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Pathology - CC > Immunology > Flashcards

Immunology Flashcards

1
Q

what are the skin barriers to infection?

A
  • tightly packed keratinised cells
  • physiological factors: low pH, low oxygen tension
  • sebaceous glands: hydrophobic oils repel, lysozyme destroys cell wall, ammonia/defensins = anti-bac
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2
Q

what are the mucosal surface barriers to infection?

A
  • secreted mucous: physical barrier, secretory IgA (prevent entry), lysozyme, lactoferrin starves bacteria of iron
  • cilia: trap/remove pathogens
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3
Q

how do commensal bacteria provide a barrier to infection?

A
  • compete for resources

- produce fatty acids and bactericidins to inhibit growth

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4
Q

what are the cells of the innate immune system?

A
  • polymohonuclear cells (neutrophils, eosinophils, basophils)
  • monocytes, macrophages
  • NK cells
  • dendritic cells
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5
Q

what are the soluble components of the innate immune system?

A
  • complement
  • acute phase proteins
  • cytokines and chemokines
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6
Q

what are the features of the cells of the innate immune system?

A
  • identical in all
  • express receptors to detect and home to sites of infection
  • express PRRs to detect PAMPs/DAMPs at site of infection
  • phagocytic capacity
  • secrete cytokines/chemokines to regulate immune response
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7
Q

what are the different polymorphonuclear cells and where are they produced?

A
  • neutrophils, eosinophils, basophils/mast cells

- produced in bone marrow, migrate rapidly to injury site

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8
Q

what do polymorphonuclear cells do?

A
  • express receptors for cytokines = detect inflammation
  • express PRRs = detect pathogens
  • express Fc receptors for Ig = detect immune complexes
  • phagocytosis
  • oxidative and non-oxidative killing (esp neutrophils)
  • release enzymes, histamine, lipid mediators of inflammation
  • secrete cytokines = regulate inflammation
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9
Q

what are the types of mononuclear cells and where do you find them?

A
  • monocytes, macrophages, lymphocytes
  • produced in bone marrow
  • circulate in blood
  • migrate to tissues to differentiate into macrophages
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10
Q

what do mononuclear cells do?

A
  • express receptors for cytokines = detect inflammation
  • express PRRs = detect pathogens
  • express Fc receptors for Ig = detect immune complexes
  • phagocytosis
  • oxidative/ non-oxidative killing
  • secrete cytokines/chemokines = regulate inflammation
  • APCs to T cells
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11
Q

how are phagocytes recruited?

A
  • cellular damage/ bacterial products = local production of cytokines/chemokines
  • cytokines = activate vascular endothelium = enhanced vascular permeability
  • chemokines = attract phagocytes
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12
Q

how are microorganisms recognised?

A
  • PRRs recognise PAMPs (bacterial sugars, DNA, RNA)

- Fc receptors bind to Fc portion of Ig

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13
Q

describe the process of opsonisation and endocytosis?

A
  • endocytosis facilitated by opsonisation
  • opsonins act as bridge between pathogen and phagocyte receptors
    e. g. antibodies to Fc receptors, complement to complement receptors
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14
Q

what are the microbial killing mechanisms?

A
  • oxidative

- non-oxidative

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15
Q

what is the process of oxidative killing?

A
  • HOCl (hydrochlorus acid) acts as oxidant and anti-microbial
    1. NADPH oxidase: oxygen to oxygen radical
    2. superoxide dismustase: oxygen radical to hydrogen peroxide
    3. myeloperoxidase: hydrogen peroxide with chloride to HOCl
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16
Q

what is the process of non-oxidative killing?

A
  • release of lysozyme and lactoferrin into phagolysosome

- enzymes present in granules, can cover against bacteria and fungi

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17
Q

how are neutrophils involved in pus formation?

A
  • phagocytosis depletes neutrophils glycogen reserves
  • followed by neutrophil death
  • as cell dies, enzymes released
  • liquify local tissues
  • accumulation of dying neutrophils = pus formation
  • lots of pus = abscess
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18
Q

what is the aim of opsonisation?

A

to facilitate phagocytosis

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19
Q

what is the purpose of NK cells?

A
  • present within blood
  • migrate to inflamed tissues
  • kills “altered self” or virus infected
  • express inhibitory receptors for self-HLA molecules = prevent mal-activation by normal-self
  • express activator receptors
  • integrate signals from inhibitory and activator receptors
  • secrete cytokines to regulate inflammation = promote DC function
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20
Q

where do dendritic cells reside and what do they represent?

A
  • reside in peripheral tissue

- represent INNATE-ADAPTIVE transition

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21
Q

what do dendritic cells express?

A
  • cytokine/ chemokine receptors = detect inflammation
  • PRRs = detect pathogens
  • Fc receptors for Ig = detect immune complexes
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22
Q

what are the 3 main functions of DCs?

A
  1. Phagocytosis (following this, DCs mature): upregulate expression of HLA, express co-stim molecules, migrate to lymph nodes
  2. present processed antigen to T cells in lymph nodes, prime adaptive immune response
  3. Express cytokines to regulate immune response
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23
Q

what are the components of adaptive immune system?

A
  • Humoral immunity: B lymphocytes, antibodies
  • Cellular immunity: T lymphocytes
  • Soluble components: cytokines, chemokines
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24
Q

what are the characteristics of cells of adaptive immune system?

A
  • wide repertoire of antigen receptors
  • exquisite specificity
  • clonal expansion
  • immunological memory
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25
Q

what are primary lymphoid organs?

A

organs involved in lymphocyte development

  1. Bone marrow: T and B cells derived, B cells mature
  2. Thymus: T cells mature
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26
Q

what are secondary lymphoid organs?

A

sites of interaction between naïve cells and microorganisms

  • spleen
  • lymph nodes
  • MALT
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27
Q

describe the process of T lymphocyte maturation

A
  1. arise from haematopoetic stem cells
  2. exported as immature cells to thymus where undergo selection
  3. mature T lymphocytes enter circulation, reside in secondary lymphoid organs
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28
Q

describe the selection and central tolerance of T cells

A
  • low affinity for HLA = not selected (avoid inadequate reactivity)
  • immediate affinity for HLA = positive selection ( 10%)
  • high affinity for HLA = negative selection (avoid autoreactivity)
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29
Q

difference between the peptides recognised by CD8 and CD4 cells?

A 
CD8+ T cells recognise peptide presented by HLA class 1 molecules
CD4+ T cells recognise peptide presented by HLA class 2 molecules
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30
Q

what cells have MHC I vs MHC II?

A
  • every cell has MHC I (HLA A, B, C)

- APCs also have MHC II (HLA DP, DQ, DR)

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31
Q

what do CD4+ helper cells do?

A
  • recognise peptides presented on HLA class II molecules (APCs)
  • immunoregulatory functions via cell interactions and cytokines (help develop full B cell response and some CD8+ T cell responses)
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32
Q

what do CD8+ cytotoxic killer cells do?

A
  • specialised cytotoxic cells that kill cells directly (peforin, granzymes, Fas ligand)
  • recognise intracellular peptides from HLA I
  • secrete cytokines (IFNg, TNFa)
  • defence against virus and tumours
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33
Q

why is T cell memory important?

A

response to successive exposures to antigen is bigger and stronger
act quicker

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34
Q

what are the different CD4+ T cell subsets?

A
  • Th1
  • Th17
  • Treg
  • TFh
  • Th2
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35
Q

what do Th1 cells do? what cytokines involved?

A

Help CD8 T cells and macrophages

IL2, IFNg, TNFa, IL10

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36
Q

what do Th17 cells do? what cytokines?

A

help neutrophil recruitment, enhance generation of autoantibodies
IL17, IL21, IL22

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37
Q

what do Treg cells do? what cytokines?

A

IL-10/TGF beta expressing

express CD25 and Foxp3

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38
Q

what do TFh cells do? What cytokines in effector profile?

A

promote germinal centre reactions and differentiation of B cells into IgA and IgG secreting plasma cells
IL2, IL10, IL21

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39
Q

how does central tolerance of B cells work?

A
  • no recognition of self in bone marrow = survive

- recognition of self in bone marrow = negative selection, avoid autoreactivity

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40
Q

describe the process of B cell activation

A
  1. B cell receptor binds to antigen
  2. some mature to plasma cells secreting IgM
  3. if signalled by CD4+ T cells in secondary lymphoid tissue, stimulated B cells rapidly proliferate
  4. undergo complex genetic rearrangement
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41
Q

what genetic rearrangements occur?

A
  1. isotype switching to IgG, IgA, IgE( TFh cells) - needs CD40:CD40L (not present in Hyper-IgM)
  2. somatic hypermutation: generate high affinity receptors
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42
Q

what are immunoglobulins?

A

soluble proteins made up of 2 heavy and 2 light chains

heavy chain determines class (IgM, IgG, IgA, IgE, IgD)

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43
Q

what are the functions of antibodys?

A
  • identify pathogens/toxins (Fab-mediated)

- interact with other components of immune response (Fc-mediated): complement, phagocytes, NK cells

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44
Q

what are the features of B cell memory?

A
  • lag time between antigen exposure to production is dec
  • number of antibodies greatly increased
  • dominated by IgG antibodies of high affinity
  • independent of help from CD4+ T lymphocytes
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45
Q

what is important to remember about IgM secreting plasma cells?

A

generated rapidly following antigen recognition

not dependent on CD4 T cell help

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46
Q

summarise the process of B cells following antigen exposure

A
  1. Dendritic cells prime CD4+ T cells
  2. CD4+T cells help for B cell differentiation (requires CD40L:CD40)
  3. B cell proliferation, somatic hypermutation, isotype switching
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47
Q

what are complement?

A

> 20 types of proteins
produced in liver
present as inactive molecules in circulation
when triggered, enzymatically activate each other in biological cascade

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48
Q

what are the 3 ways of complement activation?

A
  1. classical pathway
  2. mannose binding lectin
  3. alternative pathway
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49
Q

describe the classical pathway

A

antibody + C1 –> C2, C4 –> C3

  • changed antibody site exposes C1 binding site
  • C1 binding to antibody activates cascade
  • antibody-antigen immune complexes
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50
Q

describe the mannose binding lectin

A

MBL –> C2, C4 –> C3

  • binding of MBL to microbial cell surface CHO
  • direct stimulation of classical pathway (only C4, C2)
  • not dependent on acquired immune response
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51
Q

describe the alternative pathway

A

PAMP (LPS, teichoic acid) –> C3

  • C3 binds to bacterial cell wall components
  • involved factors B, I, P
  • not dependent on acquired immune response
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52
Q

what is the major amplification step in complement cascade?

A

C3

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53
Q

what effects does C3 activation have?

A
  • inc vascular permeability and cell movement
  • opsonisation of immune complexes = soluble
  • opsonisation of pathogens = phagocytosis
  • active phagocytes
  • promote mast cell and basophil degranulation
  • form MAC (via C5-C9) to punch holes in membrane
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54
Q

what is the function of cytokines?

A
  • protein messengers
  • immunomodulatory functions
  • autocrine or paracrine dependent actions
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55
Q

what is the function of chemokines?

A
  • direct recruitment/ homing of leukocytes in inflammatory reaction
  • CCL19 and CCL21 are ligands for CCR7 and important in directing dendritic cells to lymph nodes
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56
Q

what is immunopathology?

A

damage to host caused by immune response

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57
Q

what is the basis of auto-inflammatory or auto-immunity?

A

immunopathology in absence of infection

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58
Q

what is the difference between auto-inflammatory and autoimmunity?

A
  • autoinflammatory: driven by abnormalities in innate immune system (inappropriate activation of innate immune cells = damage)
  • autoimmunity: abnormalities in adaptive immune system (abberant T and B cell responses in primary/secondary lymphoid organs, breaking of tolerance)
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59
Q

what factors can affect protein expression?

A
  • DNA sequence
  • genetics (mutations in DNA affecting protein sequence)
  • epigenetics (heritable changes in gene expression e.g. via DNA methylation)
  • microRNA (small non-coding ssRNA which target mRNA)
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60
Q

what other way can you sub-classify auto-inflammatory/ auto-immune diseases?

A

monogenic or polygenic

monogenic = rarer

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61
Q

what is the MOA of monogenic auto-inflammatory diseases?

A
  • mutations in single gene encoding protein involved in innate immune cell function
  • abnormal signalling via cytokine pathways (TNFa, IL1 common)
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62
Q

explain the inflammasome complex

A
  1. Toxins, microbial pathogens, urate stimulate cryopyrin
  2. Cryopyrin upregulates expression of ASC
  3. Pyrin-marenostrin decreases expression of ASC
  4. Apoptosis associated speck like protein (ASC) causes release of procaspase 1
  5. Procaspase 1 causes release of IL1, NFkappaB, apoptosis
  6. NFkappaB regulates TNFa
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63
Q

name a monogenic auto-inflammatory disease

A

Familial Mediterranean Fever

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64
Q

what is the pathogenesis of Familial Mediterranean Fever?

A
  • AR
  • mutations in MEFV gene = inactivated pyrin-marenostrin (expressed mostly neutrophils)
  • get less downregulation of ASC
  • so get increased pro-caspase 1 and increased inflammation driven by neutrophils
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65
Q

clinical presentation of FMF

A
  • periodic fevers lasting 48-96 hours
  • abdo pain (peritonitis)
  • chest pain (pleurisy, pericarditis)
  • arthritis
  • rash
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66
Q

what is a long term risk of FMF and why?

A

AA amyloidosis

  • liver produced serum amyloid A as acute phase protein
  • deposits in kidneys, liver, spleen
  • deposit in kidney = proteinuria, renal failure
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67
Q

what are other associations of AA amyloidosis?

A
  • Auto-immune diseases: RA, ankylosing spondylitis, IBD
  • auto-inflammatory diseases: FMF, muckle-wells syndrome
  • chronic infections: TB, bronchiectasis, chronic osteomyleitis
  • cancer: Hodgkin’s lymphoma, RCC
  • chronic foreign body reaction
  • HIV
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68
Q

what is associated with AL amyloidosis?

A

multiple myeloma

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69
Q

treatment of FMF

A
  • colchicine (binds to tubulin in neutrophils = disrupt function)
  • IL1 and TNFa inhibitors
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70
Q

what are the monogenic autoimmune diseases to know?

A
  • abnormalities in tolerance = APS-1/ APECED
  • abnormalities of regulatory T cells = IPEX
  • abnormalities of lymphocyte apoptosis = ALPS
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71
Q

what is the pathogenesis of APS1/APECED?

A
  • AR
  • defect in autoimmune regulator AIRE (TF involved in T cell tolerance in thymus)
  • upregulated expression of self antigens by thymic cells
  • promotes T cell apoptosis
  • defects in AIRE = failure of central tolerance = autoreactive T and B cells
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72
Q

what is the pathogenesis of IPEX?

A
  • mutations in FOXP3 which is required for Treg development

- failure to negatively regulate T cell responses = auto-reactive B cells = autoantibody formation

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73
Q

what autoimmune diseases are involved in IPEX?

A

“diarrhoea, dermatitis, diabetes”

  • enteropathy
  • DM
  • dermatitis
  • hypothyroidism
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74
Q

what is the pathogenesis of ALPS?

A
  • mutations in FAS pathway (cell surface death receptor)
  • defect in apoptosis of lymphocytes
  • failure of tolerance, failure of lymphocyte homeostasis
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75
Q

S/S of ALPS

A
  • lymphocyte (lots)
  • large spleen
  • lymph nodes
  • lymphoma
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76
Q

how do polygenic autoinflammatory diseases occur?

A

mutations in genes encoding proteins involved in innate immune cell function

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77
Q

characteristics of polygenic autoinflammatory diseases

A
  • local factors at predisposed sites lead to activation of innate immune cells = tissue damage
  • HLA associations less strong
  • no autoantibodies
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78
Q

what genetic mutations have been found to be associated with Chrons (autoinflammatory)?

A
  • NOD2 gene mutations (IB1 gene on Chr16)
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79
Q

where is NOD2 expressed and what is its role?

A
  • expressed in cytoplasm of myeloid cells (macrophages, neutrophils, DC)
  • is a cytoplasmic microbial sensor
  • activation leads to TNFa release (inflammation) and it induces autophagy in DC
  • abnormal degradation of DC = inflammation
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80
Q

treatment of Chrons

A
  • corticosteroid

- anti-TNFa antibody

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81
Q

explain the polygenic nature of Chrons

A
  • genetic mutations affecting innate immune response, epigenetic factors, microRNAs
  • intestinal microbiota
  • environmental factors e.g. smoking
    these all come together to:
  • inc expression of pro-inflammatory cytokines/chemokines
  • leukocyte recruitment
  • release of proteases/free radicals
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82
Q

what is the MOA of mixed pattern diseases?

A
  • mutations in genes encoding proteins in pathways of innate and adaptive immune cell function
  • HLA associations may be present
  • autoantibodies not usual
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83
Q

what is ankylosing spondylitis?

A
  • genetic polymorphisms in >90%

- inflammation at specific sites of high tensile forces (e.g. entheses)

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84
Q

presentation of AS

A
  • low back pain/stiffness
  • enthesitis
  • large joint arthritis
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85
Q

Tx of AS

A
  • NSAIDs

- immunosuppression: anti TNFa or anti IL17

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86
Q

genetic polymorphisms of AS

A
  • HLA B27: presents antigen to CD8 T cells
  • IL23R: IL23 receptor and promoted differentiation of Th17 cells
  • ILR2: inhibits IL1 so reduces TNFa (misfunction = inc TNFa)
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87
Q

features of polygenic autoimmune diseases

A
  • mutations in genes encoding proteins in adaptive immune cell function
  • HLA associations common
  • autoantibodies found
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88
Q

why are HLA associations common?

A

HLA presentation of antigen is needed for development of aberrant T cell and T cell dependent B cell responses
break of tolerance, development of immune reactivity towards self antigens

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89
Q

what genetic polymorphisms are involved?

A

normally suppress T-cell activation but mutation means overactive T cells

  • PTPN22: normally suppresses T cell activation
  • CTLA3: expressed by T cells, transmits inhibitory signal to control T cell activation
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90
Q

in which diseases are allelic variants of PTPN22 found?

A
  • SLE
  • T1DM
  • Rheumatoid arthritis
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91
Q

in which diseases are allelic variants of CTLA4 found?

A
  • SLE
  • AI thyroid disease
  • T1DM
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92
Q

what is a type 1 hypersensitivity reaction?

A
  • rapid allergic reaction
  • pre-existing IgE antibodies to allergen
  • IgE bound to Fc receptors on mast cell and basophils
  • cell degranulation
  • release of inflammatory mediators
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93
Q

what are the different inflammatory mediators that are released?

A
  • preformed: histamine, serotonin, proteases

- synthesised: leukotrienes, prostaglandins, bradykinin, cytokines

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94
Q

what occurs as a result of these being released?

A
  • increased vascular permeability
  • leuckocyte chemotaxis
  • SM contraction
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95
Q

what antigens usually cause a type 1 reaction?

A

FOREIGN

pollens, drugs, food, insect, animal hair

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96
Q

what is a type 2 hypersensitivity reaction?

A

Antibody reacts will cellular antigen

2 mechanisms of T2 disease = destruction OR activation/blockage]

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97
Q

how does antibody dependent destruction occur?

A
  • complement activation –> cell lysis
  • antibody binds and cause release of cytotoxic granules/ membrane attack from NK cells
  • antibody binds enabling phagocytosis
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98
Q

name some syndromes that cause a T2 reaction and what the auto-antigen is against

A
  • Goodpasture disease: non-collagenous domain of BM collagen type 4
  • Pemphigus Vulgaris: epidermal cadherin
  • Graves disease: TSH receptor
  • Myasthenia gravis: ACh receptor
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99
Q

what is a type 3 hypersensitivity reaction?

A
  • antibody reacting with soluble antigen to form immune complex
  • immune complexes deposit in blood vessels
  • inflammation and damage to vessels
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100
Q

what happens when immune complexes deposit in blood vessels?

A
  • complement activation, infiltration of macrophages and neutrophils
  • cytokine and chemokine expression
  • granule release from neutrophils
  • inc vascular permeability
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101
Q

name 2 syndromes that cause a T3 hypersensitivity reaction and what the autoantigen is

A
  • SLE: DNA, histones, RNP

- RA: Fc region of IgG

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102
Q

what is a type 4 hypersensitivity reaction?

A
  • delayed type

- T cell mediated response

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103
Q

how do you get tissue destruction in type 4 reactions?

A
  • HLA I present self antigens to CD8 T cells = cell lysis
  • HLA II present self antigens to CD4 T cells = cytokine production = inflammation and tissue damage

T cell recognises it as self = destroys it

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104
Q

what syndromes cause a type 4 reaction and what is the autoantigen?

A
  • insulin dependent diabetes mellitus: pancreatic beta cell antigen
  • rheumatoid arthritis: unknown synovial antigen
  • MS/ experimental AI encephalitis: myelin basic protein
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105
Q

describe how T cells cause a T4 reaction?

A
  • T helper cells activated by APC (presenting self antigen)
  • when antigen it presented again in future, memory Th1 cells activate macrophages
  • inflammatory reaction and tissue damage
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106
Q

what specific antibodies are seen in organ specific vs systemic diseases?

A
  • organ specific diseases = organ specific antibodies

- systemic diseases = anti-nuclear antibodies

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107
Q

name some organ specific autoimmune diseases and the organ specific antibody

A
  • Goodpasture disease = anti-BM antibodies
  • Myasthenia gravis = anti-ACh antibody
  • Graves’ diseases = anti-TSH receptor antibody
  • Pernicious anaemia = anti-IF antibody
  • DM = anti-GAD antibody
  • Hasimoto’s thyroiditis = anti-thyroglobulin antibody
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108
Q

how is Graves disease mediated?

A
  • IgG antibodies stimulate TSH receptor
  • induce uncontrolled overproduction of thyroid hormones
  • -ve feedback override antibody stimulation
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109
Q

what type of reaction is Graves?

A

type 2

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110
Q

how is Hashimoto’s thyroiditis mediated?

A
  • associated with anti- TPO antibodies
  • thyroid damage and lymphocyte inflammation
  • goitre: enlarged thyroid infiltrated by T and B cells
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111
Q

what type of reaction is Hashimoto’s?

A

T2 and T4

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112
Q

how is type 1 DM mediated?

A
  • CD8 T cell infiltration of pancreas = destruction of pancreatic islet cells
  • T4 mediated
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113
Q

what antibodies are associated with T1DM?

A

antibodies pre-date development of disease

  • anti-islet cell
  • anti-insulin cell
  • anti-GAD
  • anti-IA-2
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114
Q

how is pernicious anaemia mediated?

A
  • autoantibodies against IF
  • no absorption of Vit B12
    = pernicious anaemia and Sub-acute Combined Degeneration of Cord (SCDC)
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115
Q

what type of reaction is pernicious anaemia?

A

T2

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116
Q

how is myasthenia gravis mediated?

A
  • autoantibodues against ACh receptors
  • failure of depolarisation
  • no muscle action potential
  • T2 mediated
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117
Q

how can MG be diagnosed?

A
  • Anti-ACh-R ABs
  • EMG studies normal
  • Tensilon test positive
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118
Q

how would you diagnose goodpastures?

A
  • anti-BM antibody
  • crescentic nephritis on biopsy
  • T2 reaction
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119
Q

what are the genetic predispositions of rheumatoid arthritis?

A
  • HLA-DR4 and HLA DR1 alleles: bind to citrullinated peptides with higher affinity
  • PAD2 and PAD4 polymorphisms: associated with higher levels of citrullination
  • PTPN22 polymorphism (+ CTLA4): involved in T cell activation
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120
Q

what are the roles of citrullinated peptides?

A

initiate inflammatory response

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121
Q

what environmental factors affect development of RA?

A
  • smoking: erosive disease, increased citrullination

- gum infection with porphyromonas gingivalis (bacteria expressed PAD enzyme = promotes citrullination)

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122
Q

antibodies in RhA

A
  • Anti-CCP antibody (more specific)

- Rheumatoid factor antibody

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123
Q

how are B cells involved in Rheumatoid arthritis?

A

T2 response: antibody binding to citrullinated proteins –> complement activation, macrophage activation, NK cell activation

T3 response: immune complex formation –> RF and anti-CCP, deposition with complement activation

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124
Q

how are T cells involved in Rheumatoid arthritis?

A
  • T4 response

- APCs –> CD4+ T cell –> production of IFNy and IL17 –> increased IL1, TNFa

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125
Q

what are organ non-specific autoimmune diseases?

A
  • characterised by presence of anti-nuclear antibodies
  • very common
  • test by staining of Hep2 cells
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126
Q

name some non-specific autoimmune diseased

A
  • SLE
  • systemic sclerosis
  • idiopathic inflammatory myopathy
  • ANCA-associated vasculitides
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127
Q

what are the symptoms of SLE?

A
  • CNS: seizures
  • Skin: butterfly rash, discoid lupus
  • Heart: endocarditis, myocarditis, serositis, pleuritis, pericarditis
  • Glomerulonephritis
  • Haematological: HA, leukopenia, thrombocytopenia
  • Arthritis and lymphadenopathy
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128
Q

genetic predispositions in SLE

A
  • abnormalities in clearance of apoptotic cells
  • abnormalities in cellular activation –> B cell hyperactivity and loss of tolerance
    = antibodies directed particularly at intracellular proteins
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129
Q

what type of reaction is SLE?

A

T3 hypersensitivity

  1. antibodies bind to antigens to form immune complexes
  2. immune complexes deposit in tissue (skin, joints, kidney)
  3. immune complexes activate complement = classical pathway
  4. immune complexes stimulate cells expressing Fc and complement receptors
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130
Q

what is an important immunological investigation in SLE?

A

ANA

  • measured by titre (minimal dilution at which antibody can be detected)
  • “lumpy bumpy” on ELISA
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131
Q

targets of ANA

A
  • anti-dsDNA AB (specific for SLE, high titre = severe disease, disease monitoring use)
  • anti-ENA (extractable nuclear antigen) AB (Ro, La, Sm, U1RNP)
  • anti-topoisomerase AB (diffuse CREST)
  • anti-centromere AB (limited CREST)
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132
Q

how do these targets appear on ELISA?

A
  • anti-dsDNA Ab = homogenous staining on ELISA

- anti-N Ab = speckled pattern on ELISA

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133
Q

which anti-ENAs are found in Sjogrens?

A

anti-Ro and anti-Lo

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134
Q

what other investigation can you do in SLE?

A
  • measure complement
  • formation of antibody-antigen immune complexes activates complement cascade via classical pathway
  • depletion of C4 occurs first and then depletion of C3
  • complement components become depleted if constantly consumed = act as marker of disease activity
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135
Q

what would the C3/C4 levels be in inactive, moderate and very active lupus?

A
  • inactive lupus: normal C4, C4
  • moderate active lupus: low C4
  • very active lupus: low C3 and C4
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136
Q

symptoms of anti-phospholipid syndrome

A
  • recurrent venous or arterial thrombosis
  • recurrent miscarriage
  • may occur alone (primary) or in with autoimmune disease (secondary)
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137
Q

what antibodies do you test for in anti-phospholipid syndrome?

A
  • anti-cardiolipin antibody

- lupus anti-coagulant

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138
Q

types of systemic sclerosis

A
  • diffuse cutaneous systemic sclerosis

- limited cutaneous systemic sclerosis

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139
Q

symptoms of diffuse cutaneous systemic sclerosis

A
  • CREST features
  • GI, pulmonary and renal involvement
  • skin involvement of hands and PROXIMAL PAST forearms (unlike CREST)
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140
Q

ways of detecting DCSS

A
  • anti-scl70 AB

- nucleolar pattern of immunofluorescence

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141
Q

symptoms of Limited cutaneous systemic sclerosis (CREST):

A
  • only hands involved (does not spread proximally up forearms)
  • involves peri-oral skin
Calcinosis
Raynaud's
Oesophageal dysmotility 
Sclerodactyly
Telangiectasia

primary pulmonary HTN

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142
Q

Abs notes in CREST

A

anti-centromere AB

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143
Q

types of idiopathic inflammatory myopathy

A
  • dermatomyositis (periorbital rash + Gottron’s papules = red/violet bumps on joints)
  • polymyositis (no rash)
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144
Q

describe the mechanism of dermatomyositis

A
  • within muscle = perivascular CD4 T and B cells
  • immune complex mediated vasculitis
  • T3 response
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145
Q

describe the mechanism of action of polymyositis

A
  • within muscle = CD8 T cells surround HLA calss 1 expressing myofibers
  • CD8 cells kill myofibers via perforin/granzyme
  • T4 response
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146
Q

Ix in idiopathic inflammatory myopathy

A

POSITIVE ANA

  • anti-Jo1 antibodies
  • anti-Mi2
  • Anti-SRP
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147
Q

what are the large vessel systemic vasculitis diseases?

A
  • Takayasu’s arteritis

- GCA/polymyalgia rheumatica

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148
Q

what are the medium vessel systemic vasculitis diseases?

A
  • polyarteritis nodosa

- Kawasaki disease

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149
Q

what are the small vessel ANCA-associated systemic vasculitis diseases?

A
  • microscopic polyangiitis
  • granulomatosis with polyangiitis (Wegener’s = crushed nose)
  • eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
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150
Q

what are the small vessel immune complex systemic vasculitis diseases?

A
  • anti-GBM disease
  • IgA disease
  • cryoglobulinemia
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151
Q

what is ANCA?

A
  • antibodies for antigens located in primary granules within cytoplasm of neutrophils
  • inflammation = expression of these antigens on cell surface of neutrophils
  • antibody engagement with cell surface antigens = neutrophil activation (T2 reaction)
  • activated neutrophils interact with endothelial cells
  • damage to vessels = VASCULITIS
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152
Q

what is cANCA?

A
  • cytoplasmic fluorescence
  • associated with antibodies to enzyme proteinase 3
  • occurs in >90% of patients with GPA with renal involvement
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153
Q

what is pANCA?

A
  • perinuclear staining pattern
  • associated with antibodies to myeloperoxidase
  • less sensitive/specific than cANCA
  • associated with MPA and eGPA
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154
Q

what is the main difference between ANA and ANCA?

A 
ANA = screening test for connective tissue disease
ANCA = associated with subset of small vessel vasculitis, including MPA, GPA, eGPA
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155
Q

what type of virus is HIV-1?

A

retrovirus

genes = RNA molecules

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156
Q

in general how does HIV-1 replicate?

A
  • inside a cell using reverse transcriptase to convert RNA to DNA to be integrated into host genome
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157
Q

what is the structure of HIV-1 virus?

A
  • diploid genome

- contains 9 genes that encode 15 structural, regulatory and auxiliary proteins

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158
Q

what is the target of HIV-1?

A

CD4+ T helper cells, CD4+ monocytes, CD4+ dendritic cells

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159
Q

how does HIV affect CD4+ cells?

A
  • uses host CD4 cells to replicate and move from cell to cell
  • changes function of these cells
  • so can’t mount full immune response
  • lose immune memory = depleted memory T cells
  • selective loss of CD4+ T helper cells
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160
Q

what does protection from HIV require?

A
  • ABs ( B cells): prevent infection, neutralise virus

- sufficient CD8+ T cells to eliminate latently infected cells

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161
Q

what is the HIV-1 receptor and co-receptor?

A
  • receptor: CD4 molecule/antigen

- co-receptor: CCR5 or CXCR4

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162
Q

what are the routes of transmission of HIV?

A
  • sexually
  • infected blood
  • vertical
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163
Q

what is the process of natural immunity to HIV?

A

mobilised within hours of infection

  • inflammation
  • activation of macrophages, NK cells, complement
  • release of cytokines/chemokines (those made by NK cells can reduce infection of CD4 cells by HIV)
  • stimulation of plasmacytoid dendritic cells by TLRs
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164
Q

what is the process of acquired immunity (antibody and B cells) to HIV?

A

neutralising antibodies are produced

  • anti-gp120 and anti-gp41 important in protective immunity
  • non-neutralising anti-p24 IgG produced
  • HIV remains infectious even when coated with antibodies
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165
Q

what is the normal role of CD4_ T cells (Th cells)? the cells killed by HIV infection!

A
  • recognise processed antigens (esp Gag p24 peptides) from MHC II molecules
  • coordinate immune response
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166
Q

what is the normal role in CD8+ T cells?

A
  • can suppress viral replication (can kill HIV-infected cells or other malignant cells)
  • secrete cytokines/chemokines to prevent infection –> block ebtry to CD4_ T cells
  • recognise processed antigens from MHC II
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167
Q

summarise the effects of HIV

A
  • activated infected CD4 T helper cells die
  • infected CD4 T cells disabled
  • MO/DC not activated by CD4+ T cells so cannot prime CD8+
  • CD8+ T and B cell responses diminished without help
  • CD4+ T cell memory lost
  • infected MO/DC killed by virus/CTL = defect in antigen presentation, memory not activated
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168
Q

why is HIV prone to accumulate many mutations?

A
  • replication of genome dependent on 2 low fidelity steps where errors can occur
    1. RT (RNA to DNA) - lacks proof reading mechanisms
    2. transcription of DNA into RNA copies
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169
Q

what advantageous features do these mutations allow the virus to gain?

A
  • escape from neutralising Abs
  • escape from HIV-1 specific T cells
  • resistance and escape from ARVs
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170
Q

what are the seven 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
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171
Q

what are the different therapy targets within life cycle of HIV?

A
  • attachment (Attachment inhibitors)
  • reverse transcription (RTI)
  • transcription of DNA to vural RNA
  • viral protein cleavage by proteases (PI)
  • fusion (FI)
  • integration of viral DNA into host (INI)
  • integration of viral RNA to produce viral proteins
  • assembly and budding of new HIV
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172
Q

what ending do integrase inhibitors have?

A
  • gravir
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173
Q

what ending do protease inhibitors have?

A

-avir

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174
Q

what ending do NRTIs have?

A

-ines

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175
Q

what is the median time from HIV infection to development of AIDS

A

8-10 years

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176
Q

what predicts progression and what are the different progressors?

A

viral burden predicts disease progression

  1. Rapid progressors (10%): 2-3 years
  2. Long-term non-progressors (LTNP <5%): stable CD4 and no symptoms after 10 years
  3. Exposed-seronegatives (ESN): repeatedly exposed to HIV, do not seroconvert
  4. Elite controllers (EC): suppress viral replication
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177
Q

what are the host genetic factors that can lead to someone being a LTNP?

A
  • HLA profile (slow progressor)
  • MBL alleles
  • Gc Vit-D binding factor alleles
  • heterozygosity for 32-bp deletion in chemokine-r CCR5
  • TNF c2 microsatelitte alleles
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178
Q

what are the host immune response factors seen in a LTNP? (factors that keep HIV at bay)

A
  • effective CTL, HTL and humoral responses
  • secretion of: CD8 antiviral factor, IL-16, secretion of chemokines that block HIV entry co-receptors CCR5 and CXCR4
  • maintenance of functional lymphoid tissue architecture
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179
Q

what virologic factor can cause a LTNP mechanism?

A

infection with attenuated strains of HIV

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180
Q

what are the 3 ways HIV can be detected?

A

detection via:

  1. anti-HIV antibodies (ELISA) = screening test
  2. anti-HIV antibodies (Western Blot) = confirmation test
  3. Viral load (PCR)
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181
Q

how is the CD4 count monitored and what does it correlate with?

A
  • monitored via flow cytometry

- onset of AIDS correlates with decrease in number

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182
Q

what are the 2 ways to measure ART resistance?

A
  1. Phenotypic: viral replication measured in cell cultures under pressure of increasing concentrations of ARVs
  2. Genotypic: mutations detected by sequencing amplified viral HIV genome
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183
Q

what is the outcome of HAART?

A
  • control of viral replication
  • increase in CD4 T cell counts
  • improvement in host defences
  • does not eliminate HIV from body because there is reservoir in CD4+ T cells
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184
Q

what is the HAART regime?

A

combination of >=3 ART drugs
2 backbone drugs
1 binding agent
e.g. x2 NRTIs, x1 NNRTI or INI

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185
Q

what are the different types of backbone drugs?

A
  • nucleoside reverse transcriptase inhibitors (NRTI) e.g. zidoviudine
  • nucleotide RTI e.g. Tenofovir
  • Non-NRTI e.g. Efavirenz
  • Protease inhibitor e.g. Indinavir
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186
Q

what are the different binding agents?

A
  • integrase inhibitor e.g. Raltegravir
  • attachment inhibitors e.g. Maraviroc
  • fusion inhibitors e.g. Enfuvirtide
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187
Q

what are the important HAART interactions to note?

A
  • boosted PI: block cytochrome P450
  • Efavirenz: block cytochrome P450
  • INI: interacts with indigestion remedies
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188
Q

limitations and complications of HAART

A
  • does not eradicate latent HIV
  • threat of drug resistance
  • high pill burden
  • quality of life
  • failure to restore HIV-specific T cell responses
  • significant toxicities
  • adherence
  • cost
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189
Q

what are the different ways to prevent HIV spread?

A
  • male circumcision (lots of APCs in foreskin)
  • condoms
  • PrEP (Truvada)
  • Treatment as prevention (U=U)
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190
Q

what is an allergic disorder?

A

immunological process that results in immediate and reproducible symptoms after exposure to allergen
usually IgE mediated T1 reaction

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191
Q

what is an allergen?

A

harmless substance that can trigger an IgE mediated immune response –> clinical symptoms

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192
Q

what is sensitisation?

A

detection of specific IgE either by skin prick testing or in vitro blood tests
demonstrates risk of allergic disorder but doesn’t define it

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193
Q

what does Th1 and Th17 cells recognise?

A
  • conserved structures in pathogens e.g. PAMPS
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194
Q

how are allergens differently detected and what cell leads the response?

A
  • multicellular organisms and allergens don’t have conserved structures that are recognised by immune cells
  • instead they release mediators (e.g. proteases)
  • these disturb the epithelial barriers = functional change
  • this is detected by immune system
  • gives rise to Th-2 mediated responses
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195
Q

clarity the difference in the way that the Th1/Th17 immune response is initiated differs from Th2

A
  1. PAMP –> structural feature recognition –> Th1, Th17 immune response
  2. Helminths/allergens –> functional feature recognition –> Th2 immune response
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196
Q

explain the Th2 immune response

A
  1. allergens = stressed/damaged epithelium
  2. stressed epithelium release signalling cytokines (GM-CSF, IL-25, IL-33, TSLP)
  3. these act on Th9, Th2 and ILC2 cells and promote secretion of IL4, IL5, IL9 and IL13
  4. these act on eosinophils and basophils to expel parasites/allergens but also contribute to tissue injury
  5. TLSP can also act on Tfh2 cells to release IL4 and IL21
  6. The IL4 release from Tfh2 cells stimulated Bc ells to produce IgE and IgG4
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197
Q

describe the induction of Th2 immune response

A
  • primary defect in epithelial barrier
  • follicular dendritic cells (Langerhans cells and dermal DC) promote secretion of Th2 cytokines
  • IL4 secretion is only induced by peptide-MHC presentation to TCR or naive/memory Th2 cells
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198
Q

how does the reaction differ between oral exposure and skin/respiratory exposure of allergens?

A
  • oral exposure promotes immune tolerance

- skin/respiratory exposure induces IgE sensitisation

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199
Q

why does oral exposure promote tolerance?

A
  • when allergen ingested through the oral route, T-regs (from GI mucosa) inhibit IgE synthesis
  • oral tolerance requires induction of CD4+ T regs
  • T regs inhibit multiple pro-allergic functions e.g. inhibiting DC APC function, secretion of IL-10 etc
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200
Q

describe the Th2 immune memory response when detecting an antigen

A
  1. mast cell is sensor and detects functional change
  2. allergen causes cross linking of IgE = histamine, prostaglandins, leukotrienes
  3. act on endothelium = inc permeability, SM contraction, neuronal itch
  4. expels parasite/allergen OR will be responsible for symptoms of asthma, eczema, hay fever
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201
Q

which cytokine plays a crucial role in development of Th2 immune responses? how is it induced?

A

IL4

only induced following peptide-MHC presentation to naive/memory Th2 cells

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202
Q

what causes the rapid and delayed symptoms of allergy?

A
  • RAPID (2-3 hours): release of inflammatory mediators following allergen cross linking of IgE on surface of mast cells and basophils
  • DELAYED: result of T2 cell (IL4, IL5, IL13) immune responses and eosinophil related tissue damage
  • Th2 cytokines secreted by tissue lymphocytes act on effector cells to expel pathogens/allergens and repair tissue damage
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203
Q

why is the incidence of allergic disease increasing?

A
  1. hygiene hypothesis
  2. lack of Vit D in infancy (leading to food allergy)
  3. alternation of diversity in intestinal microbiome
  4. high conc of dietary advanced glycation end-products and pro-glycating sugars which immune system mistakenly recognises as causing tissue damage
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204
Q

how is allergic disease diagnosed?

A
  1. history
  2. examination
  3. allergen-specific IgE (sensitisation) test
  4. functional allergen test
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205
Q

what do you need to ask in the history of allergic diseases?

A
  • age of onset of allergic diseasse
  • occurs minutes to 3 hours after exposure
  • symptoms (at least 2 organ systems involved)
  • symptoms reproducible
  • symptoms may be triggered by co-factors (i.e. NSAIDs in asthma)
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206
Q

allergic diseases that onset in infancy

A
  • atopic dermatitis

- food allergy (milk, egg, nuts)

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207
Q

allergic diseases that onset in childhood

A
  • asthma (house dust mite, pets)

- allergic rhinitis

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208
Q

allergic diseases that onset in adulthood

A
  • drug allergy
  • bee allergy
  • oral allergy syndrome
  • occupational allergy
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209
Q

what are the symptoms you should ask about?

A
  • skin symptoms: urticaria, angioedema
  • GI symptoms: D&V
  • Resp tract symptoms: SOB, cough, wheeze
  • vasculature symptoms: hypotension, impending doom
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210
Q

what is skin prick and intradermal testing?

A
  • use skin test solutions, positive control (histamine) and a negative control (diluent)
  • positive outcome = wheal >3mm than negative control
  • antihistamines discontinued for 48 hours before
  • more sensitive and specific than blood tests to diagnose allergy
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211
Q

advantages of skin prick tests

A
  • rapid (read after 15-20mins)
  • cheap/easy to do
  • good NPV
  • increasing size of wheals correlates with higher probability for allergy
  • patient can see response
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212
Q

disadvantages of allergen-specific IgE tests

A
  • requires experience to interpret
  • risk of anaphylaxis
  • high false positive rate
  • can’t be used in patients with dermatographism/extensive eczema
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213
Q

what is the process of IgE RAST blood tests?

A
  1. allergen bound to sponge in plastic cup, patient’s serum is addedd
  2. specific IgE (is present) binds to allergen
  3. Anti-IgE antibody tagged with fluorescent label added
  4. amount of IgE/Anti-IgE measured by fluorescent light signal
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214
Q

what are the types of blood test allergens?

A
  • aeroallergens: HDM, cat, dog, grass pollen mix, tree pollen mix
  • food: peanut, tree nut, shellfish, egg, milk, what, soy
  • venom: bee and wasp
  • drugs: Penicillin G and V, ampilliin, insulin, tetanus
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215
Q

what are the indications of IgE RAST blood tests?

A
  • pt who can’t stop antihistamines (otherwise do skin tests)
  • pt with dermatographism
  • pt with extensive eczema
  • history of anaphylaxis
  • borderline skin prick test results
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216
Q

what are the different functional allergen tests?

A
  • in vitro tests: basophil activation, serial mast cell tryptase
  • in vivo test: open or blinded allergen challenge `
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217
Q

what is the serial mast cell tryptase test?

A
  • tryptase found in mast cell granules
  • systemic degranulation of mast cells in anaphylaxis = inc tryptase
  • peak concentration = 1-2 hours, baseline = 6-12 hours
  • useful if diagnosis of anaphylaxis
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218
Q

what happens if serum tryptase doesn’t return to baseline?

A

? systemic mastocytosis

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219
Q

what is the basophil activation test?

A
  • measurement of basophil response to allergen IgE cross-linking
  • activated basophils inc expression of CD63, CD203, CD300 protein
  • used in diagnosis of food and drug allergy
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220
Q

what is the open or blinded allergen challenge?

A
  • GOLD STANDARD for food and drug allergy diagnosis
  • inc volumes of offending food/drugs ingested
  • under medical supervision
  • risk of severe reaction
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221
Q

what is important to remember about allergen specific IgE sensitisation tests?

A
  • used to detect the presence/absence of IgE antibody against external proteins
  • positive IgE test demonstrates sensitization NOT clinical allergy
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222
Q

how can the serum IgE be used for prediction of allergic symptoms?

A
  • concentration: higher levels = more symptoms
  • affinity to target: higher affinity = increased risk
  • capacity of IgE antibody to induce mast cell degranulation
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223
Q

what is component resolved diagnostics (CRD)?

A
  • blood test to detect IgE to single protein components
  • abundance and stability of protein contributes to risk of allergic disease
  • useful for peanut and hazelnut allergy
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224
Q

what are the indications for allergen component testing?

A
  • detect primary sensitisatoin
  • confirm cross-reactivity
  • define risk of serious reaction to stable allergens
  • improve diagnosis for components poorly represented in whole food extracts
  • improve diagnosis for components for unstable molecules in whole food extracts
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225
Q

define anaphylaxis

A

severe systemic hypersensitivity reaction
rapid onset, life threatening airway, breathing, circulatory problems
usually associated with skin and mucosal changes

226
Q

what are the acute onset symptoms of anaphylaxis?

A
  • skin (most frequent)
  • CVS (collapse, syncope, drop in BP)
  • Resp compromise (SOB, wheeze, stridor)
227
Q

what are the mechanisms of anaphylaxis?

A
  • IgE: mast cells, basophils, mediators = histamine, platelet activating factor
  • IgG: macrophages, neutrophils, mediators = histamine, platelet activating factor
  • complement: mast cells, macrophages, mediators = histamine, platelet activating factor
  • pharmacological: mast cells, mediators = leukotrienes, histamine
228
Q

what are examples of an IgE allergy?

A

food
insect venom
ticks
penicillin

229
Q

what are examples of an IgG allergy?

A
  • biologicals
  • blood
  • IgG trasnfusions
230
Q

what are examples of a complement cause of allergy?

A

lipid excipients
liposomes
dialysis membranes
PEG

231
Q

what are examples of a pharmacological allergy?

A
  • NSAID including aspirin
  • opiates
  • NM and quinolones drugs
232
Q

what are skin reactions that can mimic anaphylaxis (not respond to IM adrenaline)?

A

chronic urticaria

angiooedema (ACE inhibitors)

233
Q

what are throat swelling reactions that can mimic anaphylaxis (not respond to IM adrenaline)?

A

C1 inhibitor deficiency

234
Q

what are cardiovascular reactions that can mimic anaphylaxis (not respond to IM adrenaline)?

A

MI

PE

235
Q

what are respiratory reactions that can mimic anaphylaxis (not respond to IM adrenaline)?

A
  • very severe asthma
  • vocal cord dysfunction
  • inhaled FB
236
Q

what are neuropsychiatric reactions that can mimic anaphylaxis (not respond to IM adrenaline)?

A
  • anxiety

- panic disorder

237
Q

what are endocrine reactions that can mimic anaphylaxis (not respond to IM adrenaline)?

A

carcinoid

phaeochromocytoma

238
Q

what are toxic reactions that can mimic anaphylaxis (not respond to IM adrenaline)?

A

scromboid toxicity (histamine poisoning)

239
Q

what are immune reactions that can mimic anaphylaxis (not respond to IM adrenaline)?

A

systemic mastocytosis

240
Q

how is anaphylaxis diagnosed?

A
  • serial management of serum tryptase
  • samples taken at 1, 3 and 24 hrs post anaphylaxis
  • persistent rise in tryptase 24 hours after allergic reaction
241
Q

immediate management of anaphylaxis

A

IM adrenaline (1 in 1000)

242
Q

mechanisms of IM adrenaline

A

Alpha 1: peripheral vasoconstriction, reverses low BP and mucosal oedema
Beta 1: inc HR, contractility and BP
Beta 2: relaxes bronchial SM, reduces release of inflammatory mediators

243
Q

what supportive treatments can be used for anaphylaxis?

A
  • adjust body position
  • fluid replacement
  • hydrocortisone 100mg IV (prevent late phase response)
  • 100% oxygen
  • inhaled bronchodilators
  • chlorpheniramine 10mg IV (skin rash)
244
Q

what further management steps should you do?

A
  • referral to allergy clinic
  • investigate cause
  • written info on: recognition of symptoms, avoiding triggers, indications for Epi-Pen
  • emergency kit
  • copy of management plan to patient, carers, GP etc
  • pt with food anaphylaxis –> dietician
  • Medic Alert bracelet
  • patient support groups
245
Q

what is in the emergency community anaphylaxis kit?

A
  • EpiPen
  • prednisolone
  • antihistamine
246
Q

what is a food allergy?

A

adverse health effect from specific immune response that occurs reproducibly on exposure to food

247
Q

what is a food intolerance?

A

non-immune reactions

metabolic, pharmacological, unknown mechanisms

248
Q

what are the different types of food allergy?

A
  • IgE mediated reactions (anaphylaxis)
  • mixed IgE and cell mediated (atopic dermatitis)
  • Non IgE mediated (coeliac)
  • cell mediated (contact dermatitis)
249
Q

questions to ask in clinical history taking of food allergy?

A
  • what does pt mean by allergy?
  • IgE and non IgE mediated symptoms?
  • how is food prepare? co-factors?
  • Hx of atopic disease?
  • previous investigations for food allergy?
  • has elimination of food made any difference to symptoms?
250
Q

Ix in food allergy

A
  • clinical history
  • skin prick test or specific IgE blood test
  • individual allergen protein component test (help distinguish between sensitisation and allergy)
  • gold standard = blind oral food challenge
251
Q

management of food allergy

A
  • avoidance: education, dietician, acknowledge anxiety
  • anaphylaxis guidance for emergencies
  • prevention
252
Q

what are the different IgE mediated food allergy syndromes?

A
  • anaphylaxis
  • food associated exercise induced anaphylaxis
  • delayed food induced anaphylaxis to beef, pork, lamb
  • oral allergy syndrome
253
Q

what is food associated exercise induced anaphylaxis?

A
  • food induced anaphylaxis if pt exercises within 4-6 hours of ingestion
  • common triggers: wheat, shellfish, celery
254
Q

what is delayed food-induced anaphylaxis to beef, pork, lamb?

A
  • sx occur 3-6 hours after eating red meat and gelatin
  • IgE antibody to oligosaccharide in gut bacteria
  • induced by tick bites
255
Q

what is oral allergy syndrome?

A
  • limited to oral cavity
  • swelling and itch
  • sensitisation to inhalant pollen protein, leads to cross reactive IgE to food
  • resp exposure to pollen = IgE directed to homologous proteins in stone fruits, vegetables and nuts
256
Q

state the diagnostic tests for allergies

A
  • serial mast cell tryptase (diagnosis of anaphylaxis)
  • basophil activation (diagnosis of food/drug allergy)
  • allergen challenge (diagnosis of food/drug allergy)
257
Q

state the sensitivity tests for specific allergies

A
  • skin prick (intradermal): exclude allergy
  • RAST IgE blood test: exclude allergy
  • component resolved diagnostics: for specific components
258
Q

what are the different ways to boost the immune system?

A
  • vaccination
  • replacement of missing components
  • blocking immune checkpoints
  • cytokine therapy
259
Q

what are the ways to suppress the immune system?

A
  • steroids
  • anti-proliferative agents
  • plasmapheresis
  • inhibitors of cell signalling
  • agents directed at cell surface antigens
  • agents directed at cytokines
260
Q

what are the characteristics of the adaptive immune response?

A
  • B and T cells
  • wide repertoire of antigen receptors (genes rearranged, create lots of receptors, autoreactive cells generated)
  • specificity
  • clonal expansion following exposure to antigen
  • immunological memory
261
Q

what do T cells expand to form following exposure to antigen?

A

proliferate/differentiate into effector cells (cytokine secreting, cytotoxic)

262
Q

what do B cells expand to form following exposure to antigen?

A

proliferate/differentiate into:

  • T cell independent (IgM) plasma and memory cells
  • T cell dependent (IgG, IgA, IgE) plasma and memory cells (germinal centre reactoin)
263
Q

describe how immunological memory is achieved

A
  1. antigen presented by APC to CD8+ve T cell = activated T cell
  2. clonal expansion (aided by IL2 from T helper cells)
  3. 2 outcomes: death by apoptosis or survival as memory cells
264
Q

what are APCs and give examples?

A
  • cells that present peptides to T cells to initiate acquired immune response
  • DCs, macrophages, B-lymphocytes
265
Q

what are the characteristics of T cell memory?

A
  • longevity (persist without antigen due to low level proliferation in response to cytokines)
  • different cell surface proteins to access non-lymphoid tissues (where microbes enter)
  • rapid, robust response to future antigen exposure
266
Q

what are the characteristics of B cell memory?

A
  • longevity
  • pre-formed, high affinity IgG antibodies
  • rapid, robust response
267
Q

what are the aims of vaccines?

A
  • memory
  • no adverse reactions
  • practical
268
Q

what is the target for antibodies that the influenza vaccine helps target?

A

Haemagglutin (membrane fusion glycoprotein influenza virus)

269
Q

what is the TB vaccine?

A
  • BCG

- attenuated strain of bovine TB

270
Q

what does the TB vaccine provide protection against?

A
  • some protection against primary infection

- mainly provides protection against progression to active TB

271
Q

what is the Mantoux test?

A
  • checks previous exposure to TB
  • inject small amount of tuberculin
  • look for area of swelling around injection site
272
Q

what are the different types of vaccine?

A
  • live attenuated
  • inactivated/component vaccines
  • DNA vaccines
  • Dendritic cell vaccines
273
Q

give some examples of live attenuated vaccines

A
  • MMR
  • BCG
  • Yellow fever
  • typhoid
  • polio (sabin)
  • vaccinia
274
Q

how do live attenuated vaccines work?

A

organism is modified to limit pathogenesis

275
Q

advantages of life attenuated

A
  • establishes infections
  • raises broad immune response
  • activates all phases of immune system
  • often life long immunity after one dose
276
Q

disadvantages of live attenuated vaccines

A
  • storage problems
  • possible to reversion to virulence
  • spread to contacts (esp if immunosuppressed)
277
Q

name some inactivated vaccines

A
  • influenza
  • cholera
  • polio (salk)
  • HAV
  • pertussis
  • rabies
278
Q

name some component/subunit vaccines

A

HbS antigen
HPV (capsid)
- influenza

279
Q

name some toxoids (inactivated toxins) vaccines

A

diptheria

tetanus

280
Q

advantages of inactivated/component/toxoid

A
  • no mutation or reversion
  • easier storage
  • can be used in immunodeficient
  • lower cost
281
Q

disadvantages of inactivated/component/toxoid

A
  • often do not follow normal route of infection
  • poor immunogenicity
  • may need multiple injections
  • may need conjugates or adjuvants
282
Q

what are conjugate vaccines?

A

polysaccharide + protein carrier

283
Q

what is the job of the polysaccharide and protein carrier?

A
  • polysaccharide: induced T cell independent B cell response (transient)
  • protein carrier: promoted T cell dependent B cell response (long term)
284
Q

examples of conjugate vaccines

A

polysaccharide encapsulated = HiB, meningococcus, pneumococcus

285
Q

who do adjuvants do?

A
  • increase immune response without altering its specificity

- mimic action of PAMPs on TLR and other PRRs

286
Q

give some examples of adjuvants

A
  • aluminum salts
  • lipids
  • oils
  • ISCOMS
  • CpG DNA
287
Q

what is the most commonly used adjuvant in human vaccines?

A

aluminum salts

safe and effective

288
Q

MOA of aluminum salts

A
  • antigens slowly released over time = prolonged antigenic stimulation
  • induce mild inflammation = promote development of immune responses
  • activate Gr1+IL4+eosinohpuls = prime naive B cells = antibody response
289
Q

how do ISCOMs work?

A
  • immune stimulating complexes
  • enhances cell-mediated immunity
  • experimental
290
Q

how do DNA vaccines work?

A
  • plasmid containing chosen gene inserted into muscle cell
  • plasmid does not replicate but gene encodes protein that is presented at cell surface
  • mimics action of virally infected cell
  • stimulated T cell response
291
Q

advantages and disadvantages of DNA vaccines

A

Adv: mimics viral cell
Disadv: plasmid may integrate into host DNA –> could lead to AI diseases

292
Q

when are dendritic cell vaccines used?

A
  • against tumours where DC function compromised
293
Q

how do DC vaccines work?

A
  • take a pt DC cells
  • load them with tumour antigen (they are APC)
  • reintroduce them to pt
  • try to boost immune response against tumour antigen
294
Q

what are the different ways you can replace missing components?

A
  • HSCT
  • antibody replacement
  • specific immunoglobulins
  • adoptive cell transfer (ACT)
295
Q

what are the indications for HSCT?

A
  • life threatening immunodeficiency (e.g. SCID, leucocyte adhesion defect)
  • haematological malignancy
296
Q

what is antibody replacement?

A
  • giving pre formed IgG to variety of organisms
297
Q

indications for giving antibody replacement

A
  • primary antibody deficiency (Bruton’s X-linked hypogammaglobulinemia, X-linked hyper-IgM syndrome, common variable immunodeficiency)
  • secondary antibody deficiency (haem malignancies e.g. CLL/MM, after bone marroe transplantation)
298
Q

what specific immunoglobulins can be given?

A
  • HBC Ig
  • tetanus Ig
  • rabies Ig
  • VZV Ig

used for post-exposure prophylaxis

299
Q

what are the different types of ACT?

A
  • ViS-T (Virus specific T cell therapy)
  • TIL-T (Tumour infiltrating T cells)
  • TCR-T (T cell receptor T cells)
  • CAR-T (chimeric antigen receptor T cells)
300
Q

give an example of a virus specific T cell therapy

A

in EBV in immunosuppressed –> prevent development of B cell lymphoproliferative disease

  • blood lymphocytes from pt isolated and stimulated with EBV peptides
  • expansion of EBV-specific T cells and infused back into patient
301
Q

how does tumour infiltrating T cell therapy work?

A
  1. remove tumour from patient
  2. stimulate T cells within tumour with cytokines –> develop response against tumour
  3. reinfuse tumour infiltrating lymphocytes back into patient
302
Q

what is the basis of CAR-T therapy?

A
  1. T cells taken from patients and vectors insert gene fragments into T cells
  2. gene fragments encode receptors
303
Q

what is the difference between TCR therapy and CAR therapy?

A
  • TCR therapy: insert gene that encode specific TCR (e.g. recognise tumour antigen), this receptor recognises MHC presented peptides
  • CAR therapy: receptors chimeric (contains both T and B cell components), recognises cell surface CD markers
304
Q

what is standard CAR therapy?

A

targeting CD19 (present on B cells)

  • harnesses the T cells to kill the B cells
  • being used in ALL and NHL
305
Q

what immune checkpoints can be blocked?

A
  • CTL-A4

- PD-1

306
Q

how does blocking CTL-A4 boost the immune system?

A
  1. CTLA4 and CD28 both expressed by T cells, recognise same antigens on APCs (CD80, CD86)
  2. APC CD80/CD86 interact with CD28 = stimulatory signal
  3. APC CD80/CD86 interact with CTLA4 = inhibitory signal
  4. Block CTLA4 = all interactions of CD80/CD86 go though CD28 = boosted T cell response
307
Q

name an antibody specific for CTLA4 and what it is used to treat?

A

Ipilimumab

treat melanoma

308
Q

how does blocking PD-1 boost the immune response?

A
  • PD1 found on T-reg cells
  • its ligands (PDL1, PDL2) are on APCs and on some tumour cells
  • ABs against PD1 prevent inhibitory effect of binding PD1 abd PD1L = activating T cells to kill
309
Q

what ABs block PD1 and what do they treat?

A
  • Pembrolizumab, Nivolumab

- treat advanced melanoma

310
Q

what is the downside to blocking immune checkpoints?

A
  • pt develop AI diseases
311
Q

when is TNF-alpha cytokine therapy used?

A
  • hairy cell leukaemia
  • CML
  • MM
312
Q

when is IFN-beta cytokine therapy used?

A

Behcet’s disease

313
Q

when is IFN-gamma therapy used?

A
  • chronic granulomatous disease
314
Q

when is IL2 cytokine therapy used?

A

increases clonal expansion –> renal cell cancer

315
Q

what are the different ways to suppress the immune system?

A
  • steroids
  • anti-proliferative agents
  • plasmapheresis
  • inhibitors of cell signalling
  • agents directed at cell surface antigens
  • agents directed at cytokines
316
Q

what are the effects of steroids on prostaglandins?

A
  • inhibit phospholipase A2
    normally:
    1. phospholipids –> arachidonic acid (enzyme phospholipase A2)
    2. arachidonic acid –> eicosanoids e.g. prostaglandins/ leukotrienes (enzyme COX)
  • prostaglandins/leukotrienes are proinflammatory
  • steroids inhibit phospholipase A2 = dec inflammation
317
Q

what are the effects of steroids on phagocytes?

A
  • dec traffic of phagocytes to inflamed tissue
  • dec phagocytosis
  • dec release of proteolytic enzymes
318
Q

what are the effects of steroids on lymphocyte function?`

A
  • lymphopaenia (sequestration of lymphocytes in lymphoid tissue)
  • blocks cytokine gene expression
  • dec antibody production
  • promotes apoptosis
319
Q

side effects of corticosteroids

A
  • metabolic (Cushing’s): central obesity, moon face, diabetes, lipid disorders, osteoporosis, hirsutism
  • cataracts
  • glaucoma
  • peptide ulceration
  • pancreatitis
  • avascular necrosis
  • immunosuppression
320
Q

name 3 antiproliferative agents (cytotoxic agents)

A
  • cyclophosphamide
  • mycophenolate
  • azathioprine
321
Q

general MOA of anti-proliferative agents

A
  • inhibit lymphocyte proliferation via inhibiting DNA synthesis
  • cells with rapid turnover most sensitive
322
Q

what is the MOA of cyclophosphamide?

A
  • alkylating agent
  • damages DNA and prevents cell replication
  • affects B cells > T cells
323
Q

what are the major indications of cyclophosphamide?

A
  • multisystem connective tissue disease
  • vasculitis with severe send organ involvement (e.g. GPA, SLE)
  • cancer
324
Q

side effects of cyclophosphamide

A
  • toxic to proliferating cells (BM suppression, hair loss)
  • haemorrhagic cystitis
  • malignancy (bladder, haem, non-melanoma)
  • teratogenic
  • infeciton (PCP pnuemonia)
325
Q

MOA of aziothioprine

A
  • purine analogue
  • blocks de novo purine synthesis
  • prevents replication of DNA
  • affects T cells > B cells
326
Q

indications for azathioprine

A
  • transplantation
  • auto-immune disease
  • auto-inflammatory disease (e.g. Chron’s, UC)
327
Q

what are the side effects of azathioprine?

A
  • BM suppression (people with TPMT polymorphisms particularly vulnerable as can’t metabolise = CHECK)
  • hepatotoxicity
  • infection
328
Q

MOA of mycophenolate mofetil

A
  • anti-metabolite
  • blocks de novo guanosine nucleotide synthesis
  • prevents replication of DNA
  • prevents T cell > B cell
329
Q

indications of Mycophenolate Mofetil

A
  • transplantation
  • auto-immune disease
  • vasculitis
330
Q

side effects of mycophenolate mofetil

A
  • BM suppression
  • teratogenic
  • infection (Herpes reactivation, PML, JC virus)
331
Q

what is plasmapheresis?

A
  • removal of pathogenic antibodies from pt blood

- reinfused

332
Q

what are the problems with plasmapheresis?

A
  • rebound antibody production

- can co-administer an anti-proliferative agent

333
Q

indications for plasmapheresis

A

severe antibody mediated disease

  • Goodpastures
  • severe acute myasthenia gravis
  • severe transplant rejection
334
Q

what are the different things you can inhibit in cell signalling?

A
  • calcineurin (ciclosporin, tacrolimus)
  • JAK (tofacitinib)
  • PDE4 (apremilast)
335
Q

how do calcineurin inhibitors work?

A
  • prevent T cell signalling
  • block IL2 production
  • reduces activation of T cells
  • dec clonal expansion and proliferation
336
Q

side effects of calcineurin inhibitors

A
  • nephrotoxicity
  • HTN
  • neurotoxic
  • diabetogenic
337
Q

how do JAK inhibitors work?

A
  • interferes with JAK-STAT signalling
  • important in transducing signals from cytokine binding
  • influences gene transcription
  • inhibits production of inflammatory molecules
338
Q

indication of JAK inhibitors

A

RA or psoriatic arthritis

339
Q

how do PDE4 inhibitors work?

A
  • inc cAMP
  • activate PKA
  • prevent activation of TFs
    = dec in cytokine production
340
Q

indication of PDE4 inhibitord

A

psoriasis or psoriatic arthritis

341
Q

how do agents directed at cell surface antigens work?

A
  • block signalling

- cell depletion

342
Q

what do anti-thymocyte globulins cause and the indication?

A
  • causes T cell depletion

- Ix: allograft rejection, daily IV infusion

343
Q

what are the general side effects of agents directed at cell surface antigens

A
  • infusion reactions
  • infection
  • long term malignancy risk
344
Q

how does Basiliximab work and what are the indications?

A
  • anti-CD25/IL2 receptor AB
  • inhibits T cell proliferation
    Ix: prophylaxis of allograft rejection
345
Q

how does Abatacept work? what is the indication?

A
  • CTLA4 Ig fusion protein
  • opposite of Ipilimumab
  • CTLA4 normally transmits inhibitory signal
  • Abatacept causes upregulation of this so causes more reduced T cell activation = suppression
346
Q

how does Rituximab work? indications?

A
  • anti-CD20
  • this is expressed on mature B cells but NOT plasma cells = depletion of mature B cells
    Ix: lymphoma, RA, SLE
347
Q

how do vedolizumab/natalizumab work? Indications?

A
  • inhibits leucocyte migration to tissues

- Indications: IBD, remitting/relapsing MS

348
Q

how does Tocilizumab/Sarlimimab work? Indications?

A
  • anti-IL6 receptor AB
  • reduces activation of macrophages, T cells, B cells, neutrophils
    Ix: Castleman’s disease, RA
349
Q

name an anti-TNFa drug and its MOA

A
  • infliximab

- directly binds to TNFa and mops it up

350
Q

indications of anti-TNFa drug

A 
RA
Psoriasis and psoriatic arthritis
FMF
Ankylosing spondylitis
IBD
351
Q

how does a TNFa antagonist work?

A
  • decoy receptor that mops up TNFa
  • inhibits action of TNFa and TNFb
    Ix: RA, ankylosing spondylitis, psoriasis/psoritatic arthritis
352
Q

how does denosumab work?

A
  • anti-RANK-ligand
  • prevents RANKL binding to RANK on osteoclasts
  • less activation of osteoclasts so less bone resorption
353
Q

side effects of Denosumab

A
  • injection site
  • infection
  • avascular necrosis of jaw
354
Q

overall side effects of biologicals

A
  • infusion reactions
  • injection site reactions
  • acute infection
  • chronic infection (TB, HCV, HIV, JC)
  • malignancy (lymphoma - EBV, non-melanoma skin cancers - HPV, melanoma)
  • autoimmunity `
355
Q

what is the most commonly transplanted organ?

A

kidneys

356
Q

what are the 3 phases of the immune response to a transplanted graft?

A
  1. recognition of foreign antigens
  2. activator of antigen-specific lymphocytes
  3. effector phase of graft rejection
357
Q

what are the most relevant protein variations in clinical transplant?

A
  • ABO blood group
  • HLA (on Chr 6 by HLA)
  • other minor histocompatibility genes
358
Q

what are the 2 major forms/ components of rejection?

A
  • T cell mediated rejection

- antibody mediated rejection

359
Q

what are the HLA class molecules? where are they expressed?

A
  • HLA class I (A, B, C): expressed on ALL cells (meant to be most immunogenic)
  • HLA class II (DR, DQ, DP): expressed on APCs (also be upregulated on other cells under stress)
360
Q

what are the most important HLA molecules to match?

A

DR > B > A

361
Q

what are the features of HLA molecules?

A
  • highly polymorphic
  • high degree of variability
  • allows us to present a wide variety of antigens
  • number of mismatches = major determinant of risk of rejection
362
Q

how many mismatches between parent and child and siblings?

A
  • parent to child = >= 3 always matched

- sibling to sibling = 25% 6MM, 50% 3MM, 25% 0MM

363
Q

describe phase 1 of T cell mediated rejection

A
  1. to activate alloreactive T cells (against transplant), T cells require: presentation of foreign HLA antigens in MHC by APCs and costimulatory signals
  2. APCs pick up antigens from donor MHC and activate T cells in nodes
  3. leads to effector phase = inflammation can lead to graft dysfunction
364
Q

how can you determine is rejection is occuring?

A

biopsy

365
Q

what is phase 2 of T cell mediated rejection?

A

actions of activated T cells

  • proliferation
  • produce cytokines (IL2)
  • provide help to CD8+ cells
  • provide help for antibody production
  • recruit phagocytic cells
366
Q

what effects do cytotoxic T cells have inside the transplanted organ?

A
  • granzyme B (toxin)
  • perforin (punch holes)
  • Fas-ligand (apoptosis)
367
Q

what effects do macrophages have inside the transplanted organ?

A
  • phagocytosis
  • proteolytic enzymes
  • cytokine release
  • oxygen and nitrogen radicals
368
Q

what happens in the effector phase of T cell mediated rejection?

A
  • T cells will tether, roll and arrest on endothelial cell surface
  • they will crawl through into interstitium and start attacking tubular epithelium
369
Q

what are the histological features of T cell mediated rejection?

A
  • lymphocytic interstitial infiltration
  • ruptured tubular basement membrane
  • tubulitis (inflammatory cells within tubular epithelium)
  • macrophages, recruited by T cells
370
Q

what are the 2 phases to antibody mediated rejection?

A
  1. exposure to foreign antigen
  2. proliferation and maturation of B cells with antibody production
  3. effector phase: ABs bind to graft endothelium (capillaries of glomerulus and around tubules)
371
Q

what can be said about anti-HLA compared to anti-ABO?

A
  • anti-ABO ABs naturally occur

- anti-HLA ABs are not naturally occuring

372
Q

how can someone have anti-HLA ABs?

A
  • pre-formed: due to previous exposure to epitopes (e.g. previous tranplants, pregnancy, transfusion)
  • post-formed: after tranplant
373
Q

what are the action of antibodies in infection AND transplant rejection?

A
  • neutralise toxin
  • opsonise (aid phagocytosis)
  • antibody-dependant cellular cytotoxicity
  • complement activation = MAC lysis, opsonise, inflammation
374
Q

what is phase 3 with antibodies in transplantation?

A
  • ABs bind to antigens (HLA) on endothelium of blood vessels in transplant
  • ABs fix/activate complement (so get MAC = endothelial cell lysis, recruitment of inflammatory cells to microcirculation)
  • ABs can crosslink MHC molecules so activate them
  • ABs recruit mononuclear cells, NK cells, neutrophils = capillaritis
375
Q

what is the cardinal feature of antibody-mediated rekection?

A

capillaritis
= inflammatory cells in capillaries of kidney
= injury

376
Q

what can all of these AB processes lead to?

A

procoagulant tendencies
closure of microcirculation
= graft fibrosis

377
Q

what is the histology in antibody mediated rejection?

A
  • inflammatory cell infiltrate
  • capillaritis
  • immunohistochemistry (fixation of complement fragments on endothelial cell surfaces)
378
Q

what is the main difference in the damage that T cell and B cell rejection causes?

A

T cells = interstitial damage

ABs = endothelial damage

379
Q

how can graft rejection be prevented and treated?

A
  • HLA typing
  • screening for HLA-Antibodies
  • immunosuppression
380
Q

how is HLA typing done?

A

before transplant

via PCR DNA sequencing

381
Q

when do you screen for anti-HLA ABs?

A

before
at time
after transplant

382
Q

what are the 3 different assays used for anti-HLA screening?

A
  • cytotoxicity assays
  • flow cytometry
  • solid phase assays
383
Q

what do cytotoxic assays look for?

A

if recipient’s serum will kill lymphocytes of donor, in presence of complement

384
Q

what does flow cytometry look for?

A
  • inspect if recipient’s serum binds to donor’s lymphocyes

- looks at whether antibodies bind to antigen irrespective of whether they bind complement

385
Q

what do solid phase assays detect?

A
  • uses series of beads containing all possible HLA epitopes
  • see which HLA epitopes the antibodies bind to
  • can also give indication of strength of reaction
386
Q

how do you overcome organ mismatch issues?

A
  • improve transplantation across tissue barriers
  • more donors
  • organ exchange programmes
  • xenotransplantation, stem cell research
387
Q

what are the ways that T cells can be targeted using immunosuppression?

A
  • suppressing T cell activation
  • stopping IL2 release which leads to further activation
  • pathways (many involving calcineurin) involved in cell proliferation
  • targeting costimulatory signals
388
Q

what are 3 signals to activate T cells than can be targeted?

A
  1. APC MHC to T cell TCR (main signal)
  2. AOC CD80/CD86 to T celll CD28 (CD80/86 to CTLA4 suppresses immune reactions)
  3. cytokine IL2 to T cell CD25 (autocrine IL2 released to further activate)
389
Q

what management drugs are used in T cell mediated rejection?

A
  • steroids (prevent general T cell mediated rejection)
  • inhibitors of cell signalling/ calcineurin inhibitors (i.e. Tacrolimus, cyclosprorine)
  • anti-proliferative agents (e.g. mycophenolate mofetil, azathioprine)
  • inhibitors of cell surface receptors
390
Q

what are the main targets of immunosuppression for stopping antibody mediated rejection?

A
  • B cell activation
  • plasma cell secretion of ABs
  • antibody effects of endothelium
391
Q

what are the management drugs in antibody mediated rejection?

A
  • rituximab (anti-CD20): B cell depletion
  • BAFF inhibitors: target cytokines that promote B cell activation and growth
  • proteasome inhibitors: block production of ABs by plasma cells
  • complement inhibitors: block complement binding to endothelial cells
392
Q

what is a modern transplant immunosuppression regimen?

A
  • induction agent: given at time of transplant/ just before e.g. anti-CD25/52
  • baseline immunosuppression: calcineurin inhibitor + mycophenolate mofetil/ azathioprine +/- steroids
393
Q

what are the modern treatments of epsiodes of acute rejection?

A
  • cellular: steroids, OKT3, ATG

- antibody-mediated: IVIG, plasmapheresis, anti-C5, anti-CD20

394
Q

how does IVIG work?

A
  • reduces AB production through feedback and displaces troublesome ABs so they cannot exert their harmful effects
395
Q

what is a complication of HSCT?

A

GvHD

396
Q

what is the pathogenesis of HSCT?

A
  • host immune system eliminated (total body irradiation and drugs)
  • replaced by own (autologous) or HLA-matched donor (allogenic) bone marrow
  • allogenic SCT = reaction of donor lymphocytes against host tissues
  • if malignancy (e.g. leukaemia), graft can help kill these cells (graft-versus-tumour)
397
Q

what is GvHD prophylaxis?

A

methotrexate/cyclosporine

398
Q

GvHD treatment?

A

steroids

399
Q

GvHD symptoms?

A

looks like slow onset anaphylaxis with jaundice

  • rash
  • N&V
  • abdo pain
  • diarrhoea/bloody stools
  • jaundice
400
Q

what are the risk of post transplant infection?

A
  • inc risk of conventional infections

- inc risk of opportunistic infections (CMV, BK virus, PCP)

401
Q

what are the cells of the innate immune system?

A
  • phagocytes
  • cytokines and receptors
  • NK cells
402
Q

what are the cells of the adaptive immune response?

A
  • T cells

- B cells

403
Q

what diseases are caused by failure of neutrophil differentiation?

A
  • reticular dysgenesis
  • severe congenital neutropaenia (Kostmann)
  • cyclic neutropaenia
404
Q

what disease is caused by failure to express leukocyte adhesion markers?

A

Leukocyte adhesion deficiencies

405
Q

what diseases are caused by failed of oxidative killing of phagocytes?

A

chronic granulomatous disease

406
Q

what diseases are caused by failure of cytokine production in macrophages?

A

IFNy, IFNyR and IL12, IL12R deficiency

407
Q

how do phagocyte deficiencies present?

A

infections:

  • recurrent skin/mouth infections (Bacterial, fungal)
  • mycobacterial infection (TB, atypical)
408
Q

what is the treatment of phagocyte deficiencies?

A

aggressive management of infection:
- infection prophylaxis: Antibiotics (e.g. Septrin), Antifungals (e.g. Itraconazole)
- oral/IV ABx
definitive therapy:
- HSCT
- specific tx for chronic granulomatous disease (IFNg therapy)

409
Q

what are the features of NK cells?

A
  • inhibitory receptors recognise self-HLA = prevent inappropriate activation to normal self
  • activator receptors recognise heparan sulphate proteoglycans = cytotoxicity, cytokine secretion
410
Q

what do deficiencies of NK cells lead to?

A

viral infections

  • HHV infections (HSV 1/2, VZV, EBV, CMV)
  • HPV infection
411
Q

treatment of NK cell deficiencies

A
  • prophylactic aciclovir/ ganciclovir
  • HSCT
  • cytokines (IFN-a) to stimulate NK cytotoxic function
412
Q

What is the problem in leukocyte adhesion deficiency?

A
  • neutrophils lack LFA-1

- normal: CD11a/CD18 (LFA-1) on neutrophils binds to ICAM-1 on endothelium for adhesion and transmigration

413
Q

symptoms in LAD

A
  • very high neutrophil count in blood
  • absence of pus formation
  • delayed umbilical cord separation at birth
414
Q

what is the problem in chronic granulomatous disease?

A
  • failure of oxidative killing
  • can’t generate free radicals
  • absence respiratory burst
415
Q

signs and symptoms of CGD

A
  • excessive inflammation (persistent neutrophil/macrophage accumulation, failure to degrade antigens)
  • granuloma formation
  • lymphadenopathy and hepatosplenomegaly
416
Q

tests for CGD

A

DHR and NBT both negative

both detect hydrogen peroxide

417
Q

what do kostmann syndrome, reticular dysgenesis and cyclic neutropoenia all have in common?

A

failure to produce neutrophils

418
Q

what is the problem in reticular dysgenesis?

A
  • failure of stem cells to differentiate along myeloid or lymphoid lineage
  • mutation in mitochondrial energy metabolism enzyme AK2
  • AR severe SCID
419
Q

how do you differentiate Reticular dysgenesis and Kostmann?

A
  • RD has both low B and T cell numbers
420
Q

what is the overall problem in Kostmann syndrome and cyclic neutropaenia? how does it show?

A

specific failure of neutrophil maturation

no neutrophils, recurrent infections

421
Q

what is the mutation in Kostmann?

A

AR severe congenital neutropenia

mutation = HCLS1-associated protein

422
Q

what is the mutation in cyclic neutropenia?

A

AD episodic neutropenia every 4-6 weeks

mutation = neutrophil elastase

423
Q

what causes a failure of the IL12/IFNg network?

A

cytokine deficiency in 1 of:

IL12, IL12R, IFNg, IFNgR

424
Q

what is this network important in?

A

mycobacteria infection

425
Q

how does this network work?

A
  1. infection activates IL12-IFNg network
  2. infected macrophages produce IL12
  3. IL12 induces T cells to secrete IFNg
  4. IFNg feeds back to macrophages and neutrophils
  5. stimulates production of TNF
  6. Activates NADPH oxidase –> oxidative pathways
426
Q

what are the 2 kinds of NK cell deficiencies?

A
  • classical

- functional

427
Q

how do NK deficiencies present?

A

child with severe chicken pox and disseminated CMV infection

VIRAL

428
Q

what is the abnormality in classical NK deficiency?

A
  • absence of NK cells within peripheral blood

- abnormal GATA2/ MCM4 genes

429
Q

what is the abnormality in functional NK deficiency?

A
  • NK cells present but function abnormal

- abnormal FCGR3A gene

430
Q

what are the functions of complement?

A
  • inc vascular permeability/cell chemotaxis
  • promote clearance of immune complexes
  • opsonisation of pathogens –> phagocytosis
  • activate phagocytes
  • promote mast cell/ basophil degranulation
  • form the MAC
431
Q

how is the classical pathway activated?

A

antibody + C1 –> C2, C4 –> C3

  • changed antibody site exposes C1 binding site
  • C1 binding to antibody, activates cascade
  • antibody-antigen immune complexes
432
Q

how is the MBL pathway activated?

A

MBL –> C2, C4 –> C3

  • binding of MBL to microbial cell surface CHO
  • direct stimulation of classical pathway
  • not dependent on acquired immune response
433
Q

how is the alternative pathway activated?

A

PAMP (LPS, teichoic acid) –> C3

  • C3 binds to bactieral wall components
  • involves factors B, P, D
  • not dependant on acquired immune response
434
Q

what is the problem with complement deficiency?

A

may involve classical, alternative, C3 or final common pathway

435
Q

what does complement deficiency leave you susceptible to?

A

bacterial infection (esp encapsulated/NHS)
Neisseria meningitides esp. properidin def, C5-9 def
Haemophilius influenzae
Streptococcus pneumoniae

436
Q

what happens if there is an MBL deficiency?

A

common

not usually associated with immunodef

437
Q

what does a C1, C2, C4 deficiency increase your risk of?

A

inc risk of SLE/autoimmunity

438
Q

how do deficiencies in classical pathway lead to SLE/AI?

A
  • normally pathway involved in phagocyte mediate clearance of apoptotic/necrotic cells
  • if deficient = self antigens uncleared = AI, immune complexes
  • normally pathway involved in clearance of immune complexes by erythrocytes
  • if deficient = immune complex deposition = local inflammation
439
Q

what happens with a C3 nephritic factor?

A
  • anti-C3 convertase = depletes C3
440
Q

what is it associated with?

A

glomerulonephritis

partial lipodystrophy

441
Q

management of a complement deficiency?

A
  • vaccination (esp against NHS)
  • prophylactic Abx
  • treat infection aggressively
  • screening of family members
442
Q

investigations into complement deficiency?

A
  • levels of C3/C4

- functional complement tests

443
Q

what are the functional complement tests?

A
  • CH50 classical pathway (CH)

- AP50 alternative pathway (AP): properidin, factors B and D

444
Q

what are the primary lymphoid organs?

A
  • organs involved in lymphocyte development
  • bone marrow (T/B cell derivation, B cell matures)
  • thymus (site of T cell maturation)
445
Q

when is thymus most active?

A

in foetal and neonatal period

involutes after puberty

446
Q

what diseases are causes by failure of lymphocyte precursors?

A

severe combined immune def (X-linked SCID, ADA def)

447
Q

what diseases are causes by failure of thymic development?

A

22q11/2 syndromes

e.g. DiGeorge syndrome

448
Q

what diseases are caused by failure of expression of HLA molecules?

A

bare lymphocyte syndromes

449
Q

what diseases are causes by failure of signaling, cytokine production and effector functions?

A
  • IFNg/R def

- IL12/R def

450
Q

what are the clinical features of T cell def?

A
  • viral infections (CMV)
  • fungal infections (pneumocystis)
  • some bacterial infections (esp intracellular e.g. TB, salmonella)
  • early malignancy
451
Q

investigations of T cell def?

A
  • WCC and differentials (WCC higher in children than adults)
  • lymphocyte subsets (CD8, CD4, NK)
  • immunoglobulins (if CD4 T cell def)
  • functional tests of T cell activation/proliferation
  • HIV test
452
Q

what is the management of T cell immunodeficiency?

A
  • aggressive prophylaxis/treatment of infection
  • HSCT
  • enzyme replacement therapy
  • gene therapy
  • thymic transplantaion
453
Q

what is the problem in X-linked SCID?

A
  • mutation of common gamma chain on chromosome X
  • inability to respond to cytokines
  • causes early arrest of T cell/ NK cell development
  • causes production of immature B cells
454
Q

phenotype of X-linked SCID

A
  • low/absent T cells (early arrest)
  • low/absent NK cells (early arrest)
  • normal/inc B cells (immature B cells = cannot make Ig)
  • very low Ig
455
Q

what is ADA (adenosine deaminase) deficiency?

A

ADA: enzyme that lymphocytes need for cell metabolism

  • inability to respond to cytokines
  • early arrest of T cell development
  • production of no B cells
456
Q

phenotype of ADA def?

A
  • low/absent T cells
  • low/absent NK cells
  • low/absent B cells
  • Low Ig
457
Q

what is the key difference between ADA and X-linked SCID?

A

X-linked SCID: normal/increased B cells

ADA def: low/absent B cells

458
Q

why are babies protected from these in first 3 months of life?

A
  • IgG from maternal placental supply

- IgG from breast milk colostrum

459
Q

what is the deletion in Di George syndrome?

A

22q 11.2 deletion syndrome

460
Q

what is the problem in Di George?

A

developmental defect of pharyngeal puch

461
Q

features of Di George

A 
CATCH 22
Cardiac abnormalities (ToF)
Abnormal facies (high forehead, low set folded ears, micrognathia, broad nasal bridge)
Thymic aplasia (+/- oesophageal atresia)
Cleft palate
Hypocalcaemia, hyperparathyroidism
22q 11.2
462
Q

what is the phenotype for Di George?

A
  • normal B cell number
  • reduced T cell number
  • only mild impairment of immunity that improves with age
  • PCP pneumonia, atypical viral infection (need T cells to control these)
463
Q

what is bare lymphocyte syndrome (type 2)?

A
  • absent MHC class 2 expression
464
Q

phenotype in bare lymphocyte syndrome?

A

T cells = low CD4, normal CD8

B cells = normal, low IgG or IgA antibody (lack of CD4+ T cell help)

465
Q

what disease is caused by failure of B cell maturation?

A

Bruton’s X-linked agammaglobulinemia

466
Q

what disease is caused by failure of T cell costimulation?

A

X-linked hyper IgM syndrome

467
Q

what disease is caused by failure of production of IgG antibodies?

A

common variable immune def

selective antibody def

468
Q

what disease is caused by failure of IgA production?

A

selective IgA def

469
Q

what are the features of a B cell deficiency (antibody def)?

A
  • bacterial infections (Staph, Strep)
  • Toxins (tetanus, diptheria)
  • some viral infections (enterovirus)
470
Q

investigations of B cell deficiencies

A
  • WCC and differential
  • lymphocyte subsets
  • immunoglobulins and protein electrophoresis (IgG production = surrogate marker of CD4-T help function)
  • functional tests of B cell activation/proliferation (specific AB responses to known pathogens)
471
Q

management of B cell immunodeficiency?

A
  • aggressive prophylaxis/treatment of infection
  • IVIG (life long)
  • immunization (only selective IgG def, not otherwise as can’t produce IgG antibody production)
472
Q

what is the problem in Bruton’s X-linked hypogammaglobulinaemia?

A
  • abnormal B cell tyrosine kinase
  • pre B cells cannot develop to mature B cells
  • absence of mature B cells
  • no circulating Ig after 3 months
473
Q

management of Bruton’s X-linked?

A

IVIG

474
Q

what is the problem in X-linked hyper-IgM syndrome?

A
  • CD40 ligand mutation

- involved in T-B cell communication

475
Q

phenotype of hyper-IgM syndrome

A
  • B cells: normal
  • T cells: normal
  • No germinal centre development within lymph nodes and spleen
  • failure of isotype switching: IgM high, others undetectable
476
Q

what is common variable immune deficiency?

A
  • failure of production of IgG ABs
477
Q

core features of common variable immunodeficiency

A
  • low IgG/IgA/IgE
  • poor response to immunization
  • atypical SLE, recurrent bacterial infection
478
Q

clinical features of common variable immunodeficiency

A
  • recurrent bacterial infections
  • pulmonary disease
  • GI disease (IBD-like, bacterial overgrowth)
  • AI disease (haemolytic anaemia, RA, pernicious anaemia, thyroiditis, vitiligo)
  • malignancy (NHL)
479
Q

core features of IgG def

A
  • 2/3 symptomatic
  • 1/3 recurrent infections
  • absent IgA
  • normal IgM, IgG
480
Q

what are the causes of low MCV anaemia?

A
  • iron def
  • thalassaemia trait
  • anaemia of chronic disease
481
Q

when would you see hypochromic, microcytic cells?

A
  • iron def

- thalassaemia trait

482
Q

when would you see poikilocytes (tear drop cells)?

A

iron deficiency

483
Q

when would you see anisopoikilocytes (elliptocytes)?

A

iron deficiency

484
Q

when would you see basophilic stippling?

A
  • beta thalassaemia trait
  • lead poisoning
  • alcoholism
  • sideroblastc anaemia
485
Q

when would you see hypersegmented neutrophils?

A

megaloblastic anaemia
B12 def
folate def
drugs

486
Q

when would you see target cells (codocytes)?

A
  • iron def
  • thalassaemia
  • hyposplenism
  • liver disease
487
Q

when would you see howell-jolly bodies (nuclear remnants)?

A

hyposplenism

488
Q

what are the causes of iron def?

A
  • blood loss
  • poor diet
  • malabsorption
489
Q

what are the causes of megaloblastic anaemia?

A

B12/folate def from

  • poor diet
  • malabsorption
  • pernicious anaemia
490
Q

what are the causes of hyposplenism?

A
  • absent spleen (trauma, therapeutic)

- poorly functioning spleen (IBD, Coeliac’s, SCD, SLE)

491
Q

what can malabsorption cause? things that can support coeliac diagnosis

A
  • Vit D def
  • B12/folate def
  • hyposplenism
  • iron def
492
Q

deficiencies seen in Coeliac

A
  • iron
  • B12
  • folate
  • fat
  • calcium
493
Q

deficiencies in chron’s disease

A

B12

bile salts

494
Q

deficiencies seen in Pancreatic disease

A

fat
calcium
B12

495
Q

deficiencies seen in infective/post-infective causes

A

fat

folate

496
Q

Ix in coeliac

A
  • inflammatory markers (CRP, ESR)
  • serological tests
  • upper GI endoscopy
  • distal duodenal biopsy (gold standard)
  • other (faecal elastase, pancreolauryl test, CT scan, MRI small bowel)
497
Q

what is coeliac disease?

A

polygenic autoimmune disease

polygenic: several mutations affecting many proteins contribute to disease

498
Q

what mutations are found in coeliac disease?

A

HLA DQ2
HLA DQ8
most other mutations thought to affect adaptive immune response

499
Q

what is the T cell response to gluten?

A
  1. Gliadin (peptide) from gluten broken down (deaminated) by TTF
  2. deaminated gluten taken up by APCs
  3. APCs present gliadin via HLA molecules (DQ2/8) to CD4 T cells
  4. CD4 T cell activation = secretion of IFNg = inc IL-15 secretion
  5. IL-15 activated intra-epithelial lymphocytes (gamma-delta) T cells
  6. IELs kill epithelial cells
500
Q

what causes the damage to gut wall and lead to presentation of coeliac disease?

A

IELs

501
Q

what is the B cell response to gluten?

A
  1. TTG deaminates gliadin
  2. APC takes up gliadin peptides and primes CD4 T cells
  3. these T cells help B cells undergo germinal centre reactions
  4. B cells undergo isotype switching and affinity maturation = gliadin specific memory and plasms cells
502
Q

where is TTG also expressed?

A

on endomysial cells

so anti-TTG ABs can be detected as anti-endomysial cell ABs

503
Q

what are the serological tests for Coeliacs?

A

1st line screening: IgA anti-TTG (can’t be done in IgA deficient patients)
1st line diagnosis: multiple (>4) duodenal biospy (need baseline before start treatment)

504
Q

what will be seen on endoscopy in coeliac?

A
  • lack of mucosal fold

- flattened villi

505
Q

what are the key histopathological findings in Coeliac?

A
  1. villous atrophy = dec SA = malabsorption
  2. crypt hyperplasia = villous height reduced, crypts hyperplastic
  3. > 20 IELs/100 epithelial cells (normal <20)
  4. IELs = gamma-delta T cells (most are alpha-beta)
506
Q

what are other causes of villous atrophy?

A
  • giardiasis
  • chron’s disease
  • nutritional deficiencies
  • microvillous inclusion disease
  • topical sprue
  • radiation/chemo
  • GvHD
  • CVID
507
Q

what are other conditions associated with increased IELs?

A
  • dermatitis herpetiformis (linked to Coeliac)
  • Cow’s milk protein sensitivity
  • tropical sprue
  • Drugs (NSAIDs)
  • giardiasis
  • IgA def
  • post-infective malabsorption
  • lymphoma
508
Q

what are the components to management of coeliac?

A
  • dietary management
  • implications for family
  • ongoing monitoring
  • advice regarding long term complications
  • sources of patient info
509
Q

what are the complications of coeliac?

A
  • malabsorption
  • osteomalacia and osteoporosis
  • neurological disease (epilepsy, cerebral calcification)
  • lymphoma (MOST DANGEROUS) = multi-focal T cell lymphoma (difficult to treat)
  • hyposplenism
510
Q

what are the implications on the family?

A
  • practical (cost, do all family go gluten free)

- prognostic (genetic = inc risk to family members)

511
Q

what support and information should be offered?

A
  • support groups
  • medical staff
  • dieticians
  • family
512
Q

which antibodies disappear within months after institution of gluten free diet? which lasts a bit longer?

A
  • IgA anti-TTG and IgA endomysial

- IgA anti-gliadin most persistent up to 12 months

513
Q

what imaging should be used in coeliac complication monitoring?

A

DEXA scan of spine and hip every 3-5 yrs

514
Q

what is the mortality of untreated coeliacs? from what?

A

2-3 x general population (return to normal if stick to diet for 3 yrs)
from malignancy or infection

515
Q

what are some associations with coeliac disease?

A
  • dermatitis herpetiformis
  • T1DM
  • AI thyroid disease (and malabsorption can reduce absorption of some meds e.g. thyroxine)
  • Down’s
516
Q

mechanism of anaphylaxis

A
  • type 1 hypersensitivity
  • cross linking of IgE on mast cells = degranulation
  • release of histamine and leukotrienes
517
Q

what does anaphylaxis result in?

A
  • increased vascular permeability
  • smooth muscle contraction
  • inflammation and increased mucus production
  • clinical features of anaphylaxis (at least 10)
518
Q

what are the clinical features of anaphylaxis?

A
  • feeling of impending doom, loss of consciousness, death
  • angioedema of lips and mucous membrane
  • conjunctival infection, rhinorrhoea, angioedema
  • laryngeal obstruction, stridor
  • hypotension, cardiac arrhthmias, MI
  • vomiting, diarrhoea, abdo pain
  • flushing, urticaria
  • wheeze, bronchoconstriction
  • itch of palms, soles of feet and genitalia
519
Q

management of anaphylaxis?

A
  • ABC
  • mask O2
  • IM (1 in 1000) adrenaline (0.5mg for adult) and may repeat
  • IV antihistamines (10mg chlorpheniramine = oppose mast cell histamines)
  • nebulised bronchodilators
  • IV corticosteroids (200mg HC)
  • IV fluids (inc BP)
520
Q

common causes of anaphylaxis

A
  • foods: peanuts, tree nuts, fish, milk, eggs, soy products
  • insect stings; bee venom, wasp venom
  • chemicals, drugs, other foreign proteins: penicillin, IV anaesthetic agents, latex
521
Q

what are the 2 types of latex allergy?

A
  • type 1 hypersensitivity

- type 4 hypersenitivity

522
Q

what is type 1 hypersensitivity latex allergy?

A
  • acute classic anaphylactic symptoms after exposure
  • mucosal route associated with more severe reactions
  • specific pts are particularly affected (preterm, indwelling latex devices, multiple urological procedures)
  • can cross react with some foods (mostly fruits)
523
Q

what is type 4 hypersensitivity reaction?

A
  • contact dermatitis (itchy, well demarcated rash)
  • symptoms over 24-48 hours
  • not responsive to anti-histamines
  • hands and feet usually
524
Q

investigations to confirm anaphylaxis diagnosis

A
  • test for specific IgE
  • skin prick testing
  • patch testing
  • biopsy (infiltrating T-cells, granuloma formation)
525
Q

long term management of anaphylaxis

A
  • refer to allergist/immunologist
  • avoidance plan
  • alert HCPs and occupational health
  • medic-alert bracelet
  • EpiPen
  • further info sources (www.anaphylaxis.org.uk)
526
Q

what are immunological disorders associated with recurrent meningococcal meningitis?

A
  • complement deficiency (inc risk of encapsulated organisms)

- antibody deficiency (recurrent bacterial infections)

527
Q

what are neurological disorders associated with recurrent meningococcal meningitis?

A

any disturbance of blood-brain barrier

e.g. occult skull fracture, hydrocephalus

528
Q

investigations into immunological causes of recurrent meningococcal meningitis

A

COMPLEMENT:
- C3 and C4 levels
- CH50: looks at classical complement cascade, +ve result is normal
- AP50: looks at alternative complement cascade, +ve result is normal
IMMUNOGLOBULINS:
- serum IgG, IgA, IgM
- protein electrophoresis

529
Q

management of complement deficiency

A

vaccinations
daily prophylactic penicillin
high suspicion for infections

530
Q

what di you do if you suspect SLE and ABA dilution test is measured to be high?

A

measure specific ANA

  • dsDNA
  • ENA
  • cytoplasmic
531
Q

what happens if dsDNA is +ve?

A

SLE

532
Q

what happens if ENA is +ve?

A
  • Ro, La, Sm, RNP = SLE, Sjogren’s
  • SCL70, RNA Pol, Fibrillarin = Diffuse Cutaneous Scleroderma
  • Mi2, SRP = myositis
533
Q

what happens if cytoplasmic ANA is +ve?

A
  • Jo1 = SRP, myositis

- mitochondria = PBC

534
Q

how does complement testing indicate SLE?

A
  • immune complexes bind to C1a and activate classical pathway = complement consumption
  • low levels of C4 and C3 = active SLE
  • ESR and dsDNA reflect activity of SLE
535
Q

what further testing could you do in SLE?

A
  • urinalysis = proteinuria, microscopic haematuria
  • urine microscopy = red cells, red cell casts
  • renal biopsy = diffuse proliferative nephritis, immune complex, complement deposition
536
Q

what kind of reaction is SLE?

A

type 3 hypersensitivity (immune complex mediated)

537
Q

potential management options for SLE

A
  • prednisolone
  • azathioprine
  • hydroxychloroquine
  • rituximab
  • IVIG
  • mycophenolate mofetil
  • cyclophosphamide
538
Q

serum sickness symptoms

A
  • fever
  • arthralgia of large joints
  • vasculitic skin rash
  • renal function delcine
539
Q

what is the pathophysiology of serum sickness?

A
  • penicillin binds to cell surface proteins
  • acts as “neo-antigen”, stimulates very strong IgG antibody response
  • individual becomes “sensitized” to penicillin
  • next exposure to penicillin = immune complex formation, production of more IgG antibodies
  • immune complexes then deposited in small vessels = vasculitis, renal dysfunction, arthralgia
540
Q

investigations into serum sickness

A
  • low serum C3 and C4 (classical pathway activation)
  • specific IgG to penicllin
  • characteristic biopsy features (skin and kidneys): infiltration of macrophages/neutrophils, deposition of IgG, IgM, complement
541
Q

why do you get a deterioration of renal function?

A

deposition of immune complexes in glomeruli = complement/immune cell activation = inflammation
get increase in serum creatinine, proteinuria, haematuria

542
Q

why do you get disorientation in serum sickness?

A

small vessel vasculitis affecting cerebral blood vessels

can compromise oxygen supply to brain

543
Q

why do you get purpura in serum sickness?

A
  • inflamed blood vessels are likely to leak = local haemorrhage
  • become plugged with clots = compromises oxygen delivery
544
Q

management of serum sickness

A
  • discontinue Abx immediately
  • corticosteroids (dec systemic inflammation)
  • IV fluids(for fluid balance)
545
Q

what are the features suggestive of immunodeficiency?

A
  • severe infections (>1 hospitalisation/year)
  • recurrent minor infections/failure to respond to normal ABx
  • evidence of early end organ damage
  • unusual organisms
  • opportunistic organisms
  • unusual sites of infection
  • concomitant problems (failure to thrive, Fhx, hx of AI)
546
Q

what further investigations into recurrent infections?

A
  • flow cytometry (lymphocyte surface markers): quantify B cells, quantify T cells (CD4+ and CD8+), examine abnormal population
  • specific ABs to known antigens to which one has been exposed
547
Q

what test results would you see in X-linked agammaglobulinaemia?

A
  • failure of pre-B cells to mature

- failure to produce and Ig

548
Q

management of x-linked agammaglobulinemia?

A
  • pooled serum Ig

- every 3 weeks

549
Q

investigation findings in multiple myeloma

A
  • +ve free light chains
  • punched-out lytic lesions
  • pathological fractures
550
Q

what is multiple myeloma?

A

neoplastic proliferation of plasma cells

551
Q

why do you get lytic lesions in MM?

A
  • get massive expansion of single plasma cell clone = excess amounts of single Ig molecule with single specificity
  • get increased numbers of abnormal plasma cells in bone marrow
    = lytic lesions
552
Q

why do you get recurrent infections in MM?

A
  • suppression of production of normal Igs by malignant clone = functional antibody deficiency
553
Q

why do you get anaemia in MM?

A
  • expansion of malignant clones
  • crowd out normal RBC and WC precursors in bone marrow
  • produce local cytokines which inhibit bone marrow function
554
Q

why do you get a high ESR in MM?

A
  • normally RBCs do not clump as repellent -ve surface charge > attractant of plasma constituents
  • but if protein constituents of plasma increase/change = inc attractant charge, causes eythrocytes to clump together, clumped erythrocytes fall more quickly through plasma
    = inc ESR
  • rouleaux formation
555
Q

summary of what you get in multiple myeloma?

A
  • unusual/vertebral fractures
  • measure Ig/electrophoretic strip
  • skeletal survey
  • anaemia, high ESR, high Ca
  • urinary bence jones proteins
  • refer to haematologist
556
Q

what is Rheumatoid arthritis ?

A
  • peripheral, symmetrical polyarthritis with stiffness
  • > 6 weeks
  • may be associated with RF +/- anti-CCP ABs
557
Q

why is it common post-partum?

A
  • due to changes in Th cell profiles during/after pregnancy

- Th2 cells tend to predominate during pregnancy, switch back to Th1 post-partum

558
Q

what is rheumatoid factor?

A

commonly IgM directed against Fc region of human IgG

60-70% specific and sensitive

559
Q

what are anti-CCP ABs?

A
  • citrulline residues by PADI enzymes
  • polymorphisms in PADI enzymes = increased citrullinated residues
  • loss of tolerance to citrullinated peptides = ABs specific to citrullinated peptides
  • highly specific
560
Q

genetic predispositions in RA

A
  • HLA DR1 and DR4: peptide presentation on MHC II
  • PAD1 Type 2 and 4: increase citrullination of proteins
  • PTPN22: normally suppresses T cell activation. mutation suggests T cell activation is important

Pathology - CC (2 decks)

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