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P Intergrated Y2 > CP Immunology - x6 lectures > Flashcards

CP Immunology - x6 lectures Flashcards

1
Q

Define - sensitivity

A

[a/(a+c)]- measure of how good is the test in identifying people with the disease

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2
Q

Define Specificity

A

[d/(b+d)]- measure of how good is the test at correctly defining people without the disease


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3
Q

Define predictive value

A

[a/(a+b)]-The proportion of people with a positive test who have the target disorder


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4
Q

Define predictive value

A

d/(c+d) The proportion of people with a negative test who do not have the target disorder.

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5
Q

Normogram

A

probability of same finding in patients without disease

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6
Q

Types of diagnosis tests

A

Non specific - inflammatory markers

Disease specific - autoantibody testing, HLA typing

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7
Q

Non - specific markers of systemic inflammation

A 
ESR
CRP
Ferritin
Fibrinogen
Haptoglobin
Albumin
Complement
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8
Q

Antinuclear antibodies ANA

- origins

A

LE phenomena detected by Hargraves in 1948
dsDNA identified in 1957
Anti-SM in 1966

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9
Q

Detection of dsDNA and ENA’s

A 
Anti-dsDNA
Crithidia luciliae assay (protosoa)
Farr assay
ELISA
ENA’s
Immunoblots
Individual ELISA’s
Combination of antigens
>100 different antibodies described in SLE
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10
Q

Rheumatoid Factor

A

Antibody (IgM, IgG or IgA) directed against the Fc portion of IgG

Commonly found in rheumatoid arthritis but not diagnostic of the diseases (sensitivity and specificity around 70%)

Can be seen with other diseases in which polyclonal stimulation of B cells is seen (chronic infections)

High titters may be pathogenic in vasculitis

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11
Q

What is Anti-CCP (ACPA)

A

ACPA more specific for RA than Rheumatoid Factor (RF)
Similar Sensitivity to RF
useful prognostic marker
ACPA positive patients tend to have more severe and erosive disease

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12
Q

Anti-neutrophilic cytoplasmic antibodies (ANCA)

  • when 1st described
  • what specific for?
A

1982

autoantibody specific for Wegeners granulomatosis

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13
Q

Cytoplasmic cANCA

  • what is visible under fluorescence
  • what are the target antigens
A
  • Granular fluorescence of neutrophil cytoplasm with nuclear sparing

PR3 (90%)
Azurocidin
Lysozyme (1%)
MPO

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14
Q

Perinuclear pANCA

  • what is visible under fluorescence
  • what are the target antigens
A

Nucleus only

MPO (70%)
Azurocidin
B-glucuronidase
Cathepsin G (5%)*
PR3
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15
Q

Clinical Utility of ANCA testing

A

histopathology = gold standard
-ve ANCA assay do no exclude AASV
+ve ANCA with no symptoms - do not continue to treat

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16
Q

Autoimmune Liver disease

A

Anti-mitochondrial Ab specific for primary biliary sclerosis
Anti-smooth muscle and anti-liver/kidney/microsomal (LKS) Abs, found in autoimmune hepatitis
Antibodies detected by IF screening using rodent tissue block (oesophagus, liver and kidney) and antigen specific ELISA

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17
Q

Autoantibodies - Type 1 Diabetes Melatis

A 
Non pathogenic
Several types:					
islet cell antibodies					
anti-GAD65
  anti-GAD67		
anti-insulinoma antigen 2 (IA-2)			
insulin autoantibodies (IAAs)
Disappear with progression of disease and total destruction of β islet cells
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18
Q

role of autoantibodies in diagnosis of type 1 DM

A

Disease conformation
to identify relatives and patients at risk of developing autoimmune diabetes
Negative predictive value of ICA and IAA is almost 99%
Increased risk of disease development with greater number of different autoantibodies present and younger age of patient

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19
Q

Future of diagnostic testing for autoimmune diseases

A

Cytokines determination in serum
Detection of antigen specific autoimmune T and B cells
T-reg detection, ? measure of therapeutic response
Personalised medicine, genetic profiling to determine individual risk of the disease and to tailor the most appropriate therapy

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20
Q

Where is the most common genetic susceptibility for autoimmune disease?

