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FRACP Exam > Immunology > Flashcards

Immunology Flashcards

1
Q

Innate

‘Acute phase response’

A

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

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2
Q

Affinity maturation

A
  • each cycle of B cell division in germinal centre causes selection of cells with highest Ag affinity
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3
Q

Alternative pathway

A

activation: directly by pathogen surgace with endotoxins on wall of gram negative bacteria

mechanism:

  • C3 directly activated
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4
Q

Anaphylaxis

A

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

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5
Q

Antibody function

A

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

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6
Q

APCs

A

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

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7
Q

Apoptosis

A

signals: Fas ligand and TNFR1

deficiency: ALPS (autoimmune lymphoproliferative syndrome)

  • splenomegally, lymphadenopathy, AI cytopaenias
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8
Q

Asplenia protocol

A

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

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9
Q

Ataxia telangiectasia

A

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

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10
Q

Atopic dermatitis

Eczema

A

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

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11
Q

Atopy

A

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
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12
Q

Autoimmune Polyendocrine Syndrome 1

(APS1)

A

defect: autosomal recessive defect in AIRE gene

pathophysiology: failure to delete autoreactive T-cells

clinical (triad):

  1. chronic mucocutaneous candiasis: Ab to Th17
  2. AI hypoparathyroidism
  3. AI Addison’s disease
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13
Q

X-linked Lymphoproliferative Disorder

A

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

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14
Q

B cell activation

A

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
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15
Q

B cell tests

A

Ab response to polysaccharide antigens

eg. Pneumococcal (T cell indep)
- best in infants >2yrs
- response measured by IgG levels
eg. Tetanus Ab

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16
Q

T cell dependent B cell activation

A

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

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17
Q

Baked Egg and Milk

A

*>75% children tolerate these foods when baked

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18
Q

Basophils

A

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

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19
Q

C1 esterase inhibitor deficiency

(hereditary angioneurotic oedema)

A

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)

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20
Q

Cells of the innate

A

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
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21
Q

Chediak-Higashi

A

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

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22
Q

Chronic granulomatous disease

A

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)

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23
Q

Chronic Mucocutaneous Candidiasis

A

age: childhood

genetics: STAT-1 gain of function causing Th1 development above Th17

defect: lack Th17 cells

clinical: candidiasis nails, skin, mucosa, oesophagus, lungs

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24
Q

Classic pathway

A

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
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25
Q

Complement cascade

A

3 pathways:

  1. classic: C1q activated by IgM/IgG/lipoteichoic acid/phosphocholine on organisms
  2. alternative: C3b binds foreign surface
  3. lectin: C4/C2 cleaved with activation by MBL and ficolins 1-3

function:

  1. cytolysis
  2. opsonisation
  3. inflammation
  4. 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

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26
Q

Complement deficiencies

A
  • 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

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27
Q

CVID

A

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

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28
Q

Cyclic neutropaenia

A

definition: falling neutrophils in 4 week cycles

clinical: gingivostomatitis

diagnosis: twice weekly FBC for 2 months

treatment: supportive, GCSF

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29
Q

DiGeorge Syndrome

A

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

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30
Q

Eosinophils

A

type: granulocyte

stimulating factor: IL5

function: extracellular mediations

  • kill big organisms too large to be phagocytosed
  • degranulate and release enzymes in allergy
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31
Q

Food allergy

A

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)
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32
Q

Genetic risk of atopy

A

no parents= 20%

1 parents= 60%

2 parents= 80%

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33
Q

Genetics of atopy

A

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)

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34
Q

Granulocytes

A

Neutrophils/eosinophils/basophils

  • bone marrow
  • 70% of WBC in the circulation
  • live 2-3 days only
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35
Q

Haemophagocytic Lymphohistiocytosis

HLH

A

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

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36
Q

Hereditary angioedema

A

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
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37
Q

HLA markers and disease

A
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38
Q

Hyper IgE syndrome

A

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

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39
Q

Hyper IgM syndrome

A

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

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40
Q

Hypersensitivity reaction

-pseudoallergic-

A

pathophysiology: poorly understood non IgE reactions

causes:

  • vancomycin
  • contrast media
  • aspirin
  • dextran
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41
Q

Immune Cells

A
42
Q

(IPEX)

Immune dysfunction

Polyendocrinopathy

Enteropathy

X linked

A

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
43
Q

Immune tolerance

A

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)
44
Q

Immunoassays RAST

Radioallergosorbent test

A

technique: fluorescent enzyme immunoassay

pros/cons: less sensitive, more specific, more expensive

benefits: unaffected medications, people with anaphylaxis, dermatological conditions

45
Q

Immunodeficiencies adolescents

A

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

46
Q

Immunodeficiencies infants/children

>6 months

A

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

47
Q

Immunodeficiencies Newborns

<6months

A

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

48
Q

Immunodeficiencies Pathogens

A

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)

