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Path Laz (condensed) (COPY) > Immuno > Flashcards

Immuno Flashcards

1
Q

What do sebaceous glands produce that has antibacterial effects?

A

Hydrophobic oils – repels water and microorganisms

Lysozyme – destroys the structural integrity of the bacterial cell wall

Ammonia and defensins – anti-bacterial properties

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2
Q

List the cells of the innate immune system.

A

Polymorphonuclear cells

Monocytes/macrophages

NK cells

Dendritic cells

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3
Q

List the soluble components of the innate immune system.

A

Complement

Acute phase proteins

Cytokines and chemokines

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4
Q

List some key features of cells of the innate immune system.

A

Identical responses in all individuals

Cells express genetically-encoded receptors (PRRs) that allow them to detect pathogens at the site of infection

Cells have phagocytic capacity

Cells secrete mediators (e.g. cytokines/chemokines) that regulate the immune response

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5
Q

Name the resident macrophage in the liver

A

Kupffer cells

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6
Q

Name the resident macrophage in the kidney

A

Mesangial cells

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7
Q

Name the resident macrophage in the bone

A

Osteoclasts

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8
Q

Name the resident macrophage in the spleen

A

Sinusoidal lining cells

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9
Q

Name the resident macrophage in the neural tissue

A

Microglia

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10
Q

Name the resident macrophage in the connective tissue

A

Histiocytes

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11
Q

Name the resident macrophage in the skin

A

Langerhans cells

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12
Q

How do macrophages differ from polymorphonuclear cells?

A

They can process antigens and present them to T cells

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13
Q

Describe how cells of the innate immune system recognise pathogens.

A

Pattern-recognition receptors (e.g. TLR) recognise generic motifs called PAMPs (e.g. bacterial sugars, DNA and RNA)

Fc receptors on these cells allows binding to the Fc portion of immunoglobulins thereby allowing phagocytosis of immune complexes

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14
Q

Which other factors can bind to phagocytes to facilitate phagocytosis?

A

Complement components (e.g. by binding to CR1)

Acute phase proteins (e.g. CRP)

Antibodies

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15
Q

Why do neutrophils die after phagocytosis? What does this form?

A

Phagocytosis depletes the glycogen stores of the neutrophil resulting in neutrophil death

The accumulation of dying neutrophils forms pus

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16
Q

How do NK cells determine whether to lyse cells or not?

A

They have inhibitory receptors which recognise self HLA and they have activating receptors that recognise heparan sulphate proteoglycans

The balance of these signals determines the response

They kill ‘altered self’ cells (e.g. malignancy or virus-infected cells)

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17
Q

Describe the main features of dendritic cells.

A

Reside in peripheral tissues

Express receptors for cytokines/chemokines

Express pathogen recognition receptors

Express Fc receptors for immunoglobulin

Capable of phagocytosis

Present processed antigens to T cells in lymph nodes to prime the adaptive immune response

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18
Q

Which receptor is involved in the migration of dendritic cells to lymph nodes?

A

CCR7

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19
Q

What are the key features of cells of the adaptive immune response?

A

Wide repertoire of antigen receptors (NOTE: not entirely genetically encoded because of VDJ recombination)

Highly specific

Clonal expansion

Immunological memory

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20
Q

Outline the selection of T cells in the thymus.

A

Cells with low and high affinity for HLA are deleted

Cells with intermediate affinity will survive (10%)

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21
Q

Which class of HLA do CD4 and CD8 cell recognise?

A

CD4: HLA-II

CD8: HLA-I

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22
Q

Outline the functions of CD4+ T helper cells.

A

Recognise peptides derived from extracellular proteins

These peptides are presented on HLA-II (HLA-DP, DQ, DR)

Provide help for the development of a full B cell response

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

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23
Q

List the subsets of CD4+ T cell.

A

Th1

Th2

Th17

Follicular T cell

Treg

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24
Q

Describe the function of CD8+ T cells.

A

Specialised cytotoxic cells

Recognise peptides derived from intracellular proteins presented on HLA class I (A, B and C)

Kills cell directly via perforin and granzyme or expression of Fas ligand

NOTE: particularly important against viral infections and tumours

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25
Q

In what form are B cells found in the periphery?

A

IgM B cells

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26
Q

What is the early IgM response of B cells?

A

If the B cell in the periphery engages an antigen it can cause an early IgM response where the cell differentiates into an IgM secreting plasma cell

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27
Q

What is a germinal centre reaction?

A

Dendritic cells present an antigen, thereby priming the CD4+ T helper cells

CD4+ T helper cells provide help for B cell differentiation via CD40L: CD40 interaction

This causes B cell proliferation

They undergo somatic hypermutation and isotype switching (from IgM to IgG/A/E)

They will become plasma cells and produce antibodies

NOTE: this process is dependent on CD4+ T helper cells

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28
Q

Which part of an antibody detects antigen and which part is responsible for its effector function?

A

Antigen is recognised by the antigen binding region (Fab) which is made up of the variable region of both heavy and light chains

Effector function is determined by the constant region (Fc) of the heavy chain

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29
Q

How is a secondary response to T-dependent antigens different from the primary response?

A

Lag time between antigen-exposure and antibody production is decreased (to 2-3 days)

Titres of antibody produced is increased

Response is dominated by IgG antibodies with high affinity

The response is independent of help from CD4+ cells

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30
Q

Where are pre-B cells found and what do they develop into?

A

Found in the bone marrow and develop into haematopoietic stem cells

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31
Q

In what form are complement proteins present in the circulation?

A

Inactive molecules

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32
Q

Outline the classical pathway of complement activation.

A

Activated by immune complexes

Formation of antibody-antigen complexes results in a conformational change exposing a binding site for C1 on the antibody

This binding results in activation of the cascade

NOTE: this is dependent on antibodies, therefore it requires prior activation of the adaptive immune response (i.e. it does NOT occur very early in the immune response)

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33
Q

Outline the mannose binding lectin pathway of complement activation.

A

Activated by the direct binding of MBL to microbial cell surface carbohydrates

This directly stimulates the classical pathway involving C4 and C2 (but NOT C1)

NOTE: this is NOT dependent on the adaptive immune response

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34
Q

Outline the alternative pathway of complement activation.

A

Directly triggered by the binding of C3 to bacterial cell wall components

This is NOT dependent on the adaptive immune response

Involves factors B, I and P

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35
Q

State an example of bacterial cell wall components that can activate complement in Gram-positive and Gram-negative organisms.

A

Gram-negative: lipopolysaccharide

Gram-positive: teichoic acid

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36
Q

What is the major amplification step of the complement cascade?

A

C3 convertase

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37
Q

What are the effects of complement fragments that are released during complement activation?

A

Increase vascular permeability

Opsonisation of immune complexes

Opsonisation of pathogens

Activation of phagocytes

Promotes mast cell/basophil degranulation

Punches holes in bacterial membranes

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38
Q

Give three examples of failure of neutrophil production and outline their mechanism.

