Immunology

Question 1

What are the constitutive barriers to infection?

Answer 1

• Skin
• Mucosal surfaces
• Commensal bacteria

Question 2

How does the skin act as a constitutive barriers to infection?

Answer 2

• Consists of tightly packed keratinised cells - physically limits colonisation by microorganisms
• Physiological factors - low pH and low oxygen tension
• Sebaceous glands - produce hydrophobic oils, lysozymes and ammonia

Question 3

How does the mucosal surfaces act as a constitutive barriers to infection?

Answer 3

• Mucus = physical/trapping barrier - contains secretory IgA, lysozymes, antimicrobial peptides and lactoferrin
• Cilia directly trap pathogens - assisted by physical manoeuvres (sneezing/coughing)

Question 4

How does the commensal bacteria act as a constitutive barriers to infection?

Answer 4

• 100 trillion bacteria normally reside at the surfaces
• Compete with pathogenic bacteria for scarce resources
• Produce fatty acids and bactericidins - inhibit the growth of many pathogens

Question 5

What are the cells of the innate immune system?

Answer 5

Polymorphonuclear cells

• Neutrophils
• Eosinophils
• Basophils
• Monocytes and macrophages
• NK cells
• Dendritic cells

Question 6

What are the soluble components of the innate immune system?

Answer 6

• Complement
• Acute phase proteins
• Cytokines and chemokines

Question 7

What are the key features of the innate immune response?

Answer 7

Identical responses in all individuals Cells express receptors that allow them to detect and home to sites of infection Cells express genetically encoded receptors (PRRs) Phagocytic capacity to engulf pathogens Cells secrete cytokines and chemokines that regulate the immune response

Question 8

Describe the role of neutrophils.

Answer 8

• Acute inflammation/Migrate rapidly to injury site
• Express receptors for cytokines and chemokines to detect inflammation
• Express Pattern Recognition Receptors to detect pathogens
• Express Fc receptors for immunoglobulin to detect immune complexes
• Perform phagocytosis and oxidative and non-oxidative killing
• Release enzymes, histamine, lipid mediators of inflammation from granules
• Secrete cytokines and chemokines to regulate inflammation

Question 9

Describe the role of macrophages.

Answer 9

Present within tissue - Express receptors for cytokines and chemokines, express Fc receptors for immune complexes, express PRR - Perform phagocytosis and oxidative and non-oxidative killing - Secrete chemokines and cytokines to regulate inflammation - CAN process and present antigen to T cells

Question 10

Describe phagocyte recruitment.

Answer 10

• Cellular damage and bacterial products trigger local production of inflammatory mediators (cytokines and chemokines)
  
  • Cytokines activate vascular endothelium increasing permeability
  • Chemokines attract phagocytes

Question 11

How does the innate immune system recognise microorganisms?

Answer 11

Pattern recognition receptors (PRRs) - Toll-like receptors and mannose receptors recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) e.g. bacterial sugars, DNA and RNA Fc receptors on innate immune cells allows them to bind to Fc portion of immunoglobulins to allow phagocytes to recognise immune complexes

Question 12

Describe endocytosis.

Answer 12

1. Opsonins act as a bridge between the pathogen and the phagocyte receptors
2. Antibodies bind to Fc receptors on phagocytes

• Complement components can bind to complement receptors (e.g. CR1)
• Acute phase proteins (e.g. CRP) will also promote phagocytosis

Question 13

What is a phagolysosome?

Answer 13

Phagolysosome = a phagosome fused with a lysosome

• forms a protected compartment in which killing of the organism occurs

Question 14

Describe oxidative killing.

Answer 14

1. NADPH oxidase converts oxygen into reactive oxygen species - superoxide and hydrogen peroxide
2. Myeloperoxidase catalyses the production of hydrochlorous acid from hydrogen peroxide and chloride
3. Hydrochlorous acid is a highly effective oxidant and anti-microbial

Question 15

Describe non-oxidative killing.

Answer 15

Killing by release of bactericidal enzymes e.g. lactoferrin and lysozyme into the phagolysosome - The range of enzymes results in a broad range of cover against bacteria and fungi

Question 16

Answer 16

Question 17

Describe the role of natural killer cells.

Answer 17

Speacialised lymphocytes that are in the blood and may migrate to inflamed tissue

Express inhibitory receptors for self HLA class 1 which prevents inappropriate activation by normal self-cells

Express range of activatory receptors including natural cytotoxicity receptors that recognise heparan sulphate proteoglycans

Integrate signals from inhibitory and activatory receptors (usually inhibitory signals dominate)

Cytotoxic - kill ‘altered self’ cells (i.e. malignancy or virus-infected cells)

Secrete cytokines to regulate inflammation and promote dendritic cell function

Question 18

Where are dendritic cells found?

Answer 18

Peripheral tissue

Question 19

Describe the role of immature dendritic cells.

Answer 19

Detect inflammation - express receptors for cytokines and chemokines

Detect pathogens - express pathogen recognition receptors

Detect immune complexes - express Fc receptors for immunoglobulin

Capable of phagocytosis

Question 20

What triggers dendritic cells to mature?

Answer 20

They do so following phagocytosis

Question 21

Describe the role of mature dendritic cells.

Answer 21

Upregulate expression of HLA molecules

Express co-stimulatory molecules

Migrate via lymphatics to lymph nodes

Present processed antigen to T cells in lymph nodes to prime the adaptive immune system

Express cytokines to regulate the immune response

Question 22

Answer 22

Question 23

What are the components of the adaptive immune system?

Answer 23

Humoral Immunity - B lymphocytes and antibody

Cellular Immunity - T lymphocytes (CD4+ and CD8+)

Soluble Components - cytokines and chemokines

Question 24

What are the 4 key features of the adaptive immune system?

Answer 24

1. Wide repertoire of antigen receptors - VDJ recombination with mechanisms to delete or tolerate these cells
2. Exquisite specificity
3. Clonal expansion - cells with appropriate specificity will proliferate during infection
4. Immunological memory

Question 25

Define primary lymphoid organ and describe each one.

Answer 25

Organs involved in lymphocyte development

• Bone marrow - both T and B lymphocytes are derived from haematopoietic stem cells in BM but only B cells mature here
• Thymus - site of T cell maturation - most active in fetal and neonatal period, involutes after puberty

Question 26

Define the secondary lymphoid organs and state what they are.

Answer 26

Anatomical sites of interaction between naïve lymphocytes and microorganisms in which immune reaction occurs

• Spleen
• Lymph nodes
• Mucosal associated lymphoid tissue (MALT)

Question 27

Answer 27

Question 28

Describe T lymphocyte maturation.

Answer 28

1. Arise from haematopoietic stem cells
2. Exported as immature cells to thymus where they undergo selection
3. Mature T cells enter circulation and reside in secondary lymphoid organs

Question 29

What do CD8 T cells recognise?

Answer 29

Peptides presented by HLA Class I

Question 30

What do CD4 T cells recognise?

Answer 30

Peptides presented by HLA Class II

Question 31

What selection process of T cells occurs?

Answer 31

Based on affinity to HLA molecules

• Low affinity = useless so removed
• High affinity = dangerous/autoimmune so removed
• 10% develop further

Question 32

What is the role of CD4 T cells?

Answer 32

Recognise peptides derived from EC proteins

Provide help for development of full B cell response

Provide help for the development of some CD8+ T cell responses

Peptides usually presented on HLA Class 2

Immunoregulatory functions via cell: cell interactions and cytokine expression

• AKA T helper cells

Question 33

What is the role of Th1 CD4 T cells?

Answer 33

Express CD4 and secrete IFN-gamma and IL2 to help CD8 and macrophages

Question 34

What is the role of T follicular CD4 T cells?

Answer 34

Promote germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells

Question 35

What is the role of regulatory CD4 T cells?

Answer 35

Express CD25 and transcription factor Foxp3

Secrete IL10 (immunosuppressive cytokine) to inhibit immune response

Express CTLA4 to directly inhibit T cell activation

Question 36

What is the role of CD8 cytotoxic T cells?

Answer 36

Recognise peptides derived from intracellular proteins presented on HLA Class 1

Kills cells directly via perforin (pore-forming) and granzymes (expression of Fas ligand)

Secrete cytokines (e.g. IFN-gamma, TNF-alpha)

Important against viruses and tumours

Question 37

Describe T cell memory.

Answer 37

Response to successive exposures of antigen

Pool of memory T cells ready to respond to antigen

More easily activated than naïve cells

Question 38

Answer 38

Question 39

What is the tolerance mechaniusm of B cells?

Answer 39

If they recognise self then they are negatively selected/deleted

Question 40

What happens when B cells encounter antigens?

Answer 40

Early IgM Response - Cell differentiates into IgM secreting plasma cell

Germinal Centre Reaction - Somatic hypermutation and isotype switching from IgM to IgG/A/E

Question 41

Describe the process of germinal centre reactions that develop an antibody response.

Answer 41

Dependent on T helper cells

1. Dendritic cells prime CD4+ T helper cells
2. CD4+ cells then help B cell differentiation (mediated by CD40L: CD40)
3. B cells proliferate with the help of CD4 T cells
4. Undergo somatic hypermutation and isotype switching (from IgM to IgG/A/E)
5. Become plasma cells - produce antibodies

Question 42

Describe the structure of an immunoglobulin.

Answer 42

Soluble proteins made up of 2 heavy chains + 2 light chains

Heavy chain determines antibody class (e.g. M, G, A)

Effector function determined by constant region (Fc) - heavy chain

Antigen binding region (Fab) recognise antigens - heavy and light chains

Question 43

What are the functions of antibodies?

Answer 43

Identify pathogens and toxins (Fab-mediated)

Interact with other components of immune system to remove pathogens (Fc-mediated) - Complement, Phagocytes, NK cells

Particularly important in defence against BACTERIA

Question 44

How do antibodies provide defence against infection?

Answer 44

Neutralisation - binds to receptors on target molecule so it cannot bind to anything else thereby blocking interaction with cells

Question 45

Describe IgA antibodies.

Answer 45

Protection of mucosal surfaces via salivary, respiratory, gastrointestinal and lacrimal secretions = secretory function

• Dimer form with 4 binding sites found in mucosal and epithelial surfaces e.g. gut, mouth
• Monomer circulates in serum

IgA main antibody in breast milk, providing passive immunity in neonates

Question 46

Describe IgG antibodies.

Answer 46

Most abundant antibody type

Monomor

Question 47

Describe IgM antibodies.

Answer 47

Pentamer

Primary response against pathogens

Question 48

Describe IgE antibodies.

Answer 48

Parasites and Type I hypersensitivity reactions

Question 49

Describe B cell memory.

Answer 49

Decreased lag time between antigen exposure and antibody production (to 2-3 days)

Increased antibody titres produced

Response dominated by IgG antibodies of high affinity - compared to IgM in primary response

Response can be independent of help from CD4 cells

Question 50

Answer 50

Question 51

What is complement?

Answer 51

Over 20 tightly regulated linked proteins that are produced by liver

Inactive in the circulation

When activated by enzymes they activate other proteins in the biological cascade to produce a rapid, highly amplified response

Question 52

What are the 3 pathways of complement activation?

Answer 52

Classical - C1, C2 and C4

Mannose Binding Lectin (MBL) - C2 and C4

Alternative

Question 53

What is the final common pathway in complement activation?

Answer 53

All routes converge on C3

Final common pathway C5-C9 to membrane attack complex

Question 54

Describe the classical pathway of complement activation.

Answer 54

Activated by immune complexes

1. Formation of antibody-antigen immune complexes results in conformational change in antibody shape which exposes binding site for C1
2. Binding of C1 to antibody results in cascade activation (dependent on the adaptive immune response so its not an early response)

Question 55

Describe the Mannose Binding Lectin (MBL) pathway of complement activation.

Answer 55

MBL → C2, C4 → C3

• Binding of MBL to microbial cell surface CHO → Direct stimulation of classical pathway (only C4, C2)
• Not dependant on acquired immune response

Question 56

Describe the alternative pathway of complement activation.

Answer 56

Directly triggered by binding of C3 to bacterial cell wall components (lipopolysaccharide of gram-negative bacteria)

Not dependent on adaptive immune response

Involves factors: B, I, P

Question 57

Describe the common pathway of complement activation.

Answer 57

Convergence occurs at C3

1. Activation of C3 convertase = major amplification step
2. Triggers formation of membrane attack complex MAC via C5-9
3. MAC makes holes in membranes hence killing pathogen

Question 58

What are the roles of complement fragments released during complement activation?

Answer 58

Increase vascular permeability and cell trafficking to inflammation site

Opsonisation of immune complexes to keep them soluble

Opsonisation of pathogens to promote phagocytosis

Phagocyte activation

Promotes mast cells/basophil degranulation

Makes holes in bacterial membranes

Question 59

Answer 59

Question 60

What are cytokines?

Answer 60

Small protein messengers with immunomodulatory function

Autocrine and paracrine dependent action

• IL2, IL6, IL10, IL12, TNF-alpha, TGF-beta

Question 61

What are chemokines?

Answer 61

Type of cytokines

Direct recruitment of leukocytes in inflammatory response via CCL19 and CCL21 = ligands for CCR7 (receptors)

Important in directing dendritic cell trafficking to lymph nodes

Question 62

What are the causes of secondary immune deficiences?

