Immunology (MedEd) Flashcards
A 19 year old man who has sex with men presents to the GUM clinic three weeks after he has had unprotected sex with another man.
He is extremely worried he may have caught HIV as he usually has protected sex with condoms.
What is the most appropriate test to provide this patient with an accurate diagnosis?
A. Rapid point of care test
B. CD4 count
C. Viral PCR
D. Viral load
E. 4th generation Antigen and antibody test
E. 4th generation Antigen and antibody test
According to the British HIV association (BHIVA) guidelines, the median window period for this test is 17.8 days (ranging from 13-26 days). Therefore, given this patient is three weeks post-exposure , this is the most appropriate test to see if this patient has contracted HIV. It is a serological blood test that requires venepuncture
Not: A. Rapid point of care test
This is known as the finger prick test and only needs a spot of blood to be conducted. However, antibody detection has a three month (90 day) window period and so, if the initial result were negative, would need to be repeated three months after the initial exposure in order to display a true results. Therefore, this would not be an appropriate choice for this patient
A 32-year-old man presents to the emergency department with a 2-week history of shortness of breath, which has worsened to the point that he felt breathless on the short walk into the department this morning. He has noticed a nonproductive cough that started around the same time. On questioning, he reports feeling generally run down, and has experienced night sweats and 4 kg of weight loss over the past month.
On inspection of his chest, a red, vesicular unilateral rash is noted on the left side of his back in a band-like pattern. He describes a slight burning sensation in this area and describes a previous episode of similar presentation on his right side some weeks ago. On further inspection, a collection of small raised pink lesions with central umbilication is visible over his trunk. Palpation of the neck reveals has a unilateral 1-cm soft nontender, mobile cervical lymph node.
A set of observations is taken:
BP 118/83 mmHg
Temperature 38.3 °C
HR 83 bpm
O2 saturation in air was 95% initially, but has improved to 98% on repeat
RR 19 breaths per minute
A chest X-ray is arranged, which shows no obvious abnormalities. What is the most likely underlying cause of this man’s presentation?
A. Community-acquired pneumonia
B. Hodgkin lymphoma
C. Tuberculosis
D. Heart failure
E. Primary HIV infection
E. Primary HIV infection
This man has presented with a 4-week history of progressively worsening shortness of breath consistent with Pneumocystis jirovecii pneumonia. This is a common opportunistic infection in immunocompromised individuals, such as those with untreated HIV. It is important to have a low threshold for suspicion of HIV, even in absence of obvious risk factors. The other factors indicative of HIV infection in this case include a subacute history of weight loss and night sweats, cervical lymphadenopathy, and dermatological features, including recurrent shingles and molluscum contagiosum.
Not C. Tuberculosis
This is a reasonable differential for this man’s presentation; however, tuberculosis would more likely result in a chronic productive cough, with purulent or bloodstained sputum and findings on chest X-ray.
what is p24 antigen test used for? when?
An antigen test checks your blood for an HIV antigen, called p24.
The p24 antigen test is accurate 11 days to 1 month after getting infected
what is seroconversion?
Seroconversion is a sign that the immune system is reacting to the presence of the virus in the body. It’s also the point at which the body produces antibodies to HIV. Once seroconversion has happened, an HIV test will detect antibodies and give a positive result.
HIV clinical progression
when does seroconversion occur?
Up to six weeks after getting HIV, most people experience a short one- or two-week illness called a seroconversion illness eg flu-like symptoms, myalgia
-differential: EBV
What is an allergic reaction?
Immune reaction to something harmless eg nuts
define atopy:
tendency to develop IgE antibodies against innocuous antigens (allergens)
what type of T cells responsible for atopy?
Th2 cells
what is sensitisation?
sIgE antibody presence & binding to mast cells (Fc receptor on surface, irreversible binding) & basophils
-can be sensitised but not allergic
-If two IgE molecules on the surface of mast cells recognise antigen and cross-link, then this will lead to mast cell activation and in servere cases, anaphylaxis.
what are some mediators stored in granules?
- histamine (H1-4R)
- proteases eg tryptase (can be measured in blood)
- proteoglycans eg heparin
- cytokines eg TNFa
what are some consequences of mast cell release?
- vasodilation
- smooth muscle spasm (contraction)
- increased permeability
- nerve endings: itch
define allergy:
sensitisation + typical reaction history &/or positive provocation
what tests can be used to diagnose allergy?
- Skin prick tests
-positve response: wheal >2mm greater than negative control (negative control: dilutant, positive control: histamine) - Quantitative specific IgE to pollutant allergen (blood RAST: (Radioallergosorbent test):
-measure levels of IgE in serum against a particular antigen
name of swelling over the skin
urticaria (itchy, bumpy rash)
name of swelling over mucosal surfaces/softer tissues (eg eye, lips, tongue, throat)
angioedema
how does allergy affect different bodily systems?
- skin/mucosal surface; urticaria, angioedema
- GI system: oedema of intestines; vomiting, cramps, diarrhoea
- Heart: vasodilation–> low BP–> compensatory tachycardia, palpitations, pre-sycope, LOC, empty ventricle syndrome; pulmonary vasospasm, a decreased left ventricular preload, and decreased cardiac output (obstructive shock). It is theorized that all of these effects on the CV system come together to cause an “empty ventricle syndrome” when a patient in anaphylaxis is placed in an upright position (don’t put patients in upright posture
- Resp system: bronchoconstriction (smooth muscle contraction–> SOB, wheeze), itch, sneezing, nasal discharge, voice changes, stridor, asphyxiation
why is it not recommended to put patients in upright position during empty ventricle syndrome?
this can increase the workload on the heart and worsen their condition. In an upright position, blood is pulled downward by gravity, which can cause blood to pool in the lower part of the body, decreasing the amount of blood returning to the heart. This can put additional strain on the heart, which is already struggling to pump effectively.
define anaphylaxis
skin changes (urticaria/angioedema) + A, B & C problem
what are the 2 things needed to treat anaphylaxis (updated guidelines)?
- Adrenaline
- Fluids
(no steroids, no antihistamines, no bronchodilators)
how does adrenaline treat anaphylaxis (mechanisms)
a1: vasoconstriction (increases peripheral vascular resistance, decreases mucosal oedema
b1: inotropy, chronotropy
b2: bronchodilation, decreases exocytosis (stops release of granule contents)
how to treat anaphylaxis in outpatient?
-lift legs up (returns blood to right ventricle)
-epipen
anaphylaxis algorithm:
why does someone need to be kept in hospital for 6 hours after anaphylaxis?
biphasic reaction
what happens when allergen cross-links the antibodies/after triggering exocytosis from mast cells?
from phospholipid bilayer synthesises new mediators eg leukotrienes. prostaglandins/cyclines
(minutes/hours vs mast cells: seconds/minutes)
symptoms of early phase reaction vs late phase reaction:
early; itching, sneezing, rhinorrhoea, congestion
late; nasal congestion, hyperreactivity
hospital discharge plan (mnemonic):
AAAE
-avoid allergen
-educate on allergy
-action plan
-allergy referral
-no epipen given to penicillin allergy: only to accidental exposure eg nuts
differentials for allergy:
-anxiety
-vasovagal episode
-asthma attack & skin flushing
-spontaneous urticarfia/asthma
-inducible laryngeal obstruction
-sepsis
-scombroid poisoning (fresh, canned, smoked fish)
-drug side effect eg penicillin
how can allergy be diagnosed in A & E
tryptase levels
-at baseline and then >-1.2 x baseline level + 2 (eg if tryptase is 0, then positive would be 14)
what is the protein associated with peanut allergy?
Ara H2
what is PR-10
a pollen protein (pollen food syndrome, not anaphylaxis to that certain nut) ; avoid raw/in large quantities but when cooked it should be fine
how to use epipen (mnemonic)
blue to the sky, orange to the thigh (lateral)
-blue=lock, remove lock–> once clicked=injection given (hold for 10 secs), remove it–> can’t reuse it
-if not responded to 2 injections–> ITU team (think about adrenaline infusions)
-everyone that’s used an epipen should go to hospital to get 6 hour monitoring (& get epipen replaced before discharge)
what disorders are associated with recurrent meningococcal septicaemia?
- Immunological
a) Complement deficiency
Recurrent infection with encapsulated organisms
Neisseria meningitis,
Gonococcus, H influenza B, pneumococcus
b) Antibody deficiency
Recurrent bacteria infections, especially of upper and lower respiratory tract
-eg XLA (X-linked agammaglobulinaemia) deficiency where you don’t produce mature B cells
- ## NeurologicalAny disruption of blood brain barrier
Occult skull fracture
Hydrocephalus
what is XLA?
(X-linked agammaglobulinaemia) where you don’t produce mature B cells
questions in history of someone presenting with meningococcal disease? (mnemonic)
- History of other infections (SPUR)
*Serious
*Persistent
*Unusual
*Recurrent - Past medical history
-Specifically ask about neurological disease and head injury - General health and wellbeing
-Energy, weight loss, sleep, work status (eg HIV) - Family history
-Consanguinuity
-History of meningitis
what immunological investigations to perform for meningococcal septicaemia (especially if recurrent)?
- Complement (blood)
-C3 and C4
-CH50
-AP50 - Immunoglobulins
-Serum IgG, IgA and IgM
-Protein electrophoresis
what is ch50?
a functional test of the integrity of the classical complement pathway
what is ap50?
a functional test of the integrity of alternative complement pathway
what does normal c3/c4 but absent CH50/AP50 show?
Indicates deficiency of component in final common pathway (C5-9)
how is someone with complement deficiency managed?
- Meningococcal vaccination - tetravalent meninogococcal conjugate vaccine covering serogroups A,C,W,Y (MenACWY vaccine) and the meningococcal V vaccine (Men B vaccine)
- Pneumococcal vaccination – pneumococcal conjugate vaccine (Prevenar 13, PCV)and pneumococcal polysaccharide vaccine (Pneumovax 23, PPV-23)
- Haemophilus influenza vaccination – Haemophilus influenza type b vaccine (HIB vaccine)
- Daily prophylactic penicillin
- Close monitoring
what can be detected in SLE?
The indirect immunofluorescence assay (IIFA) on HEp-2 cells is widely used for detection of antinuclear antibodies (ANA).
what tests is specific for SLE?
anti-double stranded DNA (dsDNA) and anti-SM
when can Ro, La, Sm, RNP (all=ENA) antibodies be positive?
SLE, Sjogren’s
what can assess disease activity in SLE?
Immune complexes bind to
C1q and activate classical
pathway
Complement is consumed
Low levels of C4 (first) and C3 (shows activity, goes down later) complement
suggest SLE is active
-ESR and dsDNA Ab titre also reflect
activity of disease
what do immune complexes bind to in SLE?
Immune complexes bind to
C1q and activate classical
pathway
what abs are present in diffuse cutaneous scleroderma?
SCL70 (& RNA polymerase, fibrillarin)
what abs are present in diffuse cutaneous scleroderma (CREST syndrome)?
centromere
Summary of Abs in SLE:
what should you screen all lupus patients for?
anti-phospholipid antibody syndrome (Hughes syndrome)
clinical criteria for anti-phospholipid antibody syndrome (Hughes syndrome):
- Intravascular thrombosis (arterial or venous)
- Recurrent miscarriage (=> 3):
what are some signs/symptoms of anti-phospholipid antibody syndrome (Hughes syndrome):
- mild thrombocytopenia
- prominent livedo reticularis
- libmann sachs endocarditis
commonest preventable cause of recurrent miscarriage:
anti-phospholipid antibody syndrome (Hughes syndrome):
autoimmune hepatitis antibodies:
anti smooth muscle antibody, anti LKM-1 (liver kidney microsomal-1, anti-SLA (anti-soluble liver antigen)
autoimmune thrombocytopenic purpura antibodies
anti-glycoprotein 2b/3a or Ib-Ix antibody
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
- Pernicious anaemia (anti parietal cell antibodies)
- Graves’ disease (anti-TSH receptor)
- Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
- Goodpasture’s syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
- Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
- Pemphigus Vulgaris (anti-cadherin)
Lab criteria for anti-phospholipid antibody syndrome (Hughes syndrome):
- antibodies to anionic phospholipids (anti-cardiolipin antibodies)
- Antibodies to beta-2-glycoprotein 1
- Lupus anti-coagulant test
(clotting assay-prolonged APTT or DRVVT that does not correct with normal pooled plasma but corrects with phospholipids)
what is paradoxical about anti-phospholipid antibody syndrome (Hughes syndrome) testing?
-APTT is prolonged in vitro (implying it takes longer to clot, ie anticoagulant, however the syndrome is pro-thrombotic in vivo)
what is the best test to look for renal disease in lupus patients?
- urine analysis (dipstick urine to look for proteinuria, microscopic haematuria) before creatinine goes up
- Urine microscopy (red cells, red cell casts)
- Renal biopsy
-diffuse proliferative nephritis
-immune complex and complement deposition
Summary of pathophysiology of lupus:
- Increase in cellular death pathways and impaired clearance of apoptotic cells
- Formation of immunostimulatory nucleic acid complexes
- Uptake of nucleic acid complexes by pDC and generation of Type 1 interferon immune responses
- Stimulation of T and B cells, development of plasma cells, generation of anti-nuclear antibodies, with formation of anti-nuclear antibody immune complexes
- Deposition of immune complexes in renal glomeruli, joints and the skin
- Neutrophil, and macrophage recruitment: innate cell and complement activation resulting in tissue damage (Type III Gel and Combs response)
summary of drugs in SLE”:
-not allopurinol (Xanthine oxidase inhibitor used in gout)
- not adalimumab (iAnti-TNF alpha antibody.
inflammatory arthritis, not lupus as may precipitate cutaneous lupus)
-not colchicine (gout, inhibits neutrophils)
at antibodies are seen in Sjogren’s ?
Ro and La
what HLA subtype is associated with rheumatoid arthritis? (mnemonic)
HLA-DR4 (r letters in “rheum”): only subtypes (Dw4, Sw14, Dw15) & HLA Dr1
Rheum=room=4 walls in a room
what is rheumatoid factor?
- Antibody directed at the Fc region of human IgG
some symptoms of rheumatoid arthritis;
-Peripheral, symmetrical, polyarthritis with stiffness
-Persists for > 6 weeks
-May be associated with RF and/or anti-CCP Ab
-Post-partum presentation frequently described
what do assays for rheumatoid arthritis usually look for?
- Assays usually look for IgM RF although patients may sometimes also have IgG and IgA RF
what is sensitivity/specificity of rheumatoid factor?
60-70%
what is anti-CCP? specificity?
cyclic citrullinated peptides (95%; very specific)
-polymorphism mutation in PADI enzymes (petidyl arginine deiminase eg PADI type 2, type 4 and PTPN 22 also associated with SLE, T1DM)
-smoking & gingivitis ( Porphyromonas gingivalis bacteria) associated with rheumatoid arthritis
what happens in joints of RA?
synovial hypertrophy (more synovial fluid, damage to bone & cartilage: B cells, T cells & macrophages)
what does RA treatment inhibit?
