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Year 5 Pathology > Immunology > Flashcards

Immunology Flashcards

1
Q

What are some barriers to infection?

A
  • External epithelia

- Mucosal surface

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2
Q

How does external epithelia prevent pathogens getting in?

A
  • Tightly packed keratinised cells
  • Physiological factors e.g. low pH, low oxygen
  • Sebaceous glands - hydrophobic, lysozyme actin, ammonia and defensives (antimicrobial)
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3
Q

How do mucosal surfaces stop bacteria coming in?

A
  • IgA prevents bacteria/viruses attaching
  • Lysozyme/antimicrobial peptides
  • Lactoferrin
  • Cilia
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4
Q

How much bacteria do we have in our body naturally?

A

100 trillion

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5
Q

What do naturally occurring bacteria do in our body?

A
  • Compete with pathogenic microorganisms

- Produce fatty acids and bactericidins that inhibit the growth of many pathogens

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6
Q

Which pathogens reside inside of cells?

A

Viruses

Mycobacterium

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7
Q

What are the cells/soluble components of the innate immune system?

A

Polymorphonuclear (neutro, baso, eosino)
Monocytes
NK cells
Dendritic cells

Soluble components:
Complement
Acute phase proteins
Cytokines and chemokines

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8
Q

What are the functions of the innate immune system?

A

Express receptors which allow detection of pathogen and expressing receptions (PRRs)
Phagocytic capability
Secrete cytokines and chemokines

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8
Q

What are the functions of the innate immune system?

A

Express receptors which allow detection of pathogen and expressing receptions (PRRs)
Phagocytic capability
Secrete cytokines and chemokines

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9
Q

Where are polymorphonuclear cells produced?

A

Bone marrow

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10
Q

What are the functions of polymorphonuclear cells?

A

(Neutrophils, eosinophils, basophils/mast cells)
Migrate rapidly to site of injury
Express cytokine/chemokines –> detect inflammation
Express PRR –> detect pathogens
Express Fc receptors for Ig –> detect immune complexes
Phagocytosis/oxidative/non-oxidative killing –> mostly neutrophils
Release enzymes, histamine, lipid mediators

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11
Q

Where do monocytes differentiate into macrophages? What are they then capable of doing?

A

Monocytes made in bone marrow and differentiate into macrophages in the tissue

Can present processed antigen to T cells

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12
Q

What are the specific macrophages called in the following organs?

Liver
Kidney
Bone
Spleen
Lung
Neural tissue 
Connective tissue Skin
Joints
A 
Liver - Kupffer cell 
Kidney - Mesangial cell 
Bone - Osteoclast
Spleen - Sinusoidal lining cell
Lung - Alveolar macrophage
Neural tissue - Microglia
Connective tissue - Histiocyte
Skin - Langerhans cell
Joints - Macrophage like synoviocytes
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13
Q

What are the differences between polymorphonuclear cells and monocytes/macrophages?

A
  • Present in tissue

- Capable of presenting processed antigen to T cells

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14
Q

What do cytokines do?

A

Activate vascular endothelium to enhance permeability

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15
Q

What do chemokines do?

A

Chemokines attract phagocytes (macrophages already present at peripheral sites)

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16
Q

What are some types of pattern recognition receptors?

A
  • Toll-like receptors
  • Mannose receptors

These recognise pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA, RNA

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17
Q

How is endocytosis of pathogens facilitated?

A

Opsonisation - bind to phagocyte receptors (Fc)

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18
Q

What is it called when a phagosome and lysosome fuse?

A

Phagosolysosome

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19
Q

What happens in the oxidative killing of the pathogen in phagocytosis?

A

1) NADPH oxidase complex converts oxygen to reactive oxygen species - superoxide and hydrogen peroxide
2) Myeloperoxidase catalyses production of hydrochloric acid from hydrogen peroxide and chloride
3) Hydrochlorous acid is a highly effective oxidant and anti-microbial

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20
Q

What happens in the non-oxidative killing of pathogens in phagocytosis?

A

Bactericidal enzymes such as lysozyme and lactoferrin into phagolysosome:

  • enzymes present in granules
  • unique antimicrobial spectrum
  • broad coverage against bacteria and fungi
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21
Q

What happens after the neutrophil has undergone phagocytosis?

A

Depletes neutrophil and glycogen reserves –> neutrophil cell death

  • enzymes and residue released
  • dead neutrophils = pus
  • can cause abscess formation
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22
Q

How can opsonisation be mediated and facilitate phagocytosis?

A
  • Antibodies
  • Complement components
  • Acute phase proteins
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23
Q

What are the functions of natural killer cells?

A
  • Present within blood - migrate to inflamed tissue
  • Express inhibitory receptors for self-HLA
  • Express a range of activatory receptors including natural cytotoxicity receptors - that recognise heparin sulphate proteoglycans
  • Cytotoxic - altered self - malignant or viral response
  • Secrete cytokines to regulate inflammation and promote dendritic cell function
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24
Q

What are the functions of dendritic cells?

A
  • Express receptors for chemokines and cytokines
  • Express PRRs
  • Express Fc receptors for Ig
  • Capable of phagocytosis
  • Express cytokines to regulate immune response
  • Process antigen to T cells in lymph nodes to prime adaptive response
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25
Q

Where do dendritic cells reside?

A

Peripheral tissues

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26
Q

What happens to dendritic cells after phagocytosis?

A

Dendritic cells mature:

  • upregulate HLA molecules
  • express costimulatory molecules
  • migrate via lymphatics to lymph nodes - mediated by CCR7
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27
Q

Describe the lymphatic system

A
  • Naive lymphocytes enter lymph nodes from blood
  • Antigens from sites of infection reach lymph nodes via lymphatics
  • Lymphocytes and lymph return to blood via thoracic duct
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28
Q

Describe what happens with dendritic cells once they come into contact with T cells

A

Immature cells are adapted for PRR and uptake whilst mature cells are adapted for antigen presentation to prime T cell

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29
Q

What are the components of the adaptive immune system?

A
  • Humoral immunity – B lymphocytes and antibody
  • Cellular immunity – CD4, CD8 T cells
  • Cytokines and chemokines
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30
Q

What are some characteristics of the adaptive immune system?

A
  • Wide repertoire of antigen receptors
  • Exquisite specificity
  • Clonal expansion
  • Immunological memory
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31
Q

What is the function secondary lymphoid organs?

A

Anatomical sites of interaction between naïve lymphocytes and microorganisms

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32
Q

What are the secondary lymphoid organs in the body?

A
  • Spleen
  • Lymph nodes
  • Mucosal associated lymphoid tissue
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33
Q

Describe T lymphocyte maturation

A
  • Pre-T cells in bone marrow go to thymus – positive and negative selection of lymphocytes within thymus
  • T cells are exported as mature T lymphocytes to periphery
  • Arise from haematopoietic stem cells – exported as immature cells to the thymus where undergo selection
  • Mature T lymphocytes enter the circulation and reside in secondary lymphoid organs
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34
Q

Which HLA class molecules on antigen presenting cells bond to T cells?

A

CD8+ T cells recognise peptide presented by HLA class I molecules

CD4+ T cells recognise peptide presented by HLA class II molecules

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35
Q

What are the outcomes of HLA-CD+ interaction?

A
  • Low affinity for HLA – not selected to avoid inadequate reactivity
  • Intermediate affinity for HLA – positive selection ~10% original cells
  • High affinity for HLA – negative selection to avoid
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36
Q

What are the CD4+ T cell subsets?

A
  • Th1 - Help CD8+ T cells and macrophages
  • Th17 - Help neutrophil recruitment, enhance generation autoantibodies
  • Treg - IL-10/TGF beta expressing, CD25+ Foxp3+
  • TGh - Follicular helper T cells
  • Th2 - Helper T cells
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37
Q

What are functions of CD8+ cytotoxic T cells?

A
  • Specialised cytotoxic cells
  • Recognise peptides derived from intracellular proteins in associations with HLA class I (A,B,C)
  • Kills cells directly - perforin (pore-forming) and granzymes, expression of Fas ligand
  • Secrete cytokines e.g. IFN-gamma, TNF-alpha
  • Defence against viral infections and tumours
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38
Q

Describe secondary immunity

A

Pool of ‘memory’ T cells ready to respond to antigen - these are more easily activated than naïve cells

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39
Q

What are the functions of the T follicular helper cell?

A

Play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells.

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40
Q

What are the functions of T regulatory cells?

A

Subset of lymphocytes that express Foxp3 and CD25

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41
Q

What is the function of the Th1 cells?

A

Subset of cells that express CD4 , secrete IFN-gamma and IL-2

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42
Q

Describe B cell maturation in the bone marrow

A

Stem cell –> lymphoid progenitors –> Pro B cells –> Pre B cells –> IgM B cells –> IgM plasma cells, IgE, IgA, IgE, IgG

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43
Q

Describe the two outcomes of central tolerance of B cells

A

1) No recognition of self = survive

2) Recognition of self in the bone marrow = negative selection to avoid autoreactivity

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44
Q

Describe the stages involved in antigen encounter and B cells

A

1) Dendritic cells prime CD4+ T cells
2) CD4+ T cell help for B cell differentiation - requires CD40L:CD40
3) B cell proliferation, somatic hypermutation, isotype switching

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45
Q

List the different types of immunoglobulin

A
  • IgG
  • IgD
  • IgE
  • IgA - J chain
  • IgM - J chain
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46
Q

Where on the immunoglobulin is the antigen recognised by?

A

Antigen is recognised by the antigen binding regions (Fab) of both the heavy and light chains

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47
Q

Where on the immunoglobulin molecule is the effector function determined?

A

It is determined by the constant region of the heavy chain

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48
Q

Which chain on the immunoglobulin determines the antibody class?

A

The heavy chain

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49
Q

What does the Fc region of the immunoglobulin interact with?

A
  • Complement
  • Phagocytes
  • Natural killer cells
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50
Q

Describe differences in immunoglobulin levels in the primary and secondary response against T-dependent antigens

A

Primary - big IgM increase, IgG small increase after a lag
Secondary - same IgM increase as primary, massive IgG increase

Response may be independent of help from CD4+ T lymphocytes

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51
Q

Describe the process which results in B cell isotype switching and affinity maturation

A
  • Dendritic cell - takes up pathogen - processed and primes CD4+
  • CD4+ cells help CD8+ and are also primed by dendritic cells. CD8+ recognise intracellular pathogens presented on class I molecules
  • B cells can also recognise pathogen and produce early response and produce IgM
  • B cells proliferate by somatic hypermutation - produce high affinity IgG, IgA, IgE
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52
Q

Describe the function of IgA

A

Divalent antibody present within mucous which helps provide barrier to infection

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53
Q

Describe the function of IgG secreting plasma cells

A

Cell dependent on the presence of CD4+ T cell help for generation

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54
Q

Describe the function of IgM secreting plasma cells

A

Generated rapidly following antigen recognition and are not dependent on CD4+ T cell help

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55
Q

What is the function of the thoracic duct?

A

Carries lymphocytes from lymph nodes back to the blood circulation

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56
Q

What occurs in the germinal centre?

A

Where B cells proliferate and undergo affinity maturation and isotope switching

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57
Q

What occurs in the thymus?

A

Site of deletion of T cells with inappropriately high or low affinity for HLA molecules and of maturation of T cells into CD4+ or CD8+ cells

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58
Q

Describe the complement system

A

> 20 tightly regulated, linked proteins - produced by the liver, present in circulation as inactive molecules. When triggered, enzymatically activate other proteins in a biological cascade. This results in a rapid and highly amplified response.

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59
Q

Draw a diagram to show the three pathways of complement activation

A

Classical (C1,2,4) —> C3 Central —> Final common pathway C5-9 —> Membrane attack complex
MBL - mannose-binding leptin (C4,2) —> C3 Central —> Final common pathway C5-9 —> Membrane attack complex
Alternative —> C3 Central —> Final common pathway C5-9 —> Membrane attack complex

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60
Q

What are the functions of the membrane attack complex?

A

Holes in bacterial membranes
Increase vascular permeability
Immune complex = more solution
Promote phagocytosis

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61
Q

What activates the complement pathway?

A

IgG binding to the pathogen

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62
Q

Which complement protein does this correlate to?

‘Binding of immune complexes to this protein triggers the classical pathway of complement activation’

A

C1

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63
Q

Which complement protein does this correlate to?

‘Cleavage of this protein may be triggered by classical, MBL or alternative pathways’

A

C3

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64
Q

Which complement protein does this correlate to?

‘Binds to microbial surface carbohydrates to activate complement cascade in an immune complex independent manner’

A

MBL

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65
Q

Which complement protein does this correlate to?

‘Part of the final common pathway resulting in the generation of the membrane-attack complex’

A

C9

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66
Q

List the functions of cytokines

A

Small protein messengers
Immunomodulatory function
Autocrine or paracrine dependent action

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67
Q

What is the difference between a cytokine and chemokines?

A

Chemokines are subset of cytokines which can recruit homing of leukocytes in inflammatory response i.e. chemoattractants. CCL19 and CCL21 are ligands for CCR7 and dendritic cell trafficking to lymph nodes. Examples include RANTES, IL-8, MIP-1 alpha and beta.

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68
Q

What are some examples of secondary immune deficiencies?

A
  • Malnutrition
  • Infectious diseases: measles, TB, HIV, SARS-CoV-2
  • Environmental stress
  • Age extremes
  • Surgery and trauma
  • Immunosuppressive drugs
  • Genetic and metabolic diseases
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69
Q

What are some clinical features of immune deficiencies?

A
  • Infections
  • Autoimmune conditions (cytopenias) and allergic disease
  • Persistent inflammation
  • Cancer (viral associated EBV, HHV-8)
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70
Q

Which drugs are important in immune deficiency treatment?

A
  • Small molecules

- JAK inhibitors

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71
Q

What are examples of small molecular drugs used in treatment of immune deficiency?

A

Glucocorticoids and mineralocorticoids

Cytotoxic agents: methotrexate, mycophenolate, cyclophosphamide and azathioprine

Calcineurin inhibitors: cyclosporine and tacrolimus

Antiepileptic drugs (phenytoin, carbamazepine, levetiracetam

DMARD (sulphasalazine, leflunomide)

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72
Q

List 3 JAK inhibitors

A

Tofacitinib (RA, PA, AS - arthritis treatment)
Upadacitinib (PA, RA)
Ruxolitinib - JAK2 inhibitor (e.g. myelofibrosis)

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73
Q

List examples of biological agents and cellular therapy use din the treatment of immune deficiencies

A

Biologics agents: anti-CD20/CD38/BCMA monoclonals, anti-TNF-α protein and receptor antagonists

Cellular therapy: anti-CD19/BCMA CAR-T cell therapy

Antibody deficiency and bacterial/viral infections are observed with rituximab and other anti-CD20 agents

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74
Q

What are the disadvantages of using biological and cellular therapies in treating immune deficiencies?

A

Risk of infection increased with repeated courses and in patient with a history of B cell malignancy and vasculitis.

Anti-TNF agents are linked to reactivation of TB infection

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75
Q

Which cancers are B cell lymphoproliferative disorders associated with immune deficiency?

A

Multiple myeloma

Chronic lymphocytic leukaemia

Non Hodgkin’s lymphoma

Monoclonal gammopathy of uncertain significance

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76
Q

What is Good’s syndrome?

A

Paraneoplastic syndrome in people who have a thymoma and antibody deficiency:

  • Combined T and B cell (absent) defect
  • CMV PJP and muco-cutaneous candida
  • Autoimmune disease (Pure red cell aplasia, Myasthenia gravis, Lichen planus)
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77
Q

Which tests would you order in someone who has demonstrated clinical signs of immunodeficiency?

A 
Full Blood count
Hb < 10g/L 
neutrophil count
lymphocyte count 
platelet count

LFTs, U&Es, protein/albumin, urine protein/Cr ratio, serum protein electrophoresis, serum free light chains

Immunoglobulins (IgG, IgA, IgM, IgE )

Serum complement (C3, C4)

HIV test (18-80 years)

Strategy will pick up to 85% of all immune defects

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78
Q

What would isolated reduction in IgG mean?

A

Protein loosing enteropathy

Prednisolone >10mg/day

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79
Q

What would reduction in IgG and IgM mean?

A

Monitor for B cell neoplasm

History of exposure to rituximab

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80
Q

What would reduction in IgG and IgA mean?

A

? Primary antibody deficiency

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81
Q

What are the uses of serum protein electrophoresis?

A

SPE separation of serum proteins by charge

Detection of discrete bands: monoclonal identified by immunofixation with labelled IgG, IgA, IgM anti-sera.

Monoclonal protein associated with multiple myeloma, WMG, NHL and MGUS

SPE can miss free light chain disease which is seen 20% multiple myeloma cases): hence measurement of free light chains is essential for work up of B cell LPD

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82
Q

What are second line tests to investigate immune deficiencies?

A

Tetanus toxoid protein antigen

Pneumovax vaccine carbohydrate antigen (all 23 serotypes or to individual pneumococcal serotypes)

If vaccine antibody levels are low offer test immunisation with Pneumovax II and tetanus to investigate immune function

Failure to respond to vaccination is part of diagnostic criteria for a number of primary antibody deficiency syndromes and is a criteria for receipt of IgG replacement therapy for secondary antibody deficiency syndromes.

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83
Q

Which lymphocyte subsets are identified in flow cytometry?

A

CD3+CD4+ T cells

CD3+CD8+ T cells

CD3-CD56+CD16+ NK cells

CD19+ B cells

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84
Q

What are third line investigations for immune deficiencies?

A

Analysis of naïve and memory T and B cell subsets

Assessment of IgG subclasses

Determination of anti-cytokine and complement antibodies:

  • Anti-Type 1 interferon antibodies (IFN-α and IFN-ω) in SARS-CoV-2 infection
  • Anti Type 2 interferon antibodies (IFN-γ) in disseminated NTM infection
  • Anti-GM-CSF antibodies disseminated in cryptococcal infection
  • Anti-C1 inhibitor antibodies and acquired late onset angioedema ( B cell LPD and SLE)

Genetics

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85
Q

How are secondary immune deficiencies managed?

A

Treat underlying cause

Advise + education

Immunisation against respiratory viruses and bacteria

Education to treat bacterial infections promptly: may require higher and longer therapies courses (co-amoxiclav 625mg TDS for 10-14 days rather then 375mg for 5-7 days)

Prophylactic antibiotics

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86
Q

When is IgG replacement therapy used?

A

Secondary antibody deficiency syndromes:

Underlying cause of hypogammaglobinaemia cannot be reversed or reversal is contraindicated

OR

Hypogammaglobinaemia associated with drugs, therapeutic monoclonal antibodies targeted at B cells and plasma cells, post-HSCT, NHL, CLL, MM or other relevant B-cell malignancy

AND

Recurrent or severe bacterial infection despite continuous oral antibiotic therapy for 6 months

IgG <4.0g/L (excluding a paraprotein/monoclonal protein )

Failure of vaccine response to unconjugated pneumococcal or other polysaccharide vaccine challenge

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87
Q

Describe some features of HIV-1

A

Member of the lentivirus family: slow evolution of disease

Double strand RNA virus

Structural, replicative and accessory proteins

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88
Q

How does HIV-1 integrate into a host cell?

A
  • Binds to CD4 and then to chemokine co-receptor CCR5 or CXCR4
  • Replicates via a DNA intermediate
  • Integrates into host genome
    HIV DNA transcribed to viral mRNA
  • Viral RNA translated to viral proteins
  • Packaging and release of mature virus
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89
Q

What are the origins of HIV-1?

A

HIV-1 consists of 4 distinct lineages M, N, O, and P

Each lineage arose from independent transmission from chimpanzees (Group M,N,O) and gorillas (O,P)

Initial transmission of M subtype to humans occurred in SE Cameroon between 1910-1930.

Spread of Group M along Congo river (trains/migration) and established in modern Kinshasa in 1960.

Group M virus is pandemic, consists of 9 subtypes and 40 recombinant forms

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90
Q

What is the natural history of HIV-1 infection as defined by viral replication?

A
  • Acute
  • Asymptomatic but progressive
  • AIDs
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91
Q

What are the key concepts of the HIV-1 replication cycle?

A

Error prone nature of HIV RT, short generation time of viral cycle and length of infection is the driving force for viral diversity

Viral mutation has implications for the evasion of CTL immune responses, and emergence of drug resistant virus in patients with inadequate drug treatment

Up to 1010 virions are produced every day, source of virus in plasma is recently infected CD4 T cells

Integration of HIV provirus in memory CD4 T cells within 72 hours of infection leads to formation of long lived reservoir of latent infection which does not respond to current ART

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92
Q

What are characteristic features of the immunology of HIV-1 infection?

A
  1. CD4 T cell depletion
  2. Chronic immune activation
  3. Impairment of CD4 and CD8 T cell function
  4. Disruption of lymph node architecture and impaired ability to generate protective T and B cell immune responses
  5. Loss of antigen-specific humoral immune responses
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93
Q

What are some features of acute HIV-1 infection?

A

Significant increase in HIV-1 viral load in blood

‘Flu like’ symptoms in 70% of cases

Significant risk of viral transmission

Transient reduction in blood CD4+ T cells

Increase in CD8 T cell immune response which coincides with drop in VL

CD8 T cell activation (CD38+ and HLA-DR+)

Induction of HIV-1 specific antibodies

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94
Q

How is HIV-1 diagnosed?

A

4TH generation combined HIV-1 antigen/antibody tests will detect infection 1 month post acquisition of infection

Assay detect p24 antigen, gp41 from HIV-1 Group O, gp160 envelope protein HIV-1 M and gp36 HIV-2

Rapid point of care HIV-1 tests: result available within 20 minutes less sensitive than 4th generation test

HIV-1 RNA tests in cases where HIV-1 serological tests are negative but high clinical suspicion of acute HIV-1 infection

HIV-1 RNA and/or DNA tests are used to diagnose infection in children less than 18 months

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95
Q

What are the baseline investigations you would conduct in someone just diagnosed with HIV?

A

Full Blood count

Renal, liver, bone, lipid profiles and HbA1c

Sexual health screen (RPRGU, Hep A, B, C serology)

Screen for latent TB using IGRA

Baseline chest x ray and ECG

Toxoplasma serology

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96
Q

What are some HIV-1 specific tests you would conduct in someone with HIV?

A

HIV-1 viral load

HIV-1 genotype for ART drug resistance

HIV-1 tropism test to confirm co-receptor use in HIV-1 in patients who may be candidates for treatment with CCR5 antagonists

HLA-B*5701 blood test to avoid prescribing Abacavir and risk of severe hypersensitivity in those with this allele which is seen in 8% of population in NW London

Analysis of T cell counts
CD4 T cell count and percentage
CD4: CD8 T cell ratio

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97
Q

What factors influence the viral load set point outcome?

A

Viral genotype
CD8 T cell immune
Host genetics (HLA and CCR5)
Immune activation

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98
Q

What types of opportunistic infections arise as a result of HIV infection?

A
  • Infection
  • PCP
  • Toxoplasma gondii
  • Mycobacterium avian complex (MAC disease)
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99
Q

What are the types of anti-retroviral therapies available?

A

Reverse transcriptase inhibitors
NRTI
NNRTI

Boosted Protease inhibitors Ritonavir + PI
Integrase inhibitors DTG, RTG EVG

CCR5 antagonist - Maraviroc

Fusion inhibitors - T20 (rarely used)

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100
Q

What is the standard treatment of HIV in the UK?

A

2 NRTI and 1 NRTI or 2NRTI and 1 Integrase inhibitor are standard first line anti-HIV-1 treatments

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101
Q

Theoretically, how could HIV-1 be cured?

A

Berlin and London patient
Allogeneic SCT from CCRδ32 HLA matched donor

Shock and kill strategy - activate latent CD4+ cell

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102
Q

What is the difference between primary and secondary immunodeficiencies?

A

Primary - inherited
– >100 primary immune deficiencies now described
– 1:10,000 live births

Secondary – acquired
– Infection, malignancy, drugs, nutritional deficiencies
– Common
– May involve more than one component of immune system

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103
Q

What are some physiological causes of immunodeficiency?

A

– Neonates
– Pregnancy
– Older age

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104
Q

What are clinical features suggestive of immunodeficiency?

A

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

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105
Q

What are features to suggest primary immune deficiency?

A

– Family history
– Young age at presentation
– Failure to thrive

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106
Q

What are the functions of phagocytes?

A

– Essentially identical responses in all individuals
– Cells express cytokine/chemokine receptors that allow them to
home to sites of infection
– Cells express genetically encoded receptors to allow detection of
pathogens at site of infection
• pattern recognition receptors (Toll-like receptors or mannose receptors) which recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA, RNA
– Cells express Fc receptors to allow them detection of immune complexes
– Cells have phagocytic capacity that allows them to engulf the pathogens
– Cells secrete cytokines and chemokines to regulate immune response

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107
Q

What are two types of pattern recognition receptors?

A

Toll-like receptors

Mannose receptors

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108
Q

How do polymorphonuclear cells (granulocytes) fit infection?

A

Produced in bone marrow and migrate rapidly to site of injury
Release enzymes, histamine, lipid mediators of inflammation from granules.

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109
Q

What is the difference between monocytes and macrophages?

A

Monocytes are produced in bone marrow, circulate in blood and migrate to tissues where they differentiate to macrophages.
Capable of presenting processed antigen to T cells

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110
Q

What are the names of different macrophages found in the different organs?

A 
Liver - Kupffer cell 
Kidney - Mesangial cell
Bone - Osteoclast
Spleen - Sinusoidal lining cell 
Lung - Alveolar macrophage 
Neural tissue - Microglia
Connective tissue - Histiocyte
Skin - Langerhans cell
Joints - Macrophage like synoviocytes
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111
Q

Describe how neutrophils can eventually process pathogen recognition and cell death

A

1) Increased neutrophil adhesion and migration into tissues
2) Mobilisation of phagocytes and precursors from bone marrow or within tissues
3) Endothelial cell activation with increased expression of adhesion molecules
4) Phagocytosis of organisms
5) Oxidative and non-oxidative killing
6) Macrophage -T cell communication
7) Cell death and the formation of pus

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112
Q

What are types of phagocyte deficiency?

A
  1. Failure to produce neutrophils
  2. Defect of phagocyte migration
  3. Failure of oxidative killing mechanisms
  4. Cytokine deficiency
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113
Q

What are the causes of neutrophil production failure?

A

– Failure of stem cells to differentiate along myeloid or lymphoid lineage
• Reticular dysgenesis – autosomal recessive severe SCID mutation in mitochondrial energy metabolism
enzyme adenylate kinase 2 (AK2)

– Specific failure of neutrophil maturation
• Kostmann syndrome - autosomal recessive severe congenital neutropenia
classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
• Cyclic neutropenia - autosomal dominant episodic neutropenia every 4-6 weeks
mutation in neutrophil elastase (ELA-2)

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114
Q

List causes of defective phagocyte migration

A

Leukocyte adhesion deficiency

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

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115
Q

What are causes of neutrophil failure of oxidative killing mechanisms?

A

Chronic granulomatous disease

• Absent respiratory burst
– Deficiency of one of components of NADPH oxidase
– Inability to generate oxygen free radicals results in impaired killing

• Excessive inflammation
– Persistent neutrophil/macrophage accumulation
– Failure to degrade antigens

  • Granuloma formation
  • Lymphadenopathy and hepatosplenomegaly
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116
Q

How can chronic granulomatous disease be investigated?

A
  • Nitrobluetetrazolium (NBT) test
  • Dihydrorhodamine (DHR) flow cytometry test

– Activate neutrophils – stimulate respiratory burst and production of hydrogen peroxide
– NBT is a dye that changes colour from yellow to blue, following interaction with hydrogen peroxide
– DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide

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116
Q

How can chronic granulomatous disease be investigated?

A

• Nitrobluetetrazolium(NBT)test
• Dihydrorhodamine (DHR) flow cytometry test
– Activate neutrophils – stimulate respiratory burst and production of hydrogen peroxide
– NBT is a dye that changes colour from yellow to blue, following interaction with hydrogen peroxide
– DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide

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117
Q

How does cytokine deficiency cause immunodeficiency?

A

IL12, IL12R, IFNg or IFNg R deficiency:

• IL12 - IFNg network important in control of mycobacteria infection
– Infection activates IL12- IFNg network
• Infected macrophages stimulated to produce IL12
• IL12 induces T cells to secrete IFNg
• IFNg feeds back to macrophages &
neutrophils
• Stimulates production of TNF
• Activates NADPH oxidase
• Stimulates oxidative pathways
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118
Q

List the types of infections which arise due to phagocyte deficiencies

A

Bacterial infections
• Staphylococcus aureus
• Enteric bacteria

Fungal infections
• Candida albicans
• Aspergillus fumigatus and flavus

Atypical Mycobacteria
• Mycobacterial infection
• Mycobacterium tuberculosis

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119
Q

How can phagocyte deficiencies be treated?

A 
Aggressive management of infection
– Infection prophylaxis
• Antibiotics – eg Septrin
• Anti-fungals – eg Itraconazole
– Oral/intravenous antibiotics as needed
Definitive therapy
– Haematopoietic stem cell transplantation 
• ‘Replaces’ defective population
– Specific treatment for CGD 
• Interferon gamma therapy
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120
Q

What are the different types of natural killer cells deficiencies?

A

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
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121
Q

How can natural killer cell deficiencies be treated?

A
  • 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
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122
Q

What does the complement immune system involve?

A

• > 20 tightly regulated, linked proteins – produced by liver
– Present in circulation as inactive molecules
• When triggered, enzymatically activate other proteins in a biological cascade
– Results in rapid, highly amplified response

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123
Q

Which proteins does the classical pathway involve?

A

C1, C4, C2

  • Formation of antibody- antigen immune complexes
  • Results in change in antibody shape – exposes binding site for C1
  • Binding of C1 to the binding site on antibody results in activation of the cascade
  • Dependent upon activation of acquired immune response (antibody)
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124
Q

What does the mannose binding lectin pathway involve?

A
  • Activated by the direct binding of MBL to microbial cell surface carbohydrates
  • Directly stimulates the classical pathway, involving C4 and C2 but not C1
  • Not dependent on acquired immune response
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125
Q

What does the alternate complement pathway involve?

A

• Bacterial cell wall fails to regulate low level of spontaneous activation of alternate pathway
– eg lipopolysaccharide of gram negative bacteria
– teichoic acid of gram positive bacteria
• Not dependent on acquired immune response
• Involves factors B, D and Properidin
• Factor H – control protein

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126
Q

What does the final common pathway in the complement system involve?

A
  • Activation of C3 is the major amplification step in the complement cascade
  • Triggers the formation of the membrane attack complex via C5-C9
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127
Q

Which roles do complement fragments in the immune system involve?

A
  • Increases vascular permeability and cell trafficking to site of inflammation
  • Activates phagocytes
  • Opsonisation of pathogens to promote phagocytosis
  • Promotes clearance of immune complexes
  • Punches holes in bacterial membranes
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128
Q

What do deficiencies in the complement system involve?

A

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

Classical pathway deficiency (C2, C1q)
- Susceptibility to SLE
- Failure of phagocytosis of dead cells 
• Increased nuclear debris
- Failure to clear immune complexes
- Immune complex deposition in blood vessels

MBL deficiency
MBL2 mutations are common but not usually associated with immunodeficiency

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129
Q

Name a complication which arises from deficiencies in complement components

A

Meningococcal septicaemia

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130
Q

How does SLE lead to complement response dysfunction?

A

Active SLE leads to consumption of C3 and C4

Active lupus causes persistent production of immune complexes and consequent consumption of complement leading to functional complement deficiency

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131
Q

What are C3 nephritic factors?

A
  • 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
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132
Q

How are auto-immune disease and complement response related?

A

• Complement deficiency can lead to SLE
– Deficiency of early components of the classical pathway, C1q and C2, predisposes to development of SLE and conversely..

• Auto-immune disease can lead to complement deficiency
– SLE in someone with a normal complement system will lead to consumption of complement
– Autoantibodies directed against components of the complement pathway may lead to consumption of complement (usually C3)

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133
Q

How can the complement pathway investigated?

A

Quantitation of complement components
– C3, C4 routinely measured
– Other components not routinely quantified

Functional complement tests
– CH50 classical pathway – AP50 alternative pathway

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134
Q

How can patients with complement deficiencies

A
  • 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
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135
Q

What is reticular dysgenesis?

A
  • Most severe form of severe combined immunodeficiency (SCID)
  • Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
  • Fata; in early life if not corrected by bone marrow transplant
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136
Q

What is X-linked severe combined immunodeficiency (SCID)?

A

X-linked severe combined immunodeficiency (SCID) is an inherited disorder of the immune system that occurs almost exclusively in males.
45% of all severe combined immunodeficiency

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137
Q

What are the consequences of X-linked severe combined immunodeficiency (SCID)?

A

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

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138
Q

What is ADA deficiency?

A

Adenosine deaminase deficiency (ADA deficiency) is an inherited condition that damages the immune system and is a common cause of severe combined immunodeficiency (SCID).
16.5% of all severe combined immunodeficiency

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139
Q

What are the consequences of ADA deficiency?

A

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

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140
Q

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

A

1) Active transport of maternal IgG across placenta
2) IgG in colostrum
3) Neonatal production of IgG

141
Q

What is the clinical presentation of severe combined immunodeficiency?

A 
• 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
142
Q

Describe the pathophysiology and clinical features of Di George syndrome

A

22q11.2 deletion syndrome e.g. DiGeorge syndrome

  • 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
143
Q

What is bare-lymphocyte syndrome type 2?

A

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

144
Q

What is the clinical presentation of bare lymphocyte syndrome?

A
  • Unwell by 3 months of age
  • Infections of all types
  • Failure to thrive
  • Family history of early infant death
145
Q

What are some disorder of T cell effector function?

A
  • Cytokine production – IFN
  • Cytokine receptors – IL12 receptor
  • Cytotoxicity
  • T-B cell communication
146
Q

What are the clinical features of lymphocyte deficiencies?

A

T cell deficiency:

– Viral infections
• Cytomegalovirus

– Fungal infection
• Pneumocystis, Cryptosporidium

– Some bacterial infections – esp intracellular organisms
• Mycobacteria tuberculosis, Salmonella

– Early malignancy

147
Q

Which investigations would you do for T cell deficiencies?

A
  • Total white cell count and differential
  • Lymphocyte subsets
  • Immunoglobulins
  • Functional tests of T cell activation and proliferation
  • HIV test
148
Q

How is T cell immunodeficiency managed?

A

• Aggressive prophylaxis/treatment of infection

• Haematopoieitic stem cell transplantation
– To replace abnormal populations in SCID
– To replace abnormal cells - class II deficient APCs in BLS

• Enzymereplacementtherapy – PEG-ADA for ADA SCID

• Genetherapy
– Stem cells treated ex-vivo with viral vectors containing missing components. Transduced cells have survival advantage in vivo.

• Thymic transplantation
– To promote T cell differentiation in Di George syndrome
– Cultured donor thymic tissue transplanted to quadriceps muscle

149
Q

Describe how antigen encounter leads to B cell proliferation

A

1) Dendritic cells prime CD4+ T cells
2) CD4+ T cell help for B cell differentiation required CD40L:CD40
3) B cell proliferation somatic hypermutation - isotype switching to IgG, A , E

150
Q

Describe the structure and function of immunoglobulin

A

Soluble proteins made up of two heavy and two light chains:

– Heavy chain determines the antibody class
• IgM, IgG, IgA, IgE, IgD,
• Subclasses of IgG and IgA also occur

– 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)

151
Q

What is Bruton’s X linked agammaglobulinaemia?

A
  • 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
152
Q

What is the clinical presentation of X linked agammaglobulinaemia?

A

• Boys present in first few years of life
• Recurrent bacterial infections
– Otitis media, sinusitis, pneumonia, osteomyelitis, septic arthritis, gastroenteritis
• Viral, fungal, parasitic infections – Enterovirus, Pneumocystis,
• Failure to thrive

153
Q

What is hyper IgM syndrome?

A
  • 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 IgM
  • Undetectable IgA, IgE, IgG
154
Q

Define what is meant by common variable immune deficiency

A

– Marked reduction in IgG, with low IgA or IgM
– Poor/absent response to immunisation
– Absence of other defined immunodeficiency

155
Q

What are the clinical features of common variable immune deficiency?

A 
– 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

156
Q

Describe the epidemiology of selective IgA deficiency

A

Selective IgA deficiency
Prevalence = 1:600
2/3rd individuals asymptomatic
1/3rd have recurrent respiratory tract infections
Genetic component, but cause as yet unknown

157
Q

What are the clinical features of lymphocyte deficiencies?

A

Antibody deficiency (or CD4 T cell deficiency):

– Bacterial infections
• Staphylococcus, streptococcus
– Toxins
• Tetanus, diptheria
– Some viral infections 
• Enterovirus
158
Q

Which investigations could be done for B cell deficiencies?

A
  • Total white cell count and differential
  • Lymphocyte subsets
  • Serum immunoglobulins and protein electrophoresis
  • Production of IgG is surrogate marker for CD4 T cell helper function
  • Functional tests of B cell function
159
Q

How can immunodeficiency involving B cells be managed?

A

• Aggressive prophylaxis / treatment of infection

• Immunoglobulin replacement if required
– Derived from pooled plasma from thousands of donors
– Contains IgG antibodies to a wide variety of common organisms – aim of maintaining IgG levels within the normal range
– Treatment is life-long

• Immunisation
– For selective IgA deficiency
– Not otherwise effective because of defect in IgG antibody production

160
Q

What is an allograft?

A

A tissue graft from a donor of the same species as the recipient but not genetically identical

161
Q

What are the phases of the immune response transplanted graft?

A

Phase 1: recognition of foreign antigens
Phase 2: activation of antigen-specific lymphocytes
Phase 3: effector phase of graft rejection

162
Q

What are the most relevant factors to look at when finding a suitable donor?

A

Most relevant protein variations in clinical transplantation –

  1. ABO blood group (for ABO-incompatible transplantation)
  2. HLA (human leukocyte antigens)

Some other determinants – minor histocompatibility genes

163
Q

What are the two major components to rejection?

A

Two major components to rejection: – T cell-mediated rejection
– Antibody-mediated rejection (B cells)

164
Q

What is the HLA protein antigen?

A
  • Major Histocompatibility complex (MHC) (chromosome 6) found in humans
  • Cell surface proteins
165
Q

What are the two types of HLA?

A
  • HLA Class I (A,B,C)– expressed on all cells
  • HLA Class II (DR, DQ, DP) – expressed on antigen- presenting cells but also can be upregulated on other cells under stress
166
Q

Why do individuals have a variety of HLA?

A
  • To maximise diversity in defense against infections/neoplasia, each individual has a variety of HLA
  • Each individual’s HLA are derived from a large pool of population varieties
167
Q

What is the maximum number of mismatches in HLA between the recipient and donor?

A

6

168
Q

What are the mismatches between the recipients parent or siblings?

A

Parent to child: ≥3/6 matched
Sibling to sibling: 25% - 6MM
50% - 3MM
25% - 0MM

169
Q

How does HLA disparity cause rejection?

A
  • T-cell mediated

* Antibody-mediated (B cells)

170
Q

What is T-cell mediated rejection?

A

Phase 1 - presentation of donor HLA by a professional antigen presenting cell (APC), in the context of
recipient HLA

Phase 2 – T cell activation, inflammatory cell recruitment

Phase 3 – effector phase (organ damage)

171
Q

How do cytotoxic T cells cause graft damage by immune cells?

A 
– Release of toxins to kill target Granzyme B
– Punch holes in target cells 
Perforin
– Apoptotic cell death
Fas-Ligand
172
Q

What is the antibody-mediated response in rejection?

A

Phase 1 – B cells recognise foreign HLA

Phase 2 - proliferation and maturation of B cells with anti-HLA antibody production

Phase 3 – effector phase; antibodies bind to graft endothelium = intra-vascular disease

173
Q

How do antibodies cause an immune response against a pathogen?

A
  • Neutralisation of microbe and toxins
  • Opsonisation and phagocytosis of microbes
  • Antibody-dependent cellular cytotoxicity
  • Lysis of microbes
  • Phagocytosis of microbes opsonised with complement fragments
  • Inflammation
174
Q

How are anti-HLA antibodies formed?

A

Anti-HLA antibodies are not naturally occurring:
– Pre-formed – transplantation, pregnancy, transfusion
– Post-formed - arise after transplantation

175
Q

How does someone develop anti-A and anti-B antibodies?

A
  • A and B glycoproteins on red blood cells but also endothelial lining of blood vessels in transplanted organ
  • Naturally occurring anti-A and anti-B antibodies
176
Q

Which assays can be used to screen for anti-HLA antibodies?

A

3 types of assay
– Cytotoxicity assays
– Flow cytometry
– Solid phase assays

177
Q

Which antibodies cause antibody-mediated rejection?

A 
Anti-CD20
BAFF inhibitors
Proteosome inhibitors 
Complement inhibitors
CD28/B7 blockade
Anti-CD40
178
Q

How are the different complications of graft rejection treated?

A

Drug toxicity –> reduce dosage
Viral infections –> reduce dosage
Vascular disease –> BP control, vascular stent
Post transplant lymphoproliferative disease –> reduce dosage and start chemo
Recurrent glomerulonephritis –> depends on GN

179
Q

Which immunological processes does allergic disorder normally involve?

A

IgE mediated type 1 hypersensitivity reaction

180
Q

Describe the immune response to pathogens which are microbial compared to allergens/venoms

A

Microbial:
Microbial PAMP -> recognition of microbial structure -> Th1, Th17 immune response

Allergens
Allergen -> recognition by change in function e.g. loss of tissue function/disrupted epithelial barrier -> Th2 immune response

181
Q

What are the functions of innate lymphoid cells?

A

Innate lymphoid cells found at mucosal barriers (skin, respiratory and the gastrointestinal tract) which lack antigen specific receptors

Respond to a number of inflammatory cytokines (IL-33, TSLP, IL-25) IL-1 and IL-12 family cytokines member

CD4 ILC classified into ILC1, ILC2, ILC3, based on their cytokine production and transcriptional profiles with ILC1s, ILC2s, and ILC3s resembling CD4+T helper (Th)1, Th2 and Th17/22 cells, respectively.

182
Q

Which innate lymphoid cell is involved in allergic reactions?

A

ILC2 secrete IL-4, IL-5, IL-9, IL-13 and amphiregulin (AREG)

Secretion of type 2 cytokines by ILC2 implicated in allergic asthma, allergic rhinitis AD, food allergy and eosinophilic oesophagitis

Amphiregulin paly an important role in epithelial barrier repair in skin and respiratory tract
In allergic disease overcome steady state inhibition exerted by tissue CD4 T regulatory cells

183
Q

What are the features and roles of CD4 Th2 cells?

A

Signature cytokines are IL-4, IL-5, IL-13
Helps B cells to produce IgE (IL-4)
Expands and activate eosinophils (IL-5)
Stimulate mucous secretion (IL-13)

Role in host defense against helminths, parasites and tissue repair

Contribute to late stage tissue damage in allergic disease

184
Q

What do CD4 Th2 cells express?

A

Distinct CD4 T subset characterised by expression of the lineage determining transcription factor GATA-3 and the signal transduction protein STAT-6

185
Q

How do eosinophils eliminate pathogens?

A

Eliminate pathogens by secretion of cytotoxic granules, RNAase proteins and extracellular traps

Implicated in late stage tissue damage in atopic dermatitis, asthma, eosinophilic oesophagitis, and granulomatous disease

186
Q

Which key cytokine causes the development and expansion of eosinophils?

A

IL-5

187
Q

What is the function of IgE?

A

IgE function
Protection against helminth and parasitic infection

IgE induces mast and basophil degranulation associated with immediate hypersensitivity (allergic) reactions

188
Q

Which receptors does IgE have?

A

IgE binds to high affinity receptor (FceR1) on mast cells, basophils, eosinophils and DC

IgE also binds to ‘low affinity’ (FceR2) receptor on above cells as well as B cells, respiratory and gastrointestinal epithelial cells

189
Q

What are the 2 subtypes in human mast cells?

A

2 main subtype in human:
MC (Tryptase T) skin
MC (Chymotryptase CT) in airways

190
Q

What are the roles of mast cells?

A

Role in immediate and late phase immune responses to helminths, bacteria

Play an important role in allergic disorders

191
Q

How is mast cell degranulation triggered?

A

1) IgE/IgG receptors which respond to antibody-antigen cross linking
2) G-protein-coupled receptors which are ligands for soluble mediators (complement and drugs)

192
Q

What are the key mast cell receptors?

A

FcReR1(IgE)

FceR1 and FceR1IA (IgG)

MRGPRX2 (opiates, quinolones)

Cytokine receptors (Il-4, IL-9)

193
Q

What does mast cell degranulation lead to?

A

1) Recruitment of soluble proteins and inflammatory cells to site of infection
2) Increase in rate of lymphatic flow back to regional lymph nodes
3) Smooth muscle contraction in lungs and gut (may help to expel pathogens) and activation of sensory neurones (itch, sneeze)

194
Q

What does cross-linking of bound IgE by antigen result in?

A

1) Release of pre-formed inflammatory mediators from granules (histamine)
2) Release and synthesis of lipid mediators (leukotrienes, prostaglandins)
3) Synthesis of proinflammatory cytokines

195
Q

Which factors promote IgR production?

A

Antigen dose

Length of exposure

Physical properties of allergen

Route of exposure

196
Q

Which physical properties of allergic influence IgE production?

A

Source
Small water soluble proteins
Carbohydrate
Resistance to heat, digestive enzymes

197
Q

What are the differences between oral and skin/respiratory exposure to an allergen?

A

Oral exposure promotes immune tolerance (IgA and IgG) whereas skin and respiratory induces IgE sensitisation

198
Q

Summarise the Th2 immune responses in allergic reactions

A

Defects in skin epithelial barrier (atopic dermatitis) are a significant risk factor for development of IgE antibodies.

Stressed or damage epithelial cells secrete IL-25, IL-33, GM-CSF and TSLP which act on tissue immune cells (DC, basophils, type 2 innate lymphoid cells) and neurons to induce Th2 cells immune responses (IL-4, IL-5, IL-9, IL-13)

199
Q

Which cytokine plays a crucial role in Th2 immune response development?

A

IL-4 plays a crucial role in development of Th2 immune responses and is only induced following peptide-MHC presentation to naïve/memory Th2 cells

200
Q

What are the acute and dallied response of Th2?

A

Rapid onset of symptoms within 4 hours caused by release of inflammatory mediators following allergen cross linking of IgE on surface of mast cells and basophils

Delayed symptoms result from CD4T2 cell (IL-4, IL-5, IL-13) immune responses and eosinophil related tissue damage

201
Q

Describe some features of peanut allergy

A

Early oral exposure will protect against development of peanut allergy

Sensitisation to peanut and wheat can occur from exposure through the skin

Differences in preparation of peanuts (roast promotes IgE whereas boiled IgG)

202
Q

How is allergic disease diagnosed?

A

Allergen specific IgE (Sensitisation) Tests - Skin prick and intradermal test, IgE blood tests

Functional allergen tests:

In vitro tests
Basophil activation
Serial mast cell tryptase

Ex vitro tests
Open or blinded allergen challenge

203
Q

What are some clinical features of IgE allergic responses?

A

Occurs within minutes or up to 3-4 hours after exposure to allergen

Skin: angioedema (swelling of lips, tongues, eyelids) , urticaria ( wheals or ‘hives’), flushing and itch

Respiratory tract: cough, SOB wheeze, sneezing, nasal congestion and clear discharge, red itch watery eyes

Gastrointestinal tract: nausea, vomiting and diarrhoea

Blood vessels and Brain: symptoms of hypotension (faint, dizzy, blackout) and a sense of impending doom

204
Q

Describe skin-prick tests

A

A positive test is indicated by a wheal ≥ 3mm greater than the negative control

High positive and negative predictive and positive skin for aeroallergens

Allergen extracts labile for some fruit and vegetables: : prick-prick test: food and SPT

Antihistamines and some anti-depressants should be discontinued for at least 48 hours beforehand

205
Q

Compare intradermal tests to skin-prick tests

A

Application of positive, negative controls and allergens into the skin

More sensitive but less specific than SPT

Best used to follow up negative venom and drug allergy test (better than blood tests)

Can be used if SPT to allergen is negative but convincing history

Labour intensive, greater risks of anaphylaxis

206
Q

What are the 3 types of blood test which IgE can be tested for?

A

3 major providers

1) Phadia
2) Siemens
3) Hycor

All assays have excellent technical performance

207
Q

How can the risk profile be assessed after IgE blood tests?

A

Concentration: higher levels more likely to be associated with symptoms

Molecular target within whole extract or even individual epitope can be linked to symptoms

Affinity (strength of binding) to target: higher affinity associated with risk

Capacity of IgE antibody to induce mast/basophil degranulation

208
Q

What are the indications for blood sensitisation tests?

A

No access to SPT and/or IDT

Patients who can’t stop anti-histamines

Patients with a history of dermatographism, extensive eczema

Patient with a history of anaphylaxis

Decision on who needs food challenge

Prediction for resolution of egg, milk, wheat allergy

Monitor response to anti-IgE therapy

209
Q

What are the food components allergen tests?

A

Nuts - Storage proteins (2 s albumins): severe reactions

Pathogenesis-related proteins (PR10 bet v1 homologue) which are also found in tree pollens, fruits and vegetables: mild reaction

Non specific lipid transfer proteins which are also found in in fruit (peach) , tree pollen (plane), vegetables and legumes ( can be mild or severe)

Wheat
Omega-5-gliadin bettermarker of specific wheat allergy than total wheat IgE

Egg and milk
Heat stable proteins ovomucoid (egg) and caseins (estimate who outgrow allergy)

Fish and shellfish
Parvalbumin in fish, Tropomyosin in crustaceans (cross reactive)

210
Q

What is mast cell tryptase measurement used for?

A

A biomarker for anaphylaxis:

Tryptase: pre-formed protein found in mast cell granules

Systemic degranulation of mast cells during anaphylaxis results in increase in serum tryptase

Peak concentration at 1-2 hours; returns to baseline by 6-12 hours

Failure to return to baseline after anaphylaxis may be indicative of systemic mastocytosis

Useful if diagnosis of anaphylaxis is not clear (hypotension + rash during anaesthesia)

Reduced sensitivity for food induced anaphylaxis

211
Q

What is the basophil activation test?

A

Measurement of basophil response to allergen IgE cross linking

Activated basophils increase the expression of CD63, CD203, CD300 protein on cell surface

Increasing use in diagnosis of food and drug allergy: surrogate marker for challenge tests

Efforts to standardise test to use by diagnostic laboratories to reduce need for challenge tests

212
Q

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

A

Challenge tests

213
Q

What is oral allergy syndrome?

A

Limited to oral cavity, swelling and itch: only 1-2% cases progresses to anaphylaxis

214
Q

What are examples of damage to the host caused by the immune response?

A

Fevers / malaise seen in primary EBV

Abscess formation

Sacroiliac joint inflammation in an individual with axial spondyloarthritis

Anaemia due to red cell haemolysis secondary to anti-red cell antibodies

215
Q

What are auto-inflammatory diseases?

A

Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage (innate)

216
Q

How can autoimmune diseases manifest in the immune system?

A

Aberrant T cell and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens

Organ-specific antibodies may predate clinical
disease by years

Adaptive immune response plays the
predominant role in clinical expression of disease

217
Q

Which ones are monogenic or polygenic?

  • auto-inflammatory
  • mixed
  • auto-immune
A

Auto-inflammatory - monogenic + polygenic

Mixed - polygenic

Auto-immune - monogenic + polygenic

218
Q

What is a somatic mutation?

A

An alteration in DNA that occurs after conception.

219
Q

Are these diseases innate or adaptive?

  • auto-inflammatory
  • mixed
  • auto-immune
A

Auto-inflammatory - innate

Mixed - mixed innate/adaptive

Auto-immune - adaptive

220
Q

What are common monogenic mutations which cause auto-inflammatory diseases?

A

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

Abnormal signalling via key cytokine pathways involving TNF-alpha and/or IL-1 is common

221
Q

How do monogenic auto-inflammatory diseases classically present?

A

Periodic fevers

Skin/joint/serosal/CNS inflammation

High CRP

222
Q

List 4 examples of monogenic auto-inflammatory diseases

A

Muckle Wells Syndrome MWS

Familial mediterranean fever FMF

TNF receptor associated periodic syndrome TRAPS

Hyper IgD with periodic fever syndrome HIDS

223
Q

What is the inflammasome complex in monogenic auto-inflammatory diseases?

A

The inflammasome is a multiprotein intracellular complex that detects pathogenic microorganisms and sterile stressors, and that activates the highly pro-inflammatory cytokines interleukin-1b (IL-1b) and IL-18. Inflammasomes also induce a form of cell death termed pyroptosis.

224
Q

Describe the pathogenesis of familial Mediterranean fever

A

Autosomal recessive condition
Mutation in MEFV gene
MEFV gene encodes pyrin-marenostrin
Pyrin-marenostrin expressed mainly in neutrophils
Failure to regulate cryopyrin driven activation of neutrophils

225
Q

Describe the clinical presentation of Familial Mediterranean Fever

A

Periodic fevers lasting 48-96 hours associated with:
Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis
Rash

226
Q

What are some complications of Familial Mediterranean Fever?

A

AA amyloidosis - liver produces serum amyloid A as acute phase protein
Serum amyloid A deposits in kidneys, liver, spleen
Nephrotic syndrome

227
Q

How would you diagnose Familial Mediterranean Fever?

A

High CRP, high SAA

Blood sample to specialist genetics laboratory to identify MEFV mutation

228
Q

How is Familial Mediterranean Fever treated?

A

Colchicine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion

IL-1 blocker (anakinra, canukinumab)

TNF alpha blocker

229
Q

Describe the types of mutation which occur in monogenic auto-immune disease

A

Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function

Abnormality of regulatory T cells - IPEX

Abnormality of lymphocyte apoptosis - ALPS

230
Q

What does IPEX stand for?

A

Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndromeI

231
Q

Which mutations occur in IPEX?

A

Mutations in Foxp3 transcription factor (Forkhead box p3) which is required for development of Treg cells

Failure to negatively regulate T cell responses
Autoreactive B cells limited repertoire of autoreactive B cells

232
Q

Which autoimmune conditions can patients with IPEX develop?

A

Diabetes Mellitus
Hypothyroidism
Enteropathy

233
Q

What is the pathogenesis autoimmune lymphoproliferative syndrome (ALPS)?

A

Mutations within FAS pathway
Eg mutations in TNFRSF6 which encodes FAS
Disease is heterogeneous depending on the mutation

Defect in apoptosis of lymphocytes
Failure of tolerance
Failure of lymphocyte ‘homeostasis’

234
Q

What are the clinical findings in those with autoimmune lymphoproliferative syndrome (ALPS)?

A

High lymphocyte numbers with large spleen and lymph nodes

Auto-immune disease - commonly auto-immune cytopenias

Lymphoma

235
Q

Describe the features of polygenic auto-inflammatory diseases

A

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

Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage

HLA associations are usually less strong

In general these disease are not characterised by presence of auto-antibodies

Familial association studies and twin studies suggested genetic predisposition to disease

236
Q

Describe the polygenic component of autoinflammatory Crohn’s disease

A

NOD2 gene mutations are present in 30% patients (ie not necessary)

IBD1 gene on chromosome 16 identified as NOD2 (CARD-15, caspase activating recruitment domain -15)

NOD2 expressed in cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells

Intracellular receptor for muramyl dipeptide on bacterial products and promotes their clearance

Mutations also found in patients with Blau syndrome and some forms of sarcoidosis

237
Q

Describe the type of inflammation found in Crohn’s disease

A 
Expression of pro-inflammatory cytokines/chemokines
Leukocyte recruitment
Release of proteases, free radicals
Focal inflammation in/around crypts
Formation of granulomata
Tissue damage with mucosal ulceration
238
Q

How is Crohn’s disease treated?

A

Corticosteroid

Anti-TNF alpha antibody

239
Q

Describe what is meant by mixed pattern disease

A

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

HLA associations may be present

Auto-antibodies are not usually a feature

240
Q

Describe the features of axial spondyloarthritis

A

Highly heritable - 90% of the risk of developing disease is genetic

Enhanced inflammation occurs at specific sites where there are high tensile forces
(entheses - sites of insertions of ligaments or tendons)

Low back pain and stiffness
Enthesitis
Large joint arthritis

240
Q

Describe the features of axial spondyloarthritis

A

Highly heritable - 90% of the risk of developing disease is genetic

Enhanced inflammation occurs at specific sites where there are high tensile forces
(entheses - sites of insertions of ligaments or tendons)

Low back pain and stiffness
Enthesitis
Large joint arthritis

241
Q

Describe the genetic predisposition of axial spondyloarthritis

A

HLA B27 - Presents antigen to CD8 T cells. Ligand for killer immunoglobulin receptor

IL23R - Receptor for IL23 which promotes differentiation of Th17 cells

ILR2 - Decoy receptor that inhibits activity of IL1

242
Q

How can axial spondyloarthritis be treated?

A

Non-steroidal anti-inflammatory drugs

Immunosuppression
Anti-TNF alpha
Anti-IL17

243
Q

Describe the features of polygenic auto-immune disease

A

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

HLA associations are common

Aberrant B cell and T cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens

Auto-antibodies are found

244
Q

What are the genetic polymorphisms of T cell activation in polygenic autoimmune disease?

A

PTPN 22 - Protein tyrosine phosphatase non-receptor 22 suppresses T cell activation - found in SLE, T1DM, RA

CTLA4 - Cytotoxic T lymphocyte associated protein 4
Expressed by T cells and transmits inhibitory signal to control T cell activation - found in SLE, T1DM, RA, autoimmune thyroid disease

245
Q

What are the HLA associations for the following diseases?

Goodpasture disease
Graves disease
Systemic lupus erythematosus
Type I diabetes
Rheumatoid arthritis
A 
Goodpasture disease - HLA-DR3 - 10x risk
Graves disease - HLA-DR3 - 4x risk
Systemic lupus erythematosus - HLA-DR3 - 6x risk
Type I diabetes - HLA-DR3/4 - 25x risk
Rheumatoid arthritis - HLA-DR4 - 4x risk
246
Q

What is the Gel and Coombs classification of hypersensitivity?

A

Type I: Anaphylactic hypersensitivity
- Immediate hypersensitivity which is IgE mediated – rarely self antigen

Type II: Cytotoxic hypersensitivity
- Antibody reacts with cellular antigen

Type III: Immune complex hypersensitivity
- Antibody reacts with soluble antigen to form an immune complex

Type IV: Delayed type hypersensitivity
- T-cell mediated response

247
Q

How are immunopathogenic mechanisms in type II disease coordinated?

A

1) Antibody dependent destruction (NK cells, phagocytes, complement)
2) Receptor activation or blockage (sometimes

247
Q

How are immunopathogenic mechanisms in type II disease coordinated?

A

Autoantibodies can bind to receptors and cause:

1) Antibody dependent destruction (NK cells, phagocytes, complement)
2) Receptor activation or blockage (sometimes called type V reaction)

248
Q

List 4 diseases of type II antibody driven autoimmune disease

A

Goodpasture disease
Pemphigus vulgaris
Graves disease
Myaesthenia gravis

249
Q

What is the auto-antigen and symptoms of the following type II diseases?

Goodpasture disease
Pemphigus vulgaris
Graves disease
Myaesthenia gravis

A

Goodpasture disease - Noncollagenous domain of basement membrane collagen type IV - glomerulonephritis, pulmonary haemorrhage

Pemphigus vulgaris - Epidermal cadherin - skin blistering

Graves disease - Thyroid stimulating hormone (TSH) receptor - hyperthyroid

Myaesthenia gravis - acetylcholine receptor - muscle weakness

250
Q

How do type III reactions cause damage to small vessels?

A

1) Immune complex formation and deposition in blood vessels
2) Complement activation and infiltration of macrophages and neutrophils
3) Cytokine and chemokine expression, granule release from neutrophils, increased vascular permeability
4) Inflammation and damage to vessels, cutaneous vasculitis, glomerulonephritis, arthritis

251
Q

What is the auto antigen in SLE as a type III immune complex driven autoimmune disease?

A

DNA, Histones, RNP

Presents as rash, glomerulonephritis, arthritis

252
Q

Describe what occurs in type IV hypersensitivity reactions in autoimmunity CD8 T-cells

A

1) HLA class I molecules present antigen to CD8 T cells
2) Cytolytic granule release from primed CD8 T cell
3) TNF induction, HLA upregulated, inflammation, tissue damage

253
Q

Give one example of a type 4 T cell mediated disease and the autoantigen involved

A

Insulin dependent diabetes mellitus - pancreatic beta-cell antigen, beta-cell destruction: CD8+ T-cells

254
Q

Describe the pathophysiology of Graves disease

A

Excessive production of thyroid hormones

Mediated by IgG antibodies which stimulate the TSH receptor - agonist so triggers TSH production

255
Q

What is the pathophysiology of Hashimoto thyroiditis?

A

Commonest cause of hypothyroidism in iodine-replete areas
Goitre – enlarged thyroid infiltrated by T and B cells
Associated with anti-thyroid peroxidase antibodies
Some shown to induce damage to thyrocytes
Associated with presence of anti-thyroglobulin antibodies

256
Q

Describe the clinical usefulness of anti-thyroglobulin and anti-thyroid peroxidase antibodies?

A
  • Many women >65 have anti-thyroid antibodies
  • Some postmenopausal women with anti-thyroid antibodies have subclinical hypothyroidism
  • Small proportion of postmenopausal women with anti-thyroid antibodies have overt hypothyroidism
257
Q

Which cells attack the pancreas in T1DM?

A

CD8 T-cell mediated type IV pathology – recognise autoantigens presented by
MHC Class I molecules on beta cells

258
Q

Which antibodies are found in T1DM?

A

Anti-islet cell antibodies
Anti-insulin antibodies
Anti-GAD antibodies
Anti-IA-2 antibodies

258
Q

Which antibodies are found in T1DM?

A

Anti-islet cell antibodies
Anti-insulin antibodies
Anti-GAD antibodies
Anti-IA-2 antibodies

Individuals with 3-4 of the above are highly likely
to develop type I diabetes

259
Q

Describe the pathophysiology of pernicious anaemia

A

Antibodies against gastric parietal cells which secrete intrinsic factor, or antibodies against intrinsic factor itself. Intrinsic factor not able to absorb B12 as well - B12 deficiency.

260
Q

What is the autoantibody for each disease?

Pernicious anaemia
Coeliac
UC>Crohn's
Autoimmune hepatitis 
Primary biliary cholangitis
A

Pernicious anaemia - Anti-intrinsic factor antibody, Anti-gastric parietal cell antibody

Coeliac - Anti-TTG (anti-tissue transglutaminase antibody), Anti-endomyosial antibody

UC>Crohn’s - P-ANCA (anti-neutrophil cytoplasmic antibody, perinuclear staining)

Autoimmune hepatitis - P-ANCA (anti-neutrophil cytoplasmic antibody, perinuclear staining), ANA (anti-nuclear antibodies)
SMA (smooth muscle antibodies)
Anti-LKM (antibodies vs liver kidney microsomal proteins)

Primary biliary cholangitis - AMA (anti-mitochondrial antibody
P-ANCA (anti-neutrophil cytoplasmic antibody, perinuclear staining), ANA (anti-nuclear antibodies)

261
Q

How can auto-antibodies be detected in the kidneys for Goodpasture’s syndrome?

A

Fluorescein conjugated polyclonal anti-human immunoglobulin

UV source - fluorescence microscope

262
Q

Which antibodies would you find in the following diseases?
Myasthenia Gravis
Neuromyelitis optica spectrum disorder (NMOS)
Optic neuritis, encephalomyelitis
Encephalitis (may be malignancy associated)
Seizures (may be malignancy associated)

A

Myaesthenia Gravis - AChR antibody

Myaesthenia Gravis with myositis - Anti-striational antibody

Neuromyelitis optica spectrum disorder (NMOS) - Anti-AQP4 (aquaporin)

Optic neuritis, encephalomyelitis - Anti-MOG (myelin oligodendrocyte glycoprotein)

Encephalitis (may be malignancy associated) - Anti-NMDA receptor(Anti-N-methyl D-aspartate (NMDA) receptor)

Seizures (may be malignancy associated) - Anti-GABA receptor (gamma aminobutyric acid receptor)

263
Q

Which antibodies would you find in the following renal diseases?

A

Goodpasture disease - Anti-glomerular basement membrane (GBM) antibody

ANCA associated vasculitis - Microscopic polyangiitis / Eosinophilic granulomatosis with polyangiitis - P-ANCA (anti neutrophil cytoplasmic antibody, perinuclear staining, anti-myeloperoxidase)

ANCA associated vasculitis - Granulomatosis with polyangiitis - C-ANCA (anti-neutrophil cytoplasmic antibody, cytoplasmic staining, anti-proteinase 3)

264
Q

Describe the genetic predisposition of rheumatoid arthritis

A

HLA DR4 (DRB1 0401, 0404, 0405) and HLA DR1 (DRB1 0101) alleles
- Susceptible alleles share a sequence at positions 70-74 of the HLA DR beta chain
These alleles may bind ‘arthritogenic peptides’ and have been shown to bind to citrullinated peptides with high affinity

Peptidyl arginine deiminase (PAD)2 and PAD4 polymorphisms
- Polymorphisms are associated with increased citrullination
This creates a high load of citrullinated proteins

PTPN22 polymorphism

265
Q

Which environmental factors affect rheumatoid arthritis development?

A

Smoking associated with development of erosive disease
Smoking associated with increased citrullination

Gum infection with Porphyromonas gingivalis associated with rheumatoid arthritis
P gingivalis is only bacterium known to express PAD enzyme and thus promote citrullination

266
Q

Which antibody detection gives the highest specificity when it comes to diagnosing rheumatoid arthritis?

A

Antibodies to cyclic citrullinated peptide
Bind to peptides in which arginine has been converted to citrulline by peptidylarginine deiminase (PAD)
Around 95% specificity for diagnosis of rheumatoid arthritis
Around 60-70% sensitivity for diagnosis of rheumatoid arthritis

267
Q

What is rheumatoid factor?

A

A rheumatoid factor is an antibody directed against the common (Fc) region of human IgG

IgM anti-IgG antibody is most commonly tested although IgA and IgG rheumatoid factors may also be present in some individuals

Around 60-70% specificity and sensitivity for diagnosis of rheumatoid arthritis

268
Q

How can anti-nuclear antibodies be tested for?

A

Group of antibodies that bind to nuclear proteins

Test by staining of Hep-2 cells (human epidermoid cancer line)

269
Q

What is the genetic predisposition of SLE?

A

Abnormalities in clearance of apoptotic cells
- Polymyorphisms in genes encoding complement, MBL, CRP

Abnormalities in cellular activation
- Polymorphisms in genes expressing of cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules

B cell hyperactivity and loss of tolerance

Antibodies directed at intracellular proteins
? Debris from apoptotic cells that have not been cleared
Nuclear antigens - DNA, histones, snRNP
Cytoplasmic antigens - Ribosome, scRNP

270
Q

Describe the progression of SLE form antigen binding to immune complex deposition

A

Antibodies bind to antigen to form immune complexes

Immune complexes deposit in tissues
Skin, joints, kidney

Immune complexes activate complement (classical pathway)

Immune complexes stimulate cells expressing Fc and complement receptors

271
Q

What is the difference between Lupus nephritis and Goodpasture’s disease?

A

LN - type III - immune complexes deposit in basement membrane

Goodpasture’s disease - type II - antibody specific for the basement membrane (rather than immune complexes) deposit

272
Q

What are the targets of anti-nuclear antibodies?

A

dsDNA

Ro, La, Sm, U1RNP
- Ribonucleoproteins

SCL70
- Topoisomerase

Centromere

273
Q

What would you see using ELISA-based assay to investigate for anti-nuclear antibodies?

A

Homogeneous staining associated with specificity for dsDNA

274
Q

How good are measurements of anti-dsDNA antibodies in the diagnosis of SLE?

A

Are highly specific for SLE (95%)

  • Occur in ~60-70% of SLE patients
  • Very high titres = more severe disease including renal or CNS
  • Useful in disease monitoring

False positive results unusual (<3%)

275
Q

What is a speckled antibody?

A

Associated with antibodies to extractable nuclear antigens

Specificity is for some ribonucleoproteins (Ro, La, Sm, U1RNP) – confirm with ELISA

276
Q

What are examples of anti-ENA antibodies?

A

Ro, La, Sm, RNP (all are ribonucleoproteins)

  • Antibodies may occur in SLE
  • Anti-Ro and La are also characteristically found in Sjogren’s syndrome
  • Titres not helpful in monitoring disease
277
Q

How is the complement pathway activated in SLE?

A

Formation of antibody-antigen immune complexes
activate complement cascade via classical pathway
complement components become depleted if constantly consumed

Quantitation of C3 and C4 acts as a surrogate marker of disease activity

278
Q

What is the complement profile in SLE?

A

Inactive disease - normal C3, C4
Active disease - normal C3, low C4
Severe active disease - low C3, C4

279
Q

What is anti-phospholipid syndrome?

A

Recurrent venous or arterial thrombosis

Recurrent miscarriage

May be associated with livedo reticularis, cardiac valve disease

May occur alone (primary) or in conjunction with autoimmune disease (secondary)

280
Q

Which three antibodies would you test for in anti-phospholipid syndrome?

A

Three antibody tests:

1) Lupus anti-coagulant
Cannot be assessed if the patient is on anticoagulant therapy

2) Anti-cardiolipin antibody
Antibody specific for negatively charged phospholipids

3) Anti-B2 glycoprotein 1 antibody
Antibody specific for glycoprotein found associated with negatively charged phospholipids

281
Q

What is limited cutaneous systemic sclerosis (CREST)?

A 
Calcinosis
Raynauds
Esophageal dysmotility
Sclerodactyly 
Telangiectasia
282
Q

What is diffuse cutaneous systemic sclerosis?

A

Skin involvement does progress beyond forearms

  • CREST features
  • More extensive gastrointestinal disease
  • Interstitial pulmonary disease
  • Scleroderma kidney/renal crisis
283
Q

What is the difference observed in ANA staging in limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis?

A

Limited cutaneous systemic sclerosis:
Anti-centromere antibodies

Diffuse cutaneous systemic sclerosis:
Nucleolar pattern
Anti-topoisomerase antibodies (Scl70)
RNA polymerase
Fibrillarin
284
Q

What are the two types of idiopathic inflammatory myopathy?

A

Dermatomyositis
Within muscle – perivascular CD4 T cells and B cells
Immune complex mediated vasculitis

Polymositis
Within muscle – CD8 T cells surround HLA Class I expressing myofibres
CD8 T cells kill myofibres via perforin/granzymes

285
Q

What would you observe in idiopathic inflammatory myopathy?

A 
Positive ANA (in some patients) 
– extended myositis panel

1) Anti-aminoacyl transfer RNA synthetase antibody eg Jo-1 (cytoplasmic)
2) Anti-signal recognition peptide antibody (nuclear and cytoplasmic) (PM)
3) Anti-Mi2 (nuclear) (DM>PM)

286
Q

What are the three types of small vessel vasculitis associated with ANCA?

A

Small vessel vasculitis associated with ANCA – 3 types:

Microscopic polyangiitis/Microscopic polyarteritis/MPA

Granulomatosis with polyangiitis/Wegener’s granulomatosis/GPA

Eosinophilic granulomatosis with polyangiitis/Churg-Strauss syndrome/eGPA

287
Q

What are anti-neutrophil cytoplasmic antibodies?

A

Antibodies specific for antigens located in primary granules within cytoplasm of neutrophils

Inflammation may lead to expression of antigens on cell surface of neutrophils

Antibody engagement with cell surface antigens may lead to neutrophil activation (type II hypersensitivity)

Activated neutrophils interact with endothelial cells causing damage to vessels - vasculitis

288
Q

When do you get cANCA antibodies and pANCA antibodies?

A

cANCA
Cytoplasmic fluorescence
Associated with antibodies to enzyme proteinase 3
Occurs in > 90% of patients with granulomatous polyangiitis with renal involvement

p-ANCA
Perinuclear staining pattern
Associated with antibodies to myeloperoxidase
Less sensitive and specific than cANCA
Associated with microscopic polyangiitis and eosinophilic granulomatous polyangiitis

288
Q

When do you get cANCA antibodies and pANCA antibodies?

A

cANCA
Cytoplasmic fluorescence
Associated with antibodies to enzyme proteinase 3
Occurs in > 90% of patients with granulomatous polyangiitis with renal involvement

p-ANCA
Perinuclear staining pattern
Associated with antibodies to myeloperoxidase
Less sensitive and specific than cANCA
Associated with microscopic polyangiitis and eosinophilic granulomatous polyangiitis

289
Q

Is autoimmunity a feature of innate or adaptive immunity?

A

Adaptive immunity

290
Q

List all the antigen presenting cells in the body

A

Dendritic cell
Macrophage
B lymphocyte

(Macrophages include Langerhans cells, mesangial cells, Kupffer cells, osteoclasts, microglia etc.)

291
Q

What happens after T and B cells are exposed to the antigen?

A

Clonal expansion following exposure to antigen:

T cells with appropriate specificity -> proliferate and differentiate into effector cells (cytokine secreting, cytotoxic)

B cells with appropriate specificity will proliferate and differentiate to T cell independent (IgM) (memory and) plasma cells undergo germinal centre reaction and differentiate to T cell dependent IgG/A/E(M) memory and plasma cells

Plasma cells secrete high affinity specific antibodies

Immunological memory:

Pre-formed pool of high affinity specific antibodies

Residual pool of specific T and B cells with enhanced capacity to respond if re-infection occurs

292
Q

What happens to the number of CD8+ and CD4+ cells after EBV infectious mononucleosis?

A

CD8+ and CD4+ cell level drop - but there’s still a detectable level in the blood

293
Q

Describe some of the features of T cell memory

A

Longevity
Memory T cells are maintained for a long time without antigen by continual low-level proliferation in response to cytokines

Different pattern of expression of cell surface proteins involved in chemotaxis / cell adhesion
These allow memory cells to access non-lymphoid tissues, the sites of microbial entry.

Rapid, robust response to subsequent antigen exposure
There are more memory cells
These cells are more easily activated than naïve cells

294
Q

Describe some features of B cell memory

A

Pre-formed antibody
Circulating high affinity IgG antibodies

Longevity
Long lived memory B cells and plasma cells

Rapid, robust response to subsequent antigen exposure
Memory B cells are more easily and rapidly activated than naïve cells

295
Q

What would make an ideal vaccine?

A

MEMORY – preformed antibodies, memory T cells, memory B cells, to provide protective immunity

No adverse reactions

Practical considerations – one shot, easy storage, inexpensive

296
Q

Which response in the body protects humans against further influenza infections?

A

Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity - neutralising antibodies

297
Q

Name some features of the BCG vaccine

A

BCG – bacilli Calmette-Guerin:

Attenuated, strain of bovine tuberculosis
Some protection against primary infection
Some protection against progression to active TB
T cell response is important in protection

298
Q

What is a live attenuated vaccine?

A

Live organism

Modified, (attenuated) organism to limit pathogenesis

299
Q

Name some examples of live attenuated vaccines

A

MMR

BCG

Yellow fever

Typhoid (oral)

Polio (Sabin oral)

Influenza (Fluenz tetra for children 2-17 years)

300
Q

What are the advantages and disadvantages of live attenuated vaccines?

A
  • Raises immune response - protect against strains
  • Activates all phases of immune system. T cells, B cells – with local IgA, humoral IgG
  • May confer lifelong immunity, sometimes just after one dose
301
Q

What are some problems with live attenuated vaccines?

A

Possible reversion to virulence (recombination, mutation).
Vaccine associated paralytic poliomyelitis (VAPP, ca. 1: 750,000 recipients)

Spread to contacts
Spread to immunosuppressed/immunodeficient patients

Storage problems

302
Q

What are the ways of modifying inactivated vaccines to enhance immunogenicity?

A
  • Conjugate to protein carrier

- Adjuvant

303
Q

What are some methods of conjugating vaccines and name some examples of conjugated vaccines?

A

Enhances T cell immunity:

Polysaccharide plus protein carrier
Polysaccharide alone induces a T cell independent B cell response – transient
Addition of protein carrier promotes T cell immunity which enhances the B cell/antibody response

Haemophilus Influenzae B
Meningococcus
Pneumococcus (Prevenar)

304
Q

How does the addition of an adjuvant to a vaccine improve the response?

A

Adjuvant increases the immune response without altering its specificity - improved innate response
Mimic action of PAMPs (pathogen associated molecular patterns) on TLR (toll-like receptors) and other PRR (pattern recognition receptors)

Aluminium salts (humans)
Lipids – monophosphoryl lipid A (humans HPV)
Oils -Freund’s adjuvant (animals)

305
Q

What are two examples of COVID vaccines?

A

1) mRNA - covid virus has spike proteins which bind to ACE2 = infection - spike proteins expressed on T cells
2) Adenoviral vector vaccines - DNA inserted into vector (Sputnik vaccine vector) –> translation

306
Q

What is a dendritic cell vaccine?

A

Acquired defects in DC maturation and function associated with some malignancy suggests a rationale for using ex vivo–generated DC pulsed with tumour antigens as vaccines

Focus on tumour associated antigens or mutational antigens

307
Q

What are the advantages of dendritic cell vaccines?

A

e.g. Sipuleucel-TProvenge

Personalised therapy after white cells removed and exposure to antigen, then infused into patient

308
Q

When is immunoglobulin infused/antibody replacement therapy used?

A

Primary antibody deficiency:
X linked agammaglobulinaemia
X linked hyper IgM syndrome
Common variable immune deficiency

Secondary antibody deficiency:
Haematological malignancies
Chronic lymphocytic leukaemia
Multiple myeloma
After bone marrow transplantation
309
Q

What are some specific examples of when an antibody infusion is required?

