune tolerance
definition: inhibit self-reactive T cells
central: thymus
- AIRE (autoimmune regulatory gene): regulates negative selection
- dysfunction: APS
peripheral:
- regulatory T cells (CD4/CD25/FOXP3): downregulates overactivation immune system via cell-cell contact
- suppresses CD4/CD8 T cells, B cells and NK cells
- dysfunction: IPEX syndrome (single X-linked defect)
Immunoassays RAST
Radioallergosorbent test
technique: fluorescent enzyme immunoassay
pros/cons: less sensitive, more specific, more expensive
benefits: unaffected medications, people with anaphylaxis, dermatological conditions
Immunodeficiencies adolescents
XLA: dematomyositis, chronic echovirus encephalitis
Ataxia telangiectasia: sinopulmonary infections, neuro deterioration, telangiectasia
Chediak Higashi: oculocutaneous albinism, recurrent infection, TCP
C6/7/8 deficiency: recurrent neisserial meningitis
CVID: sinopulmonary infections, malabsorption, splenomegally, AI
IgA deficiency: reaction to blood produces, assoc coeliac/UC/Crohn’s
Myeloperoxidase deficiency: thrush
Immunodeficiencies infants/children
>6 months
XL lymphoproliferative: severe progression EBV
XLA: paralysis post polio vaccine, no LN
Hyper IgE: cutaneous/systemic staph infections, course facies
Chronic mucocutaneous candidiasis: thrush, nail dystrophy, endocrinopathies
Cartilage hair hypoplasia: short stature, fine hair, severe varicella
Immunodeficiencies Newborns
<6months
DiGeorge: hypocalcaemia, CVD, unusual facies
Leukocyte adhesion deficiency: delayed cord separation, leukocytosis, recurrent infections
SCID: diarrhoea, thrush, pneumonia, FTT
Wiskott Aldrich: purpura, malaena, OM, eczema
X linked hyper IgM: mouth ulcers, neutropaenia, infections
Immunodeficiencies Pathogens
B cell deficiency (no antibodies)
- pyogenic infections
T cell deficiency (no 2nd signal for B cells)
- opportunistic infections
Neutrophils (defect in respiratory burst)
- gingivitis/ulcers
NK deficiency (no cell-cell killing)
Immunodeficiency
Ab deficient: recurrent sinopulmonary/GI infections with polysaccharide encapsulated pyogenic organisms
T cell deficient: infection with intracellular organisms (fungi, viruses, listeria)
Neutrophils/monocyte deficient: high-grade bacterial infections (staph, gram -ve), invasive fungi/candidiasis
Complement C5-9: disseminated neisseria
Immunoglobulin structure
Immunoglobulins
chains: 2 heavy (5 types) and 2 light chains (2 types)
heavy chain isotypes: IgM, IgD, IgG, IgA, IgE
regions: constant + variable regions linked disulfide bond
- variable region contains hypervariability region
binding fragments: 2 Fab portions and 1 Fc portion
Immunoglobulins in Breast Milk
- high concentrations IgA (10% protein)
- tiny amount IgM/IgG declines day 5
- lymphocytes, macrophages, proteins with non-specific bactericidal activity, viral growth inihibitors, complement present
outcome: decreased diarrhoea, OM, pneumonia, bacteraemia, meningitis in first year of BF babies
Infant Immune System
Anti-polysaccharide response
- <2yrs unable to form T indep immune response
- young children prone to encapsulated organisms
- improves with age
Infections in eczema
staph aureus (76-100% patients)
- clinical: honey coloured, crusting, folliculitis, pyoderma
- treat: culture, remove crust, topical mupirocin, oral AB, bleach baths
viral infections