TNFa, Il-6, B cells and T cells
treatment of RA:
- First line treatment – conventional disease modifying anti-rheumatic drugs (DMARDs)
- Methotrexate
- Sulphasalazine, hydroxychloroquine, leflunomide
- Further treatment – biologic DMARDs and Jakinibs
- TNF-alpha antagonists (infliximab, entarcept)
- Tocilizumab. Antibody specific for IL-6 receptor – widespread effects
- Rituximab. Antibody specific for CD20. Depletes B cells (not plasma cells).
- Abatacept. CTLA-4 – Ig fusion protein. Binds to ligands of CD28 (CD80 and CD86) and thereby inhibits T cell activation.
- Jakinibs (targeted synthetic DMARDs) – inhibit signalling via cytokine receptors
what should RA patient do in case of infection (safetynet)?
stop drug & seek advice
-careful sun exposure/photosensitivity (tiny increased risk of melanoma)
what can cause high ESR but low CRP?
-multiple myeloma
-SLE
how can you test for multiple myeloma?
- serum immunoglobulins (usually IgG raised)
- serum protein electrophoresis (monoclonal band in gamma region)
- urine electrophoresis (free light chains detected)
why are MM patients susceptible to recurrent infections?
-Suppression of production of normal immunoglobulin by the malignant clone results in functional antibody deficiency
-Sometimes known as “immune paresis”
why are patients with MM anaemic?
- Space limitation: excess plasma cells (fill up bone marrow)–> crowd out capacity to produce RBCs
- Inhibitors
-Tumour may produce local cytokines which inhibit normal bone marrow function
why is ESR high in MM?
if protein constituents of plasma increase or change
Increases attractant charge
-Causes erythrocytes to clump together
-Clumped erythrocytes fall more quickly through plasma
–> higher ESR (ie rouleaux formation in blood film of ESR)
how does hypercalcaemia cause renal failure?
Hypercalcemia causes reduced glomerular filtration rate, increased sodium excretion and depletion of total body water (dehydration), leading to increased bicarbonate reabsorption and metabolic alkalosis.
-Alkalosis enhances calcium reabsorption in the distal nephron, thus, aggravating the hypercalcemia
what antibodies can be checked to check how well immune system functioning (bonus)?
- Antibodies to tetanus toxoid (T cell depdendent)
- Antibodies to HiB (after 2,3,4 months)
- Antibodies to PCV-13 (conjugate vaccine; after 2 months or 12-13 months)
what test can be used to quantify individual lymphocyte subsets?
-flow cytometry
-CD3: marker for T cells
-CD20: marker for B cells
-natural killer cells don’t express CD3 or CD19
-this one shows: NK cells (bottom left), B cells (top left), T cells (bottom right)
what does this flow cytometry show?
-this one shows: NK cells (bottom left), no B cells (top left), T cells (bottom right)
-XLA (Bruton’s tyrosine kinase mutations as it normally causes pre B cells to pro B cells)
what is overexpression of PTK associated with (Bruton’s tyrosine kinase)? drug to target it?
CLL (philadelphia chromosome, (BCR-ABL) , t(9;22). Imatinib: tyrosine kinase inhibitor
what demographic get XLA?
only males
treatment for XLA :
pooled serum immunoglobulin (every 3 weeks; SC or IV, indefinite treatment, against encapulsated bacteria eg pneumococcus/haemophilus)
what is more common B or T cell lymphoma?
B cell lymphoma (T cell eg EATL:Enteropathy-associated T-cell lymphoma, Coeliac disease)
what investigations should be done for osteomyelitis:
- Blood inflammatory markers, Blood cultures, and culture of any expressed pus (but note that samples from sinus tracts are unreliable)
- Imaging:
-X-ray - may be negative early on as periosteal reaction cannot be seen until about 7 days and bone necrosis after 10 days. It is useful in the diagnosis of chronic osteomyelitis.
-MRI - good for viewing bone and soft tissue. Imaging modality of choice*
-CT - good for identifying necrotic bone and for guiding needle for biopsy.
what investigations should be done for osteomyelitis:
- Blood inflammatory markers, Blood cultures, and culture of any expressed pus (but note that samples from sinus tracts are unreliable)
- Imaging:
-X-ray - may be negative early on as periosteal reaction cannot be seen until about 7 days and bone necrosis after 10 days. It is useful in the diagnosis of chronic osteomyelitis.
-MRI - good for viewing bone and soft tissue. Imaging modality of choice*
-CT - good for identifying necrotic bone and for guiding needle for biopsy.
RFs for osteomyelitis:
Diabetes melitis
Peripheral vascular disease
Malnutrition
Immunosuppression
Malignancy
Extremes of age
Local factors e.g chronic lymphedema, vasculitis, neuropathy etc.
A 42 year old male is brought by ambulance to A+E with sudden-onset diarrhoea and visual changes, followed by progressive dysphagia and generalized weakness. He has no past medical history, including no recent history of gastroenteritis or other infections. He takes no regular prescribed medications, though he has been taking intravenous heroin regularly for the past two years.
On examination, he is alert but his eyelids are drooping and his speech is breathy and nasal in quality. Neurological examination reveals hypotonia, reduced reflexes and reduced power in all four limbs; but the upper limbs are more severely affected than the lower limbs. Respiratory examination is unremarkable.
The patient is escalated immediately to ITU and supportive management started. Which diagnostic investigation should be ordered to confirm the diagnosis?
A. Lumbar puncture and CSF analysis
B. Electromyography (EMG)
C. Non-contrast CT head
D. Stool toxin ELISA
E. Tensilon (edrophonium) test
D. Stool toxin ELISA
Recreational intravenous drug use is the commonest cause of wound-associated botulism, and so this is a diagnosis that cannot be missed. The toxin can be identified by ELISA using stool, vomit, serum or urine samples. Once the diagnosis is confirmed, antitoxin should be administered as soon as possible but can still be beneficial even if provided weeks after inoculation or ingestion of the toxin. It can slow progression but has no effect on toxin already bound to the neuromuscular junction
Not:
A. Lumbar puncture and CSF analysis:
Although Guillain-Barre/Miller-Fisher syndrome is an important differential here, the history more strongly points towards botulism due to the patient’s recreational drug use. Classically, in GBS there is raised CSF protein is ‘albuminocytological dissociation’
Not B: EMG
This can be used to assess electrical activity of muscles and is particularly useful in neuromuscular diseases such as Guillain-Barre syndrome. It is not diagnostic
Not E: Tensilon (edrophonium) test
Although this could be a new presentation of Myasthenia gravis, it is uncommon in middle-aged males. It usually presents with more insidious symptoms, which progress over the course of weeks to months. In myasthenic crisis patients develop worsening muscle weakness and respiratory compromise, but this usually occurs in known MG patients with a clear trigger such as a respiratory tract infection
CSF findings in
elevated opening
Tetanus causative agent & treatment
-Clostridium tetanii
-Tetanus immunoglobulin
treatment of VRE (vancomycin resistan enterococci )
oxazolidinone e.g. linezolid
-However, can cause bone marrow suppression, peripheral neuropathy and optic neuritis
staph aureus vs enterococci:
Staphylococcus aureus produces the enzyme catalase and breaks down hydrogen peroxide, whereas Enterococcus faecalis does not produce the enzyme catalase
Child with recurrent bacterial and fungal infections. A dihydrorhodamine test shows that neutrophils fail to oxidise dihydrorhodamine. What is the likely diagnosis?
Chronic granulomatous disease
In this inherited condition, the phagocytes (e.g. neutrophils, monocytes, macrophages) are unable to generate reactive oxygen species, such as superoxide, hydrogen peroxide, and hypochlorous acid, which are required for the killing of certain bacteria and fungi. This leads to recurrent infections, especially with catalase-positive organisms such as Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia spp., and Aspergillus spp. The dihydrorhodamine test is used to confirm the diagnosis of CGD by assessing the ability of phagocytes to generate reactive oxygen species.
Chronic granulomatous disease (nitroblue tetrazolium test stays yellow)
-presence of colour change (to blue): neutrophils are capable of oxidative killing–> producing oxidative stress (still functioning)
diGeorge syndrome (defect of pharyngeal pouch, hypocalcaemia–> convulsions, due to aplasia of parathyroid glands)
catalase positive organisms mnemonic & which immunological deficiency is this associated with>?
PLACESS
catalase positive organisms mnemonic & which immunological deficiency is this associated with>?
PLACESS
Different types of SCID (severe combined immunodeficiency)
Innate immune cells (pictures/identify)
Rare monogenic auto-immune diseases (mnemonic)
-APECED
bad T cells that manage to get through thymic selection–> autoimmune diseases
-Autoimmune diseases: Hypoparathyroidism, addisons and vitiligo
-central tolerance breakdown problems (mutation of transcription factor AIRE (mnemonic)
Treg abnormalities (mnemonic):
IPEX: diarrhoea, diabetes and dermatitis
mutation in Fas pathway (mnemonic)
ALPS
-pt usually will have lymphoma (vs APECED)
Mnemonic for types of hypersensitivity reactions
ACID
classification of types 1-4 hypersensitivity
Type 4 hypersensitivity examples/pathophysiology:
Only type by T cells: diabetes, contact dermatitis, MS, coeliac disease
Type 2 vs Type 3 hypersensitivity (pathophysiology/examples)
Type 2: abs driving cell breakdown (cellular)
Type 3: humoral (blood) ; soluble antigens in bloodstream eg graves disease/myasthenia gravis
Type 3: Immune complexes in blood eg blood vessels eg SLE (deposit in skin/kidneys–> r=skin rashes, deposits inflammation there ef kidney disease), serum sickness
C3 deficiency with nephritic factor (type of secondary complement deficiency, like SLE)
meningococcus: encapsulated organisms (could mean hyposplenism/splenectomy), but should point towards complement deficiency. Haematuria/proteinuria–> nephritic syndrome (glomerulonephritis). fat distribution–> partial lipodystrophy
nephritic factor–> depletes c3
what are is IL-12 & IFN-gamma cytokines associated with?
mycobacterial infection (eg TB) & salmonella
2 ways in which SLE (lupus) is related to complement pathway:
- Primary deficiency of classical pathway (complement deficiency can cause lupus due to accumulation of immune complexes/self antigens–> more susceptible to SLE). Deficiency in classical pathway–> wont reach c3 and c4 part (classical pathway won’t happen so wont go all way down domino cascade to decrease C3/C4 components)
- Lupus to begin with (lupus itself can cause overconsumption of C3 and C4 due to immune complexes production–> triggering classical pathway–> overdrive of cascade)
eg primary complement deficiency causing lupus=NORMAL c3/c4 levels vs secondary complement deficiency (low C3/C4 deficiency)
A 27-year-old man is recovering on the ward following an uncomplicated open reconstruction of the lateral collateral ligament of his left knee. He initially recovers well and is eating and drinking after 24 hours. However, within 36 hours of the procedure, his temperature spikes to 38.6 °C, with a heart rate of 104 bpm and blood pressure of 106/75 mmHg. Cardiovascular and respiratory examinations are unremarkable, but inspection of the surgical site reveals severe swelling and discolouration of the knee, with blisters protruding from the surgical incision. Subcutaneous emphysema can be seen extending distally. He complains of severe pain and weakness in his lower leg that is not adequately controlled with his postoperative analgesia.
Given the likely complication that has occurred, what is the most appropriate management option for this patient at this time?
A. Fasciotomy
B. Above the knee amputation
C. Hyperbaric oxygen
D. Treatment-dose apixaban
E. Penicillin and clindamycin with surgical debridement
E. Penicillin and clindamycin with surgical debridement
This patient has developed gas gangrene postoperatively, most likely due to Clostridium perfringens. Management requires prompt antimicrobial treatment with good Gram positive, negative and anaerobic coverage. Penetrance into necrotic tissue is however often suboptimal and surgical debridement is required to prevent further spread of infection.
Not A: Fasciotomy
This would form the definitive management of compartment syndrome. This would present with intense pain, likely disproportionate to the appearance of the affected limb. This patient has a visible postoperative infection and subcutaneous emphysema on inspection, consistent with gas gangrene.
Definition of Pseudomembranous colitis:
An antibiotic-associated colitis caused by C difficile.
RFs for Pseudomembranous colitis (mnemonic):
Antibiotics most commonly associated include Cs: quinolones (ciprofloxacin), macrolides (clarithromycin), clindamycin and cephalosporins.
Other risk factors:
1. Prolonged courses
2. Multiple antibiotics
3. Immunocompromise
4. Use of PPIs
5. Increasing age
features of Pseudomembranous colitis:
- Watery +/- blood-stained diarrhoea
- Very high fevers and high white cell counts (that may occur prior to symptoms)
- Diagnosis depends on the detection of either C. difficile and its toxin in stool samples (usually three recommended). Stool culture and cytotoxin test commonly carried out.
Investigations for Pseudomembranous colitis:
- Plan abdominal X-ray and CT can be useful in severe disease, for detecting perforation or toxic megacolon.
- Avoid barium enemas!
Management ofPseudomembranous colitis:
- Rx: stop causative antibiotic. Supportive + oral vancomycin (WITH intravenous metronidazole if severe infection=a rise in white cell count and creatinine, pyrexia).
- Consider surgical intervention if any complications occur
- faecal transplant if c.difficile persists
features of tetanus:
Toxin-mediated generalized tetanus is the most common presentation
1. Descending pattern of symptoms following prodromal malaise and fever
2. Muscular spasms, abdominal rigidity, dysphagia, opisthotonus, trismus and ‘risus sardonicus’
3. Can lead to aspiration pneumonia, fractures, laryngospasm (causing asphyxia) and respiratory failure.
Diagnosis/treatment of tetanus:
Diagnosis is clinical, and patients need to be managed in ITU.
Treatment:
1. Tetanus immunoglobulin (antitoxin) must be given IV. However, any toxin already fixed to neurons cannot be neutralized and recovery of nerve function depends on regrowth and formation of new synapses.
2. Supportive care with sedation and intubation common.
3. Muscle stiffness and clonus can last months after recovery.
Prevention:
1. Vaccination: part of vaccination schedule for those under the age of 10 years, with boosters for those with unknown or incomplete status or travellers to remote areas.
Management of Tetanus:
- Prone wounds: these include those with a large amount of contact with soil/manure or containing foreign bodies, compound fractures, or those associated with sepsis.
- Give tetanus Ig for immediate protection regardless of immunization history, and if this is not up-to-date (or patient is immunocompromised) give additional booster doses of vaccine as well.
RFs for botulism/features/management:
- Can be food-borne (particularly home-preserved foods), or from wound contamination.
- Intravenous drug users are the most common group presenting with the latter. Several countries have tried to create biological weapons from the toxin.