49
Q

Immunodeficiency

A

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

50
Q

Immunoglobulin structure

A
51
Q

Immunoglobulins

A

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

52
Q

Immunoglobulins in Breast Milk

A
  • 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

53
Q

Infant Immune System

A

Anti-polysaccharide response

  • <2yrs unable to form T indep immune response
  • young children prone to encapsulated organisms
  • improves with age
54
Q

Infections in eczema

A

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
55
Q

Receptors of innate immunity

A

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)

56
Q

Allergic rhinitis

A

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

57
Q

Interferons

A

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
58
Q

Interleukins

A
59
Q

IVIg

A

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

60
Q

Kawasaki’s disease

A

incidence:

pathogenesis:

  • unknown etiology: ?post infective
  • medium blood vessel vasculitis

criteria (4 of 5 of):

  1. polymorphous rash
  2. bilateral non purulent conjunctival injection
  3. mucous membrane changes eg. dry lips, strawberry tongue
  4. peripheral changes eg. erythema palms/soles, oedema hands/feed
  5. 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
61
Q

Leukocyte adhesion deficiency

A

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%

62
Q

Lymph nodes

A

function

  1. Cleanse lymph
  2. 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
63
Q

Lymphocyte adhesion and trafficking

A

selectins: rolling and tethering vessel wall

integrins: moving from BV to tissue, stop the neutrophil to squeeze through endothelium

chemokines: presented on vascular endothelium

64
Q

Lymphocytes

A

prevalence: 25% WBC in peripheral blood

source: derived from CD34

stimulation of T/B/NK cells: IL2

stimulation T/NK cells: IL7, IL15

65
Q

Lymphocytic Interstitial Pneumonia

A

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

66
Q

Mast cells

A

role: release granules and hormonal mediators

  • mediate allergic and antiparasitic responses
  • NOT phagocytic

stimulation:

  1. direct injury: physical/chemical
  2. IgE: surface receptor
  3. Activated complement: common p/w

hormones:

tryptase, proteases, histamine, serotonin, heparin, chondroitin, thromboxane, PG D2, leukotriene, PAF, IL, TNF-a

67
Q

MB Lectin Pathway

A

activation: MBL on surface of bacteria

mechanism:

  • binds to mannin, activates proteolytic enzymes, converts C4 to C4b, C4b binds C2b and forms C3 convertase
68
Q

MHC II

A

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

69
Q

MHC I

A

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

70
Q

Myeloperoxidase deficiency

A

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
71
Q

Natural history of allergy

A

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

72
Q

Complement tests

A

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
73
Q

Neonatal Ig

A
  • Ig transferred across placenta from 6 months
  • at term levels higher than in mother
  • levels drop rapidly after birth
  • infants<1500g hypogammaglobulinaemic first week
74
Q

Neutrophils

A

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
75
Q

NK cells

A

Innate immunity

direct cell-cell killing of intracellular pathogens: microbes/cancer

mechanism:

  1. IgG coated microbes: via CD16 receptor
  2. Killer inhibitory cells: no MHC1 on tumour/infected cells
  3. Killer activating receptor
76
Q

Non IgE food allergy

A

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
77
Q

Omenn syndrome

A

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

78
Q

Paroxysmal Noctural Haemoglobinuria

A

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
79
Q

Primary immune response

A

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
80
Q

Reaction Timing

A

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
81
Q

SCID

A

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

82
Q

Secondary disorders complement

A

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

83
Q

Secondary immune response

A

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
84
Q

Selective IgA deficiency

A

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

85
Q

Serum sickness

A

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

86
Q

Skin prick testing

A

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)

87
Q

Solid organ rejection

A

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
88
Q

T cell activation

A

trigger: T cell recognises APC with MHC bound Ag

costimulation: APC B7 binds Tcell CD28

inhibition: CTLA-4

effect:

  1. proliferation: IL2 with clonal expansion (blocked by calcineurin inhibitors)
  2. differentiation of naive T cells
  3. functional differentiation
  4. memory cells
89
Q

T cell independent B cell activation

A

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
90
Q

T cell control

A

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)
91
Q

Tests for T cell deficiency

A

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
92
Q

T cells

A

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)
93
Q

Transfusion GVHD

A

cause:

  1. Immunocompromise: donor lymph not destroyed by recipient T cells
  2. 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

94
Q

Transient Hypogammaglobulinaemia of Infancy

A

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

95
Q

Type 1 immune reaction

IgE mediated immediate type hypersensitivity

A

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

96
Q

Type II immune reaction

Antibody dependent cytotoxicity

A

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

97
Q

Type III Immune reaction

Immune complex disease

A

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)

98
Q

Type IV immune reaction

Cell-mediated or delayed hypersensitivity

A

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

99
Q

Urticaria

A

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

100
Q

Vaccines with egg allergy

A

allergy due to egg ovalbumin component

  • avoid influenza, rabies, yellow fever, Q fever

Influenza: vaccines<1microg ovalbumin safe but still small risk anaphyaxis

101
Q

Wiskott-Aldrich syndrome

A

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

102
Q

X-linked Agammaglobulinaemia

A

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

FRACP Exam (23 decks)

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