Answer 62

• Malnutrition - most common globally
• Infections - HIV, Measles, TB, SARS-CoV-2
• Age extremities
• Splenic surgery/trauma
• Drugs - glucocorticoids (commonest), cytotoxic agents, chemotherapy, calcineurin inhibitors, antiepileptics, DMARDs, JAK inhibitors
• Genetic or Metabolic disease
• Haematological cancers
• Biological agents/cellular therapy - anti-CD20 etc or rituximab (antibody therapies)

Question 63

What is Good’s syndrome?

Answer 63

• Thymoma and Antibody deficiency
  
  • Combined T and B cell absence/defect
  • CMV PJP and muco-cutaneous candida
  • Increased risks of autoimmune disease
    
    • Pure red cell aplasia, Myasthenia gravis, Lichen planus

Question 64

What questions should you ask to evaluate secondary immune deficiency?

Answer 64

• Clinical history of infection
• Childhood illnesses/loss of schooling
• Other illness/PMH
• Family history of infection/autoimmune/cancers
• Medication history
• Vaccine history and any reactions

Question 65

What investigation should be done for immune defects?

Answer 65

• FISH for immunodeficiency - Picks up 85% of immune defects
  
  • Full blood count
  • Immunoglobulins
  • Serum complement (C3 and C4 – serum complex disease, SLE, C1 inhibitor deficiency (a primary immune deficiency))
  • HIV test
• First Line Investigations
  
  • Renal and liver profile
  • Calcium and bone profile
  • Total protein and albumin
  • Urine protein/Cr ratio
  • Serum protein electrophoresis (monoclonal proteins found in MM, WMG, NHL and MGUS)
  • Serum free light chains (b-lymphoma)
• Second Line Investigations
  
  • Measure conc of vaccine antibodies - tetanus (protein antigen) and pneumovax (carbohydrate antigen of 23 types)

Question 66

What does an isolated reduction in IgG suggest?

Answer 66

• Protein loosing enteropathy
• Prednisolone

Question 67

What does a reduction in IgG and IgM suggest?

Answer 67

• B cell neoplasm
• Rituximab

Question 68

What does a reduction in IgG and IgA suggest?

Answer 68

• Primary antibody deficiency

Question 69

What is the management of secondary immune deficiencies?

Answer 69

• Treat underlying cause
• Advise measures to reduce exposure
• Immunisation against respiratory viruses and bacteria and offer vaccines to household contacts
• Education to treat bacterial infections promptly (use of rescue antibiotics)
• Prophylactic antibiotics for confirmed recurrent bacterial infections
• IgG replacement therapy – if other management have failed

Question 70

Describe the structure of HIV?

Answer 70

• HIV has an icosahedral (20-faced) structure
• Double-stranded RNA
• Genome is diploid
• Contains 9 genes that encode 15 structural, regulatory and auxiliary proteins
  
  • I.E. gp120, gp41 and RT

Question 71

How does HIV replicate?

Answer 71

Inside a cell using Reverse Transcriptase to convert RNA to DNA which is integrated into the host genome

Question 72

What is the target of HIV?

Answer 72

• CD4+ T-helper cells
• CD4+ monocytes
• CD4+ dendritic cells

Question 73

What are the possible routes of transmission of HIV?

Answer 73

• Sexually
• Infected blood – transfusion, needle sharing, blood products
• Vertical (mother to child) – ante-/intra-partum, breastmilk

Question 74

Describe the life cycle of HIV?

Answer 74

1. Attachment and entry
2. Reverse transcription and DNA synthesis
3. Integration
4. Viral transcription
5. Viral protein synthesis
6. Assembly of virus and release of virus
7. Maturation

Question 75

Describe the clinical course of HIV.

Answer 75

Question 76

What are the immunological features of HIV infection?

Answer 76

• CD4 T cell depletion
• Chronic immune activation
• Impairment of CD4 and CD8 T cell function
• Disruption of lymph node architecture
• Impaired ability to generate protective T and B cell immune responses
• Loss of antigen-specific humoral immune responses

Question 77

What are the mechanisms of HIV long-term non-progressors?

Answer 77

• Host genetic factors:
  
  • HLA profile - Heterozygosity for 32-bp deletion in chemokine-r CCR5
  • MBL alleles - TNF c2 microsatellite alleles
  • Gc vitamin D-binding factor alleles
• Host immune response factors
  
  • Effective CTL, HTL and humoral responses
  • Secretion of:
    
    • CD8 antiviral factor
    • IL-16
    • Secretion of chemokines that block HIV entry co-receptors CCR5 and CXCR4
  • Maintenance of functional lymphoid tissue architecture
• Virologic factors
  
  • Infection with attenuated strains of HIV

Question 78

How is HIV diagnosed and monitored?

Answer 78

• Detection via:
  
  • Anti-HIV antibodies (ELISA) – screening test
  • Anti-HIV antibodies (Western Blot) – confirmation test
  • Viral load (viral RNA detection using PCR) – very sensitive; steps:
• ​CD4+ T Cell Counts – monitored using flow cytometry
  
  • The onset of AIDS correlates with a decrease in the number of CD4+ T cells
    
    • Antigens on T cells:
      
      • CD3, CD4, CD8, CD19, CD56

Question 79

What is the best predictor of HIV prognosis?

Answer 79

Initial baseline plasma viral load

• Higher the load the sooner the progression to AIDS if not treated

Question 80

At what CD4 T cell counts should preventative measure be taking against:

• PCP
• Toxoplasma gondii
• Mycobacterium avium complex (MAC)

Answer 80

• PCP = 200 x 10⁹/L
• Toxoplasma gondii = 100 x 10⁹/L
• Mycobacterium avium complex (MAC disease) = 75 x 10⁹/L

Question 81

How can resistance against anti-retroviral therapy be tested for?

Answer 81

• Phenotypic - viral replication is measured in cell cultures under selective pressure of increasing concentrations of antiretroviral drugs (compared to wildtype)
• Genotypic - mutations detected by sequencing amplified HIV genome

Question 82

What is contained within HAART?

Answer 82

• Combination of ≥3 ART drugs = Triple Therapy:
  
  • 2 backbone drugs - x2 NRTIs
  • ≥1 binding agent - x1 NNRTI or INI

Question 83

Name some examples of each type of ART backbone?

Answer 83

• Nucleoside Reverse Transcriptase Inhibitors (NRTI) – e.g. Zidovudine/AZT, abacavir
• Nucleotide RTI – e.g. Tenofovir
• Non-NRTI (NNRTI) – e.g. Efavirenz
• Protease inhibitor (PI) – e.g. Indinavir

Question 84

Name some examples of each type of ART binding agents?

Answer 84

• Integrase inhibitors (INI) – e.g. Raltegravir
• Attachment inhibitors (AI) – e.g. Maraviroc
• Fusion inhibitors (FI) – e.g. Enfuvirtide

Question 85

What interactions exist with HAART?

Answer 85

• PI – block cytochrome P450
• Efavirenz – P450 inducer
• INI – interacts with indigestion remedies (Gaviscon, aluminium salts, calcium salts) and is sequestered which can be very bad as some INI is absorbed but very little and so resistance is bred very quickly

Question 86

What are the limitations and complications of HAART?

Answer 86

• Adherence – most common reason for failure
• Does NOT eradicate latent HIV-1
• Fails to restore HIV-specific T cell responses
• Threat of drug resistance
• Significant toxicities
• High pill burden
• Quality of life
• Cost - >40% with no access

Question 87

What methods work to reduce the spread of HIV?

Answer 87

• Male circumcision (APCs in foreskin at a high density)
• Condoms
• PrEP (Truvada)
• TasP (Treatment as Prevention)

Question 88

What cures exist for HIV?

Answer 88

• Allogenic SCT from a CCRδ32 HLA matched donor
  
  • CCRδ32 are unable to contract HIV – found in 1% of north-west European patients
• Shock and Kill

Question 89

Describe B lymphocyte maturation.

Answer 89

1. Initially exist in periphery as IgM B cells
2. Undergo germinal centre reaction to differentiate into plasma cells expressing IgG, IgE and IgA

Question 90

What are the most relevant proteins in terms of transplantation?

Answer 90

• ABO blood group
• HLA - MHC
• Other minor histocompatibility genes

Question 91

What are the two major forms of rejection?

Answer 91

• T cell-mediated rejection
• Antibody-mediated rejection

Question 92

Where are HLA expressed?

Answer 92

• HLA Class I (A, B and C) = ALL cells
  
  • Thought to be the most immunogenic
• HLA Class II (DR, DQ, DP) = APCs
  
  • Upregulated on other cells under stress

Question 93

What are the features of HLA?

Answer 93

• They are highly polymorphic with hundreds of alleles for each locus
• High degree of variability from the areas of protein lining the peptide-binding groove which allows us to present a wide variety of antigens in that peptide-binding groove to the cells of the immune system

Question 94

What HLA molecules are the most important to match in transplantation?

Answer 94

A, B and DR

• DR > B > A

Question 95

Describe T-cell mediated rejection.

Answer 95

• Phase 1 = Activation of T-cells
  
  • Presentation of foreign HLA antigens in MHC by APCs and co-stimulatory signals activate T-cells within lymph nodes
  • This leads to effector phase of rejection → inflammation caused leads to graft dysfunction
• Phase 2 = Actions of activated T cells
  
  • Proliferation
  • Product cytokines (IL2 is important)
  • Provide help to CD8+ cells
  • Provide help for antibody production
  • Recruit phagocytic cells
• Phase 3 = Effector Phase (Image)

Question 96

What are the effects of cytotoxic T cells have on a transplanted organ?

Answer 96

• Granzyme B (toxin)
• Perforin (punch holes)
• Fas-ligand (apoptosis)

Question 97

What are the effects of macrophages have on a transplanted organ?

Answer 97

• Phagocytosis
• Proteolytic enzymes
• Cytokine release
• O₂ and N₂ radicals

Question 98

What are the histological features of T cell mediated rejection?

Answer 98

• Lymphocytic interstitial infiltration
• Ruptured tubular basement membrane
• Tubulitis - inflammatory cells within the tubular epithelium
• Macrophages

Question 99

Describe antibody mediated rejection.

Answer 99

• Phase 1: recognition of foreign antigens
• Phase 2: activation of antigen-specific lymphocytes
• Phase 3: effector phase - antibodies in graft
  
  • Antibodies bind to antigens (HLA) on the endothelium of the blood vessels in the transplanted organ
  • Antibodies activate complement
    
    • Form MAC → endothelial cell lysis
    • Recruit inflammatory cells to the microcirculation
    • Antibodies crosslink the MHC molecules
    • The antibodies can also directly recruit mononuclear cells, NK cells and neutrophils → capillaritis
• Phase 4: graft fibrosis

Question 100

What are the cardinal features of antibody-mediated rejection?

Answer 100

Capillaritis = inflammatory cells in capillaries of the kidney → injury

Question 101

What is the histology of antibody-mediated rejection?

Answer 101

• Inflammatory cell infiltrate
• Capillaritis
• Fixation of complement fragments on endothelial cell surfaces

Question 102

What kind of damage is caused by T-cell and antibody medtaited rejection?

Answer 102

• T-cells = Interstitial damage
• Antibodies = Endothelial damage

Question 103

How is graft rejection prevented?

Answer 103

• HLA typing
• Screening for anti-HLA antibodies

Question 104

Describe anti-HLA antibody screening.

Answer 104

• Cytotoxicity assays
  
  • Inspects if recipient’s serum will kill the lymphocytes of the donor
  • Positive crossmatch suggests that there is cell lysis
• Flow cytometry
  
  • Inspects if recipient’s serum binds to the donor’s lymphocytes using fluorescent anti-human immunoglobulin
• Solid phase assays
  
  • Recipient’s serum is mixed with beads and fluorescently labelled immunoglobulin is used to determine which HLA epitopes the antibodies bind to
  • Patients that have antibodies to lots of different types of antibodies are regarded as highly sensitised

Question 105

How can organ mismatch issues be overcome?

Answer 105

• Improve transplantation across tissue barriers
• More donors
• Organ exchange programmes
• Future: xenotransplantation (animals), stem cell research

Question 106

What are the 3 signals to activate T-cells?

Answer 106

• APC MHC to T-cell TCR = Main signal
• APC CD80/CD86 to T-cell CD28 - CD80/86 to CTLA4 suppresses immune reactions
• Cytokine IL-2 to T-cell CD25 - after T-cell activation, autocrine IL-2 is released to further activate

Question 107

What immunosuppressants are used in the management/prevention of T cell mediated rejection?

Answer 107

• Steroids - prevent general T-cell mediated rejection
• Inhibitors of cell signalling - Calcineurin inhibitors
• Anti-proliferative agents
• Inhibitors of cell surface receptors
  
  • Alemtuzumab = anti-CD52 monoclonal antibody that causes lysis of T cells
  • Basiliximab = anti-CD25 monoclonal antibody which targets the IL-2-R à less proliferation

Question 108

What are the main targets for immunosuppression for antibody-mediated rejection?

Answer 108

• B-cell activation
• Plasma cell secretion of antibodies
• Antibody effects on endothelium

Question 109

What immunosuppressants are used in the management/prevention of antibody-mediated rejection?