A
  • Hepatitis B immunoglobulin – needle stick/bite/sexual contact – from HepBSag+ve individual
  • Rabies immunoglobulin – to bite site following potential rabies exposure
  • Varicella Zoster immunoglobulin – women <20 weeks pregnancy or immunosuppressed where aciclovir or valaciclovir is contraindicated
  • Tetanus immunoglobulin – no specific preparation available in UK – use IVIG for suspected tetanus
310
Q

What is adoptive cell transfer?

A

T cells transferred after they have been removed, exposed to antigen, then reinserted:

Virus specific T cells

Tumour infiltrating T cells (TIL – T cell therapy)

T cell receptor T cells (TCR - T cell therapy)

Chimeric antigen receptor T cells (CAR – T cell therapy)

311
Q

When is chimeric antigen receptor T cell therapy used?

A

T cells with chimeric receptors targeting CD19
Patient’s own T cells
Genetically engineered to express receptor
Expanded in vitro

Used for acute lymphoblastic leukaemia in children
Used for some forms of non-Hodgkin lymphoma

312
Q

How does ipilimumab work?

A

T cells (CD28, CTLA4) and APC (CD80, CD86) interaction:

Ipilimumab antibody binds to CTLA4 and blocks immune checkpoint, allowing T cell activation

313
Q

What are the advantages and disadvantages of using immune checkpoint therapy like ipilimumab?

A

Very effective in conditions like metastatic melanoma

Can cause autoimmunity because of the interference in checkpoint

314
Q

Name two drugs which block immune checkpoints specific for PD-1

A

Pembrolizumab and Nivolumab

315
Q

How do PD-1 targets block the immune checkpoint?

A

Antibody binds to PD-1 on T cell interacting with PD-ligand 1 and 2 on APC
Blocks immune checkpoint
Allows T cell activation

316
Q

When are drugs containing antibodies specific for PD-1 used?

A

Advanced melanoma

Metastatic renal cell cancer

317
Q

Name 4 examples of recombinant cytokines used in the treatment of disease

A

Interleukin 2 – stimulate T cell response
Renal cell cancer

Interferon alpha 2a – immunomodulatory effect
Behcet’s

Interferon alpha – antiviral effect
Hepatitis B
Hepatitis C (with ribavirin)

Interferon gamma – enhance macrophage function
Chronic granulomatous disease

318
Q

How do corticosteroids reduce inflammation?

A

Phospholipase A2 - Breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (e.g. prostaglandins, leukotrienes) by cyclo-oxygenases

Corticosteroids inhibit phospholipase A2 - Blocks arachidonic acid and prostaglandin formation and so reduces inflammation

319
Q

How do corticosteroids affect phagocytes?

A

1) Decreased traffic of phagocytes to inflamed tissue Decreased expression of adhesion molecules on endothelium
Blocks the signals that tell immune cells to move from bloodstream and into tissues
Results in transient increase in neutrophil counts

2) Decreased phagocytosis
3) Decreased release of proteolytic enzymes

320
Q

How do corticosteroids affect lymphocyte function?

A

Lymphopenia
Sequestration of lymphocytes in lymphoid tissue
Affects CD4+ T cells > CD8+ T cells > B cells

Blocks cytokine gene expression

Decreased antibody production

Promotes apoptosis

321
Q

Name 3 cytotoxic agents which are anti-proliferative immunosuppressants

A
  • Cyclophosphamide
  • Mycophenolate
  • Azathioprine
322
Q

How do cytotoxic agents like azathioprine work?

A

Action

  • Inhibit DNA synthesis
  • Cells with rapid turnover most sensitive

Toxicity

  • Bone marrow suppression
  • Infection
  • Malignancy
  • Teratogenic
323
Q

Name the side effects of cyclophosphamide

A

Toxic to proliferating cells
Bone marrow depression
Hair loss
Sterility (male»female)

Haemorrhagic cystitis
Toxic metabolite acrolein excreted via urine

Malignancy
Bladder cancer
Haematological malignancies
Non-melanoma skin cancer

Infection
Pneumocystis jiroveci

324
Q

Name the side effects of azathioprine

A

Bone marrow suppression
Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
1:300 individuals are extremely susceptible to bone marrow suppression
Thiopurine methyltransferase (TPMT) polymorphisms
Unable to metabolise azathioprine
Check TPMT activity or gene variants before treatment if possible; always check full blood count after starting therapy

Hepatotoxicity
Idiosyncratic and uncommon

Infection
Serious infection less common than with cyclophosphamide

325
Q

What are the side effects of mycophenolate mofetil?

A

Bone marrow suppression Infection

Cells with rapid turnover (leucocytes and platelets) are particularly sensitive

Infection

Particular risk of herpes virus reactivation

Progressive multifocal leukoencephalopathy (JC virus)

326
Q

What are three examples of severe antibody mediated disease?

A

Goodpasture syndrome

Severe acute myasthenia gravis

Antibody mediated transplant rejection/ABO incompatible

327
Q

What are examples of calcineurin inhibitors?

A

Inhibit T cell proliferation/function and prevents upregulation of IL-2

Used in:
Transplantation
SLE
Psoriatic arthritis

328
Q

How does a mTOR inhibitor e.g. rapamycin work?

A

Inhibit T cell proliferation and function

Used in:
Transplantation

329
Q

What are Jakinibs?

A

Inhibitors of cell signallingJAK inhibitors

Inhibit JAK-STAT signalling (associated with cytokine receptors)

Influences gene transcription
Inhibits production of inflammatory molecules

Effective in Rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis

330
Q

Give an example of a PDE4 inhibitor and describe how it works

A

Apremilast

Inhibition of PDE4 leads
to increase in cAMP

Influences gene transcription
via protein kinase A pathway

Modulates cytokine production

Effective in psoriasis and
psoriatic arthritis

331
Q

Name 5 agents which are directed at cell surface antigens in the immune system and their actions

A 
Drugs 
T cells:
Rabbit anti-thymocyte globulin 
Basiliximab – anti-CD25
Abatacept – CTLA4-Ig

B cells
Rituximab – anti-CD20

Lymphocyte migration
Vedolizumab – anti-a4b7 integrin

Actions include

  • Block signalling
  • Cell depletion
  • Inhibit migration
332
Q

What is anti-thymocyte globulin?

A

Indications and dosing

  • Allograft rejection (renal, heart)
  • Daily intravenous infusion

Action – multiple modes

  • Lymphocyte depletion
  • Modulation of T cell activation
  • Modulation of T cell migration

Toxicity

  • Infusion reactions
  • Leukopenia
  • Infection
  • Malignancy
333
Q

What is the target of Basiliximab and what does it target?

A

Antibody directed at CD25 (IL-2Ra chain)

Indications and dosing
Prophylaxis of allograft rejection
Intravenous given before and after transplant surgery

Action
Blocks IL-2 induced signalling and inhibits T cell proliferation

Toxicity
Infusion reactions
- Infection
- Concern re long term risk malignancy

334
Q

What is Abatacept?

A

CTLA4–Ig fusion protein

Indications and dosing:

  • Rheumatoid arthritis
  • Intravenous 4 weekly
  • Subcutaneous weekly

Action
- Reduces costimulation of
T cells via CD28

Toxicity

  • Infusion reactions
  • Infection (TB, HBV, HCV)
  • Caution wrt malignancy
335
Q

What is Rituximab?

A

Antibody specific for CD20

Indications and dose

  • Lymphoma
  • Rheumatoid arthritis
  • SLE
  • 2 doses intravenous every 6-12 months (RA)

Action
- Depletes mature B cells

Toxicity

  • Infusion reactions
  • Infection (PML)
  • Exacerbation CV disease
336
Q

What is Vedolizumab?

A

Antibody specific for a4b7 integrin

Indications and dosing

  • Inflammatory bowel disease
  • Intravenous every 8 weeks

Action
- Inhibits leukocyte migration

Toxicity

  • Infusion reactions
  • Hepatotoxic
  • Infection (? PML)
  • Concern re malignancy
337
Q

What is TNFa?

A

TNFa is a pivotal cytokine in inflammation in many conditions

TNFa blockade used in Rheumatoid arthritis, Psoriasis and psoriatic arthritis, Inflammatory bowel disease, Familial Mediterranean fever

338
Q

List 4 examples of Anti-TNFa Antibodies

A

Infliximab, Adalimumab, Certolizumab, Golimumab

339
Q

When are anti-TNFa antibodies used?

A 
Indications and dosing
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriasis and psoriatic arthritis
 Inflammatory bowel disease
- Subcutaneous or intravenous

Toxicity

  • Infusion or injection site reactions
  • Infection (TB, HBV, HCV)
  • Lupus-like conditions
  • Demyelination
  • Malignancy
340
Q

What is the mechanism of action of Etanercept and which conditions can you use it to treat?

A

Inhibits TNFa and TNFb

Indications and dosing:

  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Psoriasis and psoriatic arthritis
  • Subcutaneous weekly

Toxicity:

  • Injection site reactions
  • Infection (TB, HBV, HCV)
  • Lupus-like conditions
  • Demyelination
  • Malignancy
341
Q

Which interleukin is the most prominent in causing inflammation in rheumatoid arthritis?

A

IL-6 plays an important role in inflammation in rheumatoid arthritis

IL-6 blockade using an anti-IL6 receptor antibody is effective in management of rheumatoid arthritis (and Castleman’s disease)

342
Q

Name 2 examples of IL-6 receptor blockers

A

Tocilizumab

Sarilumab

343
Q

Which interleukins are important mediators in spondyloarthritides and related conditions?

A

IL23 – IL17 pathway important in spondyloarthritides and related conditions

Axial spondyloarthritis (AS), Psoriasis and psoriatic arthritis, Inflammatory bowel disease (not anti-IL17 for IBD)

344
Q

What is Guselkumab?

A

IL-23
- IL-23 comprises p40+p19

Indications and dosing

  • Psoriasis, psoriatic arthritis
  • Subcutaneous every 8 weeks

Action
- Inhibits IL-23

Toxicity

  • Injection site reactions
  • Infection (TB)
  • Concern re malignancy
345
Q

Which cytokines are key in asthma and eczema?

A

IL-4, IL-5 and IL-13 are key cytokines in Th2 and eosinophil responses

IL-4/13 blockade using an antibody specific for the IL4 receptor alpha subunit may be used for eczema and asthma
Anti-IL13 antibody may be used for management of eczema
Anti-IL5 antibody is used for eosinophilic asthma

346
Q

When is an anti-RANK antibody like Denosumab used?

A

Indications and dosing

  • Osteoporosis
  • Subcutaneous every 6 months

Action
- Inhibits RANK mediated osteoclast differentiation and function

Toxicity

  • Injection site reactions
  • Infection – mildly immunosuppressive
  • Avascular necrosis of jaw
347
Q

What are some common side effects of immunosuppressive biological therapy?

A

Infusion reactions
Urticaria, hypotension, tachycardia, wheeze – IgE mediated
Headaches, fevers, myalgias – not classical type I hypersensitivity

Injection site reactions
Peak reaction at ~48 hours
May also occur at previous injection sites (recall reactions)
Mixed cellular infiltrates, often with CD8 T cells
Not generally IgE or immune complexes

348
Q

Which virus may reactivate in the presence of immunosuppressive biological agents?

A

John Cunningham Virus (JCV)

  • Common polyomavirus that can reactivate
  • Infects and destroys oligodendrocytes
  • Progressive multifocal leukoencephalopathy
  • Associated with use of multiple immunosuppressive agents

Year 5 Pathology (5 decks)

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