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Path 2022 > Immuno > Flashcards

Immuno Flashcards

1
Q

Components of classical complement pathway

A

Activated by antigen-Ab immune complex

C1q –> C1
C2
C4

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2
Q

Define somatic hypermutation

A

Part of germinal centre reaction
B cell receptor edited on successive rounds of antigen engagement
Continues until very high affinity

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3
Q

Components of mannose-binding lectin complement pathway

A

MBL - directly binds to microbial cell surface carbohydrates

Stimulates classical pathway C2, C4 (NOT C1)

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4
Q

Define isotope switching

A

Part of germinal centre reaction

Switch from IgM to plasma cells secreting IgG, IgE or IgA

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5
Q

Components of alternative complement pathway

A

C3 - binds to bacterial cell wall components

Factors B, I, P

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6
Q

Components of final common complement pathway

A

C3 - all pathways converge here
C5-9
Membrane attack complex

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7
Q

Oxidative killing mechanism

A

NADPH oxidase complex converts O2 into reactive oxygen species – superoxide, hydrogen peroxide

Myeloperoxidase catalyses production of hydrochlorous acid (very potent antimicrobial/oxidant) from hydrogen peroxide + chloride

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8
Q

Non-oxidative killing mechanism

A

Release of bactericidal enzymes e.g., lysozyme, lactoferrin into phagolysosome

Each enzyme has unique antimicrobial spectrum –> broad coverage (bacterial + fungi)

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9
Q

Small molecule drugs causing secondary immune deficiency

A

Glucocorticoids & mineralocorticoids

Cytotoxic agents -
methotrexate, mycophenolate, cyclophosphamide, azathioprine

Calcineurin (IL-2) inhibitors -
cyclosporine, tacrolimus

Anti-epileptic drugs - phenytoin, carbamazepine, levetiracetam

DMARDs -
sulfasalazine, leflunomide

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10
Q

Good’s syndrome - mechanism & presentation

A

T cell defect (thymoma) + B cell defect (loss of Ab secretion, absent B cells)

Presents with:
CMV PJP
Muco-cutaneous candida
AI disease (due to lack of tolerance) - pure RBC aplasia, myasthenia graves, lichen planus

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11
Q

Patterns of Immunoglobulin deficiency

A

Isolated IgG reduction - prednisolone use (>10mg/day) or protein losing enteropathy

IgM & IgG reduction - B cell neoplasm, rituximab Tx

IgA & IgG reduction - primary Ab deficiency?

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12
Q

Investigations for secondary immune deficiency

A

FISH

Full blood count
Immunoglobulins - IgG, A, M, E
Serum complement - C3, C4
HIV test (18-80 yrs)

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13
Q

Indications for IgG replacement in secondary immunodeficiency

A
  1. Underlying cause of hypogammaglobulinaemia CANNOT be reversed OR reversal CONTRAINDICATED

OR

  1. hypogammaglobulinaemia associated with: drugs, monoclonal Abs targeted at B or plasma cells, post-HCST, NHL, CLL, MM or other B cell ca.

AND

3a. recurrent or severe bacterial infection despite continuous oral Abx for 6 months
3b. IgG <4
3c. Failure of response to pneumococcal/other polysaccharide vaccine challenge

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14
Q

Purpose of HLA-B*5701 blood test in HIV

A

Should avoid prescribing Abacavir in those with allele (~8% of NW London)

Risk of severe systemic hypersensitivity syndrome –> toxic epidermal necrolysis + liver toxicity

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15
Q

What factors influence the viral load ‘set point’ in HIV infection?

A

viral genotype
CD8 T cell immune response
Host genetics - HLA, CCR5 polymorphisms

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16
Q

Mechanism of ‘cure’ in Berlin/London patient?

A

Allogeneic stem cell transplant from CCR5 mutant HLA matched donor

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17
Q

Important infections & CD4 thresholds in HIV infection

A

Kaposi’s sarcoma - CD4 400

Pulmonary TB, herpes zoster, hairy leukoplakia - CD4 300-350

Pneumocystis jirovecii - CD4 200

Mycobacterium avid complex (MAC) disease - CD4 75

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18
Q

Innate primary immunodeficiencies of phagocytes:

Conditions with failure to produce neutrophils + their mechanism?

A

Reticular dysgenesis (severe SCID) - failure of stem cells to differentiate along myeloid or lymphoid lineage (so also an ADAPTIVE condition)

kostmann syndrome - specific failure of neutrophil maturation

cyclic neutropenia - specific failure of neutrophil maturation

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19
Q

Innate primary immumodeficiencies of phagocytes:

Conditions with defect of phagocyte migration + mechanism?