Answer 109

• Rituximab - B cell depletion
• BAFF inhibitors
• Proteasome inhibitors - block production of antibodies by plasma cells
• Complement inhibitors - block complement binding to endothelial cells

Question 110

What is the modern transplant immunosuppression regimen?

Answer 110

• Induction agent = OXT3/ATG, anti-CD52, anti-CD25
  
  • Given at time of transplantation or just before to prepare the patient to receive the foreign organ
• Baseline immunosuppression = calcineurin inhibitor + mycophenolate mofetil / azathioprine ± steroids

Question 111

What is the management of acute transplant rejection?

Answer 111

• Cellular = Steroids, OKT3, ATG
• Antibody-mediated = IVIG, Plasmapheresis, Anti-C5, Anti-CD20

Question 112

Describe post-transplant malignancy.

Answer 112

• Viral-associated malignancies are much more common
  
  • Kaposi sarcoma (HHV8)
  • Lymphoproliferative disease (EBV)
• Skin cancer is 20x more common
• Risk of other cancers is also increased

Question 113

What are the features of immunodeficiency?

Answer 113

• Infection
  
  • Two major or one major and recurrent minor infections in one year
  • Atypical organisms
  • Unusual sites
  • Poor response to treatment

Question 114

What are the features of primary immune deficiency?

Answer 114

• Infection
• Family history
• Young age at presentation
• Failure to thrive

Question 115

What are the common investigations for primary immune deficiency?

Answer 115

• White cells
  
  • Full blood count
  • Lymphocyte subsets
  • White cell migration/function
• Immunoglobulins
  
  • IgM, IgG, IgA
  • Specific Igs and response to vaccination
• Complement
  
  • Complement function
  • Individual complement components

Question 116

What is the role of phagocytes?

Answer 116

• Express cytokine/chemokine receptors to locate sites of infection
• Express genetically encoded receptors for detection of pathogens at site of infection
  
  • Pattern recognition receptors which recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA, RNA
• Express Fc receptors for detection of immune complexes
• Phagocytic capacity to engulf the pathogens
• Secrete cytokines and chemokines to regulate immune response

Question 117

What are the types of primary phagocyte deficiency?

Answer 117

• Failure to produce neutrophils
  
  • Failure of stem cells to differentiate along myeloid or lymphoid lineage
    
    • Reticular dysgenesis = Autosomal recessive severe SCID
  • Specific failure of neutrophil maturation
    
    • Kostmann syndrome
    • Cyclic neutropenia
• Defect of phagocyte migration
  
  • Leukocyte adhesion deficiency
• Failure of oxidative killing mechanisms
  
  • Chronic granulomatous disease
• Cytokine deficiency
  
  • IL12, IL12R, IFNg or IFNg R deficiency

Question 118

What is Reticular dysgenesis?

Answer 118

• Autosomal recessive severe SCID
  
  • Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)

Question 119

What is Kostmann syndrome?

Answer 119

• Autosomal recessive severe congenital neutropenia
  
  • Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)

Question 120

What is Cyclic neutropenia?

Answer 120

• Autosomal dominant episodic neutropenia every 4-6 weeks
  
  • Mutation in neutrophil elastase (ELA-2)

Question 121

What is Leukocyte adhesion deficiency?

Answer 121

• Deficiency of CD18 (b2 integrin subunit)
  
  • CD11a/CD18 (LFA-1) is expressed on neutrophils
    
    • Binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration
  • In Leukocyte adhesion deficiency the neutrophils lack these adhesion molecules and fail to exit from the bloodstream
    
    • Very high neutrophil counts in blood
    • Absence of pus formation

Question 122

What are the features of leukocyte adhesion deficiency?

Answer 122

• Very high neutrophil counts in blood
• Absence of pus formation

Question 123

What are the features of chronic granulomatous disease?

Answer 123

• Absent respiratory burst
• Excessive inflammation
• Granuloma formation
• Lymphadenopathy
• Hepatosplenomegaly

Question 124

What is chronic granulomatous disease?

Answer 124

• Deficiency of one of components of NADPH oxidase
  
  • Inability to generate oxygen free radicals results in impaired killing
• Persistent neutrophil/macrophage accumulation
  
  • Failure to degrade antigens

Question 125

What are the appropriate investigations for suspected chronic granulomatous disease?

Answer 125

• Nitroblue tetrazolium (NBT) test
  
  • NBT is a dye that changes colour from yellow to blue, following interaction with hydrogen peroxide
• Dihydrorhodamine (DHR) flow cytometry test
  
  • DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide

Question 126

What infections are common in patients with phagocyte deficiency?

Answer 126

• Bacterial infections
  
  • Staphylococcus aureus
  • Enteric bacteria
• Fungal infections
  
  • Candida albicans
  • Aspergillus fumigatus and flavus
• Mycobacterial infection
  
  • Mycobacterium tuberculosis
  • Atypical Mycobacteria

Question 127

What is the management of phagocyte deficiency?

Answer 127

• Aggressive management of infection
  
  • Infection prophylaxis
    
    • Antibiotics → e.g. Septrin
    • Anti-fungals → e.g. Itraconazole
  • Oral/intravenous antibiotics as needed
• Definitive therapy
  
  • Haematopoietic stem cell transplantation
  • Specific treatment for CGD → Interferon gamma therapy

Question 128

What are the types of primary natural killer cells deficiency?

Answer 128

• Classical NK deficiency
  
  • Absence of NK cells within peripheral blood
  • Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2
• Functional NK deficiency
  
  • NK cells present but function is abnormal
  • Abnormality described in FCGR3A gene in subtype 1

Question 129

What infections are common in primary natural killer cells deficiency?

Answer 129

• Virus infection
  
  • Herpes virus infection
    
    • Herpes Simplex Virus I and II
    • Varicella Zoster Virus
    • Epstein Barr Virus
    • Cytomegalovirus
    • Papillomavirus infection → associated cancers

Question 130

What infections are common in patients with natural killer cells deficiency?

Answer 130

• No good trial data
• Prophylactic antiviral drugs such as acyclovir or gancyclovir
• Cytokines such as IFN-alpha to stimulate NK cytotoxic function
• Haematopoietic stem cell transplantation in severe phenotypes

Question 131

What are the types of primary deficiency of complement?

Answer 131

• Complement deficiency
• Classical pathway deficiency (C2, C1q)
• MBL deficiency MBL2 mutations are common but not usually associated with immunodeficiency

Question 132

What is Complement deficiency?

Answer 132

• Susceptibility to bacterial infections → especially encapsulated bacteria
  
  • Neisseria meningitides → properidin and C5-9 deficiency
  • Haemophilus influenzae
  • Streptococcus pneumoniae

Question 133

What is Classical pathway deficiency?

Answer 133

• Deficiency in C2 and C1q
  
  • Susceptibility to SLE
  • Failure of phagocytosis of dead cells
    
    • Increased nuclear debris
  • Failure to clear immune complexes
    
    • Immune complex deposition in blood vessels

Question 134

How can SLE lead to to functional complement deficiency?

Answer 134

1. Active lupus causes persistent production of immune complexes
2. Consumption of complement leading to functional complement deficiency

Question 135

How can nephritic factors lead to functional complement deficiency?

Answer 135

• Nephritic factors are auto-antibodies directed against components of the complement pathway
• Nephritic factors stabilise C3 convertases resulting in C3 activation and consumption
• Often associated with glomerulonephritis (classically membranoproliferative)
• May be associated with partial lipodystrophy

Question 136

What are the appropriate investigation for deficiency in complement?

Answer 136

• Measure C3 and C4
• Functional
  
  • CH50 - classical pathway
  • AP50 - alternative pathway

Question 137

What is the management of complement deficiences?

Answer 137

• Vaccination
  
  • Boost protection mediated by other arms of the immune system
  • Meningovax, Pneumovax and HIB vaccines
• Prophylactic antibiotics
• Treat infection aggressively
• Screening of family members

Question 138

What is the pathophysiology of SCID?

Answer 138

• Defects of Haemopoetic stem cells
  
  • Reticular dysgenesis - most severe SCID
• Defects of Lymphoid precursors
  
  • Less severe forms of SCID

Question 139

Describe X-linked SCID.

Answer 139

• 45% of all SCID
• Mutation of common gamma chain on chromosome Xq13.1
  
  • Shared by cytokine receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
  • Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells
• Phenotype
  
  • Very low or absent T cell numbers
  • Very low or absent NK cell numbers
  • Normal or increased B cell numbers but low Igs

Question 140

Describe ADA deficiency.

Answer 140

• 16.5% of all SCID
• Adenosine Deaminase Deficiency
  
  • Enzyme required for cell metabolism in lymphocytes
• Phenotype
  
  • Very low or absent T cell numbers
  • Very low or absent B cell numbers
  • Very low or absent NK cell numbers

Question 141

What protects the SCID neonate in their first 3 months of life?

Answer 141

Source of circulating IgG in the neonate

Question 142

What are the signs of SCID?

Answer 142

• Unwell by 3 months of age
• Infections of all types
• Failure to thrive
• Persistent diarrhoea
• Unusual skin disease
  
  • Colonisation of infant’s empty bone marrow by maternal lymphocytes
  • Graft versus host disease
• Family history of early infant death

Question 143

Describe T cell selection and central tolerance.

Answer 143

Question 144

Describe CD8+ T celss.

Answer 144

Specialised cytotoxic cells

• Recognise peptides derived from intracellular proteins in association with HLA class I
  
  • HLA-A, HLA-B, HLA-C
• Kill cells directly
  
  • Perforin (pore forming) and granzymes
  • Expression of Fas ligand
• Secrete cytokines
• Particularly important in defence against viral infections and tumours

Question 145

Describe CD4+ cells.

Answer 145

Specialised helper cells

• Recognise
  
  • Peptides derived from extracellular proteins
  • Presented on HLA Class II molecules (HLA-DR, HLA-DP HLA-DQ)
• Immunoregulatory functions via cell:cell interactions and expression of cytokines
  
  • Provide help for development of full B cell response
  • Provide help for development of some CD8+ T cell responses

Question 146

What are the CD4+ T cell subsets?

Answer 146

Question 147

What is DiGeorge syndrome?

Answer 147

• Deletion at 22q11.2 → TBX1 may be responsible for some features
• Usually sporadic rather than inherited
• Normal numbers B cells
• Reduced numbers T cells
• Homeostatic proliferation with age
• Immune function usually only mildly impaired and improves with age

Question 148

What are the signs of DiGeorge syndrome?

Answer 148

• High forehead
• Developmental defects in the pharyngeal pouch
  
  • Low set
  • Abnormally folded ear
  • Cleft palate
  • Small mouth and jaw
• Hypocalcaemia
• Oesophaegeal atresia
• Underdeveloped thymus
• Complex congenital heart disease

Question 149

What is the Bare lymphocyte syndrome - type 2?

Answer 149

• Defect in one of the regulatory proteins involved in Class II gene expression
  
  • Regulatory factor X
  • Class II transactivator
• Absent expression of MHC Class II molecules
• Profound deficiency of CD4+ cells
  
  • Usually have normal number of CD8+ cells
  • Normal number of B cells
  • Low IgG or IgA antibody due to lack of CD4+ T cell help

BLS type 1 also exists due to failure of expression of HLA class I

Question 150

What are the signs of bare lymphocyte syndrome?

Answer 150

• Unwell by 3 months of age
• Infections of all types
• Failure to thrive
• Family history of early infant death

Question 151

What are the clinical features of lymphocyte deficincies?

Answer 151

• T cell deficiency
  
  • Viral infections
    
    • Cytomegalovirus
  • Fungal infection
    
    • Pneumocystis
    • Cryptosporidium
  • Some bacterial infections
    
    • Especially intracellular organisms
    • Mycobacteria tuberculosis
    • Salmonella
  • Early malignancy

Question 152

What are the appropriate investigations for suspected T cell deficiences?

Answer 152

• Total white cell count and differential
• Lymphocyte subsets
  
  • Quantify CD8 T cells, CD4 T cells as well as B cells and NK cells
• Immunoglobulins
  
  • If CD4 T cell deficient
• Functional tests of T cell activation and proliferation
• HIV test

Question 153

What are the results of investigations for T cell deficiencies?

Answer 153

Question 154

What is the management of T cell immunodeficiency?

Answer 154

• Aggressive prophylaxis/treatment of infection
• Haematopoieitic stem cell transplantation
  
  • Replace abnormal populations in SCID
  • Replace abnormal cells - class II deficient APCs in BLS
• Enzyme replacement therapy
  
  • PEG-ADA for ADA SCID
• Gene therapy
• Thymic transplantation
  
  • Promote T cell differentiation in Di George syndrome
  • Cultured donor thymic tissue transplanted to quadriceps muscle

Question 155

Describe B cell central tolerance.

Answer 155

Question 156

What are the types of primary T cell immunodeficiency?

Answer 156

• SCID
• DiGeorge
• BLS

Question 157

Describe immunoglobulins?

Answer 157

• Soluble proteins made up of two heavy and two light chains
  
  • Heavy chain determines the antibody class
    
    • IgM, IgG, IgA, IgE, IgD
  • Antigen is recognised by the antigen binding regions (Fab) of both heavy and light chains
  • Effector function is determined by the constant region of the heavy chain (Fc)

Question 158

What is the function of antibodies?

Answer 158

• Identification of pathogens and toxins (Fab mediated)
• Interact with other components of immune response to remove pathogens (Fc mediated)
  
  • Complement
  • Phagocytes
  • Natural killer cells
• Particularly important in defence against bacteria of all kinds

Question 159

What is Bruton’s X-linked a-gammaglobulinaemia?

Answer 159

• Abnormal B cell tyrosine kinase (BTK) gene
  
  • Pre B cells cannot develop to mature B cells
• Absence of mature B cells
• No circulating Ig after 3 months

Question 160

What are the signs of Bruton’s X-linked a-gammaglobulinaemia?

Answer 160

• Boys present in first few years of life
• Recurrent bacterial infections
  
  • Otitis media
  • Sinusitis
  • Pneumonia
  • Osteomyelitis
  • Septic arthritis
  • Gastroenteritis
• Viral, Fungal and Parasitic infections
  
  • Enterovirus, Pneumocystis
• Failure to thrive

Question 161

What is Hyper IgM syndrome?

Answer 161

• Mutation in CD40 ligand gene (CD40L, CD154)
  
  • Member of TNF Receptor family
  • Encoded on Xq26
  • Involved in T-B cell communication
  • Expressed by activated T cells but not B cells
• Normal number circulating B cells
• Normal number of T cells but activated cells do not express CD40 ligand
• No germinal centre development within lymph nodes and spleen
• Failure of isotype switching
• Elevated serum IgM
• Undetectable IgA, IgE, IgG

Question 162

What are the signs of Hyper IgM syndrome?

Answer 162

• Boys present in first few years of life
• Recurrent infections → particularly bacterial
• Subtle abnormality in T cell function predisposes to:
  
  • Pneumocystis jiroveci infection
  • Autoimmune diseas
  • Malignancy
• Failure to thrive

Question 163

What is Common variable immune deficiency?

Answer 163

• Heterogenous group of disorders
  
  • Many different genetic defects → many unidentified
  • Failure of full differentiation/function of B lymphocytes
• Defined by
  
  • Marked reduction in IgG, with low IgA or IgM
  • Poor/absent response to immunisation
  • Absence of other defined immunodeficiency

Question 164

What are the signs of common variable immune deficiency?

Answer 164

• Recurrent bacterial infections
  
  • Pneumonia
  • Persistent sinusitis
  • Gastroenteritis
  • Often with severe end-organ damage
• Pulmonary disease
  
  • Interstitial lung disease
  • Granulomatous interstitial lung disease (also LN, spleen)
  • Obstructive airways disease
• Gastrointestinal disease
  
  • Inflammatory bowel like disease
  • Sprue like illness
  • Bacterial overgrowth
• Autoimmune disease
  
  • Autoimmune haemolytic anaemia or thrombocytopenia
  • Rheumatoid arthritis
  • Pernicious anaemia
  • Thyroiditis
  • Vitiligo
• Malignancy
  
  • Non-Hodgkin lymphoma

Question 165

What is Selective IgA deficiency?

Answer 165

• Genetic condition with unknown cause
• Prevalence = 1:600
  
  • 2/3rd = Asymptomatic
  • 1/3rd = Recurrent respiratory tract infections

Question 166

What are the types of primary B cell immunodeficiency?

Answer 166

• SCID
• Bruton’s X-linked a-gammaglobulinaemia
• Hyper IgM syndrome
• Common variable immune deficiency
• Selective IgA deficienc

Question 167

What are the appropriate investigations for suspected B cell deficiences?

Answer 167

• Total white cell count and differential
• Lymphocyte subsets
  
  • Quantify B cells as well as CD4 T cells, CD8 T cells and NK cells
• Serum immunoglobulins and protein electrophoresis
• Functional tests of B cell function
  
  • Specific antibody responses to known pathogens/immunisations → measure IgG antibodies against tetanus, Haemophilus influenzae B and S. pneumoniae
  • If specific antibody levels are low, immunise with the appropriate killed vaccine and repeat antibody measurement 6–8 weeks later

Question 168

What are the results of investigations for B cell deficiencies?

Answer 168

Question 169

What is the management of B cell immunodeficiency?

Answer 169

• Aggressive prophylaxis and Treatment of infection
• Immunoglobulin replacement if required
  
  • Contains IgG antibodies to a wide variety of common organisms
  • Treatment is life-long
• Immunisation
  
  • For selective IgA deficiency – Not otherwise effective because of defect in IgG antibody production

Question 170

What are the types of primary immunodeficiency?

Answer 170

Question 171

What are the appropriate investigations for suspected primary immunodeficiency?

Answer 171

• White cells
  
  • Full blood count
  • Lymphocyte subsets
  • Special tests for white cell migration/function
  • Adhesion molecules – eg CD18
  • Test for oxidative killing – DHR test
• Immunoglobulins
  
  • IgM, IgG, IgA
  • Specific Igs and response to vaccination
• Complement
  
  • Complement function - CH50 and AP50
  • Individual complement components

Question 172

Define Allergic Disorder.

Answer 172

Immunological process that results in immediate and reproducible symptoms after exposure to an allergen.

• Immunological process usually involves an IgE mediated type 1 hypersensitivity reaction

Question 173

Define Allergen.

Answer 173

Harmless substance that can trigger an IgE mediated immune response → clinical symptoms

Question 174

Define Sensitisation.

Answer 174

Detection of specific IgE either by skin prick testing or in vitro blood tests.

Question 175

How does the Th2 immune response occur?

Answer 175

• Stressed or damaged epithelium will release signalling cytokines
• Cytokines act on Th2, Th9 and ILC2 → promote the section of IL4, IL5 and IL13
  
  • IL-4 acts on both pathways
  • IL-4 stimulates B-cells to produce IgE and IgG4
  • These then act on eosinophils and basophils which plays a role in the expulsion of parasites and allergens but can also contribute to tissue injury
  • The TSLP and other cytokines released by the damaged epithelium can also activate follicular Th2 cells which then releases IL4

Question 176

Describe induction of Th2 immune response.

Answer 176

• The primary defect is thought to be in the epithelial barrier (i.e. eczema and skin defect)
• Follicular dendritic cells (Langerhans cells and dermal dendritic cells) promote secretion of Th2 cytokines more efficiently than other dendritic cell subtypes
• IL4 secretion is only induced by peptide-MHC presentation to TCR or naïve/memory Th2 cells

Question 177

How does oral and skin/respiratory exposure alter the Th2 immune response?

Answer 177

• Oral exposure promotes immune tolerance whereas skin and respiratory exposure induces IgE sensitisation
  
  • When an allergen is ingested through the oral route → T-regulatory cells inhibit IgE synthesis
    
    • Oral tolerance requires induction of CD4+ T-reg cells
  • T-regs inhibit multiple pro-allergic functions such as inhibiting DC APC function, secretion of IL-10, etc

Question 178

Describe the Th2 immune memory response.

Answer 178

• The sensor is the mast cell → allergen causes cross-linking of IgE → histamine, prostaglandins and leukotrienes
• These act on the endothelium → increased permeability, smooth muscle contraction and neuronal itch
• Response acts to expel parasite/allergen OR will be responsible for symptoms of asthma, eczema and hay fever

Question 179

What are the theories to why allergic disease is increasing?

Answer 179

• Hygiene Hypothesis - lack of childhood exposure to infectious agents increases susceptibility to allergic diseases by suppressing natural development of the immune system
• Lack of vitamin D in infancy - leading to food allergy
• Alternation of diversity in intestinal microbiome
• High concentration of dietary advanced glycation end-products and pro-glycating sugars - immune system mistakenly recognises as causing tissue damage (e.g. fast food and soda)

Question 180

Describe the history of allergic disease.

Answer 180

• Age of onset of the allergic disease:
  
  • Infants
    
    • Atopic dermatitis
    • Food allergy (milk, egg, nuts)
  • Children
    
    • Asthma (house dust mite, pets)
    • Allergic rhinitis
  • Adults
    
    • Drug allergy
    • Bee allergy
    • Oral allergy syndrome
    • Occupational allergy

Question 181

What are the signs and symptoms of allergic disease?

Answer 181

• Occurs minutes to 3 hours after exposure
• Symptoms – at least 2 organ systems usually involved
  
  • Skin symptoms = urticaria, angioedema
  • GI symptoms = D&V
  • Respiratory tract symptoms = SoB, cough, wheeze
  • Vasculature symptoms = hypotension, impending doom
• Symptoms reproducible
• Symptoms may be triggered by co-factors → i.e. NSAIDs in asthma, virus in children to VIF

Question 182

What are the appropriate investigations for suspected allergic disease?

Answer 182

• Allergen-specific IgE tests
  
  • Skin prick and Intradermal testing
  • IgE RAST blood tests
• Functional allergen tests
  
  • In vitro
    
    • Serial mast cell tryptase
    • Basophil activation test
  • In vivo
    
    • Open or blinded allergen challenge

Question 183

Describe the skin prick and intradermal testing.

Answer 183

• Use skin test solutions
  
  • Positive control = histamine
  • Negative control = diluent
• Positive outcome = wheal ≥3mm than negative control
• Antihistamines discontinued for 48 hours beforehand (checked with positive control)
• More sensitive and specific than blood tests to diagnose allergy in clinical practice

Question 184

What are the advantages and disadvantages of skin prick and intradermal testing?

Answer 184

• Advantages
  
  • Rapid - 15-20 mins
  • Cheap and easy
  • Excellent negative predictive value - >95%
  • Increasing size = higher probability of allergy
  • Patient can see response
• Disadvantages
  
  • Requires experience to interpret
  • Risk of anaphylaxis - 1 in 3,000
  • Poor positive predictive value/High false positive rate
  • Limited value in patients with dermatological conditions
  • False negative results with labile commercial food extracts

Question 185

Describe the method of IgE RAST blood tests.

Answer 185

1. Allergen bound to sponge in a plastic cap and patient’s serum is added
2. Specific IgE (if present) binds to allergen
3. Anti-IgE antibody tagged with a fluorescent label is added
4. Amount of IgE/Anti-IgE is measured by fluorescent light signal

Question 186

What are the indications for a IgE RAST blood test?

Answer 186

• Patients who can’t stop antihistamines (otherwise do skin test)
• Patients with dermatographism or extensive eczema
• History of anaphylaxis
• Borderline/equivocal skin prick test results

Question 187

Describe serial mast cell tryptase.

Answer 187

• Tryptase is a pre-formed protein found in mast cell granules
• Systemic degranulation of mast cells in anaphylaxis = increased serum tryptase
• Peak concentration = 1-2 hours; baseline = 6-12 hours
  
  • Failure of baseline return after anaphylaxis = query systemic mastocytosis
• Useful if diagnosis of anaphylaxis uncertain - e.g. hypotension/rash in anaesthesia
• Reduced sensitivity for food-induced anaphylaxis

Question 188

Describe basophil activation testing.

Answer 188

• Measurement of basophil response to allergen IgE cross-linking
• Activated basophils increase expression of CD63, CD203 and CD300 protein
• Increasingly used in the diagnosis of food and drug allergy

Question 189

What is the gold standard test for food and drug allergy diagnosis?

Answer 189

Allergen challenge - open or blinded

Question 190

Describe allergen testing.

Answer 190

• Increasing volumes of the offending food/drug are ingested
• Take place under close medical supervision
• Difficult to interpret mild symptoms
• Risk of SEVERE reaction

Question 191

What does a positive IgE test confirm?

Answer 191

• Demonstrates Sensitisation, not clinical allergy
  
  • Detection of IgE is necessary but not sufficient to make a diagnosis of allergic disease

Question 192

How can serum IgE be used to predict allergic symptoms?

Answer 192

• Concentration – higher levels = more symptoms
• Affinity to target – higher affinity = increased risk
• Molecular target within whole extract or even individual epitope can be linked to symptoms
• Capacity of IgE antibody to induce mast cell degranulation

Question 193

What is Component Resolved Diagnostics?

Answer 193

• Blood test to detect IgE to single protein components – abundance and stability of protein contributes to risk of allergic disease:
  
  • Useful for peanut and hazelnut allergy - may reduce need for food challenges

Question 194

What are the indications of allergen component testing?

Answer 194

• Detect primary sensitisation
• Confirm cross-reactivity
• Define risk of serious reaction for stable allergens
• Improve diagnostic sensitivity for components poorly represented in whole food extracts
• Improve diagnostic sensitivity for unstable molecules in whole food extracts

Question 195

Define Anaphylaxis.

Answer 195

Severe potentially systemic hypersensitivity reaction.

Rapid onset, life-threatening airway, breathing and circulatory problems which is usually but not always associated with skin and mucosal changes.

Question 196

What are the signs and symptoms of anaphylaxis?

Answer 196

• Skin is the most frequent organ involved (84%)
• Cardiovascular
  
  • Collapse
  • Syncope
  • Drop in BP
• Respiratory compromise
  
  • SoB
  • Wheeze
  • Stridor - more common in children

Question 197

What is the mechanism of IgE anaphylaxis?

Answer 197

• Cells
  
  • Mast cells
  • Basophils
• Mediators
  
  • Histamine
  • Platelet activating factor

Question 198

What is the mechanism of IgG anaphylaxis?

Answer 198

• Cells
  
  • Macrophages
  • Neutrophils
• Mediators
  
  • Histamine
  • Platelet activating factor

Question 199

What is the mechanism of complement anaphylaxis?

Answer 199

• Cells
  
  • Mast cells
  • Macrophages
• Mediators
  
  • Histamine
  • Platelet activating factor

Question 200

What is the mechanism of IgE anaphylaxis?

Answer 200

• Cells
  
  • Mast cells
• Mediators
  
  • Leukotrienes
  • Histamine

Question 201

What allergens causes IgE anaphylaxis?

Answer 201

• Food
• Insect venom
• Ticks
• Penicillin

Question 202

What allergens causes IgG anaphylaxis?

Answer 202

• Biologicals
• Blood and IgG Transfusions

Question 203

What allergens causes complement anaphylaxis?

Answer 203

• Lipid excipients
• Liposomes
• Dialysis membranes and PEG

Question 204

What allergens causes pharmacological anaphylaxis?

Answer 204

• NSAID including aspirin
• Opiates
• Neuromuscular drugs
• Quinolones drug

Question 205

What reactions can mimic anaphylaxis?

Answer 205

• SKIN: Chronic urticaria and angioedema (ACE inhibitors)
• THROAT SWELLING: C1 inhibitor deficiency
• CARDIOVASCULAR: Myocardial infarction and PE
• RESPIRATORY: Very severe asthma, vocal cord dysfunction, inhaled FB
• NEUROPSYCHIATRIC: Anxiety or panic disorder
• ENDOCRINE: carcinoid and phaeochromocytoma
• TOXIC: Scromboid toxicity (Histamine poisoning)
• IMMUNE: Systemic mastocytosis

Question 206

How is a diagnosis of anaphylaxis confirmed?

Answer 206

• Serial measurement of serum tryptase
  
  • Samples taken 1 hour, 3 hours and 24 hours post episode of anaphylaxis
  • The rise in tryptase concentration is directly proportional to fall in BP
• DIAGNOSIS = persistent rise in tryptase 24 hours after allergic reaction suggestive of systemic mast cell disease

Question 207

What is management of anaphylaxis?

Answer 207

• IM ADRENALINE
• Supportive Treatments
  
  • Adjust body position
  • 100% Oxygen
  • Fluid replacement
  • Inhaled bronchodilators
  • Hydrocortisone 100 mg IV (prevent late phase response)
  • Chlorpheniramine 10 mg IV (skin rash)

Question 208

What is the mechanism of adrenaline in anaphylaxis?

Answer 208

• Alpha 1 → causes peripheral vasoconstriction, reverses low BP and mucosal oedema
• Beta 1 → increases heart rate, contractility and BP
• Beta 2 → relaxes bronchial smooth muscle and reduces the release of inflammatory mediators

Question 209

Define Food Allergy and Food Intolerance.

Answer 209

• Food ALLERGY = adverse health effect from specific immune response that occurs reproducibly on exposure to food
• Food INTOLERANCE = non-immune reactions which include metabolic, pharmacological and unknown mechanisms

Question 210

What are the important questions in a clinical history for suspected allergy?

Answer 210

• What does the patient mean by allergy?
• Distinguish between IgE and non IgE mediated symptoms
• Dose, how food is prepared, and co-factors can influence clinical symptoms
• Does the patient have any history of atopic disease?
• Enquire about previous investigations for food allergy i.e. SPT, IgE blood tests and complementary medical tests
• Has elimination of food made any difference to symptoms?
• Consider other differential diagnoses (food intolerance, eating disorders, coeliac disease)

Question 211

What are the appropriate investigations for suspected food allergy?

Answer 211

• Clinical history
• Skin-prick test or specific IgE blood test
  
  • +ve = sensitisation but not necessarily allergy
  • Higher IgE levels or larger wheals indicate a higher chance of allergy
  • Individual allergen protein component can distinguish between IgE-sensitisation and IgE-mediated allergy
• Oral food challenge = gold standard

Question 212

What is the management of food allergy?

Answer 212

• Avoidance – education, dietician, acknowledge anxiety, etc.
• Anaphylaxis guidance for emergencies
• Prevention – earlier introduction in high-risk families reduces chances of later development

Question 213

What are the IgE-mediated food allergy syndromes?

Answer 213

• Anaphylaxis
• Food associated exercise induced anaphylaxis
• Delayed food-induced anaphylaxis
• Oral allergy syndrome

Question 214

What is food associated exercise induced anaphylaxis?

Answer 214

• Food induces anaphylaxis if individual exercises within 4-6 hours of ingestion
• Common food triggers are wheat, shellfish, celery

Question 215

What is delayed food-induced anaphylaxis ?

Answer 215

• Symptoms occur 3-6 hours after eating red meat and gelatin
• IgE antibody to oligosaccharide alpha-gal (α1, 3-galactose) found in gut bacteria
• Induced by tick bites which should be avoided

Question 216

What is oral allergy syndrome?

Answer 216

• Limited to oral cavity, swelling and itch
• Sensitisation to inhalant pollen protein lead to cross reactive IgE to food
• Onset after pollen allergy established: affect adults > young children
• Respiratory exposure to pollen (birch) results in IgE directed to homologous proteins in stone fruits (apple, pear) vegetables (carrot) and nuts (peanut, hazelnut)
• Cooked fruits, vegetables and nut cause no symptoms → heat labile allergens detected by component allergen tests
• 1-2% cases progresses to anaphylaxis

Question 217

Define Monogenic Auto-inflammatory Disease.

Answer 217

Mutations in a single gene encoding a protein involved in a pathway associated with innate immune cell function.

• Abnormal signalling via cytokine pathways involving TNFα or IL1 is common

Question 218

Name some monogenic auto-inflammatory disease along with the gene mutation and inheritance pattern.

Answer 218

• Muckle Wells Syndrome
  
  • NLRP3 - gain of function
  • Autosomal dominant
• Familial Cold Auto-inflammatory Syndrome
  
  • NLRP3 - gain of function
  • Autosomal dominant
• Chronic Infantile Neurological Cutaneous Articular Syndrome
  
  • NLRP3 - gain of function
  • Autosomal dominant
• TNF Receptor Associated Periodic Syndrome
  
  • TNFRSF1
  • Autosomal dominant
• Hyper IgD with Periodic Fever Syndrome
  
  • MK
  • Autosomal recessive
• Familial Mediterranean Fever
  
  • MEFV
  • Autosomal recessive

Question 219

Describe the pathogenesis of familial Mediterranean fever.

Answer 219

• Mutations in MEFV gene → Inactivated pyrin-marenostrin
  
  • Expressed mainly in neutrophils
• Increased pro-caspase 1 and increased inflammation driven by lots of neutrophils
  
  • IL-1
  • NFKappaB → TNFa
  • Apoptosis

Question 220

What are the signs and symptoms of familial Mediterranean fever?

Answer 220

• Periodic fevers lasting 48-96 hours associated with
  
  • Abdominal pain (peritonitis)
  • Chest pain (pleurisy and pericarditis)
  • Arthritis
  • Rash

Question 221

What condition do familial Mediterranean fever patients often go on to suffer with?

Answer 221

AA Amyloidosis

Question 222

What conditions are associated with AA amyloidosis?

Answer 222

• Autoimmune diseases – rheumatoid arthritis, ankylosing spondylitis, IBD (CD & UC)
• Autoinflammatory diseases – familial Mediterranean fever, Muckle–Wells syndrome
• Chronic infections – TB, bronchiectasis, chronic osteomyelitis
• Cancer – Hodgkin’s lymphoma, renal cell carcinoma
• Chronic foreign body reaction
• HIV/AIDS

Question 223

What are the appropriate investigations for suspected familial Mediterranean fever?

Answer 223

• CRP - high
• SAA - high
• Blood to specialist genetics lab to detect mutation

Question 224

What is the management of familial Mediterranean fever?

Answer 224

• Colchicine - 500μg BD
• IL-1 and TNFa inhibitors
  
  • Anakinra - IL1 receptor antagonist
  • Etanercept - TNFα inhibitor

Question 225

Define Monogenic Auto-immune Disease.

Answer 225

Mutation in a gene encoding a protein involved in the adaptive immune response.

Question 226

Name some monogenic auto-inflammatory disease along with the gene mutation.

Answer 226

• APS-1/APECED
  
  • AIRE - abnormality in tolerance
• IPEX
  
  • FOXP3 - abnormality in regulatory T cells
• ALPS
  
  • Abnormality of lymphocyte apoptosis

Question 227

Describe the pathogenesis of APS1/APECED.

Answer 227

• Defect in autoimmune regulator = AIRE mutation
  
  • Transcription factor involved in T cell tolerance in the thymus
    
    • Upregulates expression of self-antigens by thymic cells
    • Promotes T cell apoptosis
• Causes failure of central tolerance
  
  • Autoreactive T cells
  • Autoreactive B-cells - co-dependent on T cells

Question 228

What are the autoimmune diseases associated with APS1/APECED?

Answer 228

• Hypoparathyroidism - 85%
• Addison’s - 78%
• Candidiasis - 98%
• Hypothyroidism - 14%
• Diabetes - 13%
• Vitiligo - 27%
• Enteropathy - 22%

Question 229

Describe the pathogenesis of IPEX.

Answer 229

• Mutations in FOXP3 which is required for development of T-reg cells
• Failure to negatively regulate T-cell responses → auto-reactive B-cells → autoantibody formation

Question 230

What are the autoimmune diseases associated with IPEX?

Answer 230

• ‘Diarrhoea, Dermatitis and Diabetes’
  
  • Enteropathy - 98%
  • Diabetes mellitus - 35%
  • Dermatitis - 69%
  • Hypothyroidism - 35%

Question 231

Describe the pathogenesis of ALPS.

Answer 231

• Mutations in FAS pathway → e.g. mutations in TNFRSF6 to encode FAS
• Defect in apoptosis of lymphocytes
  
  • Failure of tolerance
  • Failure of lymphocyte homeostasis

Question 232

What are the signs and symptoms of ALPS?

Answer 232

• Lymphocytosis → large lymph nodes
• Splenomegaly
• Autoimmune diseases (i.e. autoimmune cytopenias)
• Lymphoma

Question 233

Define Polygenic Auto-inflammatory Diseases.

Answer 233

Mutations in genes encoding proteins involved in pathways associated with innate immune cell function.

Question 234

What are the features of polygenic auto-inflammatory disease?

Answer 234

• Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages, neutrophils with resulting tissue damage
• HLA associations are usually less strong
• These diseases are not characterised by presence of autoantibodies

Question 235

What gene has been identified to be linked to Crohn’s?

Answer 235

• IBD1 gene on Chr16 identified as NOD2 → 3 different mutations
  
  • NOD2 gene mutations are present in 30% of patients
  • Abnormal allele of NOD2 increases risk of Crohn’s by:
    
    • 1 copy present = 1.5-3x
    • 2 copies present = 14-44x
• NOD2 = a cytoplasmic microbial sensor in myeloid cells – recognises muramyl dipeptide → stimulates NFK-beta
• Activation induces autophagy in dendritic cells

Question 236

What are the clinical features of Crohn’s?

Answer 236

• Abdominal pain/tenderness
• Diarrhoea – blood, pus, mucus
• Fevers and malaise

Question 237

What is the management of Crohn’s disease?

Answer 237

• Flare-up
  
  • Corticosteroid
  • Anti TNFα antibody
• Maintenance/Remission
  
  • Diet-induced remission - whole protein modular diet
  • Aminosalicylates 5-ASA

Question 238

Define Mixed Pattern Auto-inflammatory/immune Disease.

Answer 238

Mutations in genes encoding proteins in pathways of innate AND adaptive immune cell function.

Question 239

What are the features of mixed pattern auto-inflammatory/immune disease?

Answer 239

• HLA associations may be present
• Autoantibodies not usually a feature

Question 240

What genetic polymorphisms are associated with ankylosing spondylitis?

Answer 240

Question 241

What are the signs and symptoms of ankylosing spondylitis?

Answer 241

• Inflammation at sites of high tensile force
  
  • Low back pain and stiffness
  • Enthesitis
  • Large joint arthritis

Question 242

What is the management of ankylosing spondylitis?

Answer 242

• NSAIDs
• Immunosuppression – anti TNFα or anti IL17

Question 243

Define Polygenic Autoimmune Disease.

Answer 243

Mutations in genes encoding proteins in pathways of adaptive immune cell function.

Question 244

What are the features of polygenic autoimmune disease?

Answer 244

• HLA associations common
• Autoantibodies are found

Question 245

What diseases is the HLA-DR15 allele associated with?

Answer 245

Goodpasture

Question 246

What diseases is the HLA-DR3 allele associated with?

Answer 246

• Graves
• SLE
• T1DM

Question 247

What diseases is the HLA-DR4 allele associated with?

Answer 247

• T1DM
• Rheumatoid arthritis

Question 248

What diseases is the HLA-DR1 allele associated with?

Answer 248

Rheumatoid arthritis

Question 249

What are the Gel and Coombs types?

Answer 249

• Type 1 = Immediate hypersensitivity IgE mediated
  
  • Anaphylactic hypersensitivity
• Type 2 = Antibody reacting with cellular antigen
  
  • Cytotoxic hypersensitivity
• Type 3 = Antibody soluble antigen form immune complexes
  
  • Immune complex hypersensitivity
• Type 4 = Delayed type hypersensitivity
  
  • Delayed hypersensitivity

Question 250

What is the pathogenesis of Type 1 (immediate hypersensitivity IgE mediated) autoimmune disease?

Answer 250

Rapid allergic reaction

• Pre-existing IgE antibodies to allergen → IgE bound to Fc
  
  • Common allergens = pollens, drugs, food, insect, animal hair
• Receptors on mast cells and basophils → cell degranulation
• Release of inflammatory mediators
• Increased vascular permeability, leukocyte chemotaxis and SM contraction

Question 251

What are the mechanisms of Type 2 (antibody reacting with cellular antigen) autoimmune disease?

Answer 251

Question 252

Name some Type 2 (antibody reacting with cellular antigen) autoimmune disease, their auto-antigen and symptoms.

Answer 252

• Goodpasture
  
  • Non-collagenous domain of collagen type IV BM
  • Glomerulonephritis, pulmonary haemorrhage
• Pemphigus vulgaris
  
  • Epidermal cadherin
  • Blistering of skin
• Graves
  
  • TSH receptor
  • Hyperthyroidism
• Myasthenia gravis
  
  • Acetylcholine receptor
  • Muscle weakness

Question 253

What is the mechanism of Type 3 (antibody reacting with soluble antigen to form immune complexes) autoimmune disease?

Answer 253

• Antibodies bind to soluble antigen to form circulating immune complex
• Immune complexes deposit in blood vessels
  
  • Complement activation, infiltration of macrophages and neutrophil
  • Cytokine and chemokine expression
  • Granule release from neutrophils
  • Increased vascular permeability
• Inflammation and damage to vessels
  
  • Cutaneous vasculitis
  • Glomerulonephritis
  • Arthritis

Question 254

Name some Type 3 (antibody reacting with soluble antigen to form immune complexes) autoimmune disease, their auto-antigen and symptoms.

Answer 254

• SLE
  
  • DNA, histones, RNP
  • Rash, glomerulonephritis, arthritis
• Rheumatoid arthritis
  
  • Fc region of IgG
  • Arthritis

Question 255

What is the mechanism of Type 4 (delayed type hypersensitivity) autoimmune disease?

Answer 255

• T cell mediated response → tissue destruction
  
  • HLA class 1 present SELF-antigens to CD8 T cells → cell lysis
  • HLA class 2 present SELF-antigen to CD4 T cells → cytokine production → inflammation and tissue damage

Question 256

Name some Type 4 (delayed type hypersensitivity) autoimmune disease, their auto-antigen and symptoms.

Answer 256

• T1DM
  
  • Pancreatic beta-cell
  • Diabetes
• Rheumatoid arthritis
  
  • Unknown synovial joint
  • Arthritis
• MS
  
  • Myelin basic protein → brain infiltration by CD4+ T-cells
  • Neurological features, fatigue, vision blurring/loss

Question 257

A patient present with nervousness, palpitations, heat intolerant, diarrhoea, exophthalmos. What is the diagnosis?

Answer 257

Graves’

Question 258

What is the pathophysiology of Graves’?

Answer 258

T2 hypersensitivity → IgG antibodies which stimulate TSH receptor

• Stimulating autoantibodies against TSH-receptor bind to receptor, acting as TSH agonists
• Induce uncontrolled overproduction of thyroid hormones
• Negative feedback cannot override antibody stimulation
  
  • Babies born to mothers with Graves’ may show transient hyperthyroidism

Question 259

A patient present with lethargy, dry skin and hair, constipation, cold intolerant . What is the diagnosis?

Answer 259

Hashimoto’s thyroiditis

Question 260

What is the pathophysiology of Hashimoto’s thyroiditis?

Answer 260

T2 and T4 hypersensitivity → anti-thyroid peroxidase antibodies (TPO) and anti-thyroglobulin antibodies and T + B cell thyroid infiltration

• Goitre → enlarged thyroid infiltrated by T and B cells
  
  • Antibodies are not part of the diagnosis
• Commonest cause of hypothyroidism in iodine-replete areas

Question 261

A patient present at 8yo with thirst, polyuria, malaise, urine dip confirms glycosuria. What is the diagnosis?

Answer 261

Type 1 DM

Question 262

What is the pathophysiology of T1DM?

Answer 262

T4 pathology → CD8+ T-cell (with T-cell clones) infiltration of pancreas leading to destruction of pancreatic islet cells + anti-islet cell, anti-insulin, anti-GAD and anti-IA-2 antibodies

• Individuals with 3-4 of the above antibodies likely to develop T1DM
• Detection of antibodies does not currently play a role in dx

Question 263

A patient present tired, pale, mild numbness of feet. Her blood results show anaemic (Hb 8.4), macrocytosis (MCV 108), urine dip negative (so not diabetes), folate normal, vitamin B12 very low . What is the diagnosis?

Answer 263

Pernicious anaemia

Question 264

What is the pathophysiology of Pernicious anaemia?

Answer 264

T2 reaction → autoantibodies against intrinsic factor → no absorption of vitamin B12 → pernicious anaemia and SCDC

• Vit B12 deficiency → macrocytosis, fatigue, anaemia, pallor, etc.
• Sub-acute Combined Degeneration of the Cord / SCDC à peripheral neuropathy, optic neuropathy
• Antibodies to gastric parietal cells or intrinsic factor are useful in dx

Question 265

A patient present with drooping eyelids, weakness particularly on repetitive activity, symptoms worse at end of day. What is the diagnosis?

Answer 265

Myasthenia gravis

Question 266

What is the pathophysiology of myasthenia gravis?

Answer 266

T2 reaction → autoantibodies against ACh receptors → failure of depolarisation → absence of muscle action potential

• Fluctuating weakness
• Extraocular weakness, ptosis very common
• EMG studies normal
• Anti-ACh-R ABs present in ~75% patients à useful in diagnosis
• Offspring of affected mothers may experience transient neonatal myasthenia

Question 267

What is the appropriate investigations for suspected myasthenia gravis?

Answer 267

• Tensilon test positive (House episode)
  
  • Inject edrophonium (anti-cholinesterase) to prolong life of ACh and allow it to act on the receptors

Question 268

A patient present at 48yo with haemoptysis with widespread crackles in lungs, swelling of legs and reduced urine output.

Investigations show creatinine 472, microscopic haematuria and proteinuria, CXR – widespread shadowing, elevated TLCO suggesting pulmonary haemorrhage.

Further investigations show anti-neutrophil cytoplasmic antibody -ve, anti-basement membrane antibody +ve and crescentic nephritis on biopsy

What is the diagnosis?

Answer 268

Goodpasture’s

Question 269

What is the pathophysiology of Goodpasture’s?

Answer 269

T2 reaction → autoantibodies against basement membrane

Question 270

A patient presents with pain, stiffness and swelling of multiple small joints within hands, normochromic anaemia, high ESR, CRP. What is the diagnosis?

Answer 270

Rheumatoid arthritis

Question 271

What is the pathophysiology of Rheumatoid arthritis?

Answer 271

• B cell involvement
  
  • T2 response – antibody binding to citrullinated proteins leading to
    
    • Complement activation
    • Macrophage activation via Fc R and complement receptors
    • NK cell activation with ADCC
  • T3 response
    
    • Immune complex formation – RF and anti CCP, deposition with complement activation
• T cell involvement
  
  • T4 response – antigen presenting cells → CD4+ T cell → production of IFγ and IL17 → production of MMPs and IL1, TNFα

Question 272

What factors are involved in rheumatoid arthritis?

Answer 272

• Genetic:
  
  • HLA DR4, HLA DR1 alleles → bind to citrullinated peptides with a higher affinity
  • PAD2 and PAD4 polymorphisms → associated with higher levels of citrullination
  • PTPN22 polymorphism (± CTLA4)
• Environmental
  
  • Smoking → development of erosive disease, and increased citrullination
  • Gum infection with Porphyromonas gingivalis associated with RhA
    
    • Porphyromonas gingivalis expresses PAD enzyme

Question 273

What antibodies are found in Rheumatoid Arthritis?

Answer 273

• Antibodies to cyclic citrullinated peptide (Anti CCP Antibody)
  
  • Bind to peptides in which arginine has been converted to citrulline by PAD
  • 95% specificity and 60% sensitivity for dx of RhA
• Rheumatoid factor antibody (an antibody directed against Fc region of human IgG)
  
  • IgM anti-IgG most common RF antibody tested
  • Although IgA and IgG rheumatoid factors may present in some individuals
  • 60-70% specificity and sensitivity for dx of rheumatoid arthritis

Question 274

A patient present at 19yo with 4m history of fatigue, generalised arthralgia particularly small joints of hands, hair loss, mouth ulcers, butterfly rash. What is the diagnosis?

Answer 274

Systemic lupus erythematous - SLE

Question 275

What are the conditions associated with SLE?

Answer 275

• CNS – seizures
• Skin – butterfly rash, discoid lupus
• Heart – endocarditis, myocarditis, serositis, pleuritis, pericarditis
• Glomerulonephritis
• Haematological – haemolytic anaemia, leukopenia, thrombocytopenia
• Arthritis and lymphadenopathy

Question 276

What is the pathophysiology of SLE?

Answer 276

T3 hypersensitivity → anti-nuclear antibodies

• Antibodies bind to antigens to form immune complexes
• Immune complexes deposit in tissues → skin, joints, kidney
  
  • Activate complement → classical pathway
  • Stimulate cells expressing Fc and complement receptors

Question 277

What is the genetic predisposition to SLE?

Answer 277

Question 278

What immunological investigations are there for suspected SLE?

Answer 278

• ANA → SLE = 1:640 titre
  
  • Anti-dsDNA
  • Anti-ENA
  • Anti-topoisomerase
  • Anti-centromere
• Complement
  
  • Depletion of C4 and then C3
    
    • Inactive lupus = normal C3 and C4
    • Moderate active lupus = low C4
    • Very active lupus = low C3 and C4

Question 279

What are the targets of anti-nuclear antigens in SLE?

Answer 279

• Anti-dsDNA Ab
  
  • Highly specific for SLE (95%)
  • High titres = severe disease - useful in disease monitoring
  • Homogenous staining on ELISA
• Anti-ENA Ab
  
  • Ribonucleoproteins - Ro, La, Sm, U1RNP
    
    • May be found in SLE but not needed
  • Speckled pattern on ELISA
• Anti-topoisomerase Ab - against enzymes (Anti-SCL70 AB)
  
  • Diffuse CREST
• Anti-centromere Ab
  
  • Limited CREST

Question 280

What antibodies are found in Sjogren’s syndrome?

Answer 280

Anti-ENA → anti-Ro and anti-La

Question 281

What are the signs and symptoms of anti-phospholipid?

Answer 281

• Recurrent venous or arterial thrombosis
• Recurrent miscarriage
• May occur alone/primary or in with autoimmune disease/secondary

Question 282

What are the two major antibodies in anti-phospholipid syndrome?

Answer 282

• Anti-cardiolipin antibody
• Lupus anti-coagulant → cannot be assessed if the patient is on anticoagulant therapy

Question 283

A patient presents with thickening around the mouth and microstomia. What is the diagnosis?

Answer 283

Systemic sclerosis

Question 284

What are the features of diffuse cutaneous systemic sclerosis?

Answer 284

• GI, pulmonary & renal involvement
• CREST features
  
  • Skin involvement of hands AND PROXIMAL PAST the forearms (unlike CREST)

Question 285

What is the pathophysiology of diffuse and limited cutaneous systemic sclerosis?

Answer 285

Question 286

What are the features of limited cutaneous systemic sclerosis?

Answer 286

• ONLY the hands involved (does not spread proximally up the forearms)
• Involves peri-oral skin
• CREST-P
  
  • Calcinosis
  • Raynaud’s
  • Oesophageal dysmotility
  • Sclerodactyly
  • Telangiectasia
  • Primary pulmonary HTN

Question 287

A patient presents with weakness, malaise, periorbital heliotropic rash, Gottron’s papules. What is the diagnosis?

Answer 287

Idiopathic Inflammatory Myopathy → Dermatomyositis

Question 288

Describe dermatomyositis.

Answer 288

• Periorbital rash + Gottron’s papules
  
  • Within muscle → perivascular CD4 T and B cells
  • Immune complex mediated vasculitis – T3 response

Question 289

Describe polymyositis.

Answer 289

• No rash
  
  • Within muscle – CD8 T cells surround HLA Class 1 expressing myofibres
  • CD8 cells kill myofibres via perforin/granzymes – T4 response

Question 290

What antibodies are present in idiopathic inflammatory myopathy?

Answer 290

• Positive ANA – extended myositis panel
  
  • Anti-Jo1 antibodies
  • Anti-Mi2
  • Anti-SRP (signal recognition peptide)

Question 291

Answer 291

SLE

Question 292

A patient presents at 54yo with recurrent nosebleeds and breathlessness. Cavitating pulmonary lesions on CXR. What is the diagnosis?

Answer 292

Systemic vasculitis

Question 293

What are the types of systemic vasculitis?

Answer 293

• Large vessel
  
  • Takayasu’s arteritis
  • Giant cell arteritis / polymyalgia rheumatica
• Medium vessel
  
  • Polyarteritis nodosa
  • Kawasaki disease
• Small vessel ANCA-associated
  
  • Microscopic polyangiitis
  • Granulomatosis with polyangiitis (Wegner’s - crushed nose)
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
• Small vessel immune complex
  
  • Anti-GBM disease
  • IgA disease
  • Cryoglobulinemia

Question 294

What methods can be used to boost the immune system?