- herpes simplex: eczema herpeticum
- clinical: pain, pruritis, punch out erosions, haemorrhagic crus/veiscles, widespread lesions
fungal infections
- treat: standard topical or oral
Receptors of innate immunity
receptors:
- TLR (toll like receptor): intracellular messaging via NK-kB
- CLR (C-type leptin): recognise CHO on microorganisms
- NLR (nod like receptor): detect intracellular changes
- RIG1: intracellular receptor
substrate: PAMPs (peptidoglycans, bacterial DNA, LPS), DAMPs
location: on APC
function: acute phase response (IL1/IL6/TNF)
Allergic rhinitis
onset: peaks in late childhood
clinical: cyclic exacerbations
- itching, sneezing, rhinorrhoea, conjunctival inflammation, nasal congestion, allergic shiners
associations: sinusitis, OM, eczema, asthma
diagnosis: skin prick, RAST, eosinophils
Interferons
production: released from many cell types in response to viral infection
types: IFN-a (most), IFN-b
effect:
- induce resistance to viral replication in all cells
- increase MHC-1 expression APC
- activate DC/macrophages/NK cells
Interleukins
IVIg
2 purposes:
1) Protection against infection
2) Suppression of inflammatory/immune process
product: mainly IgG (small amounts IgA/IgM) from 20,000-50,000 blood donors
mechanism: mostly anti-inflammatory response, but not understood
indications: Bcell immune deficiencies (XLA,CVID, HyperIgM), SCID, DiGeorge, Wiskcott-Aldrich
dose: 400mg/kg every 4 weeks
infusion rate related: chills, headache, fatigue, malaise, nausea, vomiting, arthralgia, myalgia
less common: abdo/chest pain, tachycardia, dyspnoea, BP change
rare: anaphylaxis, septic meningitis, renal/pulm insufficiency, DIC
screening for kids on IVIg: LFTs, Hep C
Kawasaki’s disease
incidence:
pathogenesis:
- unknown etiology: ?post infective
- medium blood vessel vasculitis
criteria (4 of 5 of):
- polymorphous rash
- bilateral non purulent conjunctival injection
- mucous membrane changes eg. dry lips, strawberry tongue
- peripheral changes eg. erythema palms/soles, oedema hands/feed
- cervical lymphadenopathy >1.5cm
- arthritis/arthralgia, liver dysfunction, jaundice, sterile pyuria
complications
- cardiac complications in up to 25% untreated
- mild coronoary artery aneurysms on day 10 post fever (more likely
- 25% of these will progress to true aneurysms, 1% giant aneurysms (>8mm)
- also myocarditions, ventricular dys, valvular regug, pericardial effusion
investigations
- ASOT/Anti DNAase B, ECHO, platelet count
treatment
- IVIg 2g/kg over 10 hours within first 10 days
- aspirin 3-5mg/kg daily for 6-8 weeks
prognosis:
- 1% with CAA
Leukocyte adhesion deficiency
genetic: AR, 1/10,000,000
LAD1: mutation 21q22.3 encoding CD18 integrin subunit
- delayed cord separation 3-45days
- increased WCC, infections but no pus, tooth eruptions (gingivitis/periodontitis), delayed wound healing, infections staph/gram -
_LAD2 (_milder): CD11/CD18 intact but defective golgi apparatus and absent selectin ligand
- neurologic defects, cranial facial dysmorphism, absent RBC ABO BG Ag
LAD 3: defect integrin adhesion/migration
- bleeding disorder, delayed cord separation, soft tissue infection
diagnosis: WCC>20, flow cytometry for CD subtypes, blood group (Bombay)
management: early BMT
prognosis: death by 5 years 75%
Lymph nodes
function
- Cleanse lymph
- Alert immune system to pathogens
structure: capsule, inner parenchyma, subcapsular sinuses
- cortex: lymphoid nodules acquire germinal centre where B cells multiply and become plasma cells
- medulla: medullary cords composed of lymphocytes, plasma cells, macrophages, reticular cells, reticular fibres
cell location:
- B cells in middle with dendritic cells
- T cells on edge in the mantle/paracortical zone
Lymphocyte adhesion and trafficking
selectins: rolling and tethering vessel wall
integrins: moving from BV to tissue, stop the neutrophil to squeeze through endothelium
chemokines: presented on vascular endothelium
Lymphocytes
prevalence: 25% WBC in peripheral blood
source: derived from CD34
stimulation of T/B/NK cells: IL2
stimulation T/NK cells: IL7, IL15
Lymphocytic Interstitial Pneumonia
pathophysiology: infiltrate of mature/immature lymphocytes, plasma cells and histiocytes in pulmonary tissue
associated: HIV (17% perinatally acquired HIV) immune deficiencies, autoimmune disease
clinical:
- insidious onset cough, tachypnoea, finger clubbing but normal auscultation
- LN, HSM and salivary gland enlargement
diagnosis: hypergammaglobulinaemia, lung biopsy
Mast cells
role: release granules and hormonal mediators
- mediate allergic and antiparasitic responses
- NOT phagocytic
stimulation:
- direct injury: physical/chemical
- IgE: surface receptor
- Activated complement: common p/w
hormones:
tryptase, proteases, histamine, serotonin, heparin, chondroitin, thromboxane, PG D2, leukotriene, PAF, IL, TNF-a
MB Lectin Pathway
activation: MBL on surface of bacteria
mechanism:
- binds to mannin, activates proteolytic enzymes, converts C4 to C4b, C4b binds C2b and forms C3 convertase
MHC II
subtypes: HLA-DQ, HLA-DR, HLA-DP
- loci highly variant and allow variation
location: ONLY on antigen presenting cells
role: present foreign antigens and activate CD4 Tcells
deficiency: type 2 bare lymph syndrome, type of SCID
MHC I
subtypes: HLA-A, HLA-B, HLA-C
location: present on all nucleated cells except RBCs and some neuronal cells
role: activate CD8 T cells
deficiency: type 1 bare lymphocyte syndrome
Myeloperoxidase deficiency
genetic: AR, MPO gene missense mutation, 1/2000
pathogenesis: decreased production hypochlorous acid causing decreased early killing or gram +ve/-ve bacteria
- neutrophils/monocytes use MPO independent mechanism to kill pathogens
clinical: normal asymptomatic
- rarely disseminated candidiasis
Natural history of allergy
onset: most apparent <1yr age
peak: prevalence 8% at 1 year
- 0.5-1.4% children: nut allergy
- 1-2% egg allergy
- 2.5% milk allergy
- 0.4-1% wheat allergy (outgrow by adolescence)
resolution: decreases to 4% by adulthood
- most allergies outgrown except seafood/nuts
predictor resolution: fall in IgE
Complement tests
Classic activity (normal at 3 months): CH100
Alternative activity (normal at 1 year): AH100
CH50 test: how much serum to lyse 50% RBC
- measures entire complement p/w
- different stimuli to test alternate pathways
Neonatal Ig
- Ig transferred across placenta from 6 months
- at term levels higher than in mother
- levels drop rapidly after birth
- infants<1500g hypogammaglobulinaemic first week
Neutrophils
Granulocyte
stimulating factor: G-CSF
Kill bacteria via 2 mechanisms:
1) Phagocytosis/Digestion
2) Respiratory burst: lysosomes degranulate into tissue causing tissues to make hydrogen peroxide.
