Immunology Flashcards
- Immunodeficiency (1)
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS
1 A 4-month-old girl is referred to a paediatrician with failure to thrive, after suffering from recurrent infections since birth, especially recurrent candida infections of her skin and mouth. Blood tests reveal a diminished T-cell count; further lymphocyte testing demonstrates non-functional B cells.
1) B
Severe combined immunodeficiency (SCID; B) causes defects in both T cells and B cells. Most common subtypes categorized into an X-linked disease (mutation of IL-2 receptor) or an autosomal recessive condition (mutation of adenosine deaminase gene which leads to a build-up of toxins and hence compromised proliferation of lymphocytes). There is hypoplasia and atrophy of the thymus and mucosa-associated lymphoid tissue (MALT). SX: diarrhoea, failure to thrive and skin disease (graft-versus-host induced, secondary to transplacental maternal T cells or blood transfusion-related caused by donor T cells).
Hyper IgM syndrome (C) = mutation in the CD40 ligand on T cells leading to impaired communication with B cells. B cells are unable to class-switch, therefore only produce IgM (leading to increased levels in the blood). Patients deficient in IgA, IgG and IgE.
In leukocyte adhesion deficiency (LAD; D) neutrophils are formed but cannot exit blood stream due to a deficit in leukocyte adhesion molecules resulting in reduced neutrophil chemotaxis. The neutrophil count is very high due to persistence in the blood stream. NBT test is positive.
Cyclic neutropenia (F) is an autosomal dominant condition = mutation in the neutrophil elastase gene (ELA2). Neutropenia occurs every 3 weeks and lasts ~6 days at a time.
AIDS (I) = reduced CD4+ T-cell count. Greater risk of developing opportunistic infections, e.g. PCP.
- Immunodeficiency (1)
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS
2 A 5-month-old boy is referred to a paediatrician after suffering with recurrent infections since his birth. His mother has noticed increased irritability. Blood tests reveal a neutrophil count of 350/μL. NBT test is normal.
2) A
Kostmann syndrome (severe congenital neutropenia; A) = result of failure of neutrophil maturation. Causes very low neutrophil count (less than 500/μL indicates severe neutropenia) and no pus formation. Kostmann syndrome is usually detected soon after birth. Presenting features = non-specific in infants, including fever, irritability and infection. The nitro-blue-tetrazolium (NBT) test can help with diagnosis; the liquid turns blue due to the normal presence of NADPH. In Kostmann syndrome, NBT test is positive and therefore normal.
Hyper IgM syndrome (C) = mutation in the CD40 ligand on T cells leading to impaired communication with B cells. B cells are unable to class-switch, therefore only produce IgM (leading to increased levels in the blood). Patients deficient in IgA, IgG and IgE.
In leukocyte adhesion deficiency (LAD; D) neutrophils are formed but cannot exit blood stream due to a deficit in leukocyte adhesion molecules resulting in reduced neutrophil chemotaxis. The neutrophil count is very high due to persistence in the blood stream. NBT test is positive.
Cyclic neutropenia (F) is an autosomal dominant condition = mutation in the neutrophil elastase gene (ELA2). Neutropenia occurs every 3 weeks and lasts ~6 days at a time.
AIDS (I) = reduced CD4+ T-cell count. Greater risk of developing opportunistic infections, e.g. PCP.
- Immunodeficiency (1)
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS
3 A 4-year-old girl is referred to a paediatrician after experiencing recurrent chest infections. Blood tests demonstrate a reduced B-cell count as well as low IgA, IgM and IgG levels.
3) G
Bruton’s agammaglobulinaemia (G) = X-linked disease that presents in childhood. Caused by a mutation of the BTK gene, which expresses a tyrosine kinase. This mutation inhibits B-cell maturation so B-cell & immunoglobulin levels are diminished. Blood tests will reveal a normal T-cell count, but diminished B-cell count as well as IgA, IgM and IgG levels. Plasma cells absent from bone marrow & lymphatics.
Hyper IgM syndrome (C) = mutation in the CD40 ligand on T cells leading to impaired communication with B cells. B cells are unable to class-switch, therefore only produce IgM (leading to increased levels in the blood). Patients deficient in IgA, IgG and IgE.
In leukocyte adhesion deficiency (LAD; D) neutrophils are formed but cannot exit blood stream due to a deficit in leukocyte adhesion molecules resulting in reduced neutrophil chemotaxis. The neutrophil count is very high due to persistence in the blood stream. NBT test is positive.
Cyclic neutropenia (F) is an autosomal dominant condition = mutation in the neutrophil elastase gene (ELA2). Neutropenia occurs every 3 weeks and lasts ~6 days at a time.
AIDS (I) = reduced CD4+ T-cell count. Greater risk of developing opportunistic infections, e.g. PCP.
- Immunodeficiency (1)
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS
4 A 48-year-old woman presents to her GP with a history of diarrhoea for 3 weeks, which occasionally contains blood. She has felt increasingly tired and feverish. The patient has had similar episodes in the past which were treated with mesalazine. She also reports recurrent chest infections since her first episode of diarrhoea.
4) E
Protein-losing enteropathy (E) is defined as the severe loss of proteins via GIT. The underlying pathophysiology may relate to mucosal disease, lymphatic obstruction or cell death leading to increased permeability to proteins. If more proteins are lost than synthesized in the body, hypoproteinaemia will result. Causes: Crohn’s dx, coeliac dx and rarely, Menetrier’s dx. Hypoproteinaemia secondary to such conditions results in fewer immunoglobulins being formed which diminishes the adaptive immune response.
Hyper IgM syndrome (C) = mutation in the CD40 ligand on T cells leading to impaired communication with B cells. B cells are unable to class-switch, therefore only produce IgM (leading to increased levels in the blood). Patients deficient in IgA, IgG and IgE.
In leukocyte adhesion deficiency (LAD; D) neutrophils are formed but cannot exit blood stream due to a deficit in leukocyte adhesion molecules resulting in reduced neutrophil chemotaxis. The neutrophil count is very high due to persistence in the blood stream. NBT test is positive.
Cyclic neutropenia (F) is an autosomal dominant condition = mutation in the neutrophil elastase gene (ELA2). Neutropenia occurs every 3 weeks and lasts ~6 days at a time.
AIDS (I) = reduced CD4+ T-cell count. Greater risk of developing opportunistic infections, e.g. PCP.
- Immunodeficiency (1)
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS
5 A 3-year-old girl is seen by a GP due to recurrent mild chest infections. The doctor notices the girl has a cleft lip. Blood tests reveal a reduced T-cell count as well as hypocalcaemia.
5) H
Di George’s syndrome (H) is caused by an embryological abnormality in the third and fourth branchial arches (pharyngeal pouches) due to a 22q11 deletion. The result is an absent or hypoplastic thymus, as well as a deficiency in T cells. There is a reduction or absence of CD4+ and CD8+ T cells as well as decreased production of IgG and IgA. B cell and IgM levels are normal. The features of Di George’s syndrome can be remembered by the mnemonic ‘CATCH’: cardiac abnormalities, atresia (oesophageal), thymic aplasia, cleft palate and hypocalcaemia.
Hyper IgM syndrome (C) = mutation in the CD40 ligand on T cells leading to impaired communication with B cells. B cells are unable to class-switch, therefore only produce IgM (leading to increased levels in the blood). Patients deficient in IgA, IgG and IgE.
In leukocyte adhesion deficiency (LAD; D) neutrophils are formed but cannot exit blood stream due to a deficit in leukocyte adhesion molecules resulting in reduced neutrophil chemotaxis. The neutrophil count is very high due to persistence in the blood stream. NBT test is positive.
Cyclic neutropenia (F) is an autosomal dominant condition = mutation in the neutrophil elastase gene (ELA2). Neutropenia occurs every 3 weeks and lasts ~6 days at a time.
AIDS (I) = reduced CD4+ T-cell count. Greater risk of developing opportunistic infections, e.g. PCP.
- Innate immunity (1): Physical barriers
A 10-year-old boy is seen by a paediatrician after suffering recurrent chest infections. His mother reports purulent sputum production and cough for the previous 2 years. Genetic testing reveals the child has a F508 mutation on chromosome 7. Which physical barrier to infection is most likely to be affected by the child’s condition?
A Skin B Gastric acid C Mucociliary clearance D Tears E Gut flora
C
Physical barriers to infection which form part of the innate immune system provide initial protection against disease-causing organisms. Impaired mucociliary clearance (C) may arise secondary to cystic fibrosis, which is the most likely answer in this scenario. Cystic fibrosis is an autosomal dominant disease which primarily affects the lungs but also the pancreas, liver and gastrointestinal system. The most common mutation is the F508 mutation on chromosome 7, which codes for the cystic fibrosis transmembrane conductance regulator (CFTR). Defective sodium and chloride ion transport across epithelial cells leads to the for- mation of viscous secretions. In the respiratory tract increased viscous secretions produced by goblet cells cause damage to the cilia, as well as diffuse lung injury, which can result in bronchiectasis.
The skin (A) is perhaps the most important physical barrier to infection. Although covered by normal flora, these bacteria are unable to penetrate the numerous layers which make up the skin. However, severe burns which break down this important barrier to infection may allow bacteria to enter the body. Small breaks in the skin that allow a small number of pathogens to enter the body are usually dealt with by other components of the innate immune system.
The low pH of gastric acid (B) produced in the stomach destroys most bacteria present in food. Bacteria that reach the large intestines must compete with commensal gut flora (E); extrinsic bacteria are therefore unable to replicate and cannot survive.
Tears (D) are produced by the lacrimal glands of the eyes. The lysozyme component reduces the risk of pathogens entering the eye. Keratoconjunctivitis sicca (‘dry eye’) is a condition that causes reduced production of tears, subsequently increasing the risk of infection.
- Diagnostic immunology
A Histocompatibility testing B Immunofluorescence C Latex fixation test D Radioallergosorbent test E Patch testing F Kveim test G Skin prick test H Western blot I Direct antiglobulin test
1 A 39-year-old homosexual man presents to accident and emergency with shortness of breath and a dry cough. A chest X-ray shows widespread pulmonary opacification. PCR confirms the diagnosis of Pneumocystis pneumoniae infection. A test is ordered to confirm the underlying diagnosis.
1) H
Western blot (H) is a technique used to detect specific proteins in a patient’s serum; it is used in the confirmatory HIV test to detect specific antibodies to HIV. The first step is to separate native proteins by gel electrophoresis. The proteins are subsequently transferred to a mem- brane on which specific antibodies present in the serum may bind to HIV proteins produced using recombinant DNA. Unbound antibodies are washed away. Enzyme-linked antibodies are then added; these determine to which protein the subject has antibodies.
Histocompatibility testing (A) is a preventative method of limiting the risk of organ transplant rejection. Major HLA antigens such as HLA-A and HLA-B are matched between donor and recipient.
Latex fixation test (C) is an agglutination technique used in the detec- tion of antibodies. It is used in the detection of rheumatoid factor.
Radioallergosorbent test (D) is a radioimmunoassay test for a variety of potential allergens. The test involves the use of radio-labelled anti-human IgE; the antibody is added, which attaches to the IgE bound to the insoluble allergen.
Patch testing (E) is a useful test to determine the causative allergen in contact dermatitis. A patch is prepared with small amounts of allergens; a positive test may be demonstrated by a spectrum of responses, from faint erythema to the presence of bullae.
- Diagnostic immunology
A Histocompatibility testing B Immunofluorescence C Latex fixation test D Radioallergosorbent test E Patch testing F Kveim test G Skin prick test H Western blot I Direct antiglobulin test
2 A 45-year-old man presents to accident and emergency with worsening shortness of breath. Examination findings are consistent with pulmonary fibrosis. Chest X-ray demonstrates the presence of bihilar lymphadenopathy. Erythema nodosum is observed on the patient’s shins.
2) F
Kveim test (F) is an investigation used to diagnose sarcoidosis. A sample of spleen from a patient with known sarcoid is injected intradermally into a suspected patient. A positive test is evidenced by the presence of non-caseating granuloma formation on biopsy of the site, 4–6 weeks after the initial injection. Although not used in the UK due to infection concerns (especially bovine spongiform encephalopathy), it is still available in many countries.
Histocompatibility testing (A) is a preventative method of limiting the risk of organ transplant rejection. Major HLA antigens such as HLA-A and HLA-B are matched between donor and recipient.
Latex fixation test (C) is an agglutination technique used in the detec- tion of antibodies. It is used in the detection of rheumatoid factor.
Radioallergosorbent test (D) is a radioimmunoassay test for a variety of potential allergens. The test involves the use of radio-labelled anti-human IgE; the antibody is added, which attaches to the IgE bound to the insoluble allergen.
Patch testing (E) is a useful test to determine the causative allergen in contact dermatitis. A patch is prepared with small amounts of allergens; a positive test may be demonstrated by a spectrum of responses, from faint erythema to the presence of bullae.
- Diagnostic immunology
A Histocompatibility testing B Immunofluorescence C Latex fixation test D Radioallergosorbent test E Patch testing F Kveim test G Skin prick test H Western blot I Direct antiglobulin test
3 A 50-year-old man with known SLE develops jaundice. On examination he is found to have conjunctival pallor and is short of breath. Blood tests reveal an elevated unconjugated bilirubin level.
3) I
Direct antiglobulin test (DAT; I) also known as direct Coombs test, is the investigation of choice for the diagnosis of autoimmune haemolytic anaemia (AIHA). Causes of AIHA include lymphoproliferative disorders, drugs (penicillin) and autoimmune diseases (SLE). The test involves the separation of RBCs from the serum which is subsequently incubated with anti-human globulin. In the case of AIHA, the anti-human globulin will agglutinate the RBCs, which is visualized as clumping of the cells.
Histocompatibility testing (A) is a preventative method of limiting the risk of organ transplant rejection. Major HLA antigens such as HLA-A and HLA-B are matched between donor and recipient.
Latex fixation test (C) is an agglutination technique used in the detec- tion of antibodies. It is used in the detection of rheumatoid factor.
Radioallergosorbent test (D) is a radioimmunoassay test for a variety of potential allergens. The test involves the use of radio-labelled anti-human IgE; the antibody is added, which attaches to the IgE bound to the insoluble allergen.
Patch testing (E) is a useful test to determine the causative allergen in contact dermatitis. A patch is prepared with small amounts of allergens; a positive test may be demonstrated by a spectrum of responses, from faint erythema to the presence of bullae.
- Diagnostic immunology
A Histocompatibility testing B Immunofluorescence C Latex fixation test D Radioallergosorbent test E Patch testing F Kveim test G Skin prick test H Western blot I Direct antiglobulin test
4 A 12-year-old girl is referred to a paediatrician after suffering with allergies to a number of foods including peanuts and eggs. Her mother wants to check if she is allergic to any other foods, inhalants or specific materials, so that she can be prevented from coming into contact with potential allergens.
4) G
Skin prick test (G) is the gold standard for investigating such type I hypersensitivity reactions. The test involves a few drops of purified allergen being pricked onto the skin. Allergens which are tested for include foods, dust mites, pollen and dust. A positive test is indicated by wheal formation, caused by cross-linking of IgE on the mast cell surface leading to histamine release.
Histocompatibility testing (A) is a preventative method of limiting the risk of organ transplant rejection. Major HLA antigens such as HLA-A and HLA-B are matched between donor and recipient.
Latex fixation test (C) is an agglutination technique used in the detec- tion of antibodies. It is used in the detection of rheumatoid factor.
Radioallergosorbent test (D) is a radioimmunoassay test for a variety of potential allergens. The test involves the use of radio-labelled anti-human IgE; the antibody is added, which attaches to the IgE bound to the insoluble allergen.
Patch testing (E) is a useful test to determine the causative allergen in contact dermatitis. A patch is prepared with small amounts of allergens; a positive test may be demonstrated by a spectrum of responses, from faint erythema to the presence of bullae.
- Diagnostic immunology
A Histocompatibility testing B Immunofluorescence C Latex fixation test D Radioallergosorbent test E Patch testing F Kveim test G Skin prick test H Western blot I Direct antiglobulin test
5 A 5-year-old boy presents to accident and emergency with purpura on his legs and buttocks, joint pain and abdominal pain. The boy’s mother states that the child had suffered from a sore throat approximately 1 week previously. The doctor would like to perform an investigation to make sure of the diagnosis.
5) B
Immunofluorescence (B) is an immunological technique used in conjunction with fluorescence microscope. Fluorophores (fluorescent chemical compounds) attached to specific antibodies are directed at antigens found within a biological specimen, most commonly a biopsy sample, to visualize patterns of staining. For example, in Henoch– Schönlein purpura, anti-IgA antibody will demonstrate IgA deposits in the capillary walls of the specimen. Immunofluorescence may be direct (use of a single antibody bound to a single fluorophore) or indirect (secondary antibody carrying the fluorophore binds to the primary antibody).
Histocompatibility testing (A) is a preventative method of limiting the risk of organ transplant rejection. Major HLA antigens such as HLA-A and HLA-B are matched between donor and recipient.
Latex fixation test (C) is an agglutination technique used in the detec- tion of antibodies. It is used in the detection of rheumatoid factor.
Radioallergosorbent test (D) is a radioimmunoassay test for a variety of potential allergens. The test involves the use of radio-labelled anti-human IgE; the antibody is added, which attaches to the IgE bound to the insoluble allergen.
Patch testing (E) is a useful test to determine the causative allergen in contact dermatitis. A patch is prepared with small amounts of allergens; a positive test may be demonstrated by a spectrum of responses, from faint erythema to the presence of bullae.
- Primary immunodeficiency (3): T-cell deficiency
A 4-year-old girl is seen by a paediatrician to investigate possible developmental delay and learning difficulties. Initial blood tests reveal hypocalcaemia, reduced CD4+ and CD8+ T-cell counts as well as deficiency in IgG and IgA. FISH analysis reveals the child has a deletion of 22q11. What is the diagnosis?
A Di George’s syndrome B Severe combined immunodeficiency C Bare lymphocyte syndrome D Wiskott–Aldrich syndrome E Interferon-gamma receptor deficiency
A
Di George’s syndrome (A) is caused by an embryological abnormality in 3rd and 4th branchial arches (pharyngeal pouches) due to a 22q11 deletion. The result is an absent or hypoplastic thymus, as well as a deficiency in T cells. There is a reduced level or absence of CD4+ and CD8+ T cells as well as decreased production of IgG and IgA. B-cell and IgM levels are normal.
Features of Di George’s syndrome = mnemonic ‘CATCH’:
- cardiac abnormalities;
- atresia (oesophageal);
- thymic aplasia;
- cleft palate;
- hypocalcaemia.
Two major subtypes of severe combined immunodeficiency (SCID; B) exist, which affect both T and B cells: X-linked disease (mutation of IL-2 receptor) and an autosomal recessive condition (mutation of adenosine deaminase gene which leads to a build-up of toxins and hence compromised proliferation of lymphocytes). Clinical feat. include diarrhoea, failure to thrive and skin disease (graft-versus-host induced, caused by transplacental maternal T cells, and blood transfusion-related caused by donor T cells). Blood transfusions are contraindicated in patients with SCID.
Bare lymphocyte syndrome (C) is caused by either deficiency in MHC I (type 1; all T cells become CD4+ T cells) or MHC II (type 2; all T cells become CD8+ T cells). Clinical manifestations include sclerosing cholangitis with hepatomegaly and jaundice.
Wiskott–Aldrich syndrome (WAS; D) is an X-linked condition caused by a mutation in WASp gene which leads to lymphocytopenia. WAS is linked to development of lymphomas, thrombocytopenia and eczema.
Interferon-gamma (IFN-gamma) released by T cells induces the activation of macrophages. Therefore, IFN-gamma receptor deficiency (E) leads to the reduced activation of macrophages and so granulomas cannot form, resulting in increased susceptibility to intracellular infections such as Mycobacterium TB and Salmonella spp.
- Primary immunodeficiency (4): B-cell deficiency
A 24-year-old man with a history of coeliac disease visits his GP after several bouts of chest and gastrointestinal infections in the past few years. Although the infections are mild, the patient is worried about the cause. What is the diagnosis?
A Severe combined immunodeficiency B Bruton’s agammaglobulinaemia C Hyper IgM syndrome D Selective IgA deficiency E Common variable immunodeficiency
D
IgA specifically provides mucosal immunity, primarily to the respiratory and gastrointestinal systems. Selective IgA deficiency (D) results from a genetic inability to produce IgA and is characterized by recurrent mild respiratory and gastrointestinal infections. Patients with selective IgA deficiency are also at risk of anaphylaxis to blood transfusions due to the presence of donor IgA. This occurs especially after a second transfusion; antibodies having been created against IgA during the primary transfusion. Selective IgA deficiency is also linked to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and coeliac disease.
The recessive form of severe combined immunodeficiency (SCID; A) is caused by a mutation of the adenosine deaminase gene leading to an accumulation of toxins and therefore compromised pro- liferation of lymphocytes; CD4+ and CD8+ T-cell levels are decreased. Reduced proliferation of lymphocytes leads to atrophy of the thymus, lymph and mucosa-associated lymphoid tissue.
Bruton’s agammaglobulinaemia (B) is an X-linked disease that presents in childhood. It is caused by a mutation of the BTK gene, which is a tyrosine kinase. This mutation inhibits B-cell maturation and as a result B-cell and immunoglobulin levels are diminished.
Hyper IgM syndrome (C) is an X-linked condition that presents in childhood. It is caused by a mutation in the CD40 ligand on T cells leading to impaired communication with B cells. B cells are unable to class-switch and therefore only produce IgM (leading to increased levels in the blood) and patient are deficient in IgA, IgG and IgE. Patients with hyper IgM syndrome are at risk of Pneumocystis jerovicci infection.
Common variable immunodeficiency (CVID; E) presents in adulthood. A mutation of MHC III causes aberrant class switching, increasing the risk of lymphoma and granulomas. Clinical features include bronchiectasis and sinusitis. Blood tests reveal a normal IgM level but decreased levels of IgA, IgG and IgE.
- Secondary immunodeficiency
A 40-year-old man is referred to an infectious disease specialist after he is admitted to hospital with Pneumocystis jerovicci pneumonia. On examination the patient also has multiple Kaposi’s sarcoma lesions on his chest and abdomen.
What is the most likely diagnosis?
A Inflammatory bowel disease B Hyposplenism C Nephrotic syndrome D AIDS E Prematurity
D
Broadly, secondary immunodeficiency can result from either reduced production of immune factors, increased loss or catabolism. Human immunodeficiency virus (HIV) is a double stranded RNA virus that causes AIDS (E). AIDS is characterized by immune dysfunction, the primary defect being a reduced CD4+ T-cell count. AIDS patients are at greater risk of developing opportunistic infections (for example, Pneumocystis jerovicci and Cryptosporidium spp.) and tumours (Kaposi’s sarcoma). Inflammatory bowel disease (IBD; A) is an inflammatory condition of the GIT that may be subdivided into ulcerative colitis (UC; affects the colon) and Crohn’s disease (CD; affects anywhere from the mouth to anus). It is mainly CD that causes protein losing enteropathy as proteins are absorbed in the small bowel. The reduced absorption of proteins in IBD results in fewer immuno- globulins being formed which affects the adaptive immune system response.
Hyposplenism (B) may arise due to splenectomy (after trauma) or sickle-cell disease, for example. Poor spleen function or absence of a spleen predisposes to encapsulated bacterial infections, for example Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. Such patients are therefore required to take necessary vaccinations and antibiotic prophylaxis.
Nephrotic syndrome (C) is characterized by renal dysfunction leading to large amounts of protein leaking from the blood to the urine. Consequently, immunoglobulins will be lost as they are passed into the urine, leading to increased risk of infection by encapsulated bacteria.
Prematurity (E) is a cause of secondary immunodeficiency as IgG is transferred across the placenta during the final 2 months of pregnancy. Premature babies will have had less IgG transferred as a fetus. As a result, such babies will be at greater risk of infec- tion before their own immune systems begin to mature (approximately 4 months after birth).
- Hypersensitivity reactions (1)
A 12yo girl has developed a runny nose, itchy eyes and nasal congestion during the summer months for the past 4 years. She is prescribed anti-histamines to help her symptoms. Which of the following cells is responsible for the initial encounter with the allergen?
A Mast cell B B cell C Macrophage D TH1 cell E TH2 cell
C
Type I hypersensitivity reactions are mediated by IgE and are assoc. with allergy and anaphylaxis. The mechanism behind the development of type I hypersensitivity reactions begins with the presentation of the allergen to professional antigen presenting cells. Professional antigen presenting cells include macrophages (C), dendritic cells and B cells. For example, if an allergen is taken up by a macrophage, it is processed intracellularly and peptides are presented via major histocompatibility complex on the cell surface to T cells of the TH2-cell (E) subclass. TH2-cell secrete IL-4, which stimulates B cell (B) proliferation.
TH1-cells (D) do not play a role in the pathogenesis of type I hypersensitivity but do contribute to type IV hypersensitivity reactions. B cells in turn produce allergen-specific antibodies of the IgE variety.
IgE binds to mast cells (A) via the Fc receptor. During a second exposure, when the allergen encounters the sensitized mast cell, the surface IgE cross-links which leads to an increased intracellular calcium concentration, facilitating the release of preformed mediators (histamine, proteases, serotonin and heparin) as well as newly formed lipid mediators (thromboxane, prostaglandin, leukotriene and platelet activating factor). These mediators correlate with the clinical features of allergic reactions. For example, histamine, leukotrienes and prostaglandins are vasodilators and contribute to the warmth, oedema and redness which are associated with allergic inflammation. Examples of diseases caused by type I hypersensitivity reactions include allergic rhinitis, food allergy and urticaria.
- Hypersensitivity reactions (2)
A 14-year-old girl with a history of eczema presents to accident and emergency with itching and tingling of her lips and tongue. The girl’s lips are evidently swollen. All observations are normal. The doctor believes her condition is due to cross-reactivity of allergens. What is the most likely trigger for her allergy?