Answer 294

• Vaccination
• Replacement of missing components
• Blocking immune checkpoints
• Cytokine therapy

Question 295

What methods can be used to suppress the immune system?

Answer 295

• Steroids
• Anti-proliferative / Cytotoxic agents
• Plasmapheresis
• Inhibitors of cell signalling
• Agents directed at cell surface antigens
• Agents directed at cytokines

Question 296

Name the antigen presenting cells.

Answer 296

• Dendritic cells
• Macrophages
  
  • Langerhans cells
  • Mesangial cells
  • Kupffer cells
  • Osteoclasts
  • Microglia
• B-lymphocytes

Question 297

Describe T-cell memory.

Answer 297

• Longevity → persist without antigen via low level proliferation in response to cytokines
• Different cell surface proteins → chemotaxis / adhesion to access non-lymphoid tissues
• Rapid, robust response to subsequent antigen exposure

Question 298

Describe B-cell memory.

Answer 298

• Longevity
• Pre-formed, high affinity IgG antibodies
• Rapid, robust response

Question 299

What are the aims of vaccines?

Answer 299

• Memory → generate protective, long-lasting immune response
• No adverse reactions
• Practical
  
  • Single shot
  • Easy storage
  • Cheap

Question 300

How does the immune system fight influenza?

Answer 300

• Although CD8 T cells control the viral load antibodies are responsible for providing a protective response
• Anti-Haemagglutinin ABs
  
  • A membrane fusion glycoprotein of influenza virus

Question 301

How does protection from an influenza vaccine last?

Answer 301

• Antibody protection begins 7 days after vaccine and last for around 6 months

Question 302

What test can be used to check for previous TB exposure?

Answer 302

• Mantoux Test
  
  • Inject a small amount of liquid tuberculin intradermally
  • Area of injection is examined 48-72 hours after tuberculin injection
  • The reaction is an area of swelling around the injection site
    
    • Positive reaction wheal:
      
      • >5mm if high-risk → immunocompromised, living with someone with TB)
      • >10mm if medium-risk → healthcare professionals
      • >15mm if low-risk

Question 303

What are the different types of vaccine?

Answer 303

• Live attenuated vaccines
• Inactivated/component vaccines
• DNA/RNA vaccines
• Adenovirus
• Dendritic cell vaccines

Question 304

Name some live attenuated vaccines.

Answer 304

• MMR
• BCG
• Yellow fever
• Typhoid
• Polio (Sabin)
• Vaccinia
• Nasal influenza (aged 5-17)

Question 305

What are the advantages and disadvantages of live attenuated vaccines?

Answer 305

• Advantages
  
  • Establishes infections - ideally mild symptoms
  • Raises broad immune response to multiple antigens - offer protection against different strains
  • Activates all phases of immune system
  • Often confer life-long immunity after one dose
• Disadvantages:
  
  • Storage problems
  • Possible reversion to virulence - vaccine associated paralytic poliomyelitis (1 in 750,000)
  • Infection in immunosuppressed
  • Spread to contacts - spread to immunocompromised/immunosuppressed

Question 306

Name some inactivated vaccines.

Answer 306

• Influenza
• Cholera
• Polio (Salk)
• HAV
• Pertussis (Whooping cough)
• Rabies

Question 307

Name some component / subunit vaccines.

Answer 307

• HbS antigen
• HPV (capsid)
• Influenza

Question 308

Name some toxoid vaccines.

Answer 308

• Diphtheria
• Tetanus

Question 309

What are the advantages and disadvantages of inactivated / component / toxoid vaccines?

Answer 309

• Advantages:
  
  • No mutation or reversion Can be used in immunodeficient patients
  • Easier storage
  • Lower cost
• Disadvantages:
  
  • Don’t follow normal route of infection
  • Poor immunogenicity
  • May require multiple injections, conjugates or adjuvants

Question 310

What are conjugate vaccines?

Answer 310

Polysaccharide + Protein carrier

• Polysaccharide induces a T cell-independent B cell response (transient)
• Protein carrier promotes T cell-dependant B cell response (long-term)
• Examples
  
  • HiB
  • Meningococcus
  • Pneumococcus

Question 311

What are adjuvant vaccines?

Answer 311

Increase the immune response without altering its specificity → mimic the action of PAMPs on TLR and other PRRs

• Useful in older people who produce a weaker immune response
• Examples of adjuvants:
  
  • Aluminium salts - Hep A and B, HiB
    
    • Mechanism is not fully understood → could be:
      
      • Prolonged antigenic stimulation
      • Induce mild inflammation → development of immune response
      • Activate Gr1+ IL4+ eosinophils → prime naïve B cells à antibody response
  • Lipids (monophosphoryl lipid A; humans)
  • Oils (Freund’s adjuvant; animals)
  • ISCOMS
  • CpG DNA

Question 312

How do mRNA vaccines work?

Answer 312

• Plasmid containing a gene of choice is harvest
• The DNA is excised and transcribed to form mRNA
• A complex containing the mRNA and lipids envelope is created - provides stability
• mRNA enters cells and the protein is synthesised → immune response when presented on cell surface - spike protein is commonly used
• Mimics the normal action of a virally infected cell and it stimulates T cell responses

Question 313

Describe adenoviral vector vaccines?

Answer 313

AstraZeneca, Sputnik COVID vaccine

1. DNA of relevant protein inserted into viral vector
2. Infect cells in vivo
3. Transcription/translation to produce protein
4. Stimulate immune response including B cells / antibodies and T cells

Question 314

What are the advantages and disadvantages of DNA/RNA vaccines?

Answer 314

• Advantages
  
  • Mimics virus cell
  • May be used to develop a cancer vaccine
• Disadvantages
  
  • Storage
  • In theory plasmid may integrate into host DNA → autoimmune diseases

Question 315

Describe dendritic cell vaccines.

Answer 315

• Malignancy not infection → used against tumours where dendritic cell function may be compromised
• Take a patient’s dendritic cells and load them with a tumour antigen and reintroduce them to the patient to try and boost the immune response against the tumour antigens
• Requires antigens specific to the tumour and distinct from normal cells
• Example
  
  • Sipuleucel-T Provenge → immunotherapy against prostate cancer

Question 316

What techniques work by replacing missing compounds?

Answer 316

• Haematopoietic stem cell transplantation
• Antibody replacement
• Specific Immunoglobulin
• Adoptive cell transfer

Question 317

What are the indications for haematopoietic stem cell transplantation?

Answer 317

• Life-threatening immunodeficiency → e.g. SCID, leucocyte adhesion defect
• Haematological malignancy

Question 318

What are the indications for antibody replacement therapy?

Answer 318

• Primary antibody deficiency
  
  • Bruton’s X-linked hypogammaglobulinemia
  • X-linked hyper-IgM syndrome
  • Common variable immunodeficiency
• Secondary antibody deficiency
  
  • Haematological malignancies
  • Post BM transplantation

Question 319

What are the indications for specific immunoglobulin?

Answer 319

• Passive immunisation – human Ig used for post-exposure prophylaxis
  
  • HBV
  • Tetanus
  • Rabies
• VZV Ig in early pregnancy (<20 weeks)
  
  • Acyclovir is contraindicated

Question 320

What are the different types of adoptive cell transfer?

Answer 320

• Virus specific T cell therapy
• Tumour infiltrating lymphocyte T cell therapy
• T cell receptor T cells
• CAR-T - Chimeric antigen receptor T cell therapy

Question 321

Describe virus specific T cell therapy.

Answer 321

1. Blood is taken from the patient or from a matched individual
2. Peripheral blood lymphocytes isolated → stimulated with pathogen peptides
3. Expansion of pathogen-specific T cells → infused back into the patient

• i.e. → EBV in those immunosuppressed to prevent development of B cell lymphoproliferative disease
  
  • Doesn’t involve any stimulation of B-cells → no B cell lymphoproliferative disease

Question 322

Describe tumour infiltrating lymphocyte T cell therapy.

Answer 322

1. Remove tumour from patient
2. Stimulate T cells within tumour with cytokines (e.g. IL-2) so they develop a response against tumour
3. Select and expand the tumour infiltrating lymphocytes and reinfuse back into the patient

Question 323

Describe T cell adoptive therapies.

Answer 323

• T cells taken from patient and viral / non-viral vectors used to insert gene fragments into T cells
• Gene fragments encode receptors
  
  • TCR therapy
    
    • Insert a gene that encodes a specific TCR (e.g. against a tumour cell antigen)
      
      • Recognises MHC presented peptides
  • CAR therapy
    
    • Receptors are chimeric (it contains both B and T cell components)
      
      • Recognises cell surface CD markers
    • Standard CAR therapy = targeting CD19
      
      • Receptors on the CAR cell have an Ig-variable domain at the end which is joined onto the remainder of the TCR
      • Signals through the usual TCR pathway but recognises CD19 through an Ig-domain → T cells to kill the B cells
      • This is increasingly being used in ALL and NHL → not useful in solid tumours

Question 324

Name 3 immune checkpoint blockers.

Answer 324

• CTL-A4 specific
  
  • Ipilimumab
• PD-1 specific
  
  • Pembrolizumab
  • Nivolumab

Question 325

Describe ipilimumab.

Answer 325

Antibody specific for CTL-A4 → treat melanoma

• CTLA4 and CD28 both expressed by T cells and both recognise the same antigens on APCs (CD80 and CD86)
  
  • APC CD80 and CD86 interact with CD28 → transmit a stimulatory signal
  • APC CD80 and CD86 interact with CTLA4 → transmit an inhibitory signal
• Binds to CTLA4 → all CD80 and CD86 interactions occur through CD28 → boosted T cell response
• Can cause autoimmune disease

Question 326

Describe Pembrolizumab and Nivolumab.

Answer 326

Specific for PD-1 → treat advanced melanoma and metastatic renal cell carcinoma

• PD-1 is found on T-regulatory cells
• Its ligands (PDL-1 and PDL-2) are present on APCs and some tumour cells → prevent death
• ABs against PD-1 prevent the inhibitory effect of binding PD1 and PD1-L → activating the T cells to kill
• Patients tend to develop autoimmune diseases - rheumatoid arthritis, thyroid disease, diabetes, SLE

Question 327

Describe some cytokine therapies.

Answer 327

• INF-a – antiviral
  
  • Hepatitis B and C
• INF-a2
  
  • Behçet’s disease
• INF-g
  
  • Chronic granulomatous disease
• IL-2 – increases clonal expansion
  
  • Renal cell cancer

Question 328

What is the mechanism of steroids in terms of immunosuppression?

Answer 328

• Effects on Prostaglandins = inhibit phospholipase A2
  
  • Phospholipids blocked from becoming prostaglandins and leukotrienes which are proinflammatory
• Effects on Phagocytes
  
  • Decrease chemotaxis
  • Decreased phagocytosis
  • Decreased release of proteolytic enzymes
• Effects on Lymphocytes
  
  • Lymphopaenia (CD4 > CD8 > B cells)
  • Blocks cytokine gene expression
  • Decreased antibody production
  • Promotes apoptosis

Question 329

What are the side effects of corticosteroids?

Answer 329

• Metabolic = Cushing’s Syndrome
  
  • Central obesity
  • Moon face
  • Diabetes
  • Lipid disorders
  • Osteoporosis
  • Hirsutism
  • Adrenal suppression
• Cataracts
• Glaucoma
• Peptic ulceration
• Pancreatitis
• Avascular necrosis
• Immunosuppression

Question 330

What are the indications for glucocorticoids?

Answer 330

• Allergic disorder
• Auto-immune
• Auto-inflammatory
• Transplantation
• Malignant disease

Question 331

What is the overall mechanism of action of cytotoxic agents?

Answer 331

Inhibit DNA synthesis → cells with rapid turnover are most affected

Question 332

What forms of toxicity are cytotoxic agents?

Answer 332

• BM suppression
  
  • Infection
  • Malignancy
• Teratogenic

Question 333

Name at least 3 cytotoxic agents.

Answer 333

• Cyclophosphamide
• Mycophenolate
• Azathioprine

Question 334

What is the mechanism of action of cyclophosphamide?

Answer 334

Alkylating agent

• Alkylates guanine base of DNA
• Damages DNA and prevent cell replication
• Affects B cells > T cells
  
  • Used in antibody-mediated disorders

Question 335

What is the mechanism of action of cyclophosphamide?

Answer 335

Alkylating agent

• Alkylates guanine base of DNA
• Damages DNA and prevent cell replication
• Affects B cells > T cells
  
  • Used in antibody-mediated disorders

Question 336

What are the indications for cyclophosphamide?

Answer 336

• Multisystem connective tissue disease
• Vasculitis with severe end-organ involvement - GPA, SLE
• Cancer

Question 337

What are the side effects of cyclophosphamide?

Answer 337

• Toxic to proliferating cells
  
  • Bone marrow suppression
  • Sterility (mainly in males)
  • Hair loss
• Haemorrhagic cystitis - toxic metabolite is excreted in urine
• Malignancy
  
  • Bladder cancer
  • Haematological malignancies
  • Non-melanoma skin cancer
• Teratogenic
• (Opportunistic) Infection

Question 338

What is the mechanism of action of azathioprine?