receptor: pattern recognition receptors (PRR) recognise pathogen assoc molecular patterns (PAMP)/danger assoc molecular patterns (DAMP)
test (nitroblue tetrazolium (NBT))
- activated neutrophils can reduce NBT producing dark blue crystals
NK cells
Innate immunity
direct cell-cell killing of intracellular pathogens: microbes/cancer
mechanism:
- IgG coated microbes: via CD16 receptor
- Killer inhibitory cells: no MHC1 on tumour/infected cells
- Killer activating receptor
Non IgE food allergy
intermediate/delayed onset and assoc FTT
FPIES (food protein induced enterocolitis)
- cows milk, chicken, rice, egg when introduced
- T cell mediated with onset 2 hours post exposure
- vomiting/diarrhoea/hypotension
Dietary protein enteropathy
- cows milk most common
- vomiting, diarrhoea, abdo distension, oedema, FTT
- spectrum of disease
Dietary protein proctitis
- cows milk/soy milk
- cell mediated
- isolated blood stool resolve <72hrs elimination
Food induced haemosiderosis (Heiner’s syndrome) RARE
- recurrent pneumonia with pulm infiltrates (haemosiderosis)
- cows milk, egg with FTT
Allergic eosinophilic esophagitis (mixed IgE/non IgE)
- cell mediated
- chronic GORD, emesis, food refusal, abdo pain, dysphagia, irritability, weight loss, FTT, oedema, protein losing enteropathy
- 50% patients atopic
Omenn syndrome
genetics: loss of RAG gene function
pathophysiology: oligocloncal proliferation of autoreactive T sells
clinical: similar to GVHD
- erythroderma, hepatosplenomegally, FTT, diarrhoea
diagnosis: increased WCC/IgE with low other Ig, increased eosinophils
treatment: BMT
Paroxysmal Noctural Haemoglobinuria
incidence: 1/50,000
genetic: mutant PIG-A/T
pathophysiology: deficiency membrane bound complement regulatory proteins CD59/CD55 making them susceptible to lysis
clinical: recurrent intravascular haemolysis
- chronic haem anaemia, BM failure, thrombosis, haemaglobinuria
Primary immune response
mechanism:
- logarithmic increase IgM day 4-10 during clonal expansion and Ab production
- plasma cells form in hours
- IgG peaks in days and lasts weeks to years
- class switching and proportion of other antibodies increases with time
- some B cells become memory cells and living in germinal matrix ready to produce fast secondary response with furthe exposure
Reaction Timing
immediate: IgE
- usually within 1 hour
delated: T cells
- >6 hours after starting medication
- dalyed amoxycillin usually 7-10 days after starting
DRESS (drug reaction with eosinophilia + systemic symptoms)
- 1-12 weeks post starting
SCID
incidence: 1/50,000, M>F
pathophysiology: thymus not developed, failure T +/- B cells with no/low Ig and poor adaptive immunity
genetics:
X-linked (47%): Xq13 encodes IL2/4/5/7/9
- B cells normal no. but defective
- poor function post BMT due to abnormal cytokine R
ADA (adenosine deaminase) deficiency (15%): 20q13
- most profound lymphopaenia
- T cell apoptosis and abnormal function
- respond well to BMT
JAK3 deficiency (6%): signalling defect assoc Yc
- poor B cell function post BMT
clinical: small lymphoid tissue, early recurrent infections, diarrhoea (rotavirus/bacterial), pneumonia (PCP), persistent candida, sepsis
- live vaccines can kill
diagnosis: lymphopaenia, absent mitogen response to PHA, low Ig
treatment: death <1yr w/o stem cell transplant, need BMT within 3.5 months
Secondary disorders complement
SCID/hypogamma: deficiency C1q due to IgG deficiency
Chronic membranoproliferative GN: C3 consumption
Cirrhosis/hepatic failure
Malnutrition/AN
Sickle cell disease: defective alternative p/w
Nephrotic syndrome
Immune complex disorders: SLE, leprosy, endocarditis, malaria, EBV, dengue, hep B
- induce complement consumption
Bacteraemic shock
IV contrast
Burns
Secondary immune response
memory cells: display IgG/IgA/IgE on surface
- no IgD
- identified presence of CD27
- live in mucosal areas
- 1% of total B cell population
secondary response:
- short lag period and rapid production isotypes other than IgM
- high affinity Ig
- derived from memory cells developed in primary response
Selective IgA deficiency
The MOST COMMON primary immune defect
Incidence: 1/700, familial or acquired, defect unknown, AD
diagnosis: absent IgA +/- IgG subclass
clinical: usually asymptomatic, recurrent sinopulmonary infections, sprue like syndrome
associations: atopy, GI disease, CVID, AI, malignancies
complications: ANAPHYLAXIS to blood products due to IgA antibodies
Serum sickness
mechanism: systemic immune mediated hypersensitivity vasculitis
cause: foreign proteins
pathophysiology: Ag and Ab combine to form immune complex that get stuck in blood vesells or tissue and activate complement and granulocytes
- results in migration of neutrophils, release of vasoactive substances and tissue damage
clinical: 7-10 days post exposure
- fever, malaise, rash, myalgia, LN, arthralgia, arthritis, nausea, diarrhoea
- lasts 1-2 weeks
rare associations: carditis, GN, guillaine barre, peripheral neuritis
diagnosis: immune complexes, low C3/C4, high ESR, mild proteinuria/haematuria
treatment: analgesia, steroids, antihistamines
Skin prick testing
benefits: rapid, sensitive, cost effective
mechanism: tiny amounts allergen into skin in contact with cutaneous mast cells
- mast cells have IgE, degranulate and release histamine, produces wheal (peak 20mins)
- late phase reactions 1-2 hr post
positive: wheal> histamine control wheal (3mm) at 10 minutes
negative predictive value: 95% change no allergy
- BUT 50% have positive test with no clinical allergy
note: infants have less positive reactions
contraindication: high risk anaphylaxis, recent anaphylaxis, meds (ACEi, beta blockers)
Solid organ rejection
hyperacute 1% graft loss
- preformed recipient Ab to HLA/ABO blood group attach graft endothelium
- within minutes of transplant
acute (5% graft loss)
- within days
- recipient CD4/CD8 T cell mediated bind donor APC with self Ag
- assoc HLA match
chronic (69% graft loss)
- after 1 year
- T cell + Ab
- characterised by interstitial fibrosis, thickening graft vessels, narrow lumina and graft failure
T cell activation
trigger: T cell recognises APC with MHC bound Ag
costimulation: APC B7 binds Tcell CD28
inhibition: CTLA-4
effect:
- proliferation: IL2 with clonal expansion (blocked by calcineurin inhibitors)
- differentiation of naive T cells
- functional differentiation
- memory cells
T cell independent B cell activation
eg. vaccines
role: some molecules (polysaccharide/lipopolysaccharide)
negatives: poor memory B cell response/maturation AB and no isotype switching
polysaccharide vaccines:
- crosslink BCR directly activating B cells and produce IgM
- eg. HiB, meningococcal, pneumococcal
- adding protein: tricks B cell to break down to peptide and display on MHCII to T cells causing cytokine production
T cell control
SELECTION
positive: those binding MHC weakly are selected
negative: those binding MHC strrongly are deleted or become regulartory
apoptosis: those not binding MHC die
TOLERANCE
central: AIRE genes produce low level tissue specific Ag in thymus to allow selection of binding T cells
peripheral:
- chronic expression self Ag w/o costimulatory molecules
- clonal ignorance in immune privileged sites
- suppression by regulatory T cells: IL2 R (CD 25+), foxp3 gene, blocks IL2 transcription, reinforces inhib cytokines (CTLA4, IL10)
Tests for T cell deficiency
Lymphocyte subsets
- lymphopaenic kids: 70% CD3+ Tcells
- CD4/CD8 subsets
CXR: for absent thymus
Candida skin testing: positive with erythema/induration
PHA: phytohaemagglutinin
- mitogen usually stimulates T cell proliferation
T cells
production/maturation: in the thymus
- TCR (2 chains: a and b) assoc CD3 complex binds Ag
- rearrange TCRs via splicing and express TCR/CD3
- selected causes apoptosis in 95% T cells
- differentiate from cortex to medulla to blood
- form CD4 or CD8 and travel to LN/spleen
- require APC B7 binding Tcell CD28 receptor for activation
CD4 (helper cells)
Th1 (stimulated IL12):
- activated Ag in MHC II
- secrete IFN-g/TNF activating macrophages/NK cells and B cell Ab secretion
- protection bacterial/viral
Th2 (stimulated IL 4):
- activated Ag in MHC II