Features of Botulism:
Patients present with visual disturbance and dysphagia. This progresses to descending weakness and flaccid paralysis, with respiratory failure in some cases
Management:
1. Management is supportive, in addition to the use of antitoxin (20% experience hypersensitivity reactions to this including serum sickness and anaphylaxis).
2. Recovery takes weeks to months, with a fatality rate of 5-10%.
what organism causes gas gangrene?
Caused by Clostridium perfringens and a number of other clostridia.
pathophysiology/diagnosis/management of gas gangrene:
- Pathophysiology of Gas Gangrene
-Life-threatening infection of traumatic or surgical wounds, with the release of alpha and theta toxins.
-These lead to necrosis and microvascular thrombosis, with localized gas (hydrogen, CO2, nitrogen, and oxygen) production. Rhabdomyolysis, renal failure, red blood cell haemolysis, sepsis and generalized shock can ensue. - Diagnosis of Gas Gangrene
-Diagnosis is dependent on the culture of specimens from the affected skin as well as blood cultures. - Management of Gas Gangrene
-Management: infection progresses rapidly so prompt therapy is essential.
-Antibiotics should be given to cover gram-negative, gram-positive and anaerobic organisms (penicillin, gentamicin, and metronidazole for example), but these cannot penetrate necrotic tissue.
-Hence, surgical debridement (and possibly amputation) is essential to control the infection.
-Hyperbaric oxygen therapy may be used to kill the anaerobic clostridia, though the evidence is lacking.
signs/symptoms of EBV after giving amoxicillin:
Transient macular rash, viral hepatitis (deranged LFTs), raised inflammatory markers
clinical features of EBV:
Fever and malaise
Sore throat
Transient macular rash
Lymphadenopathy in the neck
Mild hepatosplenomegaly
Investigations for EBV:
- FBC - shows raised lymphocytes
- Monospot test (heterophile antibodies)
Should be performed in 2nd week of illness
If negative, should be repeated in 5-7 days. - EBV viral serology can be used if under 12, immunocompromised or the Monospot remains negative but clinical suspicion is high.
- Abdominal ultrasound - if assessment of splenomegaly is needed
Management of EBV:
- Management is essentially conservative - the illness is expected to resolve within 2-4 weeks.
- Analgesia
- Avoid alcohol during illness
- Avoid ampicillin and amoxicillin - can cause an itchy maculopapular rash
- Avoid contact sports for at least 3 weeks (due to risk of splenic trauma)
Which viruses are spread via aerosols
rhinovirus, coronavirus, adenovirus and respiratory syncytial virus can be spread by airborne droplets or aerosols
eg of waterborne infection:
cholera
skin-skin contact viral spread egs:
impetigo or scabies
Diagnosis of measles:
1st: measles specific IgM and IgG serology (ELISA) is most sensitive 3-14 days after onset of the rash
2nd: measles RNA detection by PCR best for swabs taken 1-3 days after rash onset
Complications of measles (mnemonic):
- otitis media: the most common complication
pneumonia: the most common cause of death - encephalitis: typically occurs 1-2 weeks following the onset of the illness)
- subacute sclerosing panencephalitis: very rare, may present 5-10 years following the illness
- febrile convulsions
- keratoconjunctivitis, corneal ulceration
- diarrhoea
- increased incidence of appendicitis
- myocarditis
Management of measles:
- Supportive care which will normally include an antipyrexial
- Vitamin A in all children under 2
- Ribavarin may reduce the duration of symptoms but its use is not routinely recommended
A 75-year-old female presents to the emergency department with a cough and shortness of breath, which has worsened over the last week. She has a past medical history of hypertension and has recently had a viral “chest infection.” On examination, she is pyrexial, and a chest x-ray shows a cavitating lung lesion in the right lower zone.
What is the most likely causative organism?
A. Pneumocystis jirovecii (PCP)
B. Klebsiella pneumoniae
C. Staphylococcus aureus
D. Streptococcus pneumoniae
E. Tuberculosis
C. Staphylococcus aureus
Staphylococcus aureus tends to follow viral pneumonia. The young and the old are at increased risk compared to the rest of the population.
Not E: TB
Nothing in the patient’s background puts her at increased risk of tuberculosis.
Differentials for cavitating lung lesions:
- Infective
Bacterial: S. aureus, TB, Klebsiella, S. pneumoniae
Fungal: histoplasmosis, coccidiomycosis, candida (not aspergillomas, as these grow in pre-formed cavities) - Malignancy
Primary
Secondary - Rheumatological
Vasculitis: Granulomatosis with polyangiitis
Rheumatoid nodules - Other:
Sarcoidosis
Pulmonary embolism
what does IL-4 do?
B cell class switching –> specific IgE primes mast cells via Fc region
what does IL5 do?
promotes eosinophils
allergic disease investigations:
- skin prick testing: positive test=3mm+> negative control (positive control=histamine)
- IgE test (aka RAST)
- oral challenge (gold standard) : close supervision required (risk of anaphylaxis)
non-IgE mediated allergic disease pathophysiology/egs:
-loca lymphocytic destruction: subacute–> chronic
-coeliac disease; food protein-induced enterocolitis syndrome (IgA)
what histological pattern is seen in type 3 hypersensitivity reactions/organ distribution:
FIBRINOID NECROSIS : usually in kidneys, joints & blood vessels
CD4 response in type 4 hypersensitivity reaction:
ROS (reactive oxygen species) generation, lysozymes, inflammation, cytokines + immune cells
CD8 response in type 4 hypersensitivity reaction:
apoptosis & programmed cell death, perforin/granzyme release
what type of reaction is goodpasture’s syndrome/pathophysiology?
Type 2 hypersensitivity reaction
-Non-collagenous domain of basement membrane collagen type IV
-Anti GBM Ab
Linear Smooth IF staining of IgG deposits on BM
Goodpasture’s syndrome is caused by autoantibodies that recognize the basement membrane (type II hypersensitivity) of the pulmonary and renal blood vessels, resulting in glomerulonephritis and pulmonary hemorrhage. This is usually a disease of childhood.
-(Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
In T1 hypersensitivity reaction, immunoglobulin E bind to what (expressed by mast cells, basophils & eosinophils)?
Fc region
what are important determinants for someone rejecting a transplant?
- HLA/MHC compatibility
- ABO blood groups
where is HLA encoded?
chromosome 6
most important determinant of transplant rejection
DR
(DR> B>A)
HLA 1 vs 2 (MHC1 and 2) differences:
How many mismatches?
Donor (dad): A-11 from dad=1 mismatch from recipient and donor
B51 and B27=mismatch
Total mismatches over group =2, maximum mismatches=6, perfect donor=6 matches
location of antibody-mediated rejection
to do with vessels eg endothelium (intra-vascular disease)
what will definitively confirm the diagnosis of transplant rejection?
Biopsy
Induction of immunosuppressant possible agents:
ATG/OKT3 or anti CD52 or anti CD24/anti-IL2R
specific treatment for T cell transplant rejection
Methylprednisolone
ATG/OKT3
specific treatment for B cell transplant rejection
plasma exchange
IVIG
antiC5
antiCD20
what is GVHD (graft vs host disease)?
Irreversible attack of donor lymphocytes on recipient HLA causing GI, skin, bone manifestations
-Typically, this occurs when the recipient is heavily immunosuppressed (and cannot destroy the donor lymphocytes) or very young. To counteract this, immunosuppressive drugs such as methotrexate may be used.
GvHD presents typically with damage to mucosal surfaces in the area of the transplant. In the GI tract, this may present with severe diarrhoea, abdominal pain and vomiting. In the skin, typically a maculopapular rash.
concerns about DNA vaccines:
- relatively new technology (risk of DNA integrating into host)
- possible autoimmunity responses eg SLE
- need target that invokes good immune response
what is interferon alpha given for? (mnemonic)
Interpheron Alpha for Hep B and C + CML
what can interferon gamma be given for?
chronic granulomatous disease
where is interferon beta given?
MS (relapsing-remitting to halt progression of further demyelination)
what is CTLA-4 (Ipillimumab) given for?
allows T cell activation
What is PD-1 (programmed death ligand 1) aka Nivolumab) used for?
prevents T cell death used in metastatic renal cell cancer/advanced melanoma
how does tacrolimus/ciclosporin work?
Inhibits calcineurin–>prevents T cell proliferation/function via reduced IL-2 expression
how does Sirolimus, Rapamycin work?
mTor inhibitor, inhibits T cell proliferation via IL-2 pathway
how does Sirolimus, Rapamycin work?
mTor inhibitor, inhibits T cell proliferation via IL-2 pathway
cell surface antigens (immunosuppressant) examples
CD80 normally binds cd28: co-stimulatory signal to bind T cell
-CD80 is capable of binding both CD28 and CTLA-4. This ligand is expressed by APCs, and serves as one of the co-stimulatory molecules of T-cell activation. CD80 has a greater affinity for CTLA-4 over CD28.
“FEDlizumab; related to being FED in IBD)
cytokine agents (immunosuppressants) summary:
MS patient: young Scandinavian lady called Natali –> natalizumab
what is Mycophenolate mofetil? why is it used?
the pro-drug of mycophenolic acid (MPA), an antiproliferative agent that interferes with purine synthesis, thereby suppressing the immune response.
immunosuppressants (key complications) summary:
Denosumab complications: use:
avascular necrosis of jaw (similar to bisphosophonates)
-used in osteoporosis to prevent bone resoprtion
steroids complications/how to avoid?
adrenal suppression–> do NOT stop suddenly!
MMF (Mycophenolate mofetil) complications
PML: Progressive multifocal leukoencephalopathy (JC virus reactivation)
-Human polyomavirus 2, commonly referred to as the JC virus or John Cunningham virus
Azathioprine (AZT) complications:
Bone marrow suppression (check TPMT: enzyme involved in metabolism of drug or do a genetic screen to check for polymorphism)
WCC raised:
-steroids can cause transient neutrophilia because they block neutrophils from being able to escape from blood cells into the tissue
(more specific answer: neutrophilia)
-CRP may be raised in inflammatory conditions (should start coming down after steroids)
-steroids not necessarily associated with renal failure
what virus is associated with oral hairy leukoplakia?
EBV
HIV confirmatory tests:
ELISA: 1st line, Western blot: confirmation test
A first line screening test for HIV is a fourth generation Enzyme Linked Immunosorbent Assay (ELISA) test. It may result in a false positive test.
If the ELISA is positive, to confirm diagnosis, a Western Blot may be used. The combination of both methods is very accurate.
A HIV viral load of less than 40 copies per mL of blood is considered to be undetectable.
HIV life cycle and drug targets
3 different agents (prevent multiple drug resistance)
what is the term for a transplant Between genetically identical members of the same species (self transplant or from an identical twin)
isograft
What is the name given to the immunological process that must have occurred prior to a hyperacute transplant rejection?
sensitisaton
Sensitisation refers to the immunological process where, after being exposed to an antigen, an immune response is generated against the antigen.
Typically the first exposure will have no symptoms, but the second exposure results in a vigorous response.
Examples include IgE mediated allergic reactions (first exposure activates B cells, which class switch and produce IgE antibodies. These IgE antibodies bind to mast cells). Alternatively, hyperacute transplant rejection is due to preformed antibodies against ABO.
HLA types DR, DQ and DP are what class of the major histocompatibility complex (mnemonic)?
class 2
Human Leukocyte Antigen (HLA) is the human specific term for the Major Histocompatibility Complex (MHC).
HLA classes A, B and C are MHC Class 1 (one letter = class one)
HLA classes DR, DQ, DR are MHC Class 2 (two letters = class two).
The most important HLA classes with respect to transplant are DR > B > A
Up to 6 HLA subtypes may be inherited, 3 from each parent.
They are expressed in a co-dominant fashion, meaning all will be expressed.
Where are IgA antibodies typically found in the body?
mucosal surfaces
-Secretory IgA is a dimeric antibody typically found on mucosal or epithelial surfaces, such as in the mouth or gut.
It is also the main antibody found in breast milk. It is made up of two immunoglobulin molecules joined by a J chain. It may also contain a secretory component, which allows for transmigration across epithelial surfaces. As it is a dimeric antibody, there are 4 antigen binding sites. There is also a monomeric form that typically circulates in serum.
Its main function is neutralisation - blocking pathogenic ligands from binding to epithelial cell surface receptors.
Other than T lymphocytes, what cell type is primarily infected by HIV?
Macrophages
-Typically, HIV infects CD4+ T helper cells, predominantly in the gut. Less commonly it may infect macrophages.
This leads to severe immunosuppression over a period of years and eventually Acquired Immunodeficiency Syndrome (AIDS)
What are the pathogenic antibodies in bullous pemphigoid?
Anti-Hemidesmosome
-Anti-Hemidesmosome antibodies are the pathogenic antibodies in bullous pemphigoid, as they target the proteins that anchor the epidermis to the basement membrane.
antibody present in Pemphigus Vulgaris:
anti-cadherin
antibodies in pernicious anaemia:
anti parietal cell antibodies
antibodies in pernicious anaemia:
anti parietal cell antibodies
antibodies in ITP:
anti-platelet antibodies such as anti-glyoprotein IIb/IIIa
antibodies in haemolytic disease of the newborn:
maternal IgG against fetal erythrocyte antigens
A 34 year old man has severe Crohn’s disease. His gastroenterologist wishes to start a biologic drug, infliximab. What infection should be ruled out before commencing the drug?
Tuberculosis
-Monoclonal antibodies directed against TNF-alpha are associated with activation and dissemination of latent TB. TNF-alpha is vital for the control of TB infection in the lungs. If it is blocked, TB can grow unchecked. Hence, prior to starting treatment with an anti-TNF-alpha antibody, a mantoux test should be performed to exclude exposure to TB. If the mantoux is positive, an interferon gamma release assay (IGRA) is then performed. If that is also positive, the patient has latent TB and requires treatment before starting the biological therapy.
What antigen is injected intradermally as part of the mantoux screening test for tuberculosis?
Tuberculin Purified Protein Derivative
The mantoux test measures the immune response to tuberculosis antigens.
A Purified Protein Derivative of Tuberculin is injected intradermally.
The size of the induration (not erythema) is measured after 48-72 hours.
If a patient has previously been exposed to tuberculosis antigens (via any form, including previous mantoux tests or active infection) then they will react vigorously and create an area of induration around the injection site.
Immunosuppressed people will mount a weaker immune response, hence the interpretation thresholds are smaller.
Interpretation:
> 5mm is positive in HIV or immunosuppressed patients or people at very high risk of TB (such as living with someone with active TB)
> 10mm is positive in IVDU, medium risk populations such as healthcare workers or children <4 years old
> 15mm is positive in low risk populations.
Infections by what type of bacteria are more common in patients deficient in the complement protein C3?
Encapsulated
The classical pathway is associated with the serine protease C1q binding to antibodies and leading to subsequent complement activation. Dysfunction of the classical pathway may lead to Lupus.
Deficiencies in complement proteins which make up the “Membrane Attack Complex” lead to increased risk of infection from encapsulated bacteria (e.g. meningoccocus)
A 80 year old lady received 2 units of FFP 4 hours ago due to a severe nosebleed and an INR of 4.8 on admission.
She takes wafarin for a metallic heart valve. Over the last hour, she is beginning to feel short of breath, especially when lying down. She is hypotensive at 95/40 and SpO2 of 94% on 8L/min O2.
She is pyrexic at 37.8C.
What complication of blood transfusion is she suffering from?
Transfusion Related Acute Lung Injury
Transfusion related acute lung injury (TRALI) is due to the presence of leukocyte (neutrophil) antibodies causing white blood cells to aggregate in the pulmonary circulation as it passes through in the blood. The disease is characterised by acute onset pulmonary oedema, dyspnoea, severe hypoxaemia and hypotension.
Treatment is usually supportive with a good resolution within 2 days. However, severe TRALI may lead to acute respiratory distress syndrome.
What monoclonal antibody targets IL-17 and is involved in the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis?
Secukinumab is used in the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. It is a monoclonal antibody that targets IL-17, binding to it, rendering it inert and marking it for clearance by phagocytic cells.
What is the main metabolite of azathiroprine?
6-Mercaptopurine
Azathioprine is a antiproliferative immunosuppressant that particularly inhibits T cells. It is metabolised into the inert 6-mercaptopurine.
Mutations in an enzyme, TPMT (thiopurine S-methyltransferase), can mean that azathioprine is metabolised into a cytotoxic metabolite instead of 6 mercaptopurine.
Hence, before starting azathioprine all patients should have activity of the TPMT enzyme checked.
A patient is investigated for a primary immunodeficiency. Lymphocyte counts are normal. However, IgG and IgA are low. There is an excess of IgM. What condition is this patient likely to have?
Hyper IgM is characterised by high levels of IgM in blood and reduction in levels of other immunoglobulin classes. I
gM is the first antibody to be created during the immune response - all other classes of antibody require a process called class switching to occur. Class switching requires activation of CD40 on the surface of B lymphocytes to occur.
When CD40 is defective, only IgM can be produced. Typically this leads to increased infection risk, particularly Pneumocystis pneumonia.
You’re the surgical doctor on call and you’re called by the nurse to assess a patient on the ward. The patient is a 71-year-old woman admitted 6 hours ago with rectal bleeding and haemoglobin of 62g/L. You prescribed a blood transfusion of 1 unit of packed red cells which has been running for 1 hour when the nurse calls you: she’s worried because the patient has developed a fever and pruritis.
When you arrive to review the patient you find see that she looks comfortable at rest. Her observations are respiratory rate 16 breaths per minute, oxygen saturations 99%, blood pressure 128/84mmHg, heart rate 64 beats per minute, and temperature 38.7ºC. You can see that her temperature just before the transfusion started was 37.1ºC. The patient is also complaining of itchy skin over her tummy and arms and you can see a mild urticarial rash on her abdomen.
What is the next best step in the management of this patient?
A. Prescribe IV furosemide to run alongside the blood product
B. Stop the transfusion and administer treatment for anaphylaxis
C. Stop the transfusion and give 1g paracetamol IV
D. Stop the transfusion and make a severe hazards of transfusion (SHOT) report
E. Temporarily stop the transfusion and give an antihistamine
E. Temporarily stop the transfusion and give an antihistamine
During blood transfusions, minor allergic reactions may be managed by temporarily stopping the transfusion and giving an antihistamine
In this case, since the temperature has risen by <2ºC and the only other signs/symptoms are pruritis and a rash, we know this is a mild reaction. Therefore it is sufficient to prescribe an antihistamine (e.g. Chlorphenamine) and pause the transfusion - if symptoms/signs don’t worsen you can restart the transfusion.
Not B: Treatment for anaphylaxis is not necessary here as the patient has no signs/symptoms in keeping with an anaphylactic reaction (e.g. angioedema, cyanosis, respiratory distress).
Not C: Paracetamol would help bring down the temperature and provide symptomatic relief of the fever. However, stopping the transfusion permanently is unnecessary in a mild reaction. Also, an antihistamine would provide more symptomatic relief for the patient.
Not D: SHOT reports only need to be completed when a severe/life-threatening reaction occurs, or a moderate reaction if it is consistent with being transfusion-related.
blood product transfusion complications:
Blood product transfusion complications may be broadly classified into the following:
1. immunological: acute haemolytic, non-haemolytic febrile, allergic/anaphylaxis
2. infective
3. transfusion-related acute lung injury (TRALI)
4. transfusion-associated circulatory overload (TACO)
other: hyperkalaemia, iron overload, clotting
cd5 and cd19 and cd23 marker for:
B cells
-typically CLL
Doctors should measure the level/activity of which enzyme before prescribing azathioprine?
TPMT(thyropurine S-methyltransferase). is responsible for metabolizing azathioprine, and patients with a deficiency in this enzyme are at an increased risk of developing bone marrow suppression and other toxicities when taking the medication
what is Co-trimoxazole also known as?
Septrin
5 month baby has failure to thrive and recurrent infections. Investigations - mutation affecting IL2RG gene, which encodes IL2 common gamma chain. What is the diagnosis?
severe combined immunodeficiency X-linked (SCID-X1).
CAR T-cells are engineered to bind to CD19. They have immunoglobulin variable fragments to CD19 linked to cytoplasmic T-cell activation domains. They are effective in treating haem malignancies of which cell type?
B-cell leukaemias/lymphomas and acute lymphoblastic leukaemia (ALL) that express CD19 on their surface.
In bare lymphocyte syndrome which affects the HLA class II transactivator, which type of immune cell will be deficient?
CD4+ t-cells
the expression of HLA class II molecules is absent or severely reduced on the surface of antigen-presenting cells. As a result, the differentiation and maturation of CD4+ T cells into Th1 or Th2 helper cells are impaired due to the lack of co-stimulatory signals, which are mediated by the interaction between HLA class II molecules and T-cell receptors. Therefore, individuals with BLS have a deficiency in CD4+ T cells.
Difference between CD4 and CD8 T cells:
CD4 T cells are MHC-II restricted and pre-programmed for helper functions, whereas CD8 T cells are MHC I-restricted and pre-programmed for cytotoxic functions.
Mutation of CD40 ligand is associated with which form of primary immunodeficiency?
Hyper IgM syndrome
Denosumab is a monoclonal antibody specific for RANKL. What condition is it used to treat?
osteoporosis (denosumab=RANKligand inhibitor vs bisphosphonate, has a greater antiresorptive effect than bisphosphonates)
what antibodies are tested in coeliac disease?
Anti-TTG and anti-EMA antibodies are IgA. Some patients have an IgA deficiency.
When you test for these antibodies, it is important to test for total Immunoglobulin A levels because if total IgA is low because they have an IgA deficiency then the coeliac test will be negative even when they have coeliacs.
In this circumstance, you can test for the IgG version of anti-TTG or anti-EMA antibodies or simply do an endoscopy with biopsies.
what type of hypersensitivity is coeliac disease?
Type 4 hypersensitivity mediated by T-cell responses whereas allergy is usually classed as a Type I hypersensitivity mediated by E-type immunoglobulins (IgE antibodies).
seronegative spondyloarthropathy mnemonic
HLA B27 associated diseases
How is ANA detected?
ANA is typically detected using indirect immunofluorescence.
A patient’s serum is mixed with immortalised HeLa cells. Antibodies in the patient’s serum will bind to their target on the immortalised cells. The serum is washed off and a fluorescent tag that binds to human antibodies is added.
The pattern of immunofluorescence under a microscope suggests which antibodies are present.
what does this immunofluorescence pattern show?
Here is an example showing a homogenous pattern of ANA staining, suggesting the presence of anti-dsDNA antibodies.
what does this immunofluorescence show?
A “speckled” pattern, suggesting the presence of anti-centromere antibodies and hence CREST syndrome.
A 40 year old woman with Hashimoto’s Disease visits the GP for routine review of medication.
She reported feeling particularly tired recently and visited a private rheumatologist on the advice of friends.
The private rheumatologist ran an autoimmune panel of blood tests showing that she is positive for ANA, anti-TPO antibody positive and positive for rheumatoid factor. Other bloods were unremarkable except for low T3 and T4.
What condition is responsible for her symptoms?
Hashimoto’s thyroiditis
ANA and other auto-antibodies are often detectable in patients without evidence of disease. For example, approximately 10% of people are positive for rheumatoid factor - even though 10% of people don’t have rheumatoid arthritis. Diagnosis of rheumatological conditions often require a combination of symptoms and immunological evidence of disease.
What immune cell releases granzyme and perforin when activated?
T killer cells
CD8 is a co-receptor for the T cell receptor and recognises MHC class 1.
MHC class 1 is found on most nucleated cells and presents random intracellular peptides to CD8+ T cells.
If a T cell recognises a peptide-MHC class 1 complex, then the T cell activates and kills the target cell.
Please note: Simply writing “CD8” is not enough detail for the mark. CD8 is a cell surface protein. We use cell surface markers to classify T cells. Hence, CD8+ T Cells is acceptable - but CD8+ is not.
What lymphocyte lineage does cyclosporine predominantly inhibit?
T lymphocytes
Medications that inhibit Calcineurin, a protein needed for T cell proliferation, include tacrolimus or cyclosporine. Side effects include renal damage, hypertension or in the case of cyclosporine, gingival hyperplasia.
A 20 year old man is screened for primary immunodeficiencies by his GP after a number of recent, severe infections.
A full blood count was normal.
IgG and IGM low, IgA normal
Common variable immunodeficiency (GAE: low IgG, IgA, IgE: IgA (middle) can be normal)
Common Variable Immunodeficiency (CVID) is a diagnosis of exclusion in patients greater than 4 years old. The diagnostic criteria are:
Decrease in serum IgG and a decrease in one of IgM or IgA.
There is a lack of antibody response to antigens or immunisation
More than 4 years old.
Patients will have increased infections with bacteria such as Haemophilus, Strep (usually immunized against) and Staph. There is an increased rate of autoimmune conditions and malignancies. Treatment is with normal human IVIg for life.
An 9 year old boy has had recurrent chest infections and influenza like illnesses since joining primary school.
Blood tests reveal a low lymphocyte count, with very low B cells but normal T cell levels.
There as very low levels of IgM, IgA and IgG.
What immunodeficiency is this patient likely to have?
Bruton’s Agammaglobulinaemia is a rare X linked immunodeficiency caused by a mutation in the BTK gene, which codes for a tyrosine kinase required for B cell development.
Patients with this condition suffer from recurrent infections, typically from Streptococcal or Haemophilus spp. It often does not manifest until after 6 months, when the child loses passive immunity from the mother when breastfeeding.
There is a notable lack of lymphoid tissue (lack of tonsils and adenoids) or lack of lymphadenopathy during infections. There is a decrease in all immunoglobulins, though small amounts may be present. It can usually be managed by injections of normal human IVIg for life.
What antiretroviral drug is given as IV monotherapy during labour to prevent vertical transmission of HIV-1?
Zidovudine
HIV is treated using Highly Active Antiretroviral Therapy (HAART), sometimes called ART (antiretroviral therapy)
UK guidelines (BHIVA) suggest HAART should consist of three medications:
Two nucleoside reverse transcriptase inhibitors (NRTIs) and another class of drug.
Examples of the common drug classes include:
NRTI: Zidovudine, Abacavir
Non-nucleoside reverse transcriptase inhibitor: Efavirenz
Protease inhibitor: Ritonavir
Integrase inhibitor: Dolutegravir
Zidovudine is considered safe for use in pregnancy
What monoclonal antibody targets CD20 and is used in the treatment of lymphomas?
Rituximab
CD20 is classically a marker of mature (not immature) B cells. Plasma cells do not express CD20.
Targeting this cell surface protein therefore can deplete B cells without affecting plasma cell driven immunity.
Rituximab is a classic monoclonal antibody that targets CD20 and is used in the treatment of B cell driven diseases, such as some lymphomas.
What is the minimum number of Fc receptors on the surface of mast cells that must bind to an antigen to cause mast cell degranulation?
2
Immunoglobin E, IgE, is structurally very similar to IgG. It has two antigen binding sites. Is main role is in the protection against parasites and helminths. IgE uniquely binds to a special type of Fc receptor on the surface of mast cells. This binding is one of the strongest non-covalent bonds found in biological systems. This binding is therefore essentially irreversible.
If two IgE molecules on the surface of mast cells recognise antigen and cross-link, then this will lead to mast cell activation and in servere cases, anaphylaxis.
Immunoglobulin types summary
A prenatal autoimmune panel of bloods reveals positive anti-Ro antibody in the blood of a pregnant woman with SLE. What cardiological condition is her unborn baby at risk of?
congenital heart block
what’s the most common inherited immunodeficiency? what symptoms?
Selective IgA deficiency
-recurrent GI infection and respiratory tract infections
-A lack of IgA leads to infections of mucosal surfaces. Clinically, this may present as repetitive upper respiratory tract infections, ear infections or sinusitis. In most patients, the disease is mild and it is undiagnosed. There is an increased association with autoimmune diseases in patients with IgA deficiency.
what is the most severe form of SCID (symptoms):
Reticular dysgenesis
1. severe lifethreatening infections after birth
2. sensorineural deafness
3. deficiency of myeloid/lymphoid cell lineages
what is ADD deficiency?
Adenosine deaminase deficiency
-low T cells and low B cells
what’s the mutation in reticular dysgenesis?
Adenylate kinase 2 (AK2)
what’s the mutation in X-linked SCID?
mutation in gamma chain of IL-2 receptor on chromosome Xq13.1
-low T cell and NK cells
-high B cell numbers
Autoantibodies directed against Fibrillarin and Scl70 are classically associated with what autoimmune condition?
Diffuse Cutaneous Systemic Sclerosis
Antibodies associated with Diffuse Systemic Sclerosis include:
Anti-Scl70 (anti-topoisomerase)
Anti-Fibrillarin
Anti-centromere antibodies (present in around 10%)
The paediatric SpR is called to review a 21 day old infant who is pyrexic and appears unwell. The parents think he has a problem with his hearing as he has been tugging at his ear. There is pain, tenderness and swelling over the mastoid process of his left ear. Blood tests reveal a neutrophil count of 0.1 (normal range: 1.5-8.0) What primary immunodeficiency is this patient likely to have?
Kostmann Syndrome, otherwise known as severe congenital neutropenia, is characterised by frequent, severe bacterial infections (typically involving Staphylococcus)/can cause hearing loss.
There is a predilection to abscess formation and life threatening infections. Most suffers will have a severe infection in the first month of life, where a neutropenia will be identified on a full blood count.
Genetic testing may be done to identify the mutation (HAX1 protein mutation: HCLS-1 associated protein X1)
Treatment involves regular injections of granulocyte colony stimulating factor, which increases myelopoiesis and increases neutrophil levels.
what is the mutation in cyclic neutropenia?
mutation in neutrophil elastase (ELA-2)
