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Immunology Flashcards

1
Q

Define allergic disorder

A

Immunological process that results in immediate and reproducible symptoms after exposure to an allergen

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2
Q

What type of hypersensitivity reaction is allergy usually

A

Type 1 IgE mediate

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3
Q

Define sensitisation

A

Detection of specific IgE to an allergen either by skin prick or in vitro blood test
- Determines risk of allergic disorder but not synonymous with clinical symptoms of allergy

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4
Q

Which is more common, allergic disease or sensitisation

A

Sensitisation

10% population has detectable IgE against peanuts but ~2% have peanut allergy

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5
Q

Th response to parasites, worms, allergens or venoms

A

Functional feature recognition (e.g. protease release and damage of epithelial surfaces)
–> Th2 immune response

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6
Q

Th response to microbial structures (bacteria, viruses and fungi)

A

PAMPs (structural feature) recognised by TLR on dendritic cells and macrophages
–> Th1 + Th17 response

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7
Q

Th1 response

A

Characterised by INF gamma or Il-2

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8
Q

Mechanism that follows epithelial cell damage by allergen/worms/venom

A

Epithelial cells secrete signalling cytokines (IL-1a, -15, -33 & TSLP)

  • -> Cytokines act on lymphocytes (Th2, Th9 and innate lymphoid cells)
  • -> Lymphocytes secrete effector cytokines (IL-4, 5, 9, 13) = signature Th2 cytokines
  • -> Effector cytokines communicate with effector cells (eosinophils and basophils) to expel allergen/worm

Signalling cytokines also act on Tfh2

  • -> Tfh2 secretes IL-4 and IL-21
  • -> Il-4, 21 act on B cells to help make antibodies (IgE and IgG4)
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9
Q

Single tier system of immune system where sensor cells mediate effector arm of immune system
* Biological and drug targets in allergic disease

A

Cross linking of IgE receptor by allergen causes mast cell to release mediators which act on target cells (leaky endothelium, smooth muscle contraction, itching of skin /nasal cavity) to expel allergen and restore epithelial barrier

  • Histamine*
  • Leukotrienes*
  • Prostaglandins
  • Proteases
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10
Q

Oral route vs skin - effect on immune tolerance

A

Oral: Treg cells secreting Il-10. Il-10 stimulates IgG. Treg cells derived from GI mucosa inhibit IgE synthesis to keep immune system balance

Skin: Disrupted skin barrier (atopic dematitis, fillagrin mutation) –> allegen accesses dermis. Dendritic cell in dermis tells T cells to secrete Il-4 and other type 2 cytokines –> IgE antibody.
(Important in allergic march)

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11
Q

Causes of allergic disorder rise

A

Hygiene hypothesis
Lack of vitamin D in infants
Diet (lack of omega and linoeic fatty acids, delayed introduction of peanuts and eggs)
High conc of dietary advanced glycation end products and proglycating sugars (immunes system mistakes as causing tissue damage)

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12
Q

Clinical features of IgE response

A

Minutes - 3hrs after exposure to allergen
Skin: angioedema, urticaria, flushing, itching
Resp: cough, SOB, wheeze, congestion, red watery itchy eyes
GI: Nausea, vomiting, diarrhoea
CNS and vasc: Hypotension, sense of doom

AT LEAST 2 organs involved usually
REPRODUCIBLE
Clinical hx to select what allergen should be tested by skin prick/blood test

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13
Q

Allergic disease tests separated by elective or in acute episode

A

ACUTE
- Serum mast cell tryptase levels

ELECTIVE

  • SKin prick tests
  • Lab measurement of allergen specific IgE
  • Component resolved diagnostics
  • Challenge test
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14
Q

Skin prick test
What is result of a positive test?
Prior to test what meds should be stopped and why?