A

Leucocyte adhesion deficiency - neutrophil failure to exit bloodstream due to deficiency of CD18 beta-2-integrin subunit

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20
Q

Innate primary immunodeficiencies of phagocytes:

Condition with failure of oxidative killing?

A

Chronic granulomatous disease

  • NADPH oxidase component deficiency = absent respiratory burst
  • persistent neutrophil/macrophage accumulation + failure of antigen degradation = excessive inflammation, granuloma
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21
Q

Innate primary immunodeficiencies of phagocytes:

Conditions with cytokine deficiency + mechanism?

A

IL12, IL12R, IFN-y, IFN-y-R deficiencies

Cytokine network important for mycobacterial defence so deficiency = TB, atypical mycobacteria infections

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22
Q

Investigation results in innate primary immunodeficiencies of phagocytes

A

Kostmann syndrome - absent neutrophils, normal leucocyte adhesion markers, no neutrophils for NBT/DHR test

leucocyte adhesion deficiency - increased neutrophils (during infection), absent CD18, normal NBT/DHR test

Chronic granulomatous disease - normal neutrophils, normal leucocyte adhesion markers, abnormal NBT/DHR test

IL-12/IFN-y pathway deficiency - all normal

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23
Q

Treatment of innate primary immunodeficiencies

A

Prophylaxis:

  • vaccination
  • abx?

Aggressive Tx of infections

  • abx e.g. septrin
  • antifungs e.g. itraconazole
  • antivirals e.g. acyclovir

Definitive = haematopoetic stem cell transplantation

Specific Tx:

  • interferon gamma therapy for chronic granulomatous disease
  • cytokines to stimulate NK cytotoxic function
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24
Q

Innate primary immunodeficiencies of NK cells:

Conditions + mechanism?

A

Classical NK deficiency - Absence of NK cells in peripheral blood, GATA1 or MCM4 gene abnormalities

Functional NK deficiency - NK cells present but abnormal activity,
FCGR3A gene abnormality

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25
Q

Innate primary immunodeficiencies of complement:

Conditions + presentation

A

Complement deficiency (C5-9, Properidin) - bacterial infections esp encapsulated, Neisseria meningitides

Classical pathway deficiency (C2, C1q) - susceptibility to SLE (failure to clear dead cells + immune complexes)

MBL deficiency - mutations common, does not usually cause disease

NOTE: SLE can also cause complement deficiency - uses up components + forms autoantibodies against C3

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26
Q

Investigation results in innate primary immunodeficiencies of complement

A

C1q deficiency - C3+, C4+, CH50-, AP50+

Properidin deficiency - C3+, C4+, CH50+, AP50?

C9 deficiency - C3+, C4+, CH50-, AP50-

(SLE - C3+/-, C4-, CH50+/-, AP50+)

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27
Q

Adaptive primary immunodeficiencies - SCIDs

Condition + mechanism?

A

Reticular dysgenesis - failure of myeloid + lymphoid differentiation, most severe SCID, also INNATE condition

X-linked SCID - inability to respond to cytokines arrests T, NK & B cell development, mutations of common gamma chain

Other SCIDs - various pathways e.g. cytokine receptor, signalling molecule, metabolic

ADA deficiency - very low/absent T, NK and B cells, mutation in ADA enzyme needed for lymphocyte metabolism

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28
Q

Phenotype of severe combined immunodeficiency (SCID)

A

Presents ~ 3 months - before this, protected by passive transfer of maternal IgG across placenta/in colostrum

Infections

Failure to throve

Persistent diarrhoea

Skin disease - colonisation of empty BM by maternal lymphocytes (form of GvHD)

Personal/family Hx early infant death

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29
Q

Adaptive primary immunodeficiencies of T cells:

Condition + mechanism?

A

22q11.2 deletion syndrome (Di George) - failure of T cell maturation in underdeveloped thymus + syndromic features

MHC Class II deficiency (Bare lymphocyte type 2) - MHC class II molecules absent on cells, profound CD4+ T cell deficiency, normal B cell numbers but cannot produce IgA/IgG (need CD4 help for this)

MHC Class I deficiency - same features but low CD8+ T cells

T cell effector defects - variable e.g. IFN production, cytotoxicity, T/B cell communication

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30
Q

Investigation results in Adaptive primary immunodeficiencies of T cells

A

SCID: CD4-, CD8-, B cells+/-, IgM+/-, IgG-

DiGeorge (22q11.2): CD4-, CD8-, B cells+, IgM+, IgG-

Bare lymphocyte type 2/MHC Class II deficiency - CD4-, CD8+, B cells+. IgM+. IgG-

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31
Q

Treatment of adaptive primary immunodeficiencies

A

Aggressive prophylaxis + Tx of infections

Haematopoietic stem cell transplant

Specific:

  • PEG-ADA enzyme replacement for ADA SCID
  • thymic transpant (cultured donor tissue into quadriceps) for DiGeorge
  • immunoglobulin replacement (B cell types)
  • immunisation for selective IgA only (other B cell types cannot mount IgG response)
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32
Q

Adaptive primary immunodeficiencies of B cells

Condition + mechanism?