A

Reticular dysgenesis

  • Autosomal recessive severe SCID with no production of lymphoid or myeloid cells
  • Caused by failure of stem cells to differentiate along lymphoid or myeloid lineage

Kostmann syndrome

  • Autosomal recessive congenital neutropaenia

Cyclic neutropaenia

  • Autosomal dominant episodic neutropaenia
  • Occurs every 4-6 weeks
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39
Q

Name a phagocyte deficiency caused by failure of phagocyte migration.

A

Leucocyte adhesion deficiency

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40
Q

Describe the pathophysiology of leucocyte adhesion deficiency.

A

Caused by deficiency of CD18

CD18 normally combined with CD11a to produce LFA-1

LFA-1 normally binds to ICAM-1 on endothelial cells to mediate neutrophil adhesions and transmigration

A lack of CD18 means a lack of LFA-1, so neutrophils cannot enter tissues

During an infection, neutrophils will be mobilised from the bone marrow (HIGH neutrophils in the blood) but they will not be able to cross into the site of infection (NO pus formation)

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41
Q

Name a phagocyte deficiency caused by failure of oxidative killing mechanisms.

A

Chronic granulomatous disease

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42
Q

Outline the pathophysiology of chronic granulomatous disease.

A

Absent respiratory burst (deficiency of components of NADPH oxidase leads to inability to generate oxygen free radicals)

Excessive inflammation (persistent neutrophils and macrophage accumulation with failure to degrade antigens)

Granuloma formation

Lymphadenopathy and hepatosplenomegaly

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43
Q

What type of infection do patients with IL12/IL12R or IFN-gamma/IFN-gamma receptor deficiencies tend to present with?

A

Organisms that infect macrophages (usually atypical mycobacteria)

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44
Q

Name and describe the colour changes of two tests used to investigate chronic granulomatous disease.

A

Nitroblue Tetrazolium (NBT) – yellow to blue

Dihydrorhodamine (DHR) – fluorescent

NOTE: both of these tests are looking at the ability of neutrophils to produce hydrogen peroxide and oxidative stress

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45
Q

Which types of infection tend to occur in patients with phagocyte deficiency?

A

Recurrent skin and mouth infections

  • Bacteria – Staphylococcus aureus, enteric bacteria
  • Fungi – Candida albicans, Aspergillus fumigatus

Mycobacterial infections (particularly with IL12 deficiency)

  • TB, atypical mycobacteria
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46
Q

state the expected neutrophil count, leucocyte adhesion markers, NBT/DHR test and presence of pus in Kostmann syndrome

A

Absent neutrophil count

Normal leucocyte adhesion markers

No neutrophils for NBT/DHR

No pus

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47
Q

state the expected neutrophil count, leucocyte adhesion markers, NBT/DHR test and presence of pus in leukocyte adhesion deficiency

A

High neutrophil count

Absent CD18

Normal NBT/DHR

No pus

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48
Q

state the expected neutrophil count, leucocyte adhesion markers, NBT/DHR test and presence of pus chronic granulomatous disease

A

Normal neutrophil count

Normal leucocyte adhesion markers

Abnormal NBT/DHR

Pus present

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49
Q

state the expected neutrophil count, leucocyte adhesion markers, NBT/DHR test and presence of pus in IL12/IFN-gamma deficiency

A

Normal neutrophil count

Normal leucocyte adhesion markers

Normal NBT/DHR

Pus present

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50
Q

Outline the treatment of phagocyte deficiencies.

A

Aggressive management of infection (infection prophylaxis and oral/IV antibiotics when needed)

Haematopoietic stem cell transplantation

Specific treatment for chronic granulomatous disease (e.g. IFN-gamma therapy

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51
Q

What is the main risk associated with NK cell deficiency?

A

Increased risk of viral infections (e.g. HSV, CMV, EBV, VZV)

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52
Q

Outline the treatment of NK cell deficiency.

A

Prophylactic antiviral drugs (e.g. aciclovir)

Cytokines (e.g. IFN-alpha to stimulate NK cytotoxic function)

Haematopoietic stem cell transplantation

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53
Q

What is the main clinical consequence of complement deficiency?

A

Increased susceptibility to infection by encapsulated bacteria

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54
Q

Which encapsulated bacteria are particularly problematic in patients with complement deficiency?

A

Neisseria meningitidis

Haemophilus influenzae

Streptococcus pneumoniae

NOTE: susceptibility to N. meningitidis is particularly common in properidin and C5-9 deficiency

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55
Q

What are the consequences of MBL deficiency?

A

Common but NOT associated with immunodeficiency

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56
Q

List some different complement deficiencies and state which is most common.

A

C1q

C1r

C1s

C2 – MOST COMMON

C4

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57
Q

Outline the clinical phenotype of complement deficiency.

A

Almost all patients with C2 deficiency have SLE

Usually have severe skin disease

Increased risk of infection

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58
Q

How does SLE lead to a functional complement deficiency?

A

Active lupus causes persistent production of immune complexes

This leads to consumption of complement components leading to a functional complement deficiency

C3 and C4 will be low

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59
Q

What are nephritic factors?

A

Autoantibodies that are directed against components of the complement pathway

They stabilise C3 convertases (break down C3) resulting in C3 activation and consumption

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60
Q

What disease is associated with the presence of nephritic factors?

A

Glomerulonephritis (usually membranoproliferative)

It may also be associated with partial lipodystrophy

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61
Q

Which complement components may be measured in assays and why?

A

C3 and C4 are measured routinely to monitor SLE (low in active lupus)

C1 esterase inhibitor – decreased in hereditary angio-oedema

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62
Q

Name two functional complement assays and describe what they are testing.

A

CH50 – test of classical pathway (C1, 2, 4, 3, 5-9)

AP50 – test of the alternative pathway (B, D, Properidin, C3, C5-9)

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63
Q

Outline the management of complement deficiencies.

A

Vaccination (especially against encapsulated organisms)

Prophylactic antibiotics

Treat infection aggressively

Screen family members

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64
Q

Describe the stereotypical presentation of C1q deficiency

A

Severe childhood-onset SLE with normal levels of C3 and C4

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65
Q

Describe the stereotypical presentation of C3 deficiency with nephritic factor

A

Membranoproliferative nephritis with abnormal fat distribution (partial lipodystrophy)

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66
Q

Describe the stereotypical presentation of C7 deficency

A

Meningococcus meningitis with a family history of a sibling dying aged 6

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67
Q

Describe the stereotypical presentation of MBL deficiency

A

Recurrent infections when neutropaenic following chemotherapy, but previously well

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68
Q

What is anisopoikilocytosis and which type of anaemia is it associated with?

A

Variations in size and shape of cells

Associated with iron deficiency anaemia (and thalassemia trait to a lesser degree)

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69
Q

What is basophilic stippling? List some causes.

A

Basophilic appearance of red blood cells caused by the presence of aggregated ribosomal material

Causes: beta-thalassemia trait, lead poisoning, alcoholism, sideroblastic anaemia

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70
Q

Which condition do hypersegmented neutrophils tend to be present in?

A

Megaloblastic anaemia

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71
Q

In which conditions might you see target cells (codocytes)?