A

HLA region

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21
Q

How can autoimmunity arise

A

failures in central or peripheral tolerance

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22
Q

causative assoications of autoimmune diseases

A

Sex (F»M)
Age - +++ elderly
Environment - infection, trauma, smoking

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23
Q

Give an example of a disease that illustrates home many complex factors are required to bring about an autoimmune inflammation

A

Rheumatoid arthritis

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24
Q

how does autoimmunity cause clinical disease

A 
Autorective B cells and autoantibodies
Directly cytotoxic
Activation of complement
Interfere with normal physiological function
Autoreactive T cells
Directly cytotoxic
Inflammatory cytokine production
General inflammation and end-organ dammage
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25
Q

Characteristics of organ specific autoimmune disease

A

Affect a single organ
Autoimmunity restricted to autoantigens of that organ
Overlap with other organ specific diseases
Autoimmune thyroid disease is typical

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26
Q

Characteristic of systemic autoimmune disease

A

Affect several organs simultaneously
Autoimmunity associated with autoantigens found in most cells of body
Overlap with other non-organ specific diseases
Connective tissue diseases are typical

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27
Q

Hashimotos thyroiditis

A

Destruction of thyroid follicles by autoimmune process
Associated with autoantibodies to thyroglobulin and to thyroid peroxidase
Leads to hypothyrodism

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28
Q

Grave’s Disease

A

Inappropriate stimulation of thyroid gland by anti-TSH-autoantibody
Leads to hyperthyrodism

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29
Q

myasthenic

A

anti-Ach receptor block the acetylcholine receptor

progressive muscle weakness over the course of the day

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30
Q

Pernicious anaemia

A

Failure of B12 absorption
Intrinsic factor inhibited by plasma cell secretion
B12 not to absorb

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31
Q

Non-specific markers of systemic inflammation

A 
ESR
CRP
Ferritin
Fibrinogen
Haptoglobin
Albumin
Complement
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32
Q

Treatment for autoimmunity

A

Supportive
immunosuppression
preventative

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33
Q

Symptoms of systemic lupus erythmatosus (SLE)

A 
photosensitive malar rash
multiple mouth ulcers
arthralgia
alopecia
pleural effusion
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34
Q

Anti-nuclear antibodies

A

nuclei of cells = sequestered antigen

  • in SLE antibodies agains proteins and DNA in nuclei of cell created
  • Anti-nuclear antibodies bind to skin cells that have been damaged by UV light
  • Antinuclear antibodies and antigens = immune complex cause inflammation in ANY tissue
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35
Q

Lupus Nephritis

A 
Immune complex deposition
Inflammation
Leaky glomerulus
loss of renal function
scarring
irreversible renal failure
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36
Q

Treatment of SLE

A

Immunosuppression

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37
Q

What is vasculitis

A

inflammation of small vessels

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38
Q

3 types of ANCA vasculitis

A

Microscopic Polyangiitis (MPA)
Granulomatosis with Polyangiitis (GPA)
Eosinophilic Granulomatosus with Polyangiitis (EGPA)

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39
Q

Granulomatosis with Polyangiitis

AKA - Wegener’s Granulomatosis

A 
Granuloma - mass inflammed tissue
Destructive lesions in:
Nose
Sinuses
Trachea
Lung
Orbits
Polyangiitis - inflammation vessels
Inflammation of small vessels in:
Skin
Kidney
Lung
Gut

treatment - immunosuppression

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40
Q

Raynaud’s Phenomen

A

Primary

  • common young F
  • ANA negative
  • Fairly harmless

Secondary

  • ANA postive
  • Associated scleroderma, SLE, etc
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41
Q 
Scleroderma
symptoms
features
internal organs involvement
testing 
treatment
A

digital ulcers
lung fibrosis
skin fibrosis
raynauds

Fribrosis affects - lung, gut, kidneys

ANA - looking for anti centromere/anti Scl-70 antibodies

Immunosuppression - usually poor response

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42
Q

Connective Tissue Diseases

A

Immunity against ubiquious self antigens causes inflammation or fibrosis in ANY tissue

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43
Q

Define allergy and hyersensitivity

A

Undesirable, damaging, discomfort-producing and sometimes fatal reactions produced by the normal immune system (directed against innocuous antigens) in a pre-sensitized (immune) host.

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44
Q

How many immunopathological classifications

  • coombs and gell 1963
  • extended classification
A

4

5

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45
Q

Explain type 1 reaction

e.g. pollen

A 
Anaphylactic
IgE
exogenous antigen
15-30min response
basophils and eosinophil
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46
Q

Explain type 2 reaction

e.g. penicillin

A 
cytotoxic
IgG IgM
cell surface antigen
mins - hours response
antibody and compliment

Associated disease
Erythroblastosis fetalis
Goodpasture’s nephritis

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47
Q

Explain type 3

e.g. Mould

A 
Immune complex
IgG, IgM
soluble antigen
3-8 hours response
complement and neutrophils

associated disease
- SLE

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48
Q

Explain type 4

e.g. poison Ivy

A 
delayed type
None antibody
tissues and organs antigen
48-72 hours
monocytes and lymphocytes
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49
Q

How do allergies develop

A 
Barrier dysfunction
sensitization
changes in T cell subsets, dominated by Th2
IgE
ALLERGY
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50
Q

Immune response to parasitic disease

A 
Increased levels of IgE
Total
Specific to pathogen – cross-reactive
Tissue inflammation with:
eosinophilia & mastocytosis
Basophil infiltration
Presence of CD4+ T cells secreting:
IL4, IL5 & IL13
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51
Q

hygiene hypothesis

A

Stimulation by microbes is protective
Epidemiological data – Increase in Allergy
Animal Models – T1DM, EAE, Asthma
Increased atopy (Asthma) after anti-parasitic Rx
Prevention of autoimmunity (Crohn’s) by infections
Pro-biotics in pregnant women
Mechanism – Th1 Th2 deviation

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52
Q

genetic influence on allergic immune response

A 
Polygenic diseases
Cytokine gene cluster IL3,5,9,13
IL12R; IL4R
FceRI
IFNg; TNF

NOT sufficient for disease
ONLY susceptibility

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53
Q

Immune responses

- Allergens

A

Antigens that initiate an IgE-mediated response

First encounter results in innate & IgM response

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54
Q

Immune response

- conventional immune response

A

Allergen requires processing
Presentation to T cells & cytokine release
Results in delineation of T-helper subsets into different types

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55
Q

IgE mediated Allergic response

A 
Immunopathogenesis
IgE Ab mediated mast cell and basophil degranulation- release of preformed and de novo synthesized inflammatory mediators
Clinical features
Fast onset (15-30 min)
Wheal and flare
Late phase response
Eosinophils 
Central role for Th2 T cell
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56
Q

Role of Th2 T cell

A

Multiple cytokine release
Innate inflammatory response
Drive for immunoglobulin production

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57
Q

what is the ATOPIC triad

A

Asthma
rhinitis
eczema

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58
Q

Allergic Rhinitis

A

Nasal congestoin, mucus, polyps, nasal inflammation, tonsillar and adenoidal enlargement

Perennial/seasonal
House dust mite, animal danders, pollens
Treatment - Antihistamines, nasal steroids

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59
Q

Allergic Asthma

A

Airway inflammation, airway constriction and hyperactivity

In childhood - Aeroallergic stimuli- house dust mite
Immediate symptoms IgE mediated
Damage to airways - late phase response
Damaged airways - Hyper reactive to allergic stimuli

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60
Q

Atopic Dermatitis

A

Contact - allergic/non allergic
Clinically - intense itching, blistering, weeping
House dust mite - TRIGGER
Treatment - topical steroids, moisturisers

61
Q

Anaphylaxis

A

an acute potentially life threatening IgE mediated systemic hypersensitivity reaction

62
Q

Diagnosis of anaphylaxis

A 
History
Specific IgE (>0.35 KuA/L)
Skin prick test (>3mm wheal) SPT Video
Intra-dermal test
Oral challenge test – Gold standard
Basophil activation test
Component resolved diagnostics
63
Q

Basophil activation test

A

cross-linking of membrane-bound IgE, basophils upregulate the expression of specific activation markers such as CD63, CD203c and the expression of the inhibitory receptor CD300a. The exact mechanisms that govern basophil degranulation remain elusive, but it has been demonstrated that phosphorylation of p38 MAPK exerts a pivotal role in cell activation.


64
Q

Treatment for anaphylaxis

A

Antihistamine, steroids, adrenaline
Immunotherapy - for life threatening reactions, severe hayfever, animal fur
Not good - multiple allergies, food, allergic rashes

65
Q

Food allergy

A 
MAJOR FOOD ALLERGENS 
Water soluble glycoproteins 10 - 60 kd
COW’S MILK
EGG
LEGUMES - PEANUT; SOYBEAN; TREE NUTS
FISH
CRUSTACEANS / MOLLUSCS
CEREAL GRAINS
66
Q

clinical manifestations of food allergy

A 
Gastrointestinal
vomiting, diarrhoea, oral symptoms
Respiratory (upper & lower)
rhinitis, bronchospasm
Cutaneous
urticaria, angioedema
role of food in atopic dermatitis unclear
Anaphylaxis
67
Q

Pattern Recognition receptors PRR

A

Toll-like receptors (TLR’s), NOD-like receptoes (NLR’s), RigI-like receptors (RLR’s) C-type lectins (CLR’s), scavenger receptors

68
Q

Antimicrobial peptides

A

-Defensins, -defensins, cathelin, protegrin, granulsyin, histatin, secretory leukoprotease inhibitor, and probiotics

69
Q

Cells

A

Macrophages, dendritic cells, NK cells, NK-T cells, neutrophils, eosinophils, mast cells, basophils, and epithelial cells

70
Q

Complement components

A

Classic and alternative complement pathway, and proteins that bind complement components

71
Q

cytokines

A

Autocrine, paracrine, endocrine cytokines that mediate host defense and inflammation, as well as recruit, direct, and regulate adaptive immune responses

72
Q

B Lymphocytes

A

develop potential to secret antibodies: humoral immunity

73
Q

Killer/cyotoxic T lymphocytes

A

lymphocytes are able to kill. Cellular immunity

74
Q

helper T lymphocytes

A

secrete growth factors (cytokines) which control immune response: Help B lymphocytes and T lymphocytes (Helper T cells are target of HIV

75
Q

suppressor T lymphocytes

A

may damp down immune response

76
Q

binding of antibodies to antigens does the following

A 
Neutralizaion 
agglutination of microbes
precipitation of dissolved antigens
activation of complement system
leads to cell lysis
enhances phagocytosis
77
Q

Immunodeficiency

A

where the immune system is not effective enough to protect the body against infection
Can be argued that infection is always the result of transient immunodeficiency.

Usually secondary to the effects of external factors
Some are primary immunodeficiencies caused by genetic defects in individual components of the immune system.
The type of infection is a guide to underlying cause.
Laboratory tests confirm.

78
Q

Acquired Immunodeficiency

A

Many causes; transient or long-lasting; minor or major.
Stress
Surgery/burns
Malnutrition
Cancer – especially lymphoproliferative disease
Immunosuppressive effect of drugs inc. cancer therapy
Lymphocytes
Neutrophils

79
Q

Primary Immunodeficiency

A

Very rare
Extensively studied - give important clues to the working of the immune system - experiments of nature.
Often diagnosed in early childhood but can present in adult life
Recurrent infection often suggests immunological problem

80
Q

Chronic Granulomatous disease

A 
Osteomyelitis
Pneumonia
Swollen lymph nodes
Ginigivitis
Non-malignant granulomas
Inflammatory bowel disease
81
Q

Defects in b cells

A

Lead to different degrees of loss of antibody secretion.
Usually leads to recurrent bacterial infection with pyogenic organisms.
Usually diagnosed at around 1-2 years since maternal IgG protects.
Treat with antibiotics then iv IgG For life.
Most are very serious
some less serious e.g IgA deficiency.
1 in 5-700 not severely immunodeficient

82
Q

Primary B cell deficiencies

A 
Common Variable Immunodeficiency 
X-linked agammaglobulinaemia
Autosomal recessive Hyper IgM syndrome
IgA Deficiency
IgG Subclass Deficiency
Transient Hypogammaglobulinaemia of infancy
83
Q

Defects in T cells

A

Usually more dramatic since B cells also need T cell help.
Symptoms are recurrent infection with opportunistic infections, bacteria, viruses,
Fungi (candida), protozoa (pneumocystis).

84
Q

Defects in both B and T

A

Severe Combined Immunodeficiency (SCID) syndromes
Combined Immunodeficiency syndromes
Bone Marrow Transplantation curative
Gene therapy

85
Q

Primary T cell deficiencies

A

Severe Combined Immunodeficiency syndromes
Adenosine Deaminase Deficiency
Purine Nucleoside Phosphorylase Deficiency
MHC Class II Deficiency
Wiskott-Aldrich Syndrome

86
Q

Define immunomodulation

A

The act of manipulating the immune system using immunomodulatory drugs to achieve
a desired immune response.

A therapeutic effect of immunomodulation may lead to immunopotentiation, immunosuppression, or induction of immunological tolerance.

87
Q

Name 7 mechanisms of immumodulation

A 
Immunization
Replacement therapy
Immune stimulants
Immune suppressants
Anti-inflammatory agents
Allergen immunotherapy (desentization)
Adoptive immunotherapy
88
Q

Define Immunomodulators

A

Medicinal products produced using molecular biology techniques including recombinant DNA technology

89
Q

what are the classes of immunomodulators

A

Substances that are (nearly) identical to the body’s own key signaling proteins
Monoclonal antibodies
Fusion proteins

90
Q

Describe Adalimumab

A

Human IgG1, monoclonal Ab,

constant human domain Fc but with human variable domain in Fab’ region

91
Q

Describe Infliximab

A

Chimeric mouse human IgG1 monoclonal antibody,

human constant domain and murine variable domain

92
Q

Describe Etanercept

A

Fusion Protien, Fc-TNFR3 extracellular domain,

93
Q

Describer Cetrolizumab

A

humanised monovalent Fab-PEG - contains polyethylene glycol (PEG) moiety, human constant domains and human constant domains with murine variable domain

94
Q

Define Passive Immunization

A

transfer of specific, high-titre antibody from donor to recipient. Provides immediate but transient protection

95
Q

Problems with passive immunisation

A

risk of transmission of viruses

serum sickness

96
Q

types and uses of passive immunisation

A 
pooled specific human immunoglobulin
animal sera (antitoixins and antiveninins)

Uses
Hep B prophylaxis
Botulism, VZV in pregnancy, diphtheria, snake bites

97
Q

Define active immunisation

A

simulate development of protective immune response and immunological memory

98
Q

What is active immunogenic material

A

Weakened forms of pathogens
Killed inactivated pathogens
Purified materials (proteins, DNA)
Adjuvants

99
Q

What are problems with active immunisation

A

Allergy to any vaccine component
Limited usefulness in immunocompromised
Delay in achieving protection

100
Q

What are replacement therapies and immune stimulation

A

-Pooled human immunoglobulin (IV or SC) Used in Rx of antibody deficiency states
-G-CSF/GM-CSF
Act on bone marrow to increase production of mature neutrophils
-IL-2 (Stimulates T cell activation- rarely used)
-α-interferon (Main use in treatment of Hep C)
-β-interferon (Used in therapy of MS)
-γ-interferon
Can be useful in treatment of certain intracellular infections (atypical mycobacteria), also used in chronic granulomatous disease and IL-12 def

101
Q

What can be used for Immunosuppression

A 
Cortocosteroids
Cytotoxic/ agents
Anti-proliferative/activation  agents
DMARD’s
Biologic DMARD’s
102
Q

how do corticosteroids work

A

Decreased neutrophil margination
Reduced production of inflammatory cytokines
Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
Lymphopenia
Decreased T cells proliferation
Reduced immunoglobulins production

103
Q

what are the side effects of corticosteroids

A 
Carbohydrate and lipid metabolism
Diabetes
Hyperlipidaemia
Reduced protein synthesis
Poor wound healing
Osteoporosis
Glaucoma and cataracts
Psychiatric complications
104
Q

What are cortico steroids used for

A 
Autoimmune diseases 
CTD, vasculitis, RA
Inflammatory diseases
Crohn’s, sarcoid, GCA/polymyalgia rheumatica
Malignancies
Lymphoma
Allograft rejection
105
Q