A

Bruton’s X linked hypogammaglobulinaemia - preB cells cannot develop into mature B cells, no IgG production, abnormal B cell tyrosine kinase

Hyper IgM syndrome - no germinal centre development, failure of isotype switching, CD40 ligand mutation

Common variable immune deficiency - heterogeneous, low IgG (+ others), poor response to immunisation

Selective IgA deficiency - cause unknown, only 1/3 symptomatic

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33
Q

Investigation results in adaptive primary immunodeficiencies of B cells

A

Bruton’s X linked: CD4+, CD8+, B cell-, IgM-, IgG-, IgA-

Hyper IgM: CD4+, CD8+, Bcell+, IgM++, IgG-, IgA-

Common variable immune deficiency: CD4+, CD8+, Bcell+, IgM+, IgG-, IgA-

Selective IgA deficiency: CD4+, CD8+, B cell+, IgM+, IgG+, IgA-

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34
Q

CD4+ T cell effector subsets (and their polarising cytokines)

A

IL-12 & IFN-y produce Th1

IL-6 & TGF-b produce Th17

TGFb produce Treg

IL-6, IL-1b, TNFa produce TFh

IL-4, IL-6 produce Th2

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35
Q

Treatment of T cell mediated Transplant rejection

A

Steroids!!

  • methylprednisolone 3x pulses IV 60mg/kg
  • 3 days in a row
  • followed by oral taper

Anti-thymocyte globulin - ATG/OKT3

36
Q

Treatment of B cell mediated rejection

A

Remove Abs- plasma exchange
IV Ig
Anti CD5?
Anti CD20

37
Q

How does route of allergen exposure affect outcome?

A

Oral exposure promotes immune tolerance

Skin & respiratory exposure promotes sensitisation (specific IgE formation)

38
Q

Monogenic auto inflammatory disease

A

Familial Mediterranean fever
TNF receptor associated periodic syndrome (TRAPS)
Muckle Wells syndrome
Hyper IgD with periodic fever syndrome (HIDS)

39
Q

Polygenic auto inflammatory disease

A

IBD - Crohn’s disease, Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis

40
Q

Monogenic auto-immune disease

A

APS-1
APECED
ALPA
IPEX

41
Q

Polygenic autoimmune disease

A 
Rheumatoid arthritis
SLE
Myaesthenia gravis
Pernicious anaemia
Graves' disease
Primary biliary cirrhosis
ANCA associated vasculitis
Goodpasture disease
42
Q

Complication of familial Mediterranean fever?

A

AA amyloidosis

Excess serum amyloid A produced due to inflammation
Deposits in kidneys, liver, spleen
Presents with nephrotic syndrome (proteinuria) + renal failure

43
Q

IPEX clinical features

A

‘Diarrhoea, diabetes & dermatitis’

Pancreas autoAbs –> DM
Thyroid autoAb –> hypothyroidism
Enteropathy

44
Q

ALPS (Auto-immune lymphoproliferative syndrome) clinical features

A

Large spleen, lymph nodes
AI disease - esp cytopenias
Lymphoma

45
Q

Genetic polymorphisms/associations in Polygenic Autoimmune disease

A

T cell activation polymorphisms:
PTPN 22 - SLE, Rh arthritis, T1DM
CTLA4 - SLE, AI thyroid disease, T1DM

HLA susceptibility alleles:
HLA-DR15 - Goodpasture’s disease
HLA-DR3 - Graves’ disease, SLE, T1DM
HLA-DR4 - T1DM, Rh arthritis