Answer 338

Purine analogue

• Metabolised by the liver to 6-mercaptopurine = purine analogue
• Blocks de novo purine synthesis (adenine and guanine) → prevents replication of DNA
• Affects T-cells > B-cells

Question 339

What are the indications for azathioprine?

Answer 339

• Transplantation
• Auto-immune disease
• Auto-inflammatory disease (e.g. Crohn’s, UC)

Question 340

What are the side effects of azathioprine?

Answer 340

• Bone marrow suppression
  
  • Check TPMT activity before treatment started
• Hepatotoxicity
• Infection - less common than with cyclophosphamide

Question 341

What is the mechanism of action of mycophenolate mofetil?

Answer 341

Anti-metabolite

• Blocks de novo guanosine nucleotide synthesis → prevents replication of DNA
• Prevent T cell > B cell proliferation

Question 342

What are the indications for mycophenolate mofetil?

Answer 342

• Transplantation
• Auto-immune disease
• Vasculitis

Question 343

What are the side effects of mycophenolate mofetil?

Answer 343

• Bone marrow suppression
• Teratogenic
• Infection
  
  • HSV reactivation
  • Progressive multifocal leukoencephalopathy / JC virus

Question 344

What is Plasmapheresis?

Answer 344

Removal of pathogenic antibodies

• Patient’s blood is passed through a separator and their own cellular constituents are reinfused
• Plasma treated to remove Ig and is then reinfused (or replaced with albumin in plasma exchange)

Question 345

What are the issues with plasmapheresis?

Answer 345

• Rebound antibody production
  
  • Although ABs gone plasma cells are still there → limits efficacy
  • Solution = co-administer an anti-proliferative agent (cyclophosphamide)

Question 346

What are the indications for plasmapheresis?

Answer 346

• Severe antibody-mediated disease (type 2 hypersensitivity)
  
  • Goodpasture’s syndrome (anti-GBM)
  • Severe acute myasthenia gravis (anti-ACh-R)
  • Severe transplant rejection (antibodies against donor HLA)

Question 347

Name some inhibitors of cell signalling.

Answer 347

• Calcineurin
  
  • Ciclosporin
  • Tacrolimus
• mTOR
  
  • Rapamycin
• JAK
  
  • Tofacitinib
  • Ruxolotinib
• PDE4
  
  • Apremilast
  • Anagrelide

Question 348

What is the mechanism of ciclosporin and tacrolimus?

Answer 348

Inhibitors of calcineurin

1. Prevent T cell signalling
2. Blocks IL2 production
3. Reduced activation of naive T-cells after successful APC interaction
4. Reduced clonal expansion and proliferation

Question 349

What are the side effects of calcineurin inhibitors?

Answer 349

• Nephrotoxicity - ciclosporin = tacrolimus
• HTN - ciclosporin = tacrolimus
• Neurotoxic - ciclosporin = tacrolimus
• Diabetogenic - ciclosporin < tacrolimus
• Dysmorphic features - ciclosporin
  
  • Hirsutism
  • Gingival hypertrophy

Question 350

What is the mechanism of rapamycin?

Answer 350

• Inhibit T cell proliferation and function
  
  • Used in transplantation

Question 351

What is the mechanism of tofacitinib and and ruxolotinib?

Answer 351

JAK inhibitors / Jakinibs

• Tofacitinib = JAK1 and JAK 3 inhibitor
• Ruxolotinib = JAK 2 inhibitor
• Interferes with JAK-STAT signalling
• Influences gene transcription
• Inhibits the production of inflammatory molecules

Question 352

What are the indications for tofacitinib and ruxolotinib (JAK inhibitors)?

Answer 352

Rheumatoid and Psoriatic arthritis

Question 353

What is the mechanism of apremilast and anagrelide?

Answer 353

PDE4 inhibitors

• Increases cAMP → activate PKA → prevent activation of transcription factors
  
  • Decrease in cytokine production

Question 354

What are the indications for apremilast and anagrelide (PDE4 inhibitors)?

Answer 354

Rheumatoid and Psoriatic arthritis

Question 355

Match the following side effects with the most likely drug?

• Osteoporosis
• Infertility
• Progressive multifocal leukoencephalopathy
• Neutropenia (low TPMT)
• Neuphrotoxicity
• Cyclophosphamide
• Prednisolone
• Azathioprine
• Tacrolimus
• Mycophenolate

Answer 355

• Osteoporosis = Prednisolone
• Infertility = Cyclophosphamide
• Progressive multifocal leukoencephalopathy = Mycophenolate
• Neutropenia (low TPMT) = Azathioprine
• Nephrotoxicity = Tacrolimus

Question 356

Name drugs that are directed at cell surface antigens?

Answer 356

• T cells - ABA
  
  • Anti-thymocyte globulin (rabbit)
  • Basiliximab (anti-CD25, IL-2-R)
  • Abatacept (CTLA4-Ig)
• T cell migration
  
  • Vedolizumab (anti-a4b7 integrin)
  • Natalizumab (anti-a4b7 integrin)
• B cells
  
  • Rituximab (anti-CD20)
• T cell, B cell, neutrophils, macrophages
  
  • Tocilizumab (anti-IL-6 receptor)
  • Sarlimumab (anti-IL-6 receptor)

Question 357

What are the indication for anti-thymocyte?

Answer 357

• Allograft rejection - renal, heart
  
  • Daily IV infusion
• Depletes T-cells

Question 358

What are the side effects of anti-thymocyte globulin?

Answer 358

• Infusion reactions
• Leucopaenia
• Infection
• Malignancy

Question 359

What is the mechanism of basiliximab?

Answer 359

Anti-CD25 / IL-2 receptor AB – inhibits T-cell proliferation

• Targets parts of IL2 receptor (potential alpha, beta and gamma components)
  
  • Gamma chain shared amongst many IL-receptors, so not a good target
  • Alpha chain (aka CD25) more specific for the IL2 receptor

Question 360

What are the indications for basiliximab?

Answer 360

Prophylaxis of allograft rejection → before and after transplant

Question 361

What are the side effects of basiliximab?

Answer 361

• Infusion reaction
• Infection
• Long-term malignancy risk

Question 362

What is the mechanism of abatacept?

Answer 362

CTLA4-Ig fusion protein - opposite of Ipilimumab

• Abatacept = receptor made from a fusion of CTLA4 and IgG Fc component
• CTLA4 and CD28 both expressed by T cells and both recognise the same antigens on APCs (CD80 and CD86)
  
  • APC CD80 and CD86 interact with CD28 → transmit a stimulatory signal
  • APC CD80 and CD86 interact with CTLA4 → transmit an inhibitory signal
    
    • Abatacept CTLA4-Ig binds APCs’ CD80 and CD86 = upregulated CTLA4-mediated reduced T cell activation
    • Ipilimumab anti-CTLA4 binds T-cell’s CTLA4 à blocks CTLA4-mediated reduced T cell activation à up activation

Question 363

What are the indications for abatacept?

Answer 363

Rheumatoid arthritis

Question 364

What are the side effects of abatcept?

Answer 364

• Infusion reactions
• Infection → screen for chronic infection (TB, HBV, HCV) before starting
• Caution with malignancy

Question 365

What is the mechanism of rituximab?

Answer 365

Anti-CD20 - depletion of B cells

• CD20 is expressed on mature B cells but not plasma cells → depletion of mature B cells

Question 366

What are the indications for rituximab?

Answer 366

• Lymphoma
• Rheumatoid arthritis
• SLE

Question 367

What are the side effects of rituximab?

Answer 367

• Infusion reactions
• Infection - PML / JC virus
• Exacerbation of cardiovascular disease

Question 368

What is the mechanism of vedolizumab and natalizumab?

Answer 368

Anti-alpha-4-beta-7 integrin – inhibits T-cell migration

• Alpha 4 is expressed with either beta-1 or beta-7 integrin
• This complex binds to MadCAM1 to mediate leukocyte epithelial rolling and arrest to enter tissues
• Blocking this complex then inhibits leucocyte migration to tissues

Question 369

What are the indications for vedolizumab and natalizumab?

Answer 369

• IBD
• Remitting/relapsing MS

Question 370

What are the side effects of vedolizumab and natalizumab?

Answer 370

• Infusion reactions
• Infection - PML / JC virus
• Hepatotoxic
• Concerns regarding malignancy

Question 371

What is the mechanism of tocilizumab and sarlimumab?

Answer 371

Anti-IL-6 receptor AB - reduces activation of macrophages, T cells, B cells and neutrophils

• Inhibits fusion of lymphoid and myeloid cells

Question 372

What are the indications for tocilizumab and sarlimumab?

Answer 372

• Castleman’s disease - IL-6 producing tumour
• Rheumatoid arthritis

Question 373

What are the side effects of tocilizumab and sarlimumab?

Answer 373

• Infusion reactions
• Infection
• Hepatotoxic
• Elevated lipids
• Caution with malignancy

Question 374

Name drugs that are directed at cytokines?

Answer 374

• Anti-TNFa
  
  • Infliximab
  • Adalimumab
  • Certolizumab
  • Golimumab
• TNF decoy receptor
  
  • Etanercept
• Anti-IL23
  
  • Ustekinumab (also anti-IL-12)
  • Guselkumab
• Anti-IL-17
  
  • Secukinumab
• Anti-RANK ligand
  
  • Denosumab

Question 375

What is the mechanism of infliximab, adalimumab, certolizumab and golimumab?

Answer 375

Anti-TNFa - bind to TNFa

Question 376

What are the indications for infliximab, adalimumab, certolizumab and golimumab?

Answer 376

• Rheumatoid arthritis
• Ankylosing spondylitis
• Psoriasis and psoriatic arthritis
• Inflammatory bowel disease
• Familial Mediterranean fever
• Other monogenic inflammatory diseases

Question 377

What are the side effects of infliximab, adalimumab, certolizumab and golimumab?

Answer 377

• Infusion or injection site reactions
• Infection (TB, HBV, HCV)
• Lupus-like conditions
• Demyelination
• Malignancy

Question 378

What is the mechanism of etanercept?

Answer 378

TNFa antagonist / decoy receptor → Inhibits action of TNF-alpha and TNF-beta

Question 379

What are the indications for etanercept?

Answer 379

• Rheumatoid arthritis
• Ankylosing spondylitis
• Psoriasis and psoriatic arthritis

Question 380

What are the side effects of etanercept?

Answer 380

• Injection site reactions
• Infection (TB, HBV, HCV)
• Lupus-like conditions
• Demyelination
• Malignancy

Question 381

Describe IL-1 productions and state some conditions that can be managed by blocking it?

Answer 381

• Familial Mediterranean fever → MEFV gene in mutated some abnormal pyrin-marenostrin
• Gout → urate and the cryopyrin pathway
• Fever
• Adult onset Stills disease

Question 382

Describe IL-6 productions and state some conditions that can be managed by blocking it?

Answer 382

Rheumatoid arthritis

Question 383

What is the mechanism of ustekinumab?

Answer 383

Anti-p40 of IL-12 and IL-23

• Targeting p40 will inhibit both cytokines
  
  • IL-12 = p40 and p35
  • IL-23 = p40 and p19
• These cytokines mainly act on T cells and NK cells thereby modulating their activity

Question 384

What are the indications for ustekinumab?

Answer 384

• Psoriasis and psoriatic arthritis
• Crohn’s disease

Question 385

What are the side effects of ustekinumab?

Answer 385

• Injection site reactions
• Infection (TB)
• Concern about malignancy

Question 386

What is the mechanism of guselkumab?

Answer 386

Anti-p19a in IL-23

• IL-23 comprises p40 and p19
  
  • Acts on T cells and NK cells thereby modulating their activity

Question 387

What are the indications for ustekinumab?

Answer 387

• Psoriasis

Question 388

What are the side effects of ustekinumab?

Answer 388

• Injection site reactions
• Infection (TB)
• Concern about malignancy

Question 389

What is the mechanism of secukinumab?

Answer 389

Anti-IL17a

• Dimer of IL17A or IL17A/F will bind to IL17RA/RC receptor

Question 390

What are the indications for secukinumab?

Answer 390

• Psoriasis and psoriatic arthritis
• Ankylosing spondylitis

Question 391

What are the side effects of secukinumab?

Answer 391

• Infection (TB)

Question 392

Which interleukins are important in asthma and eczema?

Answer 392

• IL-4, IL-5 and IL-13 → Th2 and eosinophil response
  
  • IL-4/13 blockade antibody = asthma and eczema
  • Anti-IL-13 antibody = eczema
  • Anti-IL-5 antibody = eosinophilic asthma

Question 393

What is the mechanism of denosumab?

Answer 393

Anti-RANK-ligand antibody

• RANKL from osteoblasts acts on RANK receptor on osteoclasts → osteoclast differentiation → resorb bone
• Denosumab is an antibody directed against RANKL = prevents RANKL binding to RANK on osteoclasts

Question 394

What are the indications for denosumab?

Answer 394

Osteoporosis

Question 395

What are the side effects of denosumab?

Answer 395

• Injection site reactions
• Infection - mildly immunosuppressive as RANKL has some role in other parts of the immune system
• Avascular necrosis of the jaw