A

Use standard skin test solution and POSITIVE CONTROL (histamine) and NEGATIVE CONTROL (diluent)
- Measure local wheal and flare response to controls and allergens

Positive test = >3mm than -ve control
Stop antihistamines 48hrs before

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15
Q

Why use -ve control in skin prick tests and what is used

A

To check there isn’t spontaneous mast cell activation and granule release e.g. in dermatographism

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16
Q

CI to skin prick test

A

Do not perform if RECENT ANAPHYLAXIS

Bloods instead

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17
Q

Advantages of skin prick tests

A

High -ve predictive value
Size of wheals correlates with higher probability for allergy
Rapid
Cheap and easy

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18
Q

Serum specific IgE blood test indication

A 
Can't stop antihistamines
Dermatographism
Extensive eczema
Hx of anaphylaxis
Borderline skin prick tests
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19
Q

Serum specific IgE blood test method

A

Allergen bound to sponge
Add patients serum
Fluorescently tagged Anti-IgE antibody added
Amount of IgE/anti-IgE measured by fluorescent light

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20
Q

Advantages of serum specific IgE blood test

A

Conc of specific IgE can be used to preduct which children may outgrow allergy and should be given oral food challenge
V goof negative predictive value (but lots of false +ve)
Higher values more likely to be associated with allergic disorder so can triage pts who don’t need oral food challenge

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21
Q

Component resolved diagnostics (CRD)

Method and use

A

Blood test to detect IgE to single protein component
- For peanut and hazelnut alleger

SEED STORAGE peanut and hazelnut allergen components target heat and proteolytic STABLE protein and usually with SEVERE allergic reaction

(opposite for birch pollen homologue)

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22
Q

Criteria for anaphylaxis diagnosis

A

Anaphylaxis is highly likely when any 1 of the following 3 criteria are fulfilled:

  1. Acute onset of an illness (minutes to hours)
    Involvement of SKIN , MUCOSAL TISSUE OR BOTH, (i.e., generalised hives, pruritus, or flushing, swollen lips-tongue-uvula) and at least 1 of the following: RESP COMPROMISE (i.e., dyspnoea, wheeze-bronchospasm, stridor, reduced peak expiratory flow [PEF], hypoxaemia) or REDUCED BP OR ASSOCIATED SYMPTOMS (i.e., hypotonia/collapse, syncope, incontinence)
  2. Occurrence of 2 or more of the following symptoms or signs after exposure to a likely allergen (minutes or hours)
    Involvement of skin, mucosal tissue, or both (i.e., generalised hives, pruritus, or flushing, swollen lips-tongue-uvula)
    Respiratory compromise (i.e., dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, hypoxaemia)
    Reduced BP or associated symptoms of end-organ dysfunction (i.e., hypotonia/collapse, syncope, incontinence)
    Persistent GI symptoms (i.e., crampy abdominal pain, vomiting)
    Reduced BP after exposure to a known allergen (minutes to several hours)
  3. Systolic BP of <90 mmHg or >30% decrease from baseline.
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23
Q

Mechanism of IgG anaphylaxis

+ Examples

A

Macrophages and Neutrophils
Mediators: Histamine and PAF
Caused by: Biologics, Blood and IgG transfusions

Often requires large quantities of the allergen or systemic introduction

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24
Q

How do neuromuscular drugs, quinolones , opiates and NSAID induce anaphylaxis

A

Act on specific MAST CELL receptor

Mediators: Leukotriene + Histamine

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25
Q

Conditions that can mimic anaphylaxis

A 
Chronic urticaria, angioedema (ACEi)
MI, PE
Severe asthma, vocal cord dysfunction, inhaled FB
Anxiety/panic disorder
Carcinoid and phaeochromocytoma
Scromboid toxicity
Systemic mastocytosis
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26
Q

Treatment of anaphylaxis

A
  1. IM Adrenaline outer thigh (300microgram adult dose, 150 child)
  2. Adjust body position
  3. 100% Oxygen
  4. Fluid replacement
  5. Inhaled Bronchodilators
  6. Hydrocortisone (100mg IV) to prevent late response
  7. Chloropheniramine 10mg IV for skin rash
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27
Q