46
Q

Gel & Coomb’s Hypersensitivity Reactions

A

Type 1 = Anaphylactic, immediate, IgE mediated

Type 2 = cytotoxic, Ab reacts with cellular antigen

Type 3 = immune complex, Ab reacts with soluble antigen to form complex

Type 4 = delayed, T cell mediated

47
Q

Autoantigens/Abs in Type II Hypersensitivity Auto-immune disease

A

Goodpasture = non Collagenous domain of basement membrane collagen type IV

Pemphigus vulgaris = epidermal cadherin

Graves’ = Thyroid stimulating hormone (TSH) receptor

Hashimoto’s thyroiditis = anti-thyroid peroxidase (TPO), anti-thyroglobulin

Myaesthenia gravis = Acetylcholine receptor

Pernicious anaemia = Anti Intrinsic factor, anti gastric parietal cell

48
Q

Autoantigens/Abs in Type 3 Hypersensitivity Autoimmune disease

A

SLE = all Antinuclear Abs

Specifically:
- dsDNA!! highly specific, useful to identify relapse

  • Extractable nuclear antigens: Ro, La, Sm, ribonucleoproteins (RNP) may occur, also found in Sjogren’s, not useful for disease monitoring
  • topoisomerase Scl70
  • centromere
49
Q

Autoantigens/Abs in Type 4 hypersensitivity Autoimmune disease

A

T1DM = Anti islet cell, anti-insulin, anti-GAD, anti-IA2

3-4 Abs = highly likely to develop disease (but not used for Dx)

50
Q

Key features of Goodpasture’s syndrome (clinical & Ix)

A

Clinical:
- Haemoptysis, pulmonary haemorrhage

Ix:

  • Biopsy –> crescentic glomerulonephritis
  • Urine dip –> microscopic haematuria, proteinuria
  • Immunofluorescence –> linear Ab position along glomerular basement membrane
51
Q

Other important autoantigens/Abs

A

Coeliac = anti TTG, anti-endomysial

AI hepatitis = antinuclear (ANA), smooth muscle (SMA), anti-liver kidney microsomal proteins (anti-LKM), anti-neutrophil cytoplasmic antibody perinuclear staining (pANCA)

Primary biliary cholangitis = ANA, antimitochondrial (AMA), pANCA

Microscopic polyangiitis / Eosinophilic granulomatosis with polyangiitis = pANCA

Granulomatosis with polyangiitis = cANCA (cytoplasmic staining)

52
Q

Investigations for Antiphospholipid Syndrome

A

Lupus anticoagulant - cannot be assessed if taking anticoagulant Tx

Anti-cardiolipin Ab

Anti-B2 glycoprotein 1 Ab

53
Q

Clinical Features of Limited Cutaneous Systemic Sclerosis

A 
CREST
Calcinosis
Raynaud's
Oesophageal dysmotility
Sclerodactyly
Telangiectasia

+ primary pulmonary HTN

54
Q

Clinical Features of Diffuse cutaneous systemic sclerosis

A

CREST features plus:
more extensive GI disease
Interstitial pulmonary disease
Scleroderma of kidney –> renal crisis

Skin involvement progresses beyond forearms (unlike CREST)

55
Q

Autoantibodies seen in Systemic Sclerosis

A

Extractable nuclear antigen +ve

Specifically:
Limited = anti centromere

Diffuse:

  • anti topoisomerase Scl70
  • RNA polymerase
  • Fibrillarin
56
Q

Autoantibodies seen in Idiopathic inflammatory myopathy

A

Anti-aminoacyl transfer RNA synthetase Ab e.g. Jo1 (cytoplasmic)!!

Others:
ANA - some patients

Anti-signal recognition peptide Ab (nuclear & cytoplasmic)

Anti-Mi2 (nuclear) - more in dermatomyositis vs polymyositis

57
Q

What cytokine drives clonal expansion of T cells following antigen exposure?

A

IL-2

58
Q

Live vaccines

A 
MMR
BCG
Yellow fever
Typhoid (oral)
Polio (Sabin oral)
Influenza (Fluenz tetra for children 2-17yrs)
59
Q

Inactivated vaccines

A 
Influenza (inactivated quadrivalent)
Cholera
Bubonic plague
Polio (Salk)
Hep A
Pertussis
Rabies
60
Q

Component/subunit vaccines

A

Influenza (recombinant quadrivalent) - less common
HPV - uses capsid
Hep B (HbSAg)

61
Q

Toxoid vaccines

A

Diphtheria

Tetanus

62
Q

Conjugate vaccines

A

Haemophilus Influenzae B
Meningococcus
Pneumococcus (Prevenar)

63
Q

Which primary antibody deficiencies are treated with human normal Ig?

A

X-linked agammaglobulinaemia
X linked hyperIgM syndrome
Common variable immune deficiency

64
Q

Examples of specific human immunoglobulin Tx?