What are T cell targeted immunosuppression straregies

A

Anti- IL-2 receptors mAbs
CyA Tacrolimus
Sirolimus
Azathioprine MMF

106
Q

What drugs target lymphocytes

A

Antimetabolites

  • Azathioprine (AZA)
  • Mycophenolate mofetil (MMF)

Calcineurin inhibitors

  • Ciclosporin A (CyA)
  • Tacrolimus (FK506)

M-TOR inhibitors
-Sirolimus

IL-2 receptor mABs

  • Basiliximab
  • Daclizumab
107
Q

What do Calcineurin inhibitors do

A

CyA
Binds to intracellular protein cyclophilin
Tacrolimus (FK506)
Binds to intracellular protein FKBP-12
Mode of action
Prevents activation of NFAT
Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription
T cell effects
Reversible inhibition of T-cell activation, proliferation and clonal expansion

108
Q

Sirloins *(rapamycin)

how does it work

A

Macrolide antibiotic
Also binds to FKBP12 but different effects
Inhibits mammalian target of rapamycin (mTOR)
Mode of action
Inhibits response to IL-2
T cell effects
Cell cycle arrest at G1-S phase

109
Q

Side effects of calcineurim / mTOR

A 
Hypertension
Hirsutism
Nephrotoxicity
Hepatotoxicity
Lymphomas
Opportunistic infections
Neurotoxicity
Multiple drug interactions (induce P450)
110
Q

What are the clinical uses of calcineurim/mTOR

A

Allograft rejection

Autoimmune diseases

111
Q

Antimetabolites, how do they work?
-AZA
-MMF
T and B cell effects

A

Inhibit nucleotide (purine) synthesis

AZA
Guanine anti-metabolite
Rapidly converted into 6-mercaptopurine

MMF
Non-competitive inhibitor of IMPDH
Prevents production of guanosine triphosphate

T and B cells effects
Impaired DNA production
Prevents early stages of activated cells proliferation

112
Q

What does Methotrexate MTX do

What does Cyclophosphamide

A

Folate anatagoinists

Cross link DNA

113
Q

What are the cytotoxic side effects

A 
ALL
Bone marrow suppression
Gastric upset
Hepatitis
Susceptibility to infections
Cylophosphamide
Cystatis
MTX
pneumonitis
114
Q

What are the clinical uses of cytotoxic drugs

A

AZA/MMF
Autoimmune diseases (SLE, vasulitis, IBD)
Allograft rejection

MTX
RA, PsA, Polymyositis, vasculitis
GvHD in BMT

Cyclophosphamide
Vasculitis (Wagner’s, CSS)
SLE

115
Q

What are biologic DMARD’s

A
  • Disease modifying anti rheumatic drugs
Anti-cytokines (TNF, IL-6 and IL-1)
Anti-B cell therapies
Anti-T cell activation
Anti-adhesion molecules 
Complement inhibitors
116
Q

Anticytokines
Anti-TNF
Anti IL-6
Anti IL-1

A

Anti-TNF
First biologics to be successfully used in therapy of RA (5 different agents now licensed)
Used in a number of other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis)
Caution: increase risk of TB

Anti-IL-6 (Tocilizumab)
Blocks IL-6 receptor
Used in therapy of RA and AOSD
May cause problems with control of serum lipids

Anti-IL-1
3 different agents available (anakinra, rilonacept and canakinumab)
Used in treatment of AOSD and autoinflammatory syndromes

117
Q

Rituximab

A

Chimeric mAb against CD20- B cell surface
First approved in ’97 for treatment of chemotherapy resistant DLCL
Many uses:
Lymphomas, leukaemias
Transplant rejection
Autoimmune disorders

118
Q

Adoptive Immunotherapy
2 examples,
uses

A 
Bone marrow transplant (BMT)
Stem cell transplant (SCT)
Uses 
Immunodeficiencies (SCID)
Lymphomas and leukemias
Inherited metabolic disorders (osteopetrosis)
Autoimmune diseases
119
Q

Immunomodulators for allergy

examples

A

Immune suppressants
Allergen specific immunotherapy
Anti-IgE monoclonal therapy
Anti-IL-5 monoclonal treatment

120
Q 
allergen specific immunotherapy 
indications
mechanisms
routes
side-effects
A

Indications:
Allergic rhinoconjutivitis not controlled on maximum medical therapy
Anaphylaxis to insect venoms
Mechanisms:
Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
Development of T reg cells and tolerance
Routes:
SC or sublingual for aero-allergens
Side-effects:
Localised and systemic allergic reactions

121
Q

What is Omalizumab

A

mAb against IgE
Used in Rx of asthma
Also useful in Rx of chronic urticaria and angioedema
May cause severe systemic anaphylaxis

122
Q

What is Mepolizumab

A

mAb against IL-5
Prevents eosinophil recruitment and activation
Limited effect on asthma
No clinical efficacy in hypereosinophilic syndrome

123
Q

Who discovered MHC

A

Peter Alfred Gorer

124
Q

What is MHC

A
  • set of genes found in all vertebrate species
  • expressed at cell surface and function to present self/nonself antigens for T cell antigen receptor inspection
  • highly polymorphic
  • 50,000 – 100,000 MHC on average cell
125
Q

The Human MHC

A

6p21.3
3.6Mbp long
aka Human Leucocyte Antigens complex
3 regions
class 1 - HLA-A,B,C (classical antigents
Class 2 - HLA-DR,DQ,DP antigens
Class 3 - HSP70, TNF, C4A, C4B,C2,BF, CYP21

Class 1 genes 3-6kb
Class 2 genes 4-11 kb

126
Q

Where are class 1 and class 2 antigens found

A

Class 1
all nucleated cells

Class 2
primarily B lymphocytes, can be inducted on T lymphocytes

Both membrane bound glycoproteins

127
Q 
What are Class 1 associated with 
what are class 2 associated with
A

Class 1 - MHC encoded 45kb heavy chain non covalently associated with non polymorphic B2 micro globulin

Class 2 - MHC encoded 31-34 kd associated with A chain non covalently assoicated with 26-29 kd B chain

128
Q

How is HLA inherited

A

Mendelian inheritance, codominant expression, all inherited antigens are displayed on cell surface - HLA phenotype

129
Q

Why is HLA polymorphism significant

A

capacity of individual to mount immune response in response to antigenic challenge

130
Q

HLA Matching

A

Serology - Broad
HLA-A2, A9; B27, B15, DR1, DR2

Serology - Split
HLA-A2, A23(A9); B27, B62(B15); DR1, DR15(DR2)
HLA-A2, A24(A9); B27, B63(B15); DR1, DR16(DR2)

Molecular - Low
HLA-A02, A23; B27, B15; DRB101, DRB115
HLA-A02, A24; B27, B15; DRB101, DRB1*16

Molecular - High
HLA-A02:01, A23:01; B27:01, B15:01; DRB101:01, DRB115:01
HLA-A02:02, A23:02; B27:02, B15:02; DRB101:02, DRB115:02

131
Q

What is sensitisation

A

any even which elicits a HLA direceted immune response,
pregnancy, blood transfusion, transplantation

looked for by
serum screening
cross matching

132
Q

What is a hyper acute rejection

A

Activation clotting cascade, activation of complement

133
Q

What are the innate defences of the body

A

Skin, interferons, compliment, lysozyme, mucous membranes,

normal commensal flora

134
Q

what are the classification of immunodeficiencies

A

congenital/primary

acquired/secondary

135
Q

Neutrophil defects

Qualitative

A

Chemotaxis – rare, congenital, inadequate signalling, abnormality in receptors or NE movement
–Killing power - inherited, Chronic Granulomatous Disease. NE fail to mount a respiratory burst in phagocytosis. Deficient in NADPH oxidase so hydrogen peroxide not formed. At risk of Staph. aureus infections

136
Q

Neutorphil defect

quantitative

A

eg - cancer treatment, bone marrow malignancy, aplastic anaemia caused by drugs
“Neutropenic”
Esp. imp. when 50% will dvlp an infection. Highly lethal if not treated quickly with correct antibiotics – empirical therapy, >50% those with Pseudomonal infections will die in 24hrs if not treated

137
Q

T cell deficiencies

A

Congenital – rare
Acquired – drugs e.g. ciclosporin after transplantation (decreases graft versus host disease and rejection), steroids
Acquired – viruses e.g. HIV

138
Q 
T cell deficiencies caused by opportunistic pathogens
examples 
bacterial,
viral,
fungal
A

May be intracellular
BACTERIAL – Listeria monocytogenes (food), Mycobacteria – MTB, MAI
VIRAL – e.g. leukaemia and transplanted pnts - HSV, CMV (pre–emptive treatment), VZV. Serological testing, prophylaxis and treatment with e.g. aciclovir and ganciclovir
FUNGAL – e.g. Candida spp., Cryptococcus spp.

139
Q

T cell deficience caused by Cryptoporidium pram

  • route
  • recovery
  • treatment
A

– Sporozoa – oocysts shed by cattle/humans.
Faecal oral route.
Most patients recover after prolonged illness of up to 3 wks.
May take much longer in T-cell deficient pnts – if at all. Symptomatic treatment only (in most cases)

140
Q

T cell deficiency causes by Toxoplasma gondii

  • Family
  • route
  • presentation
A

Sporozoa.
Cats. Humans infected by contact with cat faeces/ or from e.g. transplanted heart with the bradyzoites present.
May present with lesion in brain and neurological signs.
(most immunocompetent pnts are asymptomatic)

141
Q

T cell deficiency causes by Stronglyoides stercoralis

  • Family,
  • Route
  • presentation
  • suspected in which patient (pnts) groups
A

Nematode.
Larvae penetrate skin, migrate. Normal pnts aymptomatic or rash of Larva Currens but immunocompromised get multiplication, huge invasion of tissues, eosinophilia.
May get Gram negative septicaemia as larvae move. Suspect in pnts from tropical countries or old POW pnts.

142
Q

What is hypogammaglobulinaemia

A

Antibody problems
Congenital - rare
Acquired – multiple myeloma, chronic lymphocytic leukaemia, burns
Usually encapsulated bacteria e.g. S. pneumoniae in the resp. tract or e.g. Giardia lamblia or Cryptosporidium in GIT

143
Q

what is complement deficiency

A

Hereditary, rare
Encapsulated bacteria. Need complement to help kill organisms. Earlier defect in pathway then greater no. of orgs may infect.
Classical and Alternative
e.g. C5-8 then Neisseria meningitidis is important – lysis not achieved via membrane attack complex as MAC not formed. 50-60% pnts will have 1 episode of disease in life
Frequent, serious S. pneumoniae infections as poor quality opsonisation

144
Q

Why would you need a splenectomy?

What are the implication of a splenectomy

A

Spleen - source of complement and antibody producing B-cells, removes opsonised bacteria from blood.
Causes - traumatic, surgical or functional e.g. sickle cell anaemia
Streptococcus pneumoniae, Haemophilus influenzae type B, N. meningitidis, malaria

Implications
High mortality, vaccination, prophylactic penicillin, education – seek help if unwell

145
Q

Immunocompromised after organ transplantation

A

Liver in HCV/paracetamol OD (solid organ transplants)
Stem cells in haematological malignancy.
Anti-rejection treatment suppresses cell mediated immunity to stop effects of cytotoxic and natural killer cells. Degree of immunosuppression varies on how closely the donor and recipient are matched.

146
Q

Management of infection in immunocompromised patients

A

Treat the known infection – empirical, need specimens from likely site of infection to guide therapy
E.g. remove catheters
Reverse defect if possible/stop immunosuppression

147
Q

How to investigate infections

A

History and examination
Urgent diagnosis and treatment
Blood cultures. Occasionally bone marrow cultures
Respiratory samples – esp. induced sputa, bronchoalveolar lavage and lung biopsy. Microscopy - Gram, ZN, fungal and silver stains. Viral immunofluorescence. Bacterial culture including Legionella, TB. Fungal culture, viral culture +/- PCR. Histology.
Other samples as systems suggest e.g. urine
Serology samples (e.g. Toxoplasma spp.) +/- PCR. Aspergillus antigen +/- PCR
(surveillance cultures)
Imaging studies e.g. X ray/CT chest, MRI

148
Q

How to prevent infection in immunocompromised patients

A

Hand washing /aseptic technique / protective isolation / HEPA air filtration (allografts)
Vaccines (avoid live vaccines in T-cell deficient)
Prophylactic antimicrobials (e.g. penicillin, septrin, aciclovir) and passive immunoglobulin
Special diet

P Intergrated Y2 (13 decks)

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