Mechanisms of anaphylaxis treatment

A

a1 receptor: Peipheral vasoconstriction to reverse low BP and mucosal oedema
B1 receptor : Increase HR, contractility, BP
B2 receptor: Relax bronchial smooth muscle and reduce inflammatory mediator release

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28
Q

After acute management of anaphylaxis

A

Refer to allergy/immunology clinic
Investigate cause
Written sheet on: Recognising symptoms, avoiding triggers, indications for emergency self treatment with EpiPen
Prescribe emergency kit to manage
Copy of management plan and training for patient, carers, school staff and GP
Utilise support groups
Encourage to acquire a Medic Alert braclet

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29
Q

Food allergy
vs
Food intolerance

A

Specific immune response that occurs reproducibly on exposure to a given food
vs
Non immune reactions which include metabolic, pharmacological and unknown mechanisms

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30
Q

Food allergy types

A

IgE Mediated (anaphylaxis, OAS)
Mixed IgE and cell mediated (atopic dermatitis)
Non IgE mediated (coeliac)
Cell mediated (contact dermatitis on exposure)

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31
Q

Important risk factor for food allergy

- allergy test even in absence of clinical hx

A

Moderate/severe atopic dermatitis

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32
Q

Managing food allergy

A
  1. Avoid
  2. Emergency management
  3. Prevention
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33
Q

IgE mediated food allergy syndromes

A
  1. Anaphylaxis
    - Peanut, tree nut, shellfish, milk and eggs most common
  2. FOOD ASSOCIATED EXERCISE INDUCED ANAPHYLAXIS
    - If exercise within 4-6hrs of ingestion
    - comonl wheat, shellfish, celery
  3. DELAYED FOOD INDUCED ANAPHYLAXIS TO BEEF, PORK, LAMB
  4. ORAL ALLERGY SYNDROME
    - limited to oral cavity, swelling and itch
    - Onset after pollen allergy established
    - Commonly stone fruits, veg, nuts (but not if cooked - heat labile agents detected by component allergen test)
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34
Q

Which infectious disease kills the most people world wide

A

HIV

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35
Q

What is HIV-1

A

Retrovirus
Genes composed of RNA molecules

Primarily infects immune system cells causing immunodeficiency and AIDS

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36
Q

How does HIV replicate

A

Intracellular using RT to convert RNA into DNA which is integrated into host cell’s genes

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37
Q

Organisation of HIV-1 virion

Co receptor

Receptor on cell wall which facilitates entry

Antigen for non-neutralising antibodies

Target for drugs that inhibit an enzyme that breaks down proteins

A

Retrovirus with CD4 T cells as preferred host targets angtigen

Co receptor = CXCR4/CCR5

Receptor on cell wall which facilitates entry - gp120

Antigen for non-neutralising antibodies - p24 gag IgG

Target for drugs that inhibit an enzyme that breaks down proteins - protease

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38
Q

Phases of immune response to transplanted graft

A
  1. Recognition of foreign antigen
  2. Activation of antigen specific lymphocytes
  3. Effector phase of graft rejection - activated lymphocytes cause organ damage and rejection
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39
Q

Most relevant proteins variations in clinical transplantation

A
  1. ABO blood group
  2. HLA (coded on chr 6 by MHC)
    Also are minor histocompatibility genes
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40
Q

2 major components to rejection

A 
T cell mediated
Antibody mediated (B cells)
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41
Q

What is HLA and it’s role

A

human leukocyte antigen
Are cell surface proteins

Presentation of foreign antigens on HLA molecules to T cells (to activate T cells)

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42
Q

HLA classes and variability

A

Class 1: A, B, C
- Expressed on all cells

Class 2: DR, DQ, DP
- Expressed on APC but also can be up-regulated on other under stress

HIGHLY POLYMORPHIC (variable) as 100s of alleles for each locus (everyone has 2)

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43
Q

Problem with HLA in transplant

A

Variability in HLA molecules in the population provides a source for immunisation against the transplanted organ

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44
Q

HLA structure

A 
alpha and beta chains
class 1: 3 alpha, 1 beta
class 2: 2 alpha, 2 beta

Both have a peptide binding groove (area of high variability concentrated here)

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45
Q

How many potential HLA molecules on your cell surface

A

12
DR, DQ, DP, A, B, C
1 copy from each parens

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46
Q

Which HLA types used in transplant and why.