A

Hep B - following needle stick, bite, sexual contact (with HepBSAg +ve individual)

Rabies - injected around bite site

Varicella Zoster - women <20 weeks pregnant OR immunosuppressed + acyclovir/valaciclovir contraindicated

65
Q

Important monoclonal Abs & their targets

A

Ipilimumab = anti CTLA-4 - advanced melanoma

Nivolumab = anti PD-1 - advanced melanoma, renal cell ca.

66
Q

Important cytokine-based Tx

A

PRO-IMMUNE:
Interferon gamma = Chronic granulomatous disease (neutrophil immunodeficiency)

Interferon alpha = Classical or Functional NK deficiency, Hep B or C (with ribavirin)

IL-2 = renal cell ca.

PRO-REGULATION:
Interferon alpha 2a = Behcet’s

67
Q

Corticosteroids MOA

A

On prostaglandins:

  • inhibits phospholipase A2
  • less Arachidonic acid –> less leukotrienes, prostaglandins
  • less inflammation

On phagocytes:

  • decreased expression of adhesion molecules on endothelium –> less immune cell traffic to tissues
  • decreased phagocytosis
  • decreased release of proteolytic enzymes

On lymphocytes:

  • sequestration in lymphoid tissue
  • blocks cytokine gene expression
  • decreased Ab production
  • promotes apoptosis
68
Q

Cyclophosphamide side effects

A
  • BM depression
  • hair loss
  • irreversible infertility (M>F)
  • haemorrhagic cystitis
  • malignancy: bladder, haemolytic, non melanoma skin ca.
  • Pneumocystis jiroveci infection
69
Q

Azathioprine side effects

A

BM suppression

  • TPMT polymorphism = unable to metabolise azathioprine so check before starting!
  • always check FBC before starting

Hepatotoxicity
- uncommon

Infection - but less than cyclophosphamide

70
Q

Mycophenolate mofetil side effects

A

BM suppression

Infection - herpes reactivation, progressive multifocal leukoencephalopathy (JC virus)

71
Q

Indications for plasmapharesis

A

Goodpasture syndrome
Severe acute myaesthenia gravis
Antibody mediated transplant rejection / ABO incompatibility

72
Q

Indications for Calcineurin inhibitors

A

E.g. ciclosporin, tacrolimus

Transplantation
SLE
Psoriatic arthritis
including during pregnancy

73
Q

Indications for mTOR inhibitors

A

E.g. Rapamycin, Sirolimus

Transplantation

74
Q

Tacrolimus/Ciclosporin MOA

A

Calcineurin inhibitors

Inhibit T cell proliferation/function (via reduced IL-2 expression)

75
Q

Indications for JAK inhibitors

A

Rh arthritis
Psoriatic arthritis
Axial spondyloarthritis

76
Q

Indications for PDE4 inhibitors

A

E.g. Apremilast

Psoriasis + Psoriatic arthritis

77
Q

Basiliximab MOA + Indication

A

Directed at IL-2 R alpha chain of CD25 ‘anti CD25’
Bocks IL2 signalling –> inhibits T cell proliferation

Prophylaxis of allograft rejection

78
Q

Abatacept MOA + indication

A

CTLA-4 Ig fusion protein
Reduces co-stimulation of T cells via CD28 (opposite of Ipilimumab used in melanoma)

Rheumatoid arthritis

79
Q

Rituximab MOA + Indications

A

Anti-CD20 specific Ab –> depletes mature B cells

Lymphoma
Rh arthritis
SLE

80
Q

Vedlizumab

A

Specific Ab for alpha-4-beta-7 integrin
Inhibits MadCAM1 binding to a-4-b7 integrin = failure of leucocyte migration + extravasation to tissue

‘Ved’ = Fed = Tx for IBD

81
Q

TNF-alpha Antibodies

A

‘IACG’

Infliximab
Adalimumab
Certolizumab
Golimumab

82
Q

Etanercept MOA + Indications

A

Inhibits TNF alpha and TNF beta

Rh arthritis
Ank Stond
Psoriasis & Psoriatic arthritis

83
Q

Indications for IL-1 blockade

A

Familial Mediterranean Fever
Gout
Adult onset Stills disease

84
Q

IL-6 Antibodies + Indication

A

Tocilizumab
Sarilumab

Rh arthritis
(Castleman’s disease)

85
Q

Guselkumab MOA + Indication

A

Targets p19 alpha subunit of IL-23 ‘anti IL23’

Psoriasis & psoriatic arthritis

86
Q

Indications for IL-4, 5, 13 blockade?

A

Asthma & eczema

87
Q

Denosumab MOA + Indication

A

Anti-RANK ligand Ab

Osteoporosis

Path 2022 (12 decks)

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