A

Iron deficiency

Thalassemia

Hyposplenism

Liver disease

NOTE: target cells have a high SA: V ratio

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72
Q

What are Howell-Jolly bodies? Which condition are they associated with?

A

Nuclear remnants present within red blood cells

Present in hyposplenism

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73
Q

Why might a patient with coeliac disease have a low calcium and high ALP?

A

Reduced absorption of vitamin D leads to vitamin D deficiency which causes a secondary hyperparathyroidism

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74
Q

Which investigations are typically performed in Coeliac disease?

A

CRP and ESR

Serological tests

Upper GI endoscopy and distal duodenal biopsy (GOLD STANDARD)

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75
Q

Which HLA alleles are particularly common in patients with coeliac disease?

A

HLA-DQ2 (80%) – DQA10501 and DQB102 alleles

HLA-DQ8

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76
Q

Which type of anti-gliadin antibodies may be tested when investigating coeliac disease?

A

IgA antibodies

NOTE: it is not a very sensitive test and is outdated

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77
Q

What important test should be performed before checking anti-tTG and anti-endomysial antibody levels?

A

gA levels

IgA deficiency can produce false-negative results

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78
Q

What are the characteristic histological features of coeliac disease?

A

Subtotal villous atrophy with crypt hyperplasia

Intra-epithelial lymphocytes

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79
Q

List some other causes of villous atrophy.

A

Giardiasis

Tropical sprue

Crohn’s disease

Radiation/chemotherapy

Nutritional deficiencies

Graft-versus-host disease

Microvillous inclusion disease

Common variable immunodeficiency

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80
Q

How many intraepithelial lymphocytes would you expect to see in coeliac disease?

A

More than 20 IELs/100 epithelial cells

NOTE: normal would be < 20

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81
Q

List some other causes of high intraepithelial lymphocytes.

A

Dermatitis herpetiformis

Giardiasis

Cows’ milk protein sensitivity

IgA deficiency

Tropical sprue

Post-infective malabsorption

Drugs (NSAIDs)

Lymphoma

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82
Q

List some complications of coeliac disease.

A

Malabsorption

Osteomalacia and osteoporosis

Neurological disease (epilepsy and cerebral calcification)

Lymphoma (causes multi-focal T cell lymphoma)

Hyposplenism

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83
Q

How often should a DEXA scan be performed in coeliac patients?

A

Every 3-5 years

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84
Q

List some conditions that are frequently associated with coeliac disease.

A

Dermatitis herpetiformis

Type 1 diabetes mellitus

Autoimmune thyroid disease

Down syndrome

SLE

Autoimmune hepatitis

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85
Q

Name a defect in stem cells that causes SCID and name the gene that is mutated.

A

Reticular dysgenesis – adenylate kinase 2 (AK2)

NOTE: this is a mitochondrial energy metabolism enzyme

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86
Q

What is the most common type of SCID?

A

X-linked SCID

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87
Q

Describe the typical cell counts you would expect to see in X-linked SCID.

A

Very low T cells

Very low NK cells

Normal or increased B cells

Low immunoglobulin

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88
Q

Describe the pathophysiology of ADA deficiency.

A

ADA – adenosine deaminase

This is an enzyme required by lymphocytes for cell metabolism

ADA deficiency leads to failure of maturation along any lineage

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89
Q

Describe the typical cell counts you would expect to see in ADA deficiency.

A

Very low T cells

Very low B cells

Very low NK cells

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90
Q

Describe the clinical phenotype of SCID.

A

Unwell by 3 months age (once protection by maternal IgG dissipates)

Infections of all types

Failure to thrive

Persistent diarrhoea

Unusual skin disease (colonisation of infant’s empty bone marrow by maternal lymphocytes can cause a graft-versus-host disease-like condition)

Family history of early death

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91
Q

Which cellular insults are CD8+ T cells particularly important in protecting against?

A

Viral infections

Tumour

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92
Q

Outline the immunoregulatory functions of CD4+ T cells.

A

Provide help to mount a full B cell response

Provide help for some CD8+ T cell responses

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93
Q

In which group of syndromes does the thymus gland fail to develop properly?

A

22q11.2 deletion syndromes (e.g. Di George syndrome)

This is characterised by failure of development of the pharyngeal pouch

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94
Q

What are the main clinical features of 22q11.2 deletion syndromes?

A

Facial abnormalities (high forehead, low set ears, cleft palate, small mouth and jaw)

Underdeveloped parathyroid gland (resulting in hypocalcaemia)

Oesophageal atresia

Underdeveloped thymus

Complex congenital heart disease

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95
Q

What are the immunological consequences of an underdeveloped thymus gland?

A

Normal B cell count

Low T cell count

Homeostatic proliferation with age (T cell numbers increase with age)

Immune function is mildly impaired and tends to improve with age

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96
Q

What condition is caused by a deficiency of MHC Class II? Briefly outline its pathophysiology.

A

Bare lymphocyte syndrome (BLS) type 2

Deficiency of MHC Class II means that CD4+ T cells cannot be selected in the thymus leading to CD4+ T cell deficiency

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97
Q

Describe the typical cell counts that you would expect to see in Bare Lymphocyte syndrome type 2.

A

Normal CD8+

Very low CD4+

Normal B cell count

Low IgG

NOTE: BLS Type 1 is a similar condition caused by failure of expression of HLA Class I

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98
Q

Outline the clinical phenotype of bare lymphocyte syndrome.

A

Unwell by 3 months of age

Infections of all types

Failure to thrive

Family history of early death

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99
Q

What are the common clinical features of T lymphocyte deficiencies?

A

Viral infections (e.g. CMV)

Fungal infections (e.g. PCP)

Some bacterial infections (e.g. TB, salmonella)

Early malignancy

NOTE: disorders of T cell effector function include defects in cytokine production, cytokine receptors and T-B cell communicatio

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100
Q

List some investigations that may be used for suspected T cell deficiencies.

A

Total white cell count and differentials

Lymphocyte subsets

Immunoglobulins

Functional tests of T cell activation and proliferation

HIV test

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101
Q

How are lymphocyte counts different in children compared to adults?

A

Higher in children compared to adults

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102
Q

Outline some management approaches for immunodeficiency involving T cells.

A

Aggressive prophylaxis/treatment of infection

Haematopoietic stem cell transplantation

Enzyme replacement therapy (e.g. PEG-ADA for ADA deficiency)

Gene therapy

Thymic transplantation (in Di George syndrome)

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103
Q

What determines the class of immunoglobulin?

A

Heavy chain

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104
Q

What determines the effector function of immunoglobulin?

A

Constant region of the heavy chain

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105
Q

Outline the pathophysiology of Bruton’s X-linked hypogammaglobulinaemia.

A

Prevents the maturation of B cells at that point at which they emerge from the bone marrow

Caused by an abnormal B cell tyrosine kinase (BTK) gene

This results in the absence of mature B cells and, hence, an absence of antibodies

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106
Q

Outline the clinical phenotype of Bruton’s X-linked hypogammaglobulinaemia.

A

Boys present in the first few years of life

Recurrent bacterial infections (e.g. otitis media, pneumonia)

Viral, fungal and parasitic infections

Failure to thrive

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107
Q

Outline the pathophysiology of X-linked hyper IgM syndrome.

A

Blocks the maturation of IgM B cells through germinal centres into B cells that produce other classes of immunoglobulin (i.e. prevents germinal centre reactions)

Caused by a mutation in the CD40 ligand gene

This is technically a T cell problem, however, it means that CD4+ T helper cells cannot provide help to B cells so they cannot undergo germinal centre reactions

NOTE: CD40 ligand is encoded on Xq26

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108
Q

Describe the typical biochemical results you would expect to see in X-linked hyper IgM syndrome.

A

Normal B cells

Normal T cells

No germinal centre reactions

High IgM

Absent IgG, IgA and IgE (failure of isotype switching)

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109
Q

Outline the clinical phenotype of X-linked hyper IgM syndrome.

A

Boys present in the first few years of life

Recurrent infections (mainly bacterial)

Subtle abnormality in T cell function (predisposes to PCP, autoimmunity and malignancy)

Failure to thrive

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110
Q

What is common variable immunodeficiency and what are the main features?

A

A group of disorders caused by some form of failure of differentiation of B lymphocytes

Defined by:

· Marked reduction in IgG, IgA and IgE

· Poor/absent response to immunisation

· Absence of other defined immunodeficiency

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111
Q

Outline the clinical phenotype of common variable immunodeficiency.

A

May present in adults or children

Recurrent bacterial infection (often severe)

Pulmonary disease (e.g. interstitial lung disease)

GI disease (e.g. IBD-like disease)

Autoimmune disease (e.g. AIHA)

Malignancy (e.g. NHL)

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112
Q

What are the clinical features of antibody deficiency?

A

Bacterial infections (e.g. Staphylococcus)

Toxins (e.g. tetanus)

Some viral infections (e.g. enterovirus)

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113
Q

List some investigations that may be used for suspected B cell deficiencies.

A

Total white cell count and differential

Lymphocyte subsets

Serum immunoglobulins and protein electrophoresis

Functional tests of B cell function (e.g. measure IgG antibody against a specific pathogen (e.g. S. pneumoniae), if this is low, vaccinate using a killed vaccine and check levels again in 6-8 weeks)

NOTE: IgG production is a surrogate marker for CD4+ T helper cell function

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114
Q

Which peak represents immunoglobulin in protein electrophoresis?

A

Gamma peak

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115
Q

What is the difference between autoinflammatory and autoimmune diseases?

A

Autoinflammatory – driven by components of the innate immune system

Autoimmune – driven by components of the adaptive immune system

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116
Q

Mutations in which pathways are implicated in monogenic autoinflammatory disease?

A

Innate immune cell function – abnormal signalling via key cytokine pathways involving TNF-alpha or IL-1

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117
Q

Which protein is upregulated in autoinflammatory diseases caused by a gain-of-function mutation in NLRP3? Name 3 diseases that are caused by this mutation.

A

Cryopyrin (NALP3)

Muckle Wells syndrome

Familial cold autoinflammatory syndrome

Chronic infantile neurological cutaneous articular syndrome

All of these are autosomal dominant

NOTE other examples of monogenic autoinflammatory conditions: TNF receptor associated periodic syndrome (TNF receptor mutation), Hyper IgD with periodic fever syndrome (mevalonate kinase mutation)

118
Q

Which gene mutation causes Familial Mediterranean Fever and which protein does this gene encode?

A

MEFV gene

Encodes pyrin-marenostrin which is a negative regulator of the inflammatory pathway

119
Q

Which mutations can lead to hyperactivity of the inflammasome complex?

A

Loss of function of pyrin-marenostrin

Gain of function of cryopyrin

120
Q

What is the inheritance pattern of Familial Mediterranean Fever?

A

Autosomal recessive

121
Q

Which cells contain pyrin-maronestrin?

A

Neutrophils

122
Q

Outline the clinical presentation of Familial Mediterranean Fever.

A

Periodic fevers lasting 48-96 hours associated with

· Abdominal pain (peritonitis)

· Chest pain (pleurisy, pericarditis)

· Arthritis

· Rash

123
Q

What is a complication of Familial Mediterranean Fever?

A

AA amyloidosis (due to chronic elevation of serum amyloid A)

This can deposit in the kidneys causing nephrotic syndrome and renal failure

124
Q

Outline the treatment of Familial Mediterranean Fever.

A

Colchicine 500 µg BD (binds to tubulin and disrupt neutrophil migration and chemokine secretion)

2nd line: blocking cytokines

· Anakinra – IL1 receptor blocker

· Etanercept – TNF-alpha blocker

125
Q

What does APECED stand for?

A

Autoimmune polyendocrinolpathy candidiasis ectodermal dystrophy

NOTE: it is autosomal recessive

126
Q

What mutation causes APECED? What is the role of this gene?

A

AIRE – this is a transcription factor that is responsible for the expression of self-antigens in the thymus and promotes apoptosis of self-reactive T cells

Defects in AIRE leads to a failure of central tolerance and the release of auto-reactive T cells

127
Q

Which autoimmune conditions tend to occur in APECED?

A

Hypoparathyroidism (COMMON)

Addison’s disease (COMMON)

Hypothyroidism

Diabetes mellitus

Vitiligo

128
Q

Why are patients with APECED prone to Candida infections?

A

They produce antibodies against IL17 and IL22

129
Q

What does IPEX stand for?

A

Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome

130
Q

What mutation causes IPEX? What is the role of this gene?

A

FoxP3 – required for the development of Treg cells

A lack of Tregs leads to autoantibody formation

131
Q

Which autoimmune conditions are often seen in IPEX?

A

Enteropathy

Diabetes mellitus

Hypothyroidism

Dermatitis

132
Q

What does ALPS stand for?

A

Autoimmune lymphoproliferative syndrome

133
Q

Which mutations cause ALPS?

A

Mutations in the FAS pathway leading to defects in apoptosis of lymphocytes

This leads to a failure of lymphocyte tolerance (as autoreactive lymphocytes don’t die by apoptosis) and failure of lymphocyte homeostasis (you keep producing lymphocytes)

134
Q

Describe the clinical phenotype of ALPS.

A

High lymphocyte count

Large spleen and lymph nodes

Autoimmune disease (usually cytopaenias)

Lymphoma

135
Q

What is the best known chromosomal region that is implicated in Crohn’s disease?

A

IBD1 on chromosome 16

136
Q

Outline the treatment approaches to Crohn’s disease.

A

Corticosteroids

Azathioprine

Anti-TNF-alpha antibodies

Anti-IL12/23 antibodies

137
Q

What is the strongest genetic association of ankylosing spondylitis?

A

HLA-B27

NOTE: others include IL23R, ERAP1, ANTXR2 and ILR2

138
Q

Where does ankylosing spondylitis tend to manifest?

A

At sites with high shear forces (i.e. entheses)

139
Q

What are the treatment options for ankylosing spondylitis?

A

NSAIDs

Immunosuppression (Anti-TNF-alpha and ant-IL17)

140
Q

List the autoimmune diseases associated with the following HLA polymorphisms:

A

a. DR3

Graves’ disease

SLE

b. DR3/4

Type 1 diabetes mellitus

c. DR4

Rheumatoid arthritis

d. DR15

Goodpasture’s syndrome

141
Q

Name and state the function of 2 genes that are involved in T cell activation and are often mutated in polygenic autoimmune disease.

A

PTPN22 – suppresses T cell activation

CTLA4 – regulates T cell function (expressed by T cells)

142
Q

Outline the Gel and Coombs effector mechanisms of immunopathology.

A

Type I: immediate hypersensitivity which is IgE-mediated

Type II: antibody reacts with cellular antigen

Type III: antibody reacts with soluble antigen to form an immune complex

Type IV: delayed-type hypersensitivity, T cell-mediated response

NOTE: autoimmunity is most common with type II hypersensitivity

143
Q

Outline the pathophysiology of IgE-mediated type I responses.

A

gE binds to a foreign antigen (e.g. pollen)

The Fc portion binds to mast cells and basophils leading to degranulation

NOTE: this mechanism is implicated in eczema

144
Q

What is a type V hypersensitivity reaction?

A

Antibodies activate or block cellular receptors (e.g. Graves’ disease, myasthenia gravis)

145
Q

What are the consequences of immune complex formation in type III hypersensitivity reactions?

A

Immune complexes can deposit in blood vessels (especially in the kidneys, joints and skin)

They activate complement and inflammatory cells through their Fc portion

146
Q

Give some examples of type IV hypersensitivity mediated diseases and state the autoantigen involved.

A

Insulin-dependent diabetes mellitus – pancreatic beta-cell antigen

Multiple sclerosis – myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein

147
Q

Describe the relationship between Langerhans cells and Th2 cells.

A

Langerhans cells promote the secretion of Th2 cytokines

NOTE: skin defects (i.e. epithelial barrier issues) are a significant risk factor for the development of IgE antibodies via Th2 responses

148
Q

How is oral allergen exposure different from respiratory or skin exposure with regards to developing an allergic response?

A

Oral exposure promotes immune tolerance whereas skin and respiratory exposure promotes IgE sensitisation

When an allergen is ingested orally, Tregs in the GI mucosa will inhibit IgE synthesis to keep the immune system in balance

149
Q

List some clinical features of IgE-mediated allergic responses.

A

Angioedema

Urticaria

Flushing

Itching

Cough

SOB

Wheeze

150
Q

List some elective investigations for allergic disease.

A

Skin prick and intradermal tests

Specific IgE measurement

Component resolved diagnostics

Basophil activation test

Challenge test

151
Q

List some investigations that may be conducted during an acute allergic episode.

A

Serial mast cell tryptase

Blood/urine histamine

152
Q

Does a positive specific IgE test demonstrate allergy?

A

No – it demonstrates sensitisation

153
Q

What features of the specific IgE test are used to predict risk and likelihood of symptoms?

A

Concentration - higher levels means more symptoms

Affinity to the target – higher affinity means increased risk

Capacity of IgE antibody to induce mast cell degranulation

154
Q

What are the advantages and disadvantages of skin prick testing?

A

Advantages

· Rapid (15-20 mins)

· Cheap

· High negative predictive value

· Increasing size of wheals correlates with higher probability of allergy

Disadvantages

· Operator-dependent

· Risk of anaphylaxis

· Poor positive predictive value

· Limited value in patients with dermatographism or extensive eczema

155
Q

List some indications for specific IgE tests.

A

Patients who cannot stop antihistamines

Patients with dermatographism

Patients with extensive eczema

History of anaphylaxis

Borderline skin prick results

156
Q

List some indications for allergy component testing.

A

Detect primary sensitisation

Confirm cross-reactivity

Define risk of serious reaction for stable allergens

157
Q

What is mast cell tryptase used for?

A

it is a biomarker for anaphylaxis

158
Q

When does mast cell tryptase reach peak levels and return to baseline levels?

A

Peak = 1-2 hours

Baseline = 6-12 hours

NOTE: if it fails to return to baseline, it may suggest systemic mastocytosis

159
Q

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

A

Challenge test

160
Q

List some mechanisms of anaphylaxis.

A

IgE – mast cells and basophils – histamine and PAF (triggered by food, venom, ticks, penicillin)

IgG – macrophages and neutrophils – histamine and PAF (triggered by blood product transfusions)

Complement – mast cells and macrophages – histamine and PAF (triggered by lipid excipients, liposomes, dialysis membranes)

Pharmacological – mast cells – histamine and leukotrienes (triggered by NSAIDs)

161
Q

List some reactions that can mimic anaphylaxis.

A

SKIN - Chronic urticaria and angioedema (ACE inhibitors)

THROAT SWELLING – C1 inhibitor deficiency

CVS – MI and PE

RESP – severe asthma, inhaled foreign body

NEUROPSYCH – anxiety/panic disorder

ENDOCRINE – carcinoid, phaeochromocytoma

TOXIC – scromboid toxicity (histamine poisoning)

IMMUNE – systemic mastocytosis

162
Q

Which supportive treatments are given alongside adrenaline in the management of anaphylaxis?

A

Adjust body position

100% O2

Fluid replacement

Inhaled bronchodilators

Hydrocortisone 100 mg IV

Chlorpheniramine 10 mg IV

163
Q

What is the key difference between food allergy and food intolerance?

A

The mechanism behind food intolerance is NOT immunological

164
Q

List some types of food allergy.

A

IgE mediated – anaphylaxis

Mixed IgE and cell-mediated – atopic dermatitis

Non-IgE mediated – coeliac disease

Cell-mediated – contact dermatitis

165
Q

Which organ is most commonly transplanted?

A

Kidneys

Followed by liver

166
Q

What is the average half-life of a transplanted kidney?

A

12 years

167
Q

What are the most relevant cellular proteins that can determine compatibility?

A

ABO

HLA

168
Q

Which chromosome is HLA encoded on?

A

Chromosome 6

169
Q

Which alleles encode HLA Class I and Class II?

A

Class I: A, B and C

Class II: DP, DQ, DR

170
Q

Where are HLA Class I and Class II expressed?

A

Class I: all cells

Class II: antigen-presenting cells (can be upregulated at times of stress)

171
Q

Which HLA alleles are most immunogenic?

A

A, B and DR

172
Q

What are the actions of activated T cells?

A

Proliferation

Production of cytokines (IL2 is important)

Provide help for CD8+ T cells

Provide help for antibody production

Recruit phagocytes

173
Q

Which test is used to give a definitive diagnosis of graft rejection?

A

Biopsy

174
Q

Describe the effector phase of T-cell mediated graft rejection

A

T cells tether, roll and arrest on the endothelial cell surface

They will migrate across into the interstitium and start attacking the tubular epithelium

Macrophages (recruited by T cells) may also be seen in the interstitium

175
Q

What are the typical histological features of T-cell mediated rejection?

A

Lymphocytic interstitial infiltration

Ruptured tubular basement membrane

Tubulitis (inflammatory cells within the tubular epithelium)

176
Q

What other explanation might there be for graft failure other than rejection?

A

Immunosuppressive drugs may be nephrotoxic

177
Q

What is a key difference between the production of anti-AB and anti-HLA antibodies?

A

Anti-AB antibodies are naturally occurring (pre-formed)

Anti-HLA antibodies are not naturally occurring but can be pre-formed due to previous exposure to epitopes (e.g. previous transplant, pregnancy) or post-formed (after transplantation)

178
Q

What are the main histological features of antibody-mediated transplant rejection?

A

Presence of inflammatory cells within the capillaries of the graft (HALLMARK)

Immunohistochemistry can show fixation of complement fragments on the endothelial cell surface

179
Q

What are the three main approaches to preventing graft rejection?

A

AB/HLA typing

Screening for antibodies

Overcoming organ mismatch issues

180
Q

How can organ mismatch issues be overcome?

A

Improve transplantation across tissue barriers

More donors

Organ exchange programmes

Xenotransplantation and stem cell research

181
Q

What T cell pathway is the main target for immunosuppressive drugs used in transplants?

A

The main signal is between MHC and TCR

Downstream, there are a number of pathways that involve calcineurin which result in cell proliferation

Once activated, T cells will release IL2 which has autocrine and paracrine effects on Th2 cells

These are all targets for immunosuppression

182
Q

Name two calcineurin inhibitors.

A

Tacrolimus

Ciclosporin

183
Q

Name two cell cycle inhibitors.

A

Mycofenolate mofetil

Azathioprine

184
Q

Name two drugs that target TCR.

A

Anti-CD3 antibody (OKT3)

Anti-thymocyte globulin

185
Q

Name an anti-CD52 antibody and state its effect.

A

Alemtuzumab – causes lysis of T cells

186
Q

Name an anti-CD25 antibody and state its effect.

A

Daclizumab – targets cytokine signalling

187
Q

What is rituximab?

A

Anti-CD20 – causes depletion of B cells

188
Q

How to BAFF inhibitors work?

A

Target cytokines (BAFF) that promote B cell activation and growth

189
Q

Name a proteasome inhibitor and describe how it works.

A

Bortezomib

Blocks the production of antibodies by plasma cells

190
Q

Name a complement inhibitor.

A

Eculizumab

191
Q

Outline the components of modern transplant immunosuppression regimes.

A

Induction agent (e.g. OXT3, anti-CD52, anti-CD25)

Baseline immunosuppression (e.g. calcineurin inhibitor, mycofenolate mofetil, azathioprine, steroids)

Treatment of acute rejection

· Cellular: steroids, OKT3

· Antibody-Mediated: IVIG, plasma exchange, anti-CD20

192
Q

How can GVHD be prevented?

A

Methotrexate/ciclosporin

193
Q

List some symptoms of GVHD.

A

Rash

Nausea and vomiting

Abdominal pain

Diarrhoea/bloody stools

Jaundice

194
Q

List some opportunistic infections that are more common in transplant recipients.

A

CMV

BK virus

PCP

195
Q

List some malignancies that are more common in transplant recipients.

A

Kaposi sarcoma (HHV8)

Lymphoproliferative disease (EBV)

Skin cancer

196
Q

Describe how HIV affects CD8+ T cells.

A

CD4+ T cells are disabled by HIV which means that monocytes and dendritic cells are not activated by CD4+ cells and so cannot prime CD8+ T cells

Therefore, CD8+ T cell and B cell responses are diminished in HIV

197
Q

List some advantageous features that HIV can acquire through mutation.

A

Escape from neutralising antibodies

Escape from HIV-1 specific T cells

Resistance and escape from antiretroviral drugs

198
Q

List the steps in the life cycle of HIV.

A

Attachment and entry

Reverse transcription and DNA synthesis

Integration

Viral transcription

Viral protein synthesis

Assembly of virus and release of virus

Maturation

199
Q

What are the screening and confirmatory tests for HIV?

A

Screening: HIV antibody ELISA

Confirmatory: HIV antibody Western blot

200
Q

List some antigens that are found on T cells.

A

CD3

CD4

CD8

CD19

CD56

201
Q

What are the effects of HAART?

A

Substantial control of viral replication

Increase in CD4+ count (initially because of memory cell redistribution, and later due to a rise in thymic naïve T cells)

Improvement in host defences

202
Q

What are the limitations of HAART?

A

Does not eradicate latent HIV-1

Fails to restore HIV-specific T cell responses

Threat of drug resistance

Significant toxicities

High pill burden

Adherence

Quality of life

Cost

203
Q

What are the two ways in which B cells can undergo clonal expansion once activated?

A

They can differentiate into T-cell independent IgM plasma cells

They can undergo a germinal centre reaction (with help from T helper cells) and become IgG memory and plasma cells

204
Q

Which type of T cell undergoes a more pronounced proliferation following activation?

A

CD8 > CD4

205
Q

List three types of antigen-presenting cell.

A

Dendritic cells

Macrophages

B lymphocytes

206
Q

Which cell surface receptor is used in the influenza vaccine?

A

Haemagglutinin (HA) – this is a receptor-binding and membrane fusion glycoprotein

207
Q

How long does protection from the influenza vaccine last?

A

Starts 7 days after the vaccine and protection lasts for 6 months

208
Q

What agent is used in the BCG vaccine?

A

Attenuated strain of Mycobacterium bovis

209
Q

Describe the protection that is achieved by using the BCG.

A

Some protection against primary infection

Mainly protects against progression to active TB

NOTE: T cell response is important in protection

NOTE: protection lasts for 10-15 years

210
Q

What is the Mantoux test?

A

A small amount of liquid tuberculin (PPD) is injected intradermally

The area of injection is examined 48-72 hours after the injection

A reaction would appear as a wheal around the injection site (this is suggestive of latent TB, active TB or previous BCG)

211
Q

What is a live attenuated virus vaccine? List some examples.

A

The organism is alive but modified to limit its pathogenesis

Examples: MMR, typhoid, BCG, yellow fever, polio (Sabin)

212
Q

List some examples of toxoid vaccines

A

Diphtheria

Tetanus

213
Q

List some examples of component/ subunit vaccines

A

Hep B (HBsAg)

HPV (capsid)

Influenza (HA)

214
Q

List some examples of conjugate vaccines.

A

Haemophilus influenzae type B

Meningococcus

Pneumococcus

215
Q

Describe how adjuvants work.

A

Increases the immune response without altering its specificity

They mimic the action of PAMPs on TLR and other PRRs

216
Q

List some examples of adjuvants.

A

Aluminium salts (MOST COMMON)

Lipids (monophosphoryl lipid A)

217
Q

What are dendritic cell vaccines?

A

Used against tumours

You collect some dendritic cells from the patient and load them with the antigen from the tumour to try and boost the immune response against tumour antigens

218
Q

What are the main indications for haematopoietic stem cell transplantation?

A

Life-threatening immunodeficiency (SCID)

Haematological malignancy

219
Q

List some indications for IVIG.

A

Primary antibody defect

· X-linked agammaglobulinaemia

· X-linked hyper IgM syndrome

· Common variable immunodeficiency

Secondary antibody defect

· CLL

· Multiple myeloma

· After bone marrow transplantation

220
Q

Using an example, describe how virus-specific T cells are used.

A

Used for EBV in patients who are immunosuppressed to prevent the development of lymphoproliferative disease

Blood is taken from the patient or from a donor

Peripheral blood mononuclear cells are isolated and stimulated with EBV peptides

This creates an expansion of EBV-specific T cells which are then reinfused into the patient

NOTE: tumour infiltration T cell therapy follows the same principle but uses tumour antigens

221
Q

What is ipilimumab and how does it work?

A

CTLA4 and CD28 are both expressed by T cells and they recognise antigens (CD80 and CD86) on APCs

Signalling through CD28 results in a stimulatory response

Signalling through CTLA4 results in an inhibitory response

Ipilimumab is a monoclonal antibody that blocks CTLA4 thereby removing this inhibitory response

It is used in advanced melanoma

222
Q

Explain the use of antibodies against PD-1 in treating cancer.

A

PD-1 and PD-2 ligands are present on APCs and interact via PD-1 receptors on T cells to cause an inhibitory response

They can also be expressed by some tumour cells

Pembrolizumab and nivolumab are antibodies that are specific to PD-1, thereby blocking this effect

This is also used in advanced melanoma

223
Q

List some examples of the therapeutic use of recombinant cytokines.

A

Interferon alpha – used as an adjunct in the treatment of Hep B, Hep C, Kaposi sarcoma, CML and multiple myeloma

Interferon beta – Behcet’s disease, relapsing MS

Interferon gamma – chronic granulomatous disease

224
Q

List some side-effects of corticosteroids.

A

Central obesity

Moon face

Easy bruising

Thin skin

Osteoporosis

Diabetes

Cataracts

Glaucoma

Peptic ulceration

Immunosuppression

225
Q

List some examples of anti-proliferative agents.

A

Cyclophosphamide

Mycophenolate

Azathioprine

Methotrexate

226
Q

List some indications of cyclophosphamide.

A

Multisystem connective tissue disease

Vasculitis

Anti-cancer

227
Q

List some side-effects of cyclophosphamide.

A

Toxic to proliferating cells – bone marrow suppression, sterility (mainly males), hair loss

Haemorrhagic cystitis – due to toxic metabolic (acrolein) in the urine

Malignancy – bladder cancer, haematological malignancy, non-melanoma skin cancer

Teratogenic

Infection (e.g. PCP)

228
Q

List some indications for azathioprine.

A

Transplantation

Autoimmune

Autoinflammatory (e.g. Crohn’s)

229
Q

List some side-effects of azathioprine.

A

Bone marrow suppression

Hepatoxicity

Infection

230
Q

Which precaution must you take before starting a patient on azathioprine?

A

Check TPMT activity – 1 in 300 individuals have a TPMT polymorphism which means that they are unable to metabolise azathioprine leading to bone marrow suppression

231
Q

List some indications for mycophenolate mofetil.

A

Transplantation

Autoimmune disease

Vasculitis

232
Q

List some side-effects of mycophenolate mofetil.

A

Bone marrow suppression

Teratogenic

Infection (particularly HSV reactivation and PML (JC virus))

233
Q

List some indications for plasmapheresis.

A

Severe antibody-mediated disease (e.g. Goodpasture’s, acute myasthenia gravis, severe transplant rejection)

234
Q

What are the main side-effects of calcineurin inhibitors?

A

Hypertension and nephrotoxicity (also diabetes, nephrotoxic)

235
Q

Give an example of a JAK inhibitor.

A

Tofacitinib (JAK1 and JAK2 inhibitor)

236
Q

Give an example of a PDE4 inhibitor.

A

Apremilast

237
Q

Which antigen does basiliximab target

A

Anti-CD25

238
Q

WHich antigen does abatacept target

A

CTLA4-Ig

239
Q

Which antigen does rituximab target

A

Anti-CD20

240
Q

WHich antigen does natalizumab target

A

Anti-a4 integrin

241
Q

WHich antigen does tocilizumab target

A

Anti-IL6 receptor

242
Q

List some side-effects of anti-thymocyte globulin.

A

Infusion reactions

Leukopaenia

Infection

Malignancy

243
Q

List some indications for rituximab.

A

Lymphoma

Rheumatoid arthritis

SLE

NOTE: it is given as two IV doses every 6-12 months

244
Q

What is the main indication of natalizumab?

A

Multiple sclerosis

245
Q

What are the main indications of tocilizumab?

A

Castleman’s disease (IL6-producing tumour)

Rheumatoid arthritis

246
Q

List some anti-TNFa antibodies.

A

Infliximab

Adalimumab

Certolizumab

Golimumab

247
Q

List some uses of anti-TNF alpha antibodies.

A

Rheumatoid arthritis

Ankylosing spondylitis

Psoriasis

IBD

248
Q

List some side-effects of anti-TNF alpha antibodies.

A

Infusion reactions

Infection

Lupus-like conditions

Demyelination

Malignancy

249
Q

Which antibodies is Hashimoto’s thyroiditis associated with?

A

Anti-TPO antibodies

Anti-thyroglobulin antibodies

NOTE: these can be present in normal people

250
Q

List some autoantibodies that are found in type I diabetes mellitus.

A

Anti-GAD

Anti-IA2

Anti-islet cell

Anti-insulin

251
Q

Outline the pathophysiology of pernicious anaemia.

A

Patients develop antibodies against intrinsic factor which leads to failure of absorption of vitamin B12

252
Q

What is a major complication of vitamin B12 deficiency?

A

Subacute degeneration of the spinal cord (involved the posterior and lateral columns)

NOTE: other neurological features include peripheral neuropathy and optic neuropathy

253
Q

Which antibodies are useful in the diagnosis of pernicious anaemia?

A

Anti-parietal cell antibodies

Anti-intrinsic factor antibodies

254
Q

Which investigations may be used in the diagnosis of myasthenia gravis?

A

EMG studies are usually abnormal

Tensilon test – administer very short-acting acetylcholinesterase (e.g. edrophonium bromide) which causes a rapid improvement in symptoms

255
Q

Which antibodies may be present in myasthenia gravis?

A

Anti-acetylcholine receptor antibodies

256
Q

What type of hypersensitivity reaction is myasthenia gravis?

A

Type II hypersensitivity

257
Q

List some genetic polymorphisms that predispose to rheumatoid arthritis.

A

HLA DR1

HLA DR4

PTPN22

PAD 2 and PAD 4 polymorphisms

Polymorphisms affecting TNF, IL1, IL6 and IL10

258
Q

List some environmental factors that contribute to the pathogenesis of rheumatoid arthritis.

A

Smoking is associated with the development of erosive disease (due to increased citrullination)

Gum infection by Porphyromonas gingivalis is associated with rheumatoid arthritis as it expresses PAD, thereby promoting citrullination

259
Q

Name and describe the antibodies that are often detected in the diagnosis of rheumatoid arthritis.

A

Anti-cyclic citrullinated peptide antibodies – bind to peptides where arginine has been converted to citrulline, 95% specific, 60-70% sensitive

Rheumatoid factor – IgM antibody directed against Fc region of human IgG

NOTE: there are IgA and IgG variants of RF

260
Q

What happens to joints affected by rheumatoid arthritis?

A

The synovium becomes inflamed forming a pannus

This invades articular cartilage and adjacent bone

There is also an increased synovial fluid volume

261
Q

What are antinuclear antibodies and how are they tested?

A

Group of antibodies against nuclear proteins

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

NOTE: these are very common and are often present in healthy individuals

262
Q

Which type of hypersensitivity reaction is SLE?

A

Type III hypersensitivity – antibodies bind to antigens forming immune complexes which deposit in tissues (e.g. skin, joints, kidneys) and activated complement via the classical pathway

These antibodies can also stimulate cells that express Fc receptors

263
Q

What are the two types of ANA and how can they be distinguished?

A

Anti-dsDNA – homogenous staining pattern, they are highly specific for SLE and high titres are associated with severe disease (useful for disease monitoring)

Anti-ENA4 (extractable nuclear antigens such as ribonucleoproteins (e.g. Ro, La, Sm))

264
Q

Which disease are anti-Ro and anti-La antibodies characteristically found in?

A

Sjogren’s syndrome

NOTE: these antibodies are not helpful in monitoring disease activity

265
Q

List some other autoantibodies that are implicated in autoimmune disease.

A

Scl70, RNA polymerase, fibrillarin – diffuse cutaneous systemic sclerosis

Mi2, SRP – idiopathic inflammatory myopathies

266
Q

Other than dsDNA, which other quantifiable component can be measured as a surrogate marker for disease activity in SLE?

A

C3 and C4 – C4 will decrease before C3

NOTE: we measure unactivated complement proteins

267
Q

What triad defines antiphospholipid syndrome?

A

Recurrent venous or arterial thrombosis

Recurrent miscarriage

Thrombocytopaenia

268
Q

Which antibodies are tested for in antiphospholipid syndrome?

A

Anti-cardiolipin antibody – immunoglobulins directed against phospholipids and b2 glycoprotein-1

Lupus anticoagulant – prolongation of phospholipid-dependent coagulation tests.

NOTE: cannot be assessed if the patient is on anticoagulant therapy

NOTE: both tests should be performed as 40% of patients have disconcordant antibodies

269
Q

Which cells are particularly important in the pathophysiology of systemic sclerosis?

A

Th2 and Th17

270
Q

What are the main features of limited cutaneous systemic sclerosis?

A

Skin involvement does not extend beyond the forearms

Calcinosis

Raynaud’s phenomenon

Esophageal dysmotility

Sclerodactyly

Telangiectasia

NOTE: also pulmonary hypertension

271
Q

What are the main features of diffuse cutaneous systemic sclerosis?

A

Skin involvement extends beyond the forearms

CREST features

More extensive gastrointestinal disease

Interstitial pulmonary disease

Renal cysts

272
Q

Which antibodies are seen in limited and diffuse cutaneous systemic sclerosis?

A

Limited – anti-centromere

Diffuse – anti-topoisomerase 2 (aka anti-Scl70)

273
Q

Describe the differences between the histology of dermatomyositis and polymyositis.

A

Dermatomyositis – perivascular CD4+ T cell and B cells are seen, this can cause an immune complex-mediated vasculitis (type III response)

Polymyositis – CD8+ T cells surround HLA Class I expressing myofibres, CD8+ T cells kill these myofibres via granzyme/perforin (type IV response)

274
Q

Which antibodies are seen in dermatomyositis

A

anti-aminoacyl tRNA synthetase (e.g. Jo-1), anti-Mi2

275
Q

Which antibodies are seen in polymyositis

A

anti-signal recognition peptide antibody

276
Q

Which classification system is used for systemic vasculitides?

A

Chapel Hill

277
Q

Which small vessel vasculitides are associated with ANCA?

A

Microscopic polyangiitis (pANCA)

Churg-Strauss syndrome (pANCA)

Granulomatosis with polyangiitis (cANCA)

278
Q

Outline the management of anaphylaxis.

A

ABCDE approach

Respiratory support if necessary

Oxygen by mask

IM adrenaline (0.5 mg)

IV antihistamine (10 mg chlorpheniramine)

IV corticosteroid (200 mg hydrocortisone)

IV fluids

Nebulised bronchodilators

NOTE: steroids take about 30 mins to start working but they are important in preventing rebound anaphylaxis

279
Q

List some common causes of anaphylaxis.

A

Foods: peanuts, fish, shellfish, milk, eggs, soy

Insect stings: bee venom, wasp venom

Chemicals, drugs and other foreign proteins: penicillin, IV anaesthetic, latex

280
Q

What can a type I hypersensitivity reaction to latex cross-react with?

A

Avocado

Apricot

Banana

Passion fruit

Papaya

NOTE: basically quite a lot of fruit

281
Q

Describe the appearance of biopsy of urticarial tissue in anaphylaxis.

A

Infiltrating T cells

Granulomas

282
Q

List some disorders associated with recurrent meningococcal meningitis.

A

Complement deficiency (increases risk of encapsulated organisms)

Antibody deficiency (causes recurrent bacterial infections)

Neurological (disturbance of blood-brain barrier (e.g. hydrocephalus, occult skull fracture))

283
Q

Which investigation are typically used to investigate complement deficiency?

A

CH50 (classical pathway)

AP50 (alternative pathway)

C3 and C4

284
Q

Which condition is characterised by a failure to produce any immunoglobulin?

A

X-linked agammaglobulinaemia – failure of pre-B cells to mature in the bone marrow leading to failure of production of antibodies

285
Q

Which investigation is used to diagnose multiple myeloma?

A

Serum protein electrophoresis – shows a monoclonal band (this can be stained to check whether it is composed of heavy or light chains)

286
Q

Which red blood cell abnormality may you see in the blood film of a patient with multiple myeloma?

A

Rouleaux formation

NOTE: you may also see Bence-Jones protein in the urine

287
Q

What are the key clinical features of rheumatoid arthritis?

A

Peripheral, symmetrical polyarthritis with stiffness lasting > 6 weeks

288
Q

When does rheumatoid arthritis commonly present and what is a possible explanation for this?

A

Post-partum – Th2 cells predominate during pregnancy and this switches back to Th1 post-partum

289
Q

Describe how specific HLA alleles can predispose to the development of rheumatoid arthritis.

A

HLA-DR4 (60-70%) and HLA-DR1

290
Q

Outline the management of rheumatoid arthritis.

A

First-line: methotrexate

Other options: TNF-alpha antagonists, rituximab, abatacept (CTLA4-Ig fusion protein), tocilizumab (antibody against IL6 receptor)

291
Q

List some risks of biological therapy for rheumatoid arthritis.

A

TB

Opportunistic infections

Malignancy

Path Laz (condensed) (COPY) (5 decks)

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