A

A, B and DR because most variable, most immunogenic

Mismatches expressed as minimum
0:0:0
to maximum
2:2:2

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47
Q

Mechanism of T cell mediated rejection

A

Phase 2 - T cell activation by foreign antigen (presented through MHC to CD3 receptor)
–> specific T cells activated
–> Produce Il-2
Cytokines stimulate activation and proliferation of T cells

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48
Q

What happens when a T cell is activated?

transplant lec

A 
Proliferate
Produces cytokines (IL-2)
Helps activating CD8+ T cells
Helps antibody production
Recruits phagocytic cells
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49
Q

Which APC is involved in activating T cells in transplant mediated rejection?
Where does this occur?

A

Both donor and recipient

Some in grafted organ
A lot in lymph nodes (by circulating naive T cells) - Will come into contact with APC, mount immune reaction against epitope being presented, become activated. T cells re-enter the circulation and hone to the graft - 3rd phase with organ damage.

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50
Q

Cells involved in T cell mediated rejection

Their mechanism of action

A

CD4+ T cells:
- graft infiltration by alloreactive T cells

Cytotoxic T cells (CD8+):

  • Release toxin to kill target
  • Granzyme B
  • Punch holes in target cells
  • Perforin
  • Apoptotic cell death
  • Fas-ligand

Macrophages

  • Phagocytosis
  • Release proteolytic enzymes
  • Produce cytokines
  • Produce oxygen radicals and nitrogen radicals
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51
Q

Phages of antibody-mediated rejection

A
  1. Exposure to foreign antigen
  2. Proliferation and maturation of B cells with antibody production
  3. Effector phase; antibodies bind to graft EPITHELIUM
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52
Q

Antibody mediated rejection in kidneys.

A

Microcirculation gets lined with antibodies - injury to microcirculation. (capillaries of glomerulus and around tubules, arterial)

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53
Q

Which auto-antibodies are important in rejection and which are naturally occurring?

A

Anti-A or anti-B - naturally occurring

Anti-HLA - not naturally occurring

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54
Q

Complement role in rejection

Which type of rejection

A

Recruited to site of antibodies
Cause phagocytosis or lysis
C3a and C5a recruit lots of inflammatory cells

In antibody-mediated rejection

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55
Q

Prevention and treatment of graft rejection

A

Prevent

  • AB/HLA matching
  • Screening for anti-HLA antibodies
  • Immunosuppression: dampen the immune system of recipient

Treating
- More immunosuppression

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56
Q

Important to consider with immunosuppression in rejection

A

Balance need with risk of infection, malignancy, drug toxicity

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57
Q

AB/HLA matching
In who
How

Important for which organ transplants

A

For all organ transplants
Encourage living donation from blood relatives
PCR-based DNA sequence analysis (of HLA allele sequence)

Kidney and Bone marrow

Not so much for heart and lung

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58
Q

Screening for antibodies in transplantation

Types of assays

A

Before
At time of transplant
After transplant - repeat to check for new antibody production regularly

  1. Cytotoxic assay
  2. Flow cytometry
  3. Solid phase assays - most common - refined read out of different epitopes and intensity for each
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59
Q

Treatment of rejection

T cell mediated rejection options

A

1) Steroids
2) Calcineurin inhibhitors e.g. cyclosporine + tacrolimus
3) Cell cycle inhibition e.g. azathioprine and mycophenolate mofetil
4) Monocolanal antibodies against CD3 T cell receptor e.g. antithymocyte globulin, OKT3
5) Alemtuzumab
6) Daclizumab against CD25 (the Il-2 receptor)

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60
Q

Calcineurin inhibitors mechanism of action

Examples

Uses

A

Immune suppression - preventing interleukin-2 (IL-2) production in T cells.