A Penicillin B Eggs C Nickel D Dust mite E Fruit
E
This patient has signs and symptoms confined to her mouth. Together with the doctor’s suspicions regarding the underlying pathogenesis, oral allergy syndrome (OAS) is the most likely diagnosis. OAS occurs sec- ondary to cross-reactivity of antigens inhaled in the mouth, otherwise known as pollen–food allergy. For example, a patient may be sensi- tized to birch pollen; when pollen is breathed in, IgE is created which cross-reacts with fruit (E) which has been ingested causing release of histamine from mast cells resulting in local inflammation. Known cross- reactants include birch pollen/stone fruits, mugwort pollen/celery and ragweed pollen/melon. All symptoms are confined to the mouth only and include swelling, itching and tingling of the tongue, lips and uvula. There is often a history of atopic disease. Management includes avoiding ingestion of the allergen, anti-histamines and prophylactically carrying an EpiPen in patients who have a history of anaphylaxis.
Allergy to penicillin (A) may result in either acute urticaria or in severe cases, anaphylaxis. Acute urticaria lasts for less than 6 weeks, characterized by intermittent rashes which last less than 24 hours at a single site. Systemic IgE activation results in anaphylaxis characterized by swell- ing of the lips, shortness of breath and signs of shock in severe cases.
Eggs (B) are a primary cause of food allergy in children; egg allergy usually resolves by the age of 8 years. Most food allergies are IgE medi- ated; as some are not, the gold standard to test for food allergies is the double-blind food challenge. Other causes of food allergy include nuts, shellfish, milk and wheat.
Nickel (C) causes contact dermatitis, a type IV hypersensitivity reaction. A reaction takes 1–2 days to develop (delayed) leading to desquamation of the skin. As histamines are not involved in type IV reactions, there is no response to anti-histamines.
Dust mites (D) cause allergic rhinitis, symptomatically characterized by loss of smell, rhinorrhoea and nasal/eye itchiness.
- Hypersensitivity reactions (3)
A 21-year-old woman is at a Thai restaurant, eating her main course when she suddenly develops shortness of breath, wheeze and swelling of her lips. The patient has a known peanut allergy. What is the most appropriate treatment in the first instance?
A Allergen avoidance B Adrenaline C Oral anti-histamines D Doxepin E Nasal steroids
B
This patient is suffering an anaphylactic attack as a result of peanut allergy. Other potential causes of anaphylaxis include penicillin, ani- mal venom and latex. The pathophysiology of anaphylaxis involves IgE binding to the allergen with subsequent systemic release of histamine causing vasodilation and contraction of bronchial smooth muscle. Clinical features include swollen lips, shortness of breath, wheeze and signs of shock. Anaphylaxis is therefore a medical emergency and intra- muscular (IM) adrenaline (B) is the primary treatment; many patients who suffer from severe allergy are educated in the use of an EpiPen.
IM adrenaline is the best (and life-saving) choice due to its fast acting vasocontrictive and bronchodilator effects. Non-IgE mediated systemic histamine release by mast cells is known as an anaphylactoid reaction. Causes include opioids, NSAIDs, contrast agents and exercise. Clinical features are similar to anaphylaxis reaction.
As allergies such as allergic rhinitis, oral allergy syndrome and urticaria are IgE mediated causing release of histamine by mast cells, oral anti-histamines (C) are the main-stay treatment for such conditions. Anti- histamines used in allergic disease are H1 receptor antagonists which negate the effects of histamine. Although effective in treating mild symptoms, oral anti-histamines take longer to have an effect than IM adrenaline.
Nasal steroids (E) may be prescribed to alleviate symptoms of rhinorrhoea, itching and nasal congestion. Patients with known triggers to allergy, such as specific foods, irritants or environmental conditions, are also encouraged to practice allergen avoidance (A) as a conservative measure in managing their symptoms.
Doxepin (D) is indicated in the management of chronic urticaria.
- Hypersensitivity reactions (4)
A demanding mother takes her 6-year-old son to see the GP. She is concerned by his numerous allergies, including pollen and various foods. She is keen for her son to have allergy testing to determine the substances he is allergic to. Which of the following would be the best test for investigating allergy in this child?
A Radioallergosorbent test B Skin prick test C Double-blind challenge D Serum tryptase levels E Total serum IgE
B
There are a battery of tests available for the investigation of IgE mediated hypersensitivity and the triggers which might be causative of such a reaction. This patient has an allergy to pollen and food: the skin prick test (B) is gold standard for investigating type I hypersensitivity reactions. The test involves a few drops of purified allergen being pricked onto the skin. Allergens which are tested for include foods, dust mites, pollen and dust. A positive test is indicated by wheal formation, caused by cross-linking of IgE on the mast cell surface leading to histamine release.
Radioallergosorbent test (RAST test; A) is also used to test for a variety of potential allergens. The test involves patient serum being added to a range of insoluble allergens. If antibodies are present to the allergen, these will bind. Radio-labelled anti-human IgE antibody is then added, which binds to the IgE bound to the insoluble allergen. Once the unbound IgE is washed away the radioactivity is measured; the greater the radioactivity the stronger the reaction to the allergen. Radioactivity-based tests have been replaced by enzyme- and fluorescence-based assays. The difficulty with RAST testing is that low IgE levels may be present in the serum which could lead to false nega- tive results.
Double-blind challenges (C) are reserved for food allergies where there is some doubt after a skin prick or RAST test. This must be conducted at a centre where necessary equipment is available in case of anaphylaxis.
Serum tryptase levels (D) are useful in diagnosing anaphylaxis reaction.
Measuring total serum IgE (E) is not very informative in investigating allergy.
- Hypersensitivity reactions (5)
A 56-year-old diabetic man is undergoing a kidney transplant as a result of chronic renal failure. After the operation, the man immediately develops fever and has no urine production. Background checks reveal there was an error in ABO matching of the donor and recipient; the donor’s blood group was A, while the recipient’s is O. Which of the following immune components is the first to initiate a response in this case?
A Natural-killer cells B C1 C Neutrophil D Mannose binding lectin E Macrophages
B
This patient has suffered hyperacute rejection of his graft as a result
of ABO incompatibility; secondary to a previous sensitizing event, the recipient has developed antibodies that have attacked the allograft. This is an example of a type II hypersensitivity reaction. Type II hypersensitivity reactions are IgG and IgM antibody mediated; the antigen is fixed to tissues or cell surface. Tissue or organ damage is restricted to those areas where the antibody target exists. Binding of the antibody to the target antigen causes activation of the classical complement pathway, beginning with C1 (B); activation of C1 has a number of effects. Fragments C3a and C5a are subsequently generated and attract macrophages (E).
The final common pathway of complement activation involves factors C5–C9 forming the membrane attack complex (MAC) which inserts into the target cell membrane, causing lysis. The classical pathway also leads to binding of C3b onto the target cell surface membrane, which causes recruitment of effector cells such as macrophages, natural-killer cells (NK cells; A) and neutrophils (C). Effector cells cause significant damage by lysing target cells by an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism.
Mannose binding lectin (MBL; D) is part of the lectin complement pathway, which is not involved in type II hypersensitivity reactions. Further examples of type II hypersensitivity reactions include myasthenia gravis, pemphigus vulgaris, haemolytic anaemia and haemolytic disease of the newborn.
- Hypersensitivity reactions (6)
54yo woman is referred to a dermatologist after developing blisters which she first noticed in her mouth but have now appeared on her right arm. O/E: Nikolsky’s sign is positive and immunofluorescent staining demonstrates the presence of acantholytic cells. What is the most likely target for antibodies in this case?
A Gastric parietal cell B Rhesus antigen C Acetylcholine receptor D Demoglein 1 E M proteins on group A streptococci
D
Type II hypersensitivity reactions involve the presence of antibodies that target antigens fixed to the target cell surface membrane. The patient in question has clinical features of pemphigus vulgaris. Such features include blistering of the skin and Nikolsky’s sign is positive (slight rubbing of the skin results in separation of the outermost layer). Pemphigus vulgaris results from antibodies directed towards demoglein 1 (D) and demoglein 3, which are epidermal cadherins of the epidermis. Antibodies causing damage to cadherin proteins result in the loss of linkages between keratinocytes, hence causing the presence of charac- teristic acantholytic cells on biopsy.
Gastric-parietal cell (A) antibodies are a feature of pernicious anaemia and lead to parietal cell loss and hence reduced intrinsic factor production; this causes reduced vitamin B12 absorption. As a result patients present with vitamin B12 deficiency, features of which include tiredness (anaemia) as well as sensory or motor defects.
Rhesus antigens (B) are found on the surface of erythro- cytes. As with ABO, the rhesus (Rh) blood group system is a clinically important system used for matching in blood transfusions. The most commonly used Rh antigen in matching is the D antigen. Antibodies directed against the Rh antigen result in autoimmune haemolytic anaemia (AIHA). The direct Coombs test, which detects antibodies bound to the surface of erythrocytes, is positive in AIHA.
The acetylcholine receptor (C) located at the neuromuscular junction is the target for auto-antibodies in myasthenia gravis. presents with fatigability of muscles, after periods of movement but recover after rest. In severe cases, muscles of breathing may become affected, leading to respiratory distress.
In post-streptococcal rheumatic fever, antibodies to M-proteins present on the surface of group A streptococci (E) cross-react with cardiac myosin; this results in the inflammatory features of rheumatic fever which include fever, raised ESR/CRP, leukocytosis and carditis. Rheumatic fever occurs as a result of molecular mimicry whereby pathogens produce antigens that are molecularly very similar to self antigens.
- Hypersensitivity reactions (7)
A 35-year-old woman presents to her GP with intermittent fatigue and joint pain which began 1 month previously. On examination, the patient has a malar rash on her face. Blood tests reveal anaemia. What is the most likely target for autoantibodies in this disease process?
A Mouldy hay B Chlamydia trachomatis C DNA D Antiserum proteins E Hepatitis B virus antigen
C
In contrast to type II hypersensitivity reactions, type III hypersensitivity reactions are characterized by antibodies targeting antigens that are not fixed to a cell surface. This patient has symptoms and signs of SLE - a multisystem disorder which may manifest in a number of ways - fever, fatigue, loss of appetite, malar rash, mouth ulcers, photosensitivity, serositis and joint pains. DNA (C) is the target for circulating anti-ds DNA antibodies in SLE. Many of the clinical features of SLE result from antibody-immune complex deposition. The presence of anti-Smith antibodies suggests interstitial lung disease involvement.
Chronic exposure to mouldy hay (A) is the cause of farmer’s lung, an example of an extrinsic allergic alveolitis. Actinomycetes are the most common pathogens found in hay dust, which are subsequently inhaled. Inhalation over prolonged periods of time leads to immune complex formation as antibodies combine with the inhaled allergen; the immune complexes are deposited in the walls of the alveoli. Chronic exposure leads to pulmonary fibrosis, with associated shortness of breath, cyanosis and cor pulmonale.
Antibodies directed at Chlamydia trachomatis (B) may trigger a reactive arthritis (Reiter’s syndrome). Clinical features include arthritis, dysuria, conjunctivitis and uveitis. As this phenom- enon is autoimmune, synovial fluid cultures are negative.
Proteins in antiserum (D) are the cause of serum sickness, a self-limiting condition that occurs when antiserum derived from a non-human animal source is injected intravenously, resulting in immune complex hypersensitivity.
HBsAg (E) may be associated with the development of polyarteritis nodosa (PAN), a vasculitis of small and medium sized vessels. Immune complexes are deposited within such vessels leading to fibrinoid necrosis and neutrophil infiltration; as a result the vessel walls weaken resulting in the formation of multiple aneurysms.
- Immunodeficiency (2)
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor
1 A 4-year-old boy is referred to a paediatrician after suffering recurrent chest infections over the preceding few months. The boy has a history of eczema as well as recurrent nose bleeds. Blood tests reveal a reduced IgM level but raised IgA and IgE levels.
1) H
Wiskott–Aldrich syndrome (WAS; H) is an X-linked condition which is caused by a mutation in the WASp gene; the WAS protein is expressed in developing haematopoietic stem cells. WAS is linked to the develop- ment of lymphomas, thrombocytopenia and eczema. Clinical features include easy bruising, nose bleeds and gastrointestinal bleeds secondary to thrombocytopenia. Recurrent bacterial infections also result. Blood tests reveal a reduced IgM level and raised IgA and IgE levels. IgG levels may be normal, reduced or elevated.
Nephrotic syndrome (C) is characterized by renal dysfunction leading to large amounts of protein leaking from the blood to the urine. Consequently, immunoglobulins will be lost as they are passed into the urine, leading to increased risk of infection by encapsulated bacteria.
Sickle cell anaemia (E) leads to hyposplenism; poor spleen function predisposes to encapsulated bacterial infections, for example Streptococcus pneumoniae. Such patients are therefore required to take necessary vac- cinations and antibiotic prophylaxis.
Reticular dysgenesis (G) is characterized by the absolute deficiency in both granulocytes and lymphocytes, leading to severe sepsis only a few days after birth.
Interferon-gamma receptor deficiency (I) leads to the reduced activation of macrophages and consequently, granulomas cannot form. This results in increased susceptibility to intracellular infections such as Mycobacterium tuberculosis and Salmonella spp.
- Immunodeficiency (2)
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor
2 A 20-year-old man presents to his GP with signs of a mild pneumonia. The patient states he has had several similar episodes in the past. Further investigations by an immunologist reveal the patient has a genetic condition caused by a mutation of MHC III.
2) B
Common variable immunodeficiency (CVID; B) presents in adulthood. A mutation of MHC III causes aberrant class switching, increasing the risk of lymphoma and granulomas. Patients with CVID also have a predisposition to developing autoimmune diseases. Recurrent infections caused by Haemophilus influenzae and Streptococcus pneumoniae are common. Clinical sequelae include bronchiectasis and sinusitis. Blood tests reveal a reduced B-cell count, a normal/reduced IgM level and decreased levels of IgA, IgG and IgE.
Nephrotic syndrome (C) is characterized by renal dysfunction leading to large amounts of protein leaking from the blood to the urine. Consequently, immunoglobulins will be lost as they are passed into the urine, leading to increased risk of infection by encapsulated bacteria.
Sickle cell anaemia (E) leads to hyposplenism; poor spleen function predisposes to encapsulated bacterial infections, e.g. Streptococcus pneumoniae. Such patients are therefore required to take necessary vaccinations and antibiotic prophylaxis.
Reticular dysgenesis (G) is characterized by the absolute deficiency in both granulocytes and lymphocytes, leading to severe sepsis only a few days after birth.
Interferon-gamma receptor deficiency (I) leads to the reduced activation of macrophages and consequently, granulomas cannot form. This results in increased susceptibility to intracellular infections such as Mycobacterium tuberculosis and Salmonella spp.
- Immunodeficiency (2)
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor
3 A 3-year-old girl is referred to a paediatrician after concerns about recurrent skin infections she has suffered from since birth. A nitro-blue-tetrazolium test is negative (remains colourless).
3) F
Chronic granulomatous disease (F) is an X-linked disorder causing deficiency of NADPH oxidase. As a result, neutrophils cannot produce the respiratory burst required to clear pathogens. The disease is characterized by chronic inflammation with non-caseating granulomas. Clinical features include recurrent skin infections (bacterial) as well as recurrent fungal infections. The disease is usually detected by the age of 5 and is diagnosed using the nitro-blue-tetrazolium (NBT) test, which remains colourless due to NADPH deficiency (if NADPH is present the solution turns blue). The patient will have a normal neutrophil count as there is no defect in neutrophil production.
Nephrotic syndrome (C) is characterized by renal dysfunction leading to large amounts of protein leaking from the blood to the urine. Consequently, immunoglobulins will be lost as they are passed into the urine, leading to increased risk of infection by encapsulated bacteria.
Sickle cell anaemia (E) leads to hyposplenism; poor spleen function predisposes to encapsulated bacterial infections, for example Streptococcus pneumoniae. Such patients are therefore required to take necessary vaccinations and antibiotic prophylaxis.
Reticular dysgenesis (G) is characterized by the absolute deficiency in both granulocytes and lymphocytes, leading to severe sepsis only a few days after birth.
Interferon-gamma receptor deficiency (I) leads to the reduced activation of macrophages and consequently, granulomas cannot form. This results in increased susceptibility to intracellular infections such as Mycobacterium tuberculosis and Salmonella spp.
- Immunodeficiency (2)
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor
4 A 4-year-old boy is referred to a paediatrician after a period of mild but chronic diarrhoea. On examination the child is found to have icteric sclera and hepatomegaly. Following blood tests, the doctor has a high suspicion that the child could have a defect in MHC I.
4) D
Bare lymphocyte syndrome (D) is caused by either deficiency in MHC I (type 1; all T cells become CD4+ T cells) or MHC II (type 2; all T cells become CD8+ T cells). Clinical manifestations include sclerosing cholan- gitis with hepatomegaly and jaundice.
Nephrotic syndrome (C) is characterized by renal dysfunction leading to large amounts of protein leaking from the blood to the urine. Consequently, immunoglobulins will be lost as they are passed into the urine, leading to increased risk of infection by encapsulated bacteria.
Sickle cell anaemia (E) leads to hyposplenism; poor spleen function predisposes to encapsulated bacterial infections, for example Streptococcus pneumoniae. Such patients are therefore required to take necessary vac- cinations and antibiotic prophylaxis.
Reticular dysgenesis (G) is characterized by the absolute deficiency in both granulocytes and lymphocytes, leading to severe sepsis only a few days after birth.
Interferon-gamma receptor deficiency (I) leads to the reduced activation of macrophages and consequently, granulomas cannot form. This results in increased susceptibility to intracellular infections such as Mycobacterium tuberculosis and Salmonella spp.
- Immunodeficiency (2)
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor
5 A 22-year-old woman visits her GP after several chest infections in the past few years. As well as the chest infections, the patient reports that she has had several bouts of diarrhoea over the same time period.
5) A
Selective IgA deficiency (A): IgA specifically provides mucosal immunity, primarily to the respiratory and gastrointestinal systems. Selective IgA deficiency results from a genetic inability to produce IgA and is characterized by recurrent mild respiratory and gastrointestinal infections. Patients also at risk of anaphylaxis to blood transfusions due to the presence of donor IgA. This occurs especially after a second transfusion; antibodies having been created against IgA during the primary transfusion. Selective IgA deficiency is also linked to autoimmune diseases such as RA, SLE and coeliac disease.
Nephrotic syndrome (C) is characterized by renal dysfunction leading to large amounts of protein leaking from the blood to the urine. Consequently, immunoglobulins will be lost as they are passed into the urine, leading to increased risk of infection by encapsulated bacteria.
Sickle cell anaemia (E) leads to hyposplenism; poor spleen function predisposes to encapsulated bacterial infections, for example Streptococcus pneumoniae. Such patients are therefore required to take necessary vac- cinations and antibiotic prophylaxis.
Reticular dysgenesis (G) is characterized by the absolute deficiency in both granulocytes and lymphocytes, leading to severe sepsis only a few days after birth.
Interferon-gamma receptor deficiency (I) leads to the reduced activation of macrophages and consequently, granulomas cannot form. This results in increased susceptibility to intracellular infections such as Mycobacterium tuberculosis and Salmonella spp.
- Innate immunity (2): Complement investigations.
A 62-year-old woman sees her GP for a regular check-up. On examination, she has notable deformities of her hands, including swan-neck and Boutonniere deformities of her fingers. Blood tests reveal a raised CRP. Which of the following investigation results will most likely feature?
A Reduced AH50 and normal CH50 B Reduced C1 inhibitor C Reduced C3 and C4 D Reduced C3 and normal C4 E High CH50
E
The complement system is composed of the classical, lectin and alternative pathways. These individual pathways culminate in the formation of the membrane attack complex (MAC), which traverses cell surface membranes of pathogens, causing cell lysis. Components of the complement system can be quantified in order to differentiate possible diagnoses.
CH50 (total complement activity) measures the level of factors of the classical and final pathways (C1–C9). As complement factors are acute phase proteins, a high CH50 (E) indicates acute or chronic inflammation. Together with the raised CRP and clinical features, this patient is likely to suffer from RA. SLE is a systemic autoimmune disease characterized by antibody-immune complex formation and deposition. The classical complement pathway is composed of C1, C2 and C4.
Reduced C3 and C4 (C) levels are typical of SLE as a result of complex formation (hence consumption) in an attempt to eliminate immune complexes. C3 and C4 may also be reduced in SLE due to immunodeficiency which predisposes to developing the disease.
In membranoproliferative glomerulonephritis (MPGN), anti-nephritic antibodies cause consumption of complement factors, especially C3. As a result, complement profiling reveals a reduced C3 but normal C4 (D); MPGN type III reflects this pattern particularly well.
AH50 is a laboratory investigation to test for abnormalities of the alternative pathway, which involves factors C3, B, D and P. reduced AH50 and normal CH50 (A) suggest possible deficiency of one or more of the alternative pathway factors; this predisposes to infection by encapsulated bacteria.
Reduced C1 inhibitor (B) levels indicate hereditary angioedema, characterized by facial swelling; in severe cases the airway can become compromised leading to respiratory distress.
- Hypersensitivity reactions (8)
A 34-year-old woman notices an itchy and desquamating, erythematous rash on her wrist, which has emerged approximately 3 days after wearing a new brace- let. Which cytokine is the first to be released during the initial exposure to the allergen?
A IL-10 B IFN- gamma C IL-2 D TNF- alpha E IL-12
E
Type IV hypersensitivity (delayed type) reactions are those that are mediated by T cells of the immune system. These types of reactions require two exposures to the allergen. During the first encounter, antigen presenting cells such as macrophages engulf the allergen and presents peptides on the cell surface via major histocompatibility com- plex. CD4+ T cells recognize the peptide and bind to the macrophage. The macrophage then releases IL-12 (E) which leads to the production of memory CD4+ T cells of the TH1 variety. During the second expo- sure, the macrophage will once again take up the allergen and pre- sent peptide to CD4+ T cells. On this occasion however, the sensitized memory T cell releases IFN-gamma (B), IL-2 (C) and IL-3 thereby activating macrophages, inducing the production of TNF-alpha (D); the result is tissue injury and chronic inflammation. As type IV hypersensitivity reactions are cell-mediated, there is a lag time of approximately 48–72 hours before clinical symptoms and signs are visible. IL-10 (E) is not involved in type IV hypersensitivity reactions; IL-10 is produced by TH2 cells which causes inhibition of TH1 cells. As a consequence, IFN- would not be produced to activate macrophages and so type IV hypersensitivity would not occur. An example of a disease process caused by type IV hypersensitivity is contact dermatitis occurring secondary to nickel exposure, as is the case in this clinical scenario.
- Hypersensitivity reactions (9)
A 56-year-old woman presents to her GP with blurry vision. On examination the woman has some bilateral weakness in her legs. The patient mentions that her vision seems to become more blurry just after she has had a bath. What is the most likely target in this disease process?
A Pancreatic beta-cell proteins B Nickel C Proteolipid protein D Synovial membrane proteins E Tuberculin
D
Type IV hypersensitivity reactions are mediated by T cells and have
a delayed onset. Proteolipid protein (C) and myelin basic protein are oligodendrocyte proteins implicated in the pathogenesis of multiple sclerosis (MS). Multiple sclerosis is a demyelinating disease in which the myelin sheaths surrounding neurons of the brain and spinal cord are destroyed. Associated with the disease process is the antigenic stimulation of CD4+ T cells which in turn activate CD8+ cytotoxic T cells and macrophages; these are directed at oligodendrocyte proteins, causing destruction of oligodendrocytes and myelin. Clinical features of MS include optic neuritis, urinary/bowel incontinence, weakness of the arms/legs and dysphagia. Uhthoff’s phenomenon describes the worsen- ing of symptoms that occurs after exposure to higher than ambient temperatures. Pancreatic -cell proteins (A) are the antigenic target for cytotoxic CD8+ T cells in type 1 diabetes mellitus (T1DM). The patho- genesis involves the destruction of -cells in the islets of Langerhans in the pancreas by CD8+ T cells. -cells are the storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. Presenting features of T1DM include polyuria, polydipsia and weight loss. Nickel (B) is a hapten and binds with skin proteins. It is detected by Langerhan’s antigen presenting cells in the skin causing contact dermatitis. This results in a lesion resembling eczema with oedema and scaling. Synovial membrane antigens (D) are the target for T cells in rheumatoid arthritis (RA). RA is defined as a chronic systemic inflammatory disease causing a systemic, inflamma- tory polyarthritis. The Mantoux test involves the intradermal injection of purified protein derivative tuberculin (E). It is used as a test of previous exposure to Mycobacterium tuberculosis. A positive test depends upon a combination of induration size 48–72 hours after the injection, as well as disease risk factors.
- Transplantation and rejection (1)
A 40-year-old diabetic man is to undergo a kidney transplant as a consequence of stage 5 chronic kidney disease. The patient has an identical twin who is will- ing to donate a kidney, and has been HLA matched at all loci. Which term best describes the type of organ transplant proposed?
A Autograft B Split transplant C Allograft D Isograft E Xenograft
D
Transplants of organs are indicated in situations where function is lost following end-stage disease. In this case the patient in question has stage 5 chronic kidney disease, also known as end-stage kidney failure, an irreversible pathology. Transplant is the only cure for such a condition. The patient has an identical twin (monozygotic) and hence is genetically very similar. A transplant from the patient’s twin is known as an isograft (D); as the two individuals will have a similar genetic profile and the organ has been matched for human leukocyte antigen (HLA), chance of rejection is rare.
Allograft (C) transplants are those where the donor is of the same species as the recipient but not identi- cal. As the donor and recipient are genetically different, the organ must be matched in terms of HLA compatibility, as well as ABO blood group. HLA and ABO matching minimizes the risk of organ rejection. The use of immunosuppressive agents is another method of reducing the risk of transplant rejection. An example of a split transplant (B) is a liver that may be divided and shared between two recipients. An autograft (A) is defined as the transplant of tissue to the same patient. Examples include skin grafts and venous graft for use in coronary artery bypass graft (CABG) operations. As the tissue or organ is derived from ‘self’ there is zero chance of rejection.
A xenograft (E) is defined as an organ transplant from one species to another. An example of such a transplant is of a porcine heart valve in an aortic valve replacement which is very successful. However, in general with xenografts, there is a high risk of rejection and disease carried in the animal tissue.
