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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
Innate primary immunodeficiencies of complement: Conditions + presentation
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
26
Investigation results in innate primary immunodeficiencies of complement
C1q deficiency - C3+, C4+, CH50-, AP50+ Properidin deficiency - C3+, C4+, CH50+, AP50? C9 deficiency - C3+, C4+, CH50-, AP50- (SLE - C3+/-, C4-, CH50+/-, AP50+)
27
Adaptive primary immunodeficiencies - SCIDs Condition + mechanism?
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
28
Phenotype of severe combined immunodeficiency (SCID)
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
29
Adaptive primary immunodeficiencies of T cells: Condition + mechanism?
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
30
Investigation results in Adaptive primary immunodeficiencies of T cells
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-
31
Treatment of adaptive primary immunodeficiencies
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)
32
Adaptive primary immunodeficiencies of B cells Condition + mechanism?
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
33
Investigation results in adaptive primary immunodeficiencies of B cells
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-
34
CD4+ T cell effector subsets (and their polarising cytokines)
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
35
Treatment of T cell mediated Transplant rejection
Steroids!! - methylprednisolone 3x pulses IV 60mg/kg - 3 days in a row - followed by oral taper Anti-thymocyte globulin - ATG/OKT3
36
Treatment of B cell mediated rejection
Remove Abs- plasma exchange IV Ig Anti CD5? Anti CD20
37
How does route of allergen exposure affect outcome?
Oral exposure promotes immune tolerance Skin & respiratory exposure promotes sensitisation (specific IgE formation)
38
Monogenic auto inflammatory disease
Familial Mediterranean fever TNF receptor associated periodic syndrome (TRAPS) Muckle Wells syndrome Hyper IgD with periodic fever syndrome (HIDS)
39
Polygenic auto inflammatory disease
IBD - Crohn's disease, Ulcerative colitis Osteoarthritis Giant cell arteritis Takayasu's arteritis
40
Monogenic auto-immune disease
APS-1 APECED ALPA IPEX
41
Polygenic autoimmune disease
``` Rheumatoid arthritis SLE Myaesthenia gravis Pernicious anaemia Graves' disease Primary biliary cirrhosis ANCA associated vasculitis Goodpasture disease ```
42
Complication of familial Mediterranean fever?
AA amyloidosis Excess serum amyloid A produced due to inflammation Deposits in kidneys, liver, spleen Presents with nephrotic syndrome (proteinuria) + renal failure
43
IPEX clinical features
'Diarrhoea, diabetes & dermatitis' Pancreas autoAbs --> DM Thyroid autoAb --> hypothyroidism Enteropathy
44
ALPS (Auto-immune lymphoproliferative syndrome) clinical features
Large spleen, lymph nodes AI disease - esp cytopenias Lymphoma
45
Genetic polymorphisms/associations in Polygenic Autoimmune disease
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
Gel & Coomb's Hypersensitivity Reactions
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
Autoantigens/Abs in Type II Hypersensitivity Auto-immune disease
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
Autoantigens/Abs in Type 3 Hypersensitivity Autoimmune disease
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
Autoantigens/Abs in Type 4 hypersensitivity Autoimmune disease
T1DM = Anti islet cell, anti-insulin, anti-GAD, anti-IA2 3-4 Abs = highly likely to develop disease (but not used for Dx)
50
Key features of Goodpasture's syndrome (clinical & Ix)
Clinical: - Haemoptysis, pulmonary haemorrhage Ix: - Biopsy --> crescentic glomerulonephritis - Urine dip --> microscopic haematuria, proteinuria - Immunofluorescence --> linear Ab position along glomerular basement membrane
51
Other important autoantigens/Abs
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
Investigations for Antiphospholipid Syndrome
Lupus anticoagulant - cannot be assessed if taking anticoagulant Tx Anti-cardiolipin Ab Anti-B2 glycoprotein 1 Ab
53
Clinical Features of Limited Cutaneous Systemic Sclerosis
``` CREST Calcinosis Raynaud's Oesophageal dysmotility Sclerodactyly Telangiectasia ``` + primary pulmonary HTN
54
Clinical Features of Diffuse cutaneous systemic sclerosis
CREST features plus: more extensive GI disease Interstitial pulmonary disease Scleroderma of kidney --> renal crisis Skin involvement progresses beyond forearms (unlike CREST)
55
Autoantibodies seen in Systemic Sclerosis
Extractable nuclear antigen +ve Specifically: Limited = anti centromere Diffuse: - anti topoisomerase Scl70 - RNA polymerase - Fibrillarin
56
Autoantibodies seen in Idiopathic inflammatory myopathy
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
What cytokine drives clonal expansion of T cells following antigen exposure?
IL-2
58
Live vaccines
``` MMR BCG Yellow fever Typhoid (oral) Polio (Sabin oral) Influenza (Fluenz tetra for children 2-17yrs) ```
59
Inactivated vaccines
``` Influenza (inactivated quadrivalent) Cholera Bubonic plague Polio (Salk) Hep A Pertussis Rabies ```
60
Component/subunit vaccines
Influenza (recombinant quadrivalent) - less common HPV - uses capsid Hep B (HbSAg)
61
Toxoid vaccines
Diphtheria | Tetanus
62
Conjugate vaccines
Haemophilus Influenzae B Meningococcus Pneumococcus (Prevenar)
63
Which primary antibody deficiencies are treated with human normal Ig?
X-linked agammaglobulinaemia X linked hyperIgM syndrome Common variable immune deficiency
64
Examples of specific human immunoglobulin Tx?
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
Important monoclonal Abs & their targets
Ipilimumab = anti CTLA-4 - advanced melanoma Nivolumab = anti PD-1 - advanced melanoma, renal cell ca.
66
Important cytokine-based Tx
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
Corticosteroids MOA
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
Cyclophosphamide side effects
- BM depression - hair loss - irreversible infertility (M>F) - haemorrhagic cystitis - malignancy: bladder, haemolytic, non melanoma skin ca. - Pneumocystis jiroveci infection
69
Azathioprine side effects
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
Mycophenolate mofetil side effects
BM suppression Infection - herpes reactivation, progressive multifocal leukoencephalopathy (JC virus)
71
Indications for plasmapharesis
Goodpasture syndrome Severe acute myaesthenia gravis Antibody mediated transplant rejection / ABO incompatibility
72
Indications for Calcineurin inhibitors
E.g. ciclosporin, tacrolimus | Transplantation SLE Psoriatic arthritis including during pregnancy
73
Indications for mTOR inhibitors
E.g. Rapamycin, Sirolimus Transplantation
74
Tacrolimus/Ciclosporin MOA
Calcineurin inhibitors | Inhibit T cell proliferation/function (via reduced IL-2 expression)
75
Indications for JAK inhibitors
Rh arthritis Psoriatic arthritis Axial spondyloarthritis
76
Indications for PDE4 inhibitors
E.g. Apremilast Psoriasis + Psoriatic arthritis
77
Basiliximab MOA + Indication
Directed at IL-2 R alpha chain of CD25 'anti CD25' Bocks IL2 signalling --> inhibits T cell proliferation Prophylaxis of allograft rejection
78
Abatacept MOA + indication
CTLA-4 Ig fusion protein Reduces co-stimulation of T cells via CD28 (opposite of Ipilimumab used in melanoma) Rheumatoid arthritis
79
Rituximab MOA + Indications
Anti-CD20 specific Ab --> depletes mature B cells Lymphoma Rh arthritis SLE
80
Vedlizumab
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
TNF-alpha Antibodies
'IACG' Infliximab Adalimumab Certolizumab Golimumab
82
Etanercept MOA + Indications
Inhibits TNF alpha and TNF beta Rh arthritis Ank Stond Psoriasis & Psoriatic arthritis
83
Indications for IL-1 blockade
Familial Mediterranean Fever Gout Adult onset Stills disease
84
IL-6 Antibodies + Indication
Tocilizumab Sarilumab Rh arthritis (Castleman's disease)
85
Guselkumab MOA + Indication
Targets p19 alpha subunit of IL-23 'anti IL23' Psoriasis & psoriatic arthritis
86
Indications for IL-4, 5, 13 blockade?
Asthma & eczema
87
Denosumab MOA + Indication
Anti-RANK ligand Ab Osteoporosis

Path 2022 (12 decks)

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