- secrete IL4, IL5, IL6, IL13 and activate mast cells/eosinophils/basophils and B cell Ab secretion
- protection parasites
Th17 (stimulated TGFb, IL6, IL23):
- secrete IL17
- causes inflammation, protection fungal, causes psoriasis
CD8 (cytotoxic)
- viral peptide in MHC I complex
- induce cell death via injecting granzymes into cell which activates caspase
- release cytokines (IFNg, TNFa) into surrounds
- protection fungi (non systemic)
Transfusion GVHD
cause:
- Immunocompromise: donor lymph not destroyed by recipient T cells
- Specific HLA mismatch: recipient doesn’t recognise donor as non-self, but donor recognises and mounts response
clinical: 4-30d post transfusion, diarrhoea, vomiting, anorexia, cough, pancytopaenia
diagnosis: biopsy of skin, satellite dyskeratosis
prognosis: ALWAYS fatal
prevention: use irradiated blood products
Transient Hypogammaglobulinaemia of Infancy
definition: delayed maturation of antibody production with low IgG +/- IgA
incidence: common in preterm infants less than 6 months, males 60%, assoc atopy
mechanism: delay in normal synthesis of Ig unti after maternal IgG catabolism
outcome: resolved by 4 years
treatment: antibiotic prophylaxis, rarely IVIg
Type 1 immune reaction
IgE mediated immediate type hypersensitivity
mechanism: Ag exposure causing IgE mediated activation of mast cells and basophils causing release of vasoactive substances (histamine, prostaglandin, leukotrienes)
clinical: anaphylaxis, angioedema, bronchospasm, urticaria
Type II immune reaction
Antibody dependent cytotoxicity
incidence: rare
timing: usually 5-10 days post high dose exposure
mechanism: drug acts as an Ag and directly binds cell’s antibody causing injury
examples: hemolytic anaemia, thrombocytopaenia, neutropaenia
Type III Immune reaction
Immune complex disease
incidence: uncommon
onset: 1 or more weeks to develop with high dose drugs
mechanism: drug binds drug specific IgG and forms complexes that deposit and cause damage to joints, blood vessels, glomeruli
- deposition of immune complexes causes complement activation and recruitment or neutrophil
examples: serum sickness (fever, urticarial rash, arthralgia, lymphadenopathy, low complement)
Type IV immune reaction
Cell-mediated or delayed hypersensitivity
mechanism: NOT Ab mediated, Ag exposure directly activates T cells causing tissue injury
examples: contact dermatitis, some morbilliform reactions, severe exfoliate dermatoses (SJS), interstitial nephritis, drug induced hepatitis
Urticaria
incidence: 20% population
clinical: pruritic erythematous plaque
causes:
- infection (viral, bacterial, fungal) 80%
- ingestion (medical, food)
- injection/infusion
- inhalation
onset: acute <6 weeks chronic >6 weeks
mechanism: mast cell release mediators
systemic disorders: urticarial vasculitis, mastocytosis, SLE, RA, Sjogrens, cutaneous small vessel vasculitis, malignancies
Vaccines with egg allergy
allergy due to egg ovalbumin component
- avoid influenza, rabies, yellow fever, Q fever
Influenza: vaccines<1microg ovalbumin safe but still small risk anaphyaxis
Wiskott-Aldrich syndrome
definition: X linked recessive B/T cell defect
genetic: Xp11.23, WASP
clinical: thrombocytopaenia, eczema, immunodef
- 1st year: atopic dermatitis, recurrent infections (pneumonia, meningitis, OM, PJP, HSV) with encapsulated organisms/viruses
diagnosis: LARGE platelets, leukopaenia, low IgM, high IgA/E, normal IgG, poor Ab response to mitogens
associations: AI, malignancies esp EBV associated
treatment: monthly IVIg
X-linked Agammaglobulinaemia
incidence: 1/4000
genetics: XLR q22 deletion (1/3 new mut)
defect: Bruton tyrosine kinase deficiency causes blockade at Pre-B-1 stage
diagnosis: ALL Ig <95th centile
- NO circulating B cells but pre B-cells in marrow
- normal T cell function, neutropaenia 20%
- poor vaccination response, BTK on flow cytometry
clinical (early onset 6 months):
- small tonsils, no LN, no spleen
- recurrent sinopulmonary infections with pyogenic/encapsulated infections
- progressive dermatomyositis, malabsorption
management: chest physio, IVIg