- Transplantation and rejection (2)
A 45-year-old man, who has blood group O, has undergone a liver transplant secondary to chronic alcoholic liver disease which has led to cirrhosis. One hour after the operation the patient develops a fever and pain in his right upper quad- rant. It is soon realized that the donor had blood group B. Which of the following best describes the type of allograft rejection?
A Hyperacute rejection B Acute cellular rejection C Chronic rejection D Acute vascular rejection E Graft-versus-host disease
A
Patients who are due to undergo a transplant are matched with a donor for human leukocyte antigen (HLA) and ABO blood group. In this case, there has been an error in ABO matching which is a recipe for hyper- acute rejection (A). Hyperacute rejection occurs within minutes to hours, and is mediated by pre-formed antibodies against antigens on the surface of the donor organ. The binding of pre-formed antibodies to the donor organ activates the complement pathway and clotting cascade, leading to thrombosis and ultimately rejection of the donor organ. Acute cellular rejection (B) occurs approximately 1 week after transplantation. It is T-cell mediated (type IV hypersensitivity reaction). In cases where there is HLA-mismatch, antigen presenting cells present peptides that are made of foreign HLA to CD4+ T cells, coordinating an immune response against the donor organ. This involves mac- rophages, CD8+ T cells, B-cell and pro-inflammatory cytokines (IFN- and TNF- ) directed towards the donor organ. Acute vascular rejection (D) may occur with transplant of a xenograft. It is an antibody reaction, which may either be due to a pre-formed antibody (not detected at cross-match) or a new antibody produced by activated B cells. The pathogenesis is similar to hyperacute rejection, but occurs 4–6 days after transplantation. Chronic rejection (C) involves both immune and non-immune reactions; it may occur months to years after transplanta- tion. The pathogenesis involves smooth muscle growth which causes blockage of graft vessel lumens leading to ischaemia and fibrosis. Risk factors include HLA-mismatches, multiple acute rejections, hypertension and hyperlipidaemia. Graft-versus-host disease (GVHD; E) is a compli- cation of allogeneic stem cell transplantation. It occurs when immune cells transferred in the donated stem cells recognize the recipient tissue as foreign causing a graft-versus-host reaction.
- Transplantation and rejection (3)
A 54-year-old man is to undergo a heart transplant as a result of severe heart failure. Prior to the operation the transplant team initiate an immunosuppressive regimen using a drug that inhibits calcinurin. Which of the following drugs is this most likely to be?
A Cyclosporine A B OKT3 C Azathioprine D Corticosteroids E Daclizumab
A
Cyclosporine A (A) inhibits the protein phosphatase calcineurin. This causes IL-2 secretion from T cells, a cytokine which stimulates T-cell proliferation; the production of T cells is reduced, hence minimizing organ rejection. A common side effect is gum hyperplasia.
OKT3 (muromonab-CD3; B) is a mouse monoclonal antibody targeted at the human CD3 molecule used to treat rejection episodes in patients who have undergone allograft transplantation. Administration of the antibody efficiently clears T cells from the recipient’s circulation, T cells being the major mediator of acute organ rejection. Primary indications = acute corticosteroid-resistant rejection of renal, heart and liver transplants. Anaphylaxis is a major potential adverse effect of using murine proteins.
Azathioprine (C) is an antimetabolite agent used in immunosuppressive therapy. Azathioprine is metabolized into 6-mercaptopurine (6-MP), a purine analogue that prevents DNA synthesis, thereby inhibiting the proliferation of cells; lymphocytes are most affected. Antigen presenting cells present non-self proteins (from the allograft) to T cells which in turn produce IL-2 to stimulate T-cell proliferation. However, 6-MP inhibits this proliferation and so reaction between T cells and the allograft is minimized.
Corticosteroids (D) are used as an immunosuppressive agent in both the prevention and treatment of transplant rejection. Corticosteroids inhibit phospholipase A2 thereby blocking prostaglandin formation as well as a series of inflam- matory mediators. The immunosuppressive effects of corticosteroids are numerous and include reducing the number of circulating B cells, inhibiting monocyte trafficking, inhibiting T-cell proliferation and reducing the expression of a number of cytokines, for example, IL-1, IL-2 and TNF- .
Prednisolone is used prophylactically before transplantation to prevent rejection; methylprednisolone is used in the treatment of rejection. IL-2 receptor antibody (daclizumab; E) targets the CD25 of IL-2 receptors expressed on the surface of activated T cells. It is especially used in kidney transplant patients to prevent organ rejection. Common side effects of all immunosuppressants include increased risk of infec- tions, hepatotoxicity and malignancy.
- Human immunodeficiency virus
A 35-year-old man presents to the GP with fever, lymphadenopathy and a sore throat. Blood tests reveal a leukocytosis and Western blot is positive for HIV infection. Which of the following proteins is responsible for binding to CD4+ T cells to initiate infection?
A Gag protein B gp120 C gp41 D Reverse transcriptase E CCR5
B
The human immunodeficiency virus (HIV) is a spherical virus with a lipid envelope. Risk factors for transmission include anal intercourse, infected blood products, intravenous drug use and vertical transmis- sion. Structurally, HIV consists of a core, capsid and envelope. The first step in HIV infection involves binding of the envelope glycoprotein gp120 (B) to the CXCR4 receptor on the cell surface of the CD4+ T cell. Once bound the HIV envelope undergoes structural change allowing
the glycoprotein gp41 (C) to penetrate the CD4+ T-cell wall to stabilize the attachment. Once bound, HIV can inject viral RNA and replicating enzymes, including reverse transcriptase (D), integrase and protease, into the target cell. The RNA undergoes reverse transcription via reverse tran- scriptase to form cDNA, which is integrated into the host DNA by inte- grase. CD4+ cell death occurs by one of three mechanisms. The infected CD4+ T cells may be killed by cytotoxic CD8+ T cells; budding of HIV may cause CD4+ T cells to burst; infected CD4+ T cells may fuse with uninfected CD4+ T cells forming giant cells (syncytia) that balloon and die. The Gag protein (A) provides infrastructural support for HIV. HIV may also bind to macrophages via the cell surface receptor CCR5 (E). Macrophages infected by HIV are not destroyed but are used as replicat- ing reservoirs as well as a means of gaining entry to the central nervous system as macrophages are able to cross the blood–brain barrier. HIV infection may progress to acquired immunodeficiency syndrome (AIDS) which is defined by a CD4+ count less than 200cells/μL of blood or an AIDS-defining illness, for example infection by Mycobacterium avium intracellulare, Candia albicans oesophagutus and toxoplasmosis. Patients with AIDS are also at increased risk of developing Kaposi’s sarcoma, non-Hodgkin’s lymphoma and cervical cancer.
- Vaccines
A 13-year-old boy is immunized against an acid-fast bacillus species after a negative Mantoux test. Which term best describes this form of vaccination that has been administered?
A Live attenuated B Inactivated C Subunit D Conjugated E Passive immunity
A
The boy in this case has had a Mantoux test to determine if he has a latent tuberculosis (TB) infection. The test is negative and hence he
can be given the Bacillus Calmette–Guèrin (BCG) vaccine to provide immunity against TB. The BCG vaccine is a live attenuated (A) vaccina- tion, prepared using a weakened live bovine tuberculosis bacillus. Other examples of live attenuated vaccines include polio (Sabin), MMR and typhoid. Live attenuated vaccines provide long-term immunity and pro- tection against a number of reactive strains; they do not require boost- ers or adjuvants as such vaccines trigger a sufficiently strong immune response. Live attenuated vaccines are contraindicated in immunocom- promised patients. In inactivated (B) vaccines pathogens are destroyed so they are unable to replicate but retain the ability to induce an immune response. Examples include vaccines against cholera, hepatitis A virus and rabies. Inactivated vaccines are suitable for patients with immunodeficiency but require boosters. Subunit (C) vaccines are char- acterized by the use of antigenic proteins (not whole organisms) and include hepatitis B virus (recombinant), pneumococcal, diphtheria, teta- nus and pertussis vaccines. Conjugated (D) vaccines are those used to immunize against encapsulated bacteria such as influenza, pneumococ- cus and Nissseria meningitides. Passive immunity (E) describes immuni- ty derived from the transfer of immunoglobulin. This form of immunity lasts approximately 3 weeks as the immunoglobulin proteins are broken down within the body. Examples of passive immunity include the use of human rabies immunoglobulin (HRIg) in rabies cases, as well as pro- phylactic and post-exposure use for hepatitis A infection (must be given within 2 weeks of exposure).
- Immune-based therapies (1)
A 3-year-old boy is referred to a paediatrician after experiencing recurrent chest infections. Blood tests demonstrate a reduced B-cell count as well as low IgA, IgM and IgG levels. Genetic testing reveals a defect in the BTK gene. What is the best therapeutic modality for this child?
A IFN-alpha B IFN-beta C IFN-gamma D Intravenous IgG E Haematopoietic stem cell transplant
D
A primary role for immune-based therapies is to boost the immune response to improve protection against infection and malignancy, espe- cially in those who are immunodeficient. Bruton’s agammaglobulinaemia is characterized by a mutation of the BTK gene, a tyrosine kinase. This mutation leads to inhibition of B-cell maturation and as a consequence B-cell and immunoglobulin levels are diminished. Blood investigations will reveal decreased circulating B cells as well as immunoglobulins. Patients are at risk of recurrent infections, particularly encapsulated bacteria, and must therefore receive passive immunity to protect against such pathogens. Intravenous IgG (D) is not a cure for Bruton’s agam- maglobulinaemia but prolongs survival. Treatment must be continued throughout life. Intravenous IgG is also used in the treatment of hyper IgM syndrome, common variable immunodeficiency as well as second- ary antibody deficiencies. Haematopoietic stem cell transplant (HSCT; E) involves the transplant of multipotent haematopietic stem cells which may either be autologous (from self) or allogenic (from a donor). In either case, myeloablative techniques are used to destroy the remain- ing cells of the bone marrow which leads to increased risk of infection throughout the course of the treatment. HSCT is indicated in diseases such as severe combined immunodeficiency (SCID), leukaemia and mul- tiple myeloma.
Interferons are signalling proteins involved in the immune system in response to pathogens and tumour cells. They act via the Janus kinase- STAT (Jak-STAT) pathway to produce further anti-viral, anti-proliferative and immunoregulatory factors. IFN- (A) is used in the treatment of hepatitis B, hepatitis C, Kaposi’s sarcoma and chronic myeloid leukaemia. IFN- (B) is indicated in the treatment of multiple sclerosis, but its mech- anism of action is unknown. IFN- (C) is used in the treatment of chronic granulomatous disease, a disease in which phagocytes lack the enzyme NADPH, and hence neutrophils are unable to clear pathogens.
- Immune-based therapies (2)
A 49-year-old woman with known rheumatoid arthritis is seen in the rheumatology clinic. She has been taking a medication over a long period of time which is used to control proliferation of her white blood cells. The patient explains that she has been feeling tired recently and has suffered with low moods. Routine blood tests reveal she has a macrocytic megaloblastic anaemia.
A Cyclophosphamide B Mycophenolate mofetil C Azathioprine D Methotrexate E Cisplatin
D
Anti-proliferative agents broadly inhibit DNA synthesis and thereby interfere with cell proliferation, especially those cells with a high turn- over, for example leukocytes. In this case, the side effects suggestive
of folate deficiency point to methotrexate (D) as the correct answer. Methotrexate is an anti-metabolite and anti-folate drug indicated for the treatment of cancer as well as autoimmune diseases including rheu- matoid arthritis and systemic lupus erythematosus. Methotrexate inhib- its dihydrofolate reductase (DHFR), an enzyme involved in the synthesis of the nucleoside thymidine; thymidine is essential for DNA synthesis. As folate is required for the synthesis of purine, production of this base is also disrupted. Ultimately, proliferation of leukocytes is interrupted. Side effects include those of folate deficiency (macrocytic megaloblas- tic anaemia, loss of appetite, tiredness, weakness and depression). The low white cell count that results predisposes to infection; this is an adverse effect of all anti-proliferative drugs. Cyclophosphamide (A) is an alkylating agent, attaching an alkyl group to the guanine base of DNA. This causes damage to the DNA structure and therefore prevents cell replication; cyclophosphamide affects B-cell replication more than
T cells. Complications of therapy include bone marrow suppression,
hair loss and carcinogenic properties that may cause transitional cell carcinoma of the bladder. Mycophenolate mofetil (B) is the pro-drug of mycophenolic acid which inhibits inosine monophosphate dehydroge- nase (IMPDH), an enzyme required in guanine synthesis; impaired gua- nine synthesis reduces the proliferation of both T and B cells, but T cells are affected to a greater extent. Side effects include bone marrow sup- pression (particularly low white blood cells and platelets). Azathioprine (C) is metabolized in the liver to 6-mercaptopurine which causes the inhibition of purine synthesis and preferentially inhibits T-cell activa- tion and proliferation. A proportion of the population have a thiopu- rine methyltransferase (TPMT) polymorphism, rendering them unable to metabolize azathioprine; patients therefore have a predisposition to azathioprine toxicity. Cisplatin (E) is a chemotherapeutic agent which cross-links with DNA and interferes with cell proliferation. Side effects include nephrotoxicity, neurotoxicity and ototoxicity.
- Immune-based therapies (3)
A 45-year-old man, who suffers from myasthenia gravis’ presents to accident and emergency with difficulty in breathing. Assisted ventilation is administered. Which of the following is the best option for the initial management of the patient’s condition?
A Ciclosporin B Tacrolimus C Rapamycin D Corticosteroids E Plasmapheresis
E
The patient in question has symptoms and signs suggestive of severe myasthenia gravis (myasthenic crisis), typified by paralysis of the respir- atory muscles requiring ventilator assistance. The best treatment in this scenario is plasmapheresis (E), a method of rapidly removing circulating anti-acetylcholine receptor antibodies from the circulation; effects last only for a short period. The patient’s own plasma is treated to remove immunoglobulins, and then reinfused. Other indications for plasmapher- esis include Goodpasture’s syndrome (anti-glomerular basement mem- brane proteins).
Pharmacological treatment of myasthenia gravis primary involves the use of acetylcholinesterase inhibitors. However, immunosuppressive agents, such as corticosteroids (D), also have a role. Corticosteroids inhibit phospholipase A2, thereby blocking prostaglandin formation as well as a spectrum of inflammatory mediators. The immunosuppressive effects of corticosteroids are numerous and include reducing the number of circulating B cells, inhibiting monocyte trafficking, inhibiting T-cell proliferation and reducing the expression of a number of cytokines, for example, IL-1, IL-2 and TNF- . Prednisolone is used prophylactically before transplantation to prevent rejection; methylprednisolone is used in the treatment of rejection. Side effects are frequent, however, and include osteoporosis, diabetes mellitus and hypertension.
Inhibitors of cell signalling which have been used in the management of myasthenia gravis include ciclosporin (A). Ciclosporin inhibits the pro- tein phosphatase calcineurin. This in turn inhibits IL-2 secretion from
T cells, a cytokine which stimulates T-cell proliferation. Adverse effects include nephrotoxicity, hepatotoxicity, diarrhoea and pancreatitis. Side effects of cyclosporine use include gum hyperplasia. Other inhibitors of cell signalling, although not indicated in myasethenia gravis manage- ment, include tacrolimus (B) and rapamycin (sirolimus; C). Tacrolimus
is a calcineurin inhibitor that inhibits T-cell proliferation by binding to FK-binding protein-1A (FKBP-1A), ultimately preventing T-cell activa- tion. Rapamycin inhibits T-cell proliferation by binding to FKBP-1A. Its advantage lies in its low nephrotoxicity in comparison to other immu- nosuppressive agents.
- Innate immunity (3): Cellular response
A 25-year-old woman, who has a history of allergy to nuts, is taken to accident and emergency after eating a dessert containing peanuts. She has an evident wheeze with an increased respiratory rate, swelling of her lips and itchy skin. Which cell of the innate immune system is most likely to be responsible for her symptoms?
A Natural-killer cells
B Dendritic cells
C Eosinophils
D Mast cells
E Neutrophils
D Mast cells (D) are involved in the inflammatory process that occurs in allergy and anaphylaxis (the diagnosis in this case), but also provide a protective function against pathogens. Mast cells are activated by one of three mechanisms: direct injury (toxins or drugs), cross-linking of IgE receptors or by activated complement proteins. Once activated, mast cells release granules containing histamine and heparin. Histamine causes vasodilatation leading to the characteristic features of inflam- mation (oedema, warmth and redness of the skin). The ‘flare and wheal’ skin reaction is a feature of histamine release by mast cells. Mast cells play a role in diseases such as asthma, eczema and allergic rhinitis. Anaphylaxis is characterized by systemic degranulation of mast cells leading to life-threatening shock. Natural killer cells (NK cells; A) are responsible for destroying tumour cells and virus-infected cells. NK cells are unique in that they have the ability to kill such cells in the absence of antibodies and major histocompatibility complex. Dendritic cells (B) are antigen-presenting cells (APCs) involved in bridging the gap between the innate and adaptive immune response. Once dendritic cells are activated, they migrate to the lymph nodes to facilitate the adaptive immune system. Eosinophils (C) protect against parasitic infection. Such pathogens stimulate release of granule contents into the extracellular space, which surround the parasite and lead to clearance. Neutrophils (E) are the most common of the granulocytes. Neutrophils are responsible for the innate protection against bacterial pathogens. Stored within neu- trophils are a host of bactericidal lysosomes which contain lysozyme, acid hydrolases and myeloperoxidase. Opsonized pathogens are internal- ized by neutrophils forming a phagosome. Lysosomal contents enter the phagosome leading to respiratory burst and lysis of the pathogen.