Cyclosporine, Tacrolimus

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61
Q

Treatment of rejection

Antibody-mediated rejection options

A

1) Plasma exchange (physically remove antibody from circulation)
2) Anti-CD20 (rituxumab)
3) Target cytokines that promote B cell activation and growth (palivizumab)
4) Proteosome inhibitors
5) Complement inhibitors

62
Q

Transplant immunosuppression

Summary

A

Induction agents
Baseline agents
Treatment of acute rejection

63
Q

Indications from HSC transplant

A

Haem and lymphoid cancers

Acquired or inherited deficiencies in marrow cells e.g. errors of metabolism or immunodeficiencies

64
Q

HSC transplant - process outline

And worry about..

A

Eliminate host immune response (total body irriadiation; cyclophosphamide; other drugs)
Replace with own or HLA matched donor bone marrow
Allogenic HSCT leads to reaction of donor lymphocytes against host tissue
GVHD prophylaxis for all patients - methotrexate/cyclosporine

65
Q

GVHD cause
Presentation
Treatment

A

Injury by preparative regime before HSCT
Mainly manifests in skin, liver and gut
Corticosteroids

66
Q

Risks of HSCT beside GVHD

A 
Infection
Malignancy 
- Viral associated x 100: Kaoposi's sarcoma (HHV8), lymphoproliferative disease (EBV)
- Skin cancer x 20
- Risk of other cancers x 2/3
67
Q

Classification of immunodeficiemcies

A
  1. Primary (single gene mutation)
  2. Secondary (e.g infecion, malnutrition, drugs, haem malignancy) - more common.
  3. Physiological (neonates, pregnancy, old age)
68
Q

Secondary immune deficiencies

A
  1. Infection: HIV, measles, mycobacterium
  2. Biochem: Malnutrition, specific mineral deficiency, renal impairment
  3. Malignancy: Myeloma, Leukaemia, Lymphoma
  4. Drugs: Corticosteroids, Cytotoxic agents, antiproliferative immunosuppresants
69
Q

Clinical features suggestive of immunodeficiency

A

2 major
or
1 major and recurrent minor infections
in one year

70
Q

Cells of the innate immune system

+ soluble components

A

Polymorphonuclear cells
Monocytes + macrophages
Dendritic cells
NK cells

Complement
Cytokines
Acute phase proteins

71
Q

Properties of phagocytes

A 
Express pattern recognition receptors
Express Fc receptors
Express cytokine/chemokine receptors
Secrete cytokines and chemokines
Have phagocytic capacity
72
Q

Polymorphonuclear cell properties

A

Short lived

Same as phagocytes:
Express pattern recognition receptors
Express Fc receptors
Express cytokine/chemokine receptors
Secrete cytokines and chemokines
Have phagocytic capacity

+ Release enzymes, histamine, lipid mediators of inflammation from granules

73
Q

Monocytes and macrophages properties

A 
Same as phagocytes:
Express pattern recognition receptors
Express Fc receptors
Express cytokine/chemokine receptors
Secrete cytokines and chemokines
Have phagocytic capacity

+ Capable of presenting processed antigen to T cells

Longer lived than neutrophils

74
Q

Reticular dysgenesis
Inheritance
Mutation

A

Failure of stem cells to differentiate along myeloid or lymphoid lineage
= Most severe form of SCID
No lymphocytes, neutrophils, monocytes, platelets

Autosomal recessive
AK2

Fatal in v early life unless BMT

75
Q

Kostmann syndrome
Inheritance
Mutation

A

Failure to of neutrophil maturation - congenital neutropenia
Autosomal recessive
HAX1

No neutrophils, normal leukocyte adhesion markers, DHR can’t do as no neutrophils and no pus

76
Q

Cyclic neutropenia
Inