Immunology

What are the features of Shwachman-Diamond Syndrome?

- Biallelic defects in SBDS gene (Haters Be Hating, Shwachman Be Diamonding S) - Gene is involved in ribosome biogenesis and mitosis and is expressed in all human tissue - Skeletal abnormalities - Pancreatic insufficiency - Neutropaenia - Short stature/failure to thrive

What is Bare Lymphocyte Syndrome?

- Form of SCID - Caused by MHC-II deficiency = cant activate CD4 cells → CIITA gene or RFX gene → code for transcription factors that regulate the expression of MHCII genes - BLS II is more common - Susceptible to fungal and viral infections - Diarrhoea is very common - Also have reduced IgG, IgA etc - Reduced T-cells with normal B and NK counts

What are the features of Common Variable Immunodeficiency (CVID)?

- Mainly unknown genetic basis → B-cells can not differentiate into plasma cells - Affects males and females equally → usually 2nd/3rd decade, rarely <10yo - Recurrent infections with encapsulated bacteria - Non-caseating granulomas common - Deficiency in at least 2 classes of Ig (usually IgG and IgA +/- IgM) - Poor vaccine response (DTP, pneumococcal) - Low switched memory B-cells - Increased risk of autoimmune disease → AIHA, ITP Most common complications: infection, lymphocytic infiltrative pneumonia, autoimmunity → Patients are prone to recurrent infections: URTI/LRTI (H influenzae, S pneumoniae, M catarrhalis, S aureus, PCP, M pneumoniae), OM, sinusitis, diarrhea and malabsorption from Giardia lamblia infection (Rx metronidazole). Eczema common, sinopulmonary infection This is a hypogammaglobulinaemia with phenotypically normal B cells. Infections are similar to XLA but less severe. Equal sex distribution (unlike XLA). Clinical features: normal or enlarged tonsils, lymph nodes; splenomegaly ~ 25% patients. Treatment is with immunoglobulin replacement.

What are the features of Hyper-IgM syndrome?

- Most commonly X-linked Hyper IgM due to gene encoding the CD40 ligand (CD40 ligand deficiency) on T cells → unable to class switch from IgM - Deficiency of IgG, IgA and IgE but normal/high IgM - Increased susceptibility to PJP - Frequently neutropaenia or autoimmune diseae - IVIG/SCIG, prophylactic Abx (bactrim for PJP) - Tx HSCT

How does Bloom syndrome differ from Ataxia Telangiectasia?

- Small stature - Telangiectasias - Facial rash (erythematous photosensitive) - Immunodeficiency - Increased risk of leukaemias from ionising radiation - No ataxia

What are the features of X-linked agammaglobulinaemia? What virus causes chronic disease?

- XLAGG - X-linked - Defect in Bruton tyrosine kinase (BTK gene) → required for B-cell maturation → no mature B-cells present (normal precursors in bone marrow!) - Classic presentation: male infant, recurrent invasive infections since 6 months (passive immunity from mother weaned); absent adenoids and palatine tonsils Enteroviruses can cause inflammation of nearly every organ, but in XLA, infections often manifest as dermatomyositis or chronic meningoencephalitis. - Levels of Ab to Ag given in routine immunisations abnormally low (whereas transient in hypogammaglobulinaemia of infancy) Tx: Treat with IVIG, SCIG, avoid live vaccines

If Rubella vaccine is inadvertently given to a woman in the first four weeks of pregnancy the risk of vaccine related birth defects is closest to: a) 1%. b) 5%. c) 10%. d) 20%. e) 50%.

1% Pregnancy is contraindication to rubella vaccine administration Rubella vaccine virus may cross the placenta and infect fetus However, there have been NO cases of congenital rubella syndrome reported in women inadvertently vaccinated in early pregnancy Given the theoretical risk, women are advised to avoid pregnancy for 28 days following vaccination

What are the features of Chronic Granulomatous disease?

2/3 X-linked (CYBB gene resulting in gp91 deficiency) (Chronic Yuck Baby Bumps) Disorder of neutrophil function in which there is a deficiency of the oxidative burst. → Neutrophils migrate to sites of inflammation but cannot generate oxidative burst to effectively kill pathogens → Results in immune cells surrounding infection, forming a granuloma, but cannot do anything further → Commonly catalase positive organisms S. aureus, Aspergillus, Burkholderia, Salmonella Dihydrorhodamine (DHR) oxidation is the test of choice, which will show no DHR conversion Tx: prophylaxis (TMP-SMX, itraconazole), inerferon-gamma, HSCT (survival >90%)

What are the features of Complete DiGeorge Syndrome?

22q deletion syndrome Absent T-cells with thymic aplasia only <0.5% of patients Normal B and NK numbers May or may not have detectable thymus at cardiac surgery Treatment is BMT or Thymic transplant

If the full immunisation schedule has been properly administered to a two-year-old, which one of the following gives the LEAST effective protection? a) Diphtheria. b) Haemophilus influenzae type b. c) Measles. d) Pertussis. e) Rubella.

A: Diphtheria - estimated efficacy of diphtheria toxoid in prevention of diphtheria disease is 97% B: Haemophilus influenzae type b - protective efficacy of 2-3 doses of HiB conjugate vaccines is ≥95%. C: Measles - anti-measles antibodies develops in 95% of individuals vaccinated at age 12 months, 98% if vaccinated at 15 months. It usually leads to long-term immunity, >99% develop antibodies if the first dose of the two dose series is given no ealier than 12 months of age. D: Pertussis - efficacy of 3-4 doses of DTPa in preventing moderate to severe pertussis disease range from 59-89%. E: Rubella - one dose of MMR produces seroconversion rate of about 95% with fairly comparable durability of antibodies to natural infection. The correct answer is D.

What are the 4 primary types of hypersensitivity reactions?

ACID I: Allergic (IgE-mediated → mast cells) II: Cytotoxic (IgG antibody mediated → complement activation and opsonisation → MAC & phagocytes) III: Immune-complex mediated (IgG/IgA → complement activation) IV: Delayed (T-cells → cytokines; antibody independent)

What are the features of Ataxia Telangiectasia (AT)?

Autosomal recessive (ATM gene → DNA repair gene) - Presents first with ataxia by 5yo - Telangiectasia (conjunctivae, skin,e ars, neck) → Immunodeficiency → sinopulmonary disease, bronchiectasis - Increased risk cancer (DNA repair gene lost) → sensitive to ionising radiation, AFP and CEA elevated

Neutrophils are a critical component of the innate immune system. They are located within numerous body compartments. During a state of health (no infection or inflammation), which of the following represents the greatest proportion of neutrophils? a) Circulating in the peripheral blood. b) Bone marrow reserve pool. c) Peripheral tissues. d) Marginated pool (attached to the walls of blood vessels.)

B. The bone marrow reserve pool represents the largest pool of neutrophils and is thus critical to fighting infection. Conditions such as myelodysplasia and the effects of chemotherapy are likely to have significant risks of bacterial infection due to their impact on this neutrophil pool. D: The marginated pool is the second largest pool in a state of health. A: This answer is incorrect. This represents the pool of neutrophils detectable by blood sampling. Circulating neutrophils represent ~3% of the total neutrophil count.

What are the features of LymphocytIc/Lymphoid Interstitial Pneumonia (LIP)?

Benign lymphoproliferative disorder characterised histologically by diffuse interstitial and alveolar infiltration with polyclonal lymphocytes and plasma cells. - Failure to thrive - Recurrent infections - Generalised lymphadenopathy, salivary gland enlargement - Digital clubbing is usually noted at presentation - Hepatosplenomegaly - Associated with HIV, EBV, autoimmune - Viral illness can cause exacerbation of signs and symptoms

The protein shared by the alternate and classical complement systems is: a) C1. b) C2. c) C3. d) C4b. e) Properdin.

C3 The classical and alternative pathway interact with each other through the ability of both to activate C3. Cleavage of C3 can be achieved through C3 convertase of the classical pathway, C142 or of the alternative pathway C3bBb.

A six-month old girl presents to ED with profuse vomiting after a meal. Her mother gave her a small amount of egg yolk today for the first time, mixed with apple and pineapple puree. She has been breastfeeding and growing well and has recently started solids. She takes no regular medication, has no known allergies and is up to date with immunisations. She has eczema which is controlled with emollients. She was born at term by NVD with no concerns at birth. Airway is patent. Sats 94% on air. She is tachypnoeic but has no increased work of breathing and her chest is clear. Heart sounds are normal. CRT 2 secs. She appears pale and beside glucose is 1.8. VBG shows a compensated metabolic acidosis. Which of the following is the most likely diagnosis? a) Egg allergy. b) Food protein-induced enterocolitis syndrome (FPIES). c) Hereditary fructose intolerance. d) Fructose malapbsorption.

C: Hereditary fructose intolerance presents when a child consumes fructose for the first time. Children develop profuse vomiting, hypoglycaemia and lactic acidosis. In this case, the child is tachypnoeic to compensate. If children continue to consume fructose, they may go on to develop liver and renal failure. Some children naturally avoid fructose. It is caused by a deficiency of aldolase B which leads to impaired fructose metabolism. Avoidance of fructose prevents most complications. Food protein-induced enterocolitis syndrome (FPIES) is an allergy that is not IgE mediated. Children present with severe diarrhoea and vomiting following protein ingestion (most commonly cows' milk, or in the case of solids, rice). This child does not have diarrhoea and has not ingested cows' milk or rice. Children may have a raised white cell count and be misdiagnosed as infection. They do not usually have hypoglycaemia.

A four-month-old baby of Chinese descent, bottle-fed with a cows' milk-based formula, has a history of diarrhoea and positive faecal reducing substances. He has normal bowel motions when changed to soy formula. He is inadvertently given a cows' milk-based formula and ten minutes later he has profuse watery diarrhoea and rapidly becomes shocked. Which one of the following is the most likely explanation for the above response? a) Delayed hypersensitivity T cell reaction. b) Food protein-induced enterocolitis. c) IgE-mediated immediate-onset food sensitivity. d) IgG immune complex formation. e) Lactase deficiency.

C: IgE-mediated immediate-onset food sensitivity. Type I reactions (i.e. immediate hypersensitivity reactions) involve IgE-mediated release of histamine and other mediators from mast cells and basophils, which are the key mediators in anaphylaxis. Continuous or repeated exposure to an can result in chronic allergic inflammation. Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils can release many mediators (e.g. major basic protein), which can cause tissue damage and thus increase inflammation. This can result in structural and functional changes to the affected tissue. Food protein-induced enterocolitis is not Ig-E mediated, but an example of cell mediated hypersensitivity. It presents with irritability and protracted vomiting 1-3 hours after feeding, and chronically can cause bloody diarrhoea and bloating. Hypotension occurs in about 15%.

What are the clinical differences between Cartilage-hair hypoplasia and Schimke immunouseous dysplasia?

Cartilage-hair hypoplasia is an autosomal recessive disorder where children have immunodeficiency, short limbed dwarfism and sparse, fine hair. Hair may appear normal on clinical examination and only be detected as fine on microscopic examination. Children have increased risk of Hirschsprung disease, haematological malignancies and autoimmune disorders → mutations in the ribonuclease mitochondrial RNA processing gene. Schimke immuneouseous dysplasia is an autosomal recessive disorder which presents with short stature, spondyloepiphyseal dysplasia, immunodeficiency and progressive renal failure. Children may also have skin and eye abnormalities. Children with Schimke immuneouseous dysplasia develop nephrotic syndrome secondary to focal segmental glomerulosclerosis and will progress to renal failure. (Schimulates FSGS)

What are the clinical differences between Chediak-Higashi syndrome and Griscelli syndrome?

Chediak-Higashi syndrome presents with partial oculocutaneous albinism and immunodeficiency but not the mentioned hair findings. Giant cytoplasmic granules in leukocytes and platelets is pathognomonic for Chediak-Higashi syndrome. Griscelli syndrome is a rare, autosomal-recessive disorder caused by a mutation in the intracellular trafficking genes which leads to partial oculocutaneous albinism and immunodeficiency. Hair shaft findings are pathognomic: large, irregular clumps of melanin granules are distributed near the medulla of the hair shaft. The shaft appears uniformly white under polarised light microscopy. Blood film is normal.

Which cell types have Class I HLAs? Which cell types have Class II HLAs?

Class I HLAs: all cells except mature RBCs → present antigen to CD8+ T-cells which destroy the cell (e.g. GVHD) Class II HLAS: APCs (B-cells, macrophages, dendritic cells) → present antigens to CD4+ T-cells.

Defects in which of the following is NOT associated with Neisseria infections? a) Factor D. b) Properdin. c) C5-C9. d) Mannose binding lectin.

Complement disorders present with recurrent sinopulmonary bacterial infections, sepsis, and/or meningitis. The pathogens most commonly implicated are encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis. A: Factor D deficiency is a rare disorder which occurs in children of consanguineous parents and is associated with Meningococcal sepsis. B: Properdin deficiency should be considered in a male who presents with an unusual Neisseria serotype and/or a family history of Neisseria infection. C: In C5-C9 deficiency, children are usually otherwise healthy but have recurrent Neisseria infections of an unusual serotype. D: Mannose binding lectin deficiency is not associated with Neisseria infections but may cause increased susceptibility to rheumatic fever. The correct answer is D.

What are the features of Transient Hypogammaglobulinaemia of Infancy (THI)?

Decreased serum IgG with or without decreased IgA and IgM in an infant older than 6 months. - Usually, a term infant has IgG levels similar to the mother, which gradually falls. - Infants do not produce their own IgG until 2-3 months - Physiological nadir in immunoglobulin Normal/near normal antibody responses to protein immunisations.

Which one of the following biologically active components of the complement cascade is most directly responsible for the formation of transmembrane channels leading to cell lysis? a) C3a. b) C3b. c) C4a. d) C5a. e) C5-9.

E) C5-9 The Membrane Attack Complex is the lytic pathway of complement function and can be initiated via either C3b¯Bb¯3b or C4b¯2a¯3b. It is responsible for forming transmembrane channels which cause cell lysis.C5b is the first molecule of the MAC (very short-lived and biologically active). C5b rapidly attaches to cell surfaces and binds to one C6 molecule. The C5bC6 then binds to one C7 molecule and can then bind to the cell membrane via the C7. This then enables the binding of one C8 molecule. It is the C8 which inserts into the cell membrane and enables C9 to bind. These polymerise within the cell membrane (1-16 C9 molecules) resulting in a small pore being formed which causes cell lysis by osmotic shock.

Which of the following vaccines is LEAST likely to induce long term immunologic memory? a) Bacille Calmette-Guérin (BCG). b) Diphtheria-tetanus-pertussis. c) Haemophilus influenzae type B conjugate. d) Hepatitis B. e) Pneumococcal polysaccharide.

E: Pneumococcal polysaccharide. Immunologic responsiveness and efficacy is unpredictable in children < 2yrs age. A: BCG. Vaccine protection lasts 10-15 years B: DTP. Pertussis antibody wanes after 3-5 years, not measurable after 12 years. C: HiB. Vaccine will last until the child is at least 5 years old. D: Hep B. Despite some decline in anti-HBs titres with time, most vaccinated people remain protected against HBV infection.

A ten-month-old girl was admitted following the acute onset of generalised rash. This occurred 15 minutes after ingestion of a meal in a restaurant. Her usual diet includes cow milk based formula, fruit and vegetables, chicken, beef, rice cereal and wheat. Which of the following would be the most likely precipitant? a) Egg. b) Monosodium glutamate (MSG). c) Peanut. d) Shellfish. e) Strawberry.

Egg is the second most common allergy of childhood, and milk is already mentioned as being tolerated.

What are encapsulated organisms?

Encapsulated Bacteria are bacteria encased by a polysaccharide capsule. This capsule aids in evading phagocytosis and the host immune system. In healthy patients, the spleen plays a central role in opsonizing and phagocytosing encapsulated bacteria, thus removing these organisms from the bloodstream. Asplenia results in impaired opsonisation and increased susceptibility to infections by these organisms (SNKHSCP + extraintestinal E. coli)

Which one of the following vaccines is most likely to be damaged by freezing? a) Haemophilus influenzae type b conjugate. b) Hepatitis B. c) Measles-mumps-rubella. d) Meningococcal polysaccharide. e) Oral polio.

Generally the live viruses should be frozen in temperatures < 5 degrees prior to use. Hep B has been shown in an Indonesian study to be damaged when frozen.The correct answer is B.

Abnormalities in which component of the immune system are most responsible for gingivitis?

Gingivitis is common in patients with neutropenia.

Haemophagocytic lymphohistiocytosis is a disorder of immune dysregulation that can be primary or secondary to other immune deficiency syndromes, infections and malignancies. Diagnosis is established using a combination of clinical and laboratory findings. Which of the following is true? a) Marked elevation of ferritin is a sensitive and specific finding in HLH. b) Demonstration of haemophagocytosis is required for diagnosis. c) Treatment is usually not required as the disease course is self-limiting. d) There is no role for haematopoietic stem cell transplantation in the treatment of primary (inherited) HLH.

HLH is not uncommon, and most often occurs in young children. The classical presentation is of a progressive sterile febrile illness that leads to multi-organ dysfunction syndrome. A: This is the correct answer. Serum ferritin in the thousands is common, and this finding becomes more sensitive and specific as levels rise. One series reports a serum ferritin of >10 000 being 90% sensitive and 96% specific. B: This is not correct. Haemophagocytosis is the histological finding of red blood cells within ones own phagocytes. It is a supportive feature of HLH but is not required for diagnosis. C: This is not correct. Untreated HLH is almost universally fatal. D: This is not correct. Primary HLH can occur due to any number of genetic defects, mostly relating to NK and Cytotoxic T cell function. HSCT is the only curative treatment for primary HLH. The correct answer is A.

What are the features of C1 esterase inhibitor deficiency? How is it managed?

Hereditary Angioedema (HAE) HAE is a rare autosomal dominant condition in which C1 esterase inhibitor levels are reduced (HAE type I) or poorly functional (HAE type II). HAE is diagnosed by the finding of low C1 esterase inhibitor level or function. C4 level is also low during episodes of angioedema. Patients with c1 esterase inhibitor deficiency experience angioedema without urticaria typically affecting skin and mucosal tissue of the upper respiratory tract and GI system. As such, they can experience severe abdominal pain swelling which is usually self-limiting. However, laryngeal involvement can case fatal asphyxiation. Intubation is difficult once the anatomy of the upper airway is distorted by the swelling, and therefore, it should be performed immediately if there are any signs of respiratory distress or stridor. Other pharmacological treatment during acute attacks include C1INH concentrate derived from human plasma (most widely used), recombinant human C1INH, synthetic b2-receptor antagonist. Patients need to avoid exacerbating factors such as ACE inhibitors and stress. If mild/moderate, a 3 day course of tranexamic acid may be considered to shorten the duration of symptoms (12-25 mg/kg/dose (max 1.5g) 3-4 times per day) Antihistamines and corticosteroids have no role in the management of HAE related angioedema.

Interleukin 1 (IL-1) is primarily produced by which one of the following cell types? a) B cells. b) Large granular lymphocytes. c) Macrophages. d) Neutrophils. e) T cells.

IL-1 and IL-2 are produced by macrophages and polymorphs and have a target effect on T/B/NK cells. Their target effect is generally on T/B/NK cells to proliferate, differentiate and class switch. The correct answer is C.

What is the most common congenital immunodeficiency? What is the incidence?

IgA deficiency is the most common congenital immunodeficiency (1:500, 0.2%); most are asymptomatic. Symptoms can be seen at any age; >2/3 children with low levels of IgA are asymptomatic. Approx 1/3 have sinopulmonary infections → higher risk of mucosal infections increased risk of allergy, autoimmune disease (Coeliac disease, thyroid, IgA, T1DM) Risk of anaphylaxis from blood products (30-40%) due to antibodies against IgA IVIG not required (as IgG ok) and relative contraindicated (as may cause anaphylaxis → low IgA product with antihsitamine premed) Some patients go on to develop CVID Many medications can cause reversible IgA deficiency (e.g. phenytoin, lamotrigine, carbamazepine, captopril, thyroxine). Cyclosporin A can cause permanent IgA deficiency which persists even after the drug has been stopped.

Which one of the following major immunoglobulin classes in the human fixes the alternate complement pathway? a) IgA. b) IgD. c) IgE. d) IgG. e) IgM.

IgA molecules do not activate the classical complement pathway, but may activate the alternative complement pathway. IgG and IgM are capable of activating the classical complement pathway.

Which type of hypersensitivity are each of the following? IgA vasculitis Oral allergy syndrome Tuberculin reaction Serum sickness Type 1 Diabetes Immune thrombocytopaenia Graft vs. Host Disease Shellfish allergy Glomerulonephritis SLE Myaesthenia gravis Poison ivy Hay fever Graves disease Multiple sclerosis

IgA vasculitis: Type 3 Oral allergy syndrome: Type 1 Tuberculin reaction: Type 4 Serum sickness: Type 3 Type 1 Diabetes: Type 4 Immune thrombocytopaenia: Type 2 Graft vs. Host Disease: Type 4 Shellfish allergy: Type 1 Glomerulonephritis: Type 3 SLE: Type 3 Myaesthenia gravis: Type 2 Poison ivy: Type 4 (contact dermatitis) Hay fever: Type 1 Graves disease: Type 2 Multiple sclerosis: Type 4

Which of the following immunoglobulins fix complement when they bind to antigen? a) Only IgG. b) IgG and IgA. c) IgG, IgA and IgM. d) IgG and IgM. e) Only IgM.

IgG and IgM Complement is a group of serum proteins which work with complement antibody activity to eliminate pathogens. Complement is not antigen-specific and it is activated immediately in the presence of pathogen, so it is considered part of innate immunity. However, antibody activates some complement proteins, so complement activation is also part of humoral immunity. A complement-fixing antibody is one that activates complement when reacted with antigen. IgG fixes complement. Note that not all subclasses fix equally well (e.g. IgG4 does not fix complement). IgM is a good complement fixing Ig. IgA does not fix complement unless aggregated. Therefore, the correct answer is D.

What is Leukocyte Adhesion Deficiency (LAD)?

Immunodeficiency disorder involving both B and T cells and is characterized by an inability of leukocytes to migrate to the site of infection to kill offending microbes Autosomal recessive LAD1 is the most common: ITBG2 gene → aberrant CD18 protein expression (beta chain of B2 integrin) → neutrophils cannot extravasate and fight infection → Omphalitis and delayed umbilical cord separation (also LAD3), recurrent bacteria infection (staph), including DESTRUCTIVE gingivitis, pneumonia → Biopsy of ulcers sow absence of neutrophils / pus (c.f. pyoderma gengrenosum) → Often leukocytosis (making lots but can't get to infection) Treat: HSCT

What is IPEX syndrome? What is the gene associated? What is the classical triad?

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX syndrome) is a rare autoimmune disease. Caused by mutations in the FOXP3 gene (X-chromosome) The classical triad describes the most common symptoms of IPEX: intractable diarrhea, type 1 diabetes, and eczema. Symptoms usually begin shortly after birth. Other symptoms include: thyroid disease, kidney dysfunction, blood disorders, frequent infections, autoimmune hemolytic anemia, and food allergies, among others

A seven-year-old boy has trodden on a bee and presents to the emergency department with swelling and redness of the foot spreading to mid-calf. He has been stung on one previous occasion with only minor redness and swelling. He has a history of mild intermittent asthma. There are no other symptoms. What is the best management now, and for possible future stings?

Large local reactions develop over hours to days, and involve swelling of extensive areas >10 cm that are contiguous with the sting site, and may last for days. Localised skin responses to biting insects are likely caused by vasoactive or irritant materials derived from insect saliva (not IgE), thus antihistamines may not have a significant response except for symptom control of itch. For local cutaneous reactions, treatment with cold compresses, topical medications to relieve itch and occasionally the use of a systemic antihistamine or oral analgesic are appropriate. Steroids may have some effect in reducing inflammation but are not required. Remove any sting present by scraping. The risk of a systemic reaction after a large local reaction is only 5-10%, thus, venom immunotherapy is not recommended and carrying an Epipen is considered optional.

What is the management of anaphylaxis?

Lie the patient down, administer IM adrenaline 10 microg/kg (or use their Epipen) repeated every 5 minutes, consider fluid bolus and adrenaline infusion if refractory cardiovascular signs. NB: Initial management is IM not IV. 10microg/kg IV is the arrest dose of adrenaline, bolus dose is 1 microg/kg IV.

Deficiency in which component of the complement system leads to predisposition to meningococcal disease?

Meningococcal disease occurs in 50 to 60% of homozygous affected individuals with late/terminal complement component deficiencies of C5, C6, C7, C8 or C9, which are critical in supporting complement-dependent bactericidal activity against Neisseria spp.

What are the features of SCID? What is the most common gene affected?

Most common: X-linked SCID (IL-2Rɣ defect) 50% 15-20% AR adenosine deaminase (ADA) deficiency Presentation: - Sepsis - Chronic lung infections - Eczematous-like skin lesions - Diarrhoea - FTT - Candidiasis, severe nappy rash - PJP, CMV pneumonia - No tonsils, no thymic shadow Absence of thymus shadow on CXR Severe lymphopaenia from birth NNST: T-cell receptor excision circles (TRECs) are excised "junk" DNA which are surrogate measurement of T-cells Tx: HSCT X-linked SCID: - Absence of ɣc (aka. IL-2Rɣ) gene (common gamma chain, found on IL-2R, IL-7R, IL-4R etc.) - No T-cells or NK-cells - IL-2Rɣ component of several cytokine receptors including IL-2, IL-4, IL 7 i.e. signal transduction in T and B cell receptors Lack of IL2RG function results in near-complete absence of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes. → high B-cells (CD19) but no Ig production ADA deficiency SCID: 15-20% of cases T-, B- and NK- cells dATP accumulates in lymphocytes leading to toxicity Spectrum of disease → may present in adulthood PJP, Candidiasis, EBV, CMV, varicella

What are the features of neonatal onset multi-system inflammatory disease (NOMID)?

Most severe and rarest form of cryopyrin-associated periodic syndrome (CAPS) Autosomal dominant → almost all spontaneous Most commonly NLRP3 gene (only 50%) Very rare, auto-inflammatory disorder Presents at or within days of birth (often premature, SGA): - Recurrent, short fevers - Urticarial, migratory rash, or maculopapular - Overgrowth arthropathy, most commonly knees - Chronic aseptic meningitis → developmental delay, seizures - Hearing loss affects 75%, progressive, bilateral → specifically associated with CAPS compared to other periodic fever syndrome - Eye problems (uveitis, conjunctivitis, optic atrophy) - Macropcephaly - Hepatosplenomegaly

What innate immune cell plays a role in cancer immunity? What is the mechanism of this role?

Natural Killer cell - Do not express T-cell or B-cell receptors - Recognise cell with reduced or no MHC Class I (which some cancer cells down-regulate to allow evasion by T-cells)

What are the features of Netherton Syndrome?

Netherton syndrome is a severe disorder of cornification caused by (SPINK5; AR) mutations, that presents with the three following characteristics: Ichthyosiform erythroderma - inflamed, red, scaly skin Trichorrhexis invaginata ('bamboo hair') - short, brittle, lustreless hair Atopic diathesis - predisposition to allergy problems. Trichorrhexis invaginata of hair is also known as "bamboo hair" and is pathognomonic of Netherton syndrome.

What are the common chemotactic molecules that signal for neutrophil migration and activation?

Neutrophils are one of the earliest cell types recruited to areas of inflammation. The complement components C3a and C5a and the cytokines IL-1b and IL-6 are chemotactic molecules for neutrophil migration and activation. Killing of pathogens is by both phagocytosis and secreted proteins.

What is Omenn syndrome? What are the genes associated with it?

Omenn syndrome is a variant of SCID (severe combined immunodeficiency). Recombinase activating gene 1 defect and recombinase activating gene 2 defect (RAG1 and 2) are associated with Omenn syndrome. Unable to eliminate self reactive antibodies, so have lots of self antigens → presentation similar to GvHD. Children present with recurrent infections, exudative erythroderma, lymphadenopathy, hepatosplenomegaly, chronic persistent diarrhoea, and failure to thrive. Also check for 22q11 deletion (complete DiGeorge!) Tx: HSCT

What are the criteria for HLH? What is the management?

Pathogenesis: cytotexic defect → lack of target cell kill → uncontrolled activation of lymphocytes → inflammatory cytokines → activation of macrophages

What group of patients have the highest risk of latex allergy?

Patients who are frequently exposed to latex as a result of multiple surgeries (esp. abdominal) (not just spina bifida) Most common is Type 4 delayed, but Type 1 can occur → against Hevein protein The most high profile is children with spina bifida, who were sensitised through direct mucosal exposure as a result of multiple surgeries and frequent bladder catheterisation. Interesting cross reactivity with multiple fruits and vegetables (PeeKaBoo PACT: Papaya, Kiwi, Banana, Potato, avocado, cestnut, tomato)

What is the likelihood of outgrowing the following IgE mediated hypersensitivity reactions: Penicillin Egg Bee venom Peanut Treenut (caser, almonds etc. Soy bean

Penicillin: 50-75% after 15 years Egg: 70% by 16 years Dairy: 80% by 16 years Bee venom: 95-97% via immunotherapy Peanut: 20% by age 6 Treenut: 9% by age 6 Soy bean: Similar to milk (80%)

What is Hyper-IgE syndrome?

Rare, primary immunodeficiency distinguished by the clinical triad of atopic dermatitis, recurrent skin staphylococcal infections, and recurrent pulmonary infections. The two most common forms result from variants in STAT3, causing loss of function (STAT3-LOF), and DOCK8. The dermatitis in HIES resembles classic atopic dermatitis. The distribution is not different, but it may have distinctive features. The rash is often present at birth or within the first few weeks, unlike atopic dermatitis (which appears after 3 months of age). These patients are also at increased risk of osteoporosis and spontaneous bone fractures. It is inherited as an autosomal dominant disease.

Which of the following genes is most commonly associated with severe congenital neutropaenia? a) ELANE. b) HAX1. c) WASP. d) G6PC3.

Severe congenital neutropaenia is rare - approximately two per million. Most cases of neutropenia are acquired and are due to increased destruction, granulocyte apoptosis, or decreased granulocyte production. A: ELANE gene mutation is an autosomal dominant mutation which accounts for 60% of cases of severe congenital neutropaenia (SCN). It was discovered when multiple children who were born SCN as a result of sharing the same affected sperm donor.

A well 14-year-old girl is travelling to Zimbabwe and Malawi on an exchange program for three months. She leaves in six weeks. She plans to visit villages and attend school. Which one of the following plans is most appropriate for preventing hepatitis A virus (HAV) infection during her visit? a) HAV vaccination and immunoglobulin given now. b) HAV vaccination given now. c) HAV vaccination now, test for antibody titres before departure and if negative administer immunoglobulin. d) HAV vaccination within one week of departure. e) Immunoglobulin administered as close as practical to the time of her departure.

Single dose HAV vaccination now The majority of studies demonstrate almost a 100% seroconversion rate after a primary vaccination course in both adults and children. Furthermore, the antibody concentration achieved with the Hep A vaccine (HAV) is much greater (nearly 15 times in one report) than the concentrations reached with protective doses of immune globulin. The response is also much more long-lasting. One study showed 100% were still seropositive at week 24 post Hep A vaccination whereas 0% were still seropositive at week 20 after IVIG. Individuals with recent exposure to HAV who have not previously received HAV vaccine should be administered a single dose of single-antigen HAV vaccine or immune globulin (0.02 ml/kg) as soon as possible. For healthy individuals aged 12 months to 40 years, single-antigen HAV at the age-appropriate dose is preferred. For children aged <12 months, immunocompromised individuals, patients with chronic liver disease, and individuals for whom vaccine is contraindicated, IG should be used.

What is the chance of recurrence of anaphylaxis in a child stung by a bee? What about the sibling of a child who has anaphylaxis to a bee sting?

The Apidae family (honey bees) and the Vespidae family (yellow jackets, yellow hornets, white-faced hornets, and paper wasps) belong to the order Hymenoptera and account for most of the stings that lead to anaphylactic reactions. Children who have had a previous anaphylactic reaction have a 30% risk of recurrence. In Adults it can be up to 60%. VIT is safe and highly effective - reducing to risk to 5%. People with local reactions have a low risk of a future anaphylactic reaction. A family history does not put a child at increased risk - the risk of anaphylaxis is <1%. Venom specific IgE is not indicated because it is common to have a positive test but not to exhibit symptoms when exposed. Asymptomatic sensitisation may be >30%. There is no indication for testing as a positive result without a history of anaphylaxis does not predict future risk.

BCG (Bacille Calmette-Guérin) vaccine is most likely to reduce the risk of: a) cutaneous tuberculosis. b) latent tuberculous infection. c) pulmonary tuberculosis. d) tuberculous adenitis. e) tuberculous meningitis.

The major role of BCG vaccination is the prevention of serious and life-threatening disease such as disseminated tuberculosis and tubercular meningitis in children. The BCG vaccine does not prevent infection with M tuberculosis. Two meta-analyses of the various trials concluded that the vaccine is efficacious against miliary and meningeal tuberculosis.

A six-week-old infant received her six-week immunisations. She was noted to be "floppy" with colour change within 10 seconds of the injections. There was taken to the emergency department for assessment. There were no cardiorespiratory concerns and there was no rash. The infant however remained floppy and was poorly responsive. There was no convulsive activity and her vitals were all within normal range. She received a dose of adrenaline for presumed anaphylaxis and then a dose of midazolam for possible seizures. What did she have? What vaccine?

This patient has had a hypotonic hyporesponsive episode (HHE) that is classically associated with the vaccine for pertussis. It occurs in children less than two years old. There is sudden onset of muscle limpness, reduced responsiveness and pallor or cyanosis after vaccination. It can last from six minutes to several hours and is commonly mistaken for anaphylaxis or seizures. Typically, patients with reduced consciousness secondary to anaphylaxis would have a low blood pressure which this patient did not have.

A four-year-old boy was seen in the allergy clinic. He has been complaining of perioral and oral pruritis and tingliness following ingestion of mangos. This is associated with a mild rash around his mouth. There are no cardio-respiratory or gastrointestinal involvement. The sensation appears within five minutes of eating mangos, and it usually resolves within 30 minutes of eating. He is otherwise well, and this does not significant impact on his lifestyle. He does not experience this when he eats dried mango. How would you manage this boy? a) Pre-medication with antihistamines whenever he eats mango. b) Strict avoidance of mango as he is at risk of developing systemic reactions. c) Immunotherapy for allergens related to mango. d) Continue to eat dried mango or in forms in which it does not cause symptoms.

This patient has oral allergy syndrome (OAS). Features of OAS include itchiness, tingling sensation and mild swelling and rash around the mouth, lips and palate and occurs with plant foods such as fruits and vegetables. It may be accompanied by nausea and abdominal discomfort. The symptoms occur within 10 minutes of ingestion and usually resolves soon after swallowing. Very rarely does OAS result in a systemic reaction akin to anaphylaxis. OAS is managed by dietary avoidance of the offending plant food in the form in which it causes symptoms. Cooking, baking, or even briefly microwaving the food is usually sufficient to alter the allergen protein for the patient to tolerate eating. If the symptoms are mild, strict avoidance may not be necessary. Premedicating with antihistamine is not generally recommended as it lacks evidence. The use of immunotherapy is established for allergic rhinitis and allergic asthma but lacks consistent efficacy for OAS. This patient does not have any evidence of a systemic reaction and therefore strict avoidance is not necessary as the risk of anaphylaxis is low. The correct answer is D.

What are the causes of delayed fever / inflammatory markers? How does it present?

Toll-like receptor defects (PID) TLR: innate immune system IRAK4 and MyD88 deficiencies Very rare AR disorders Present with invasive pneumococcal infections < 2 yo (Less so Staphylococcal and pseudomonas) Delayed onset and weak fever with low inflammatory response / markers due to impaired production of pro-inflammatory cytokines (IL-1 and IL-6)

A premature, low-birth-weight baby in SCBU was born at 28 weeks by emergency c-section. She required resuscitation at birth and CPAP for 10 days. She had 48 hours of antibiotics for suspected sepsis, which were stopped when no organisms were cultured from her blood sample at birth. She became anaemic at 29 weeks and was requiring CPAP so received a blood transfusion. She was weaned from CPAP to nasal prong oxygen (NPO2) three days later. She stopped NPO2 two days later. She is fed via nasogastric tube. At 31 weeks corrected gestational age, she develops a rash, fever and diarrhoea. Blood results reveal pancytopaenia and deranged liver function tests. A skin biopsy reveals satellite dyskeratosis. What is the most likely cause of her recent deterioration?

Transfusion-associated Graft Versus Host Disease (Ta GVHD) The key to this scenario is the biopsy result of satellite dyskeratosis. This pathognomonic of transfusion associated GVHD (Ta GVHD). Other characteristic findings include vacuolization of the basal layer and a histiocytic infiltrate. Ta GVHD occurs when lymphocytes from donated blood are either not recognised by the patient or the patient's immune system is unable to destroy them. The skin, bone marrow, and gastrointestinal track are most often affected. It occurs 4-30 days after transfusion but usually occurs in the second week post transfusion. It is rare and difficult to treat but can be prevented by the use of irradiated blood products. Children with immunodeficiency (either primary or secondary to chemotherapy), haematological malignancy or haematopoeic cell transplantation, and premature low birth weight babies are at risk. Children in these groups should receive irradiated blood.

Which one of the following capsular polysaccharides of Neisseria meningitidis is LEAST immunogenic? a) A. b) B. c) C. d) W-135. e) Y.

Unfortunately, the group B polysaccharide is a very poor immunogen in humans probably due to the similarity of its immunochemical structure to human intracellular adhesion molecules. A meningococcal B vaccine has been developed in the last couple of years. This is not included as part of the routine immunisation schedule, but can be obtained privately. The correct answer is B.

What are the features of Wiskott Aldrich Syndrome?

X-linked disorder WEXIT: Wiskott Aldrich Syndrome: Eczema X-linked (Xp11.22 → WASP gene) Immunodeficiency Thrombocytopaenia (micro) Boys present with bleeding → prolonged bleeding from circumcision, blood diarrhoea Staph skin infection Recurrent sinopulmonary infections, chronic OM Elevated serum IgE

What are the clinic differences between X-linked Agammaglobulinaemia and X-linked Hyper-IgM syndrome?

XLA: - Defect in BTK gene → no mature B-cells present - Severe, presents after 6 months once passive Ig waned - Absent adenoids + tonsils - No B-cells → very low/undetectable immunoglobulin XHIGM: - Defect in CD40 ligand on CD4+ T-cells - Unable to class switch from IgM - Presents with failure to thrive and opportunistic infections (PJP is presenting problem in 40%), OM, sinusitis → Cryptosporidium, cholangiocarcinoma - Normal B-cell number but low IgG/A/E, normal/high IgM - BMT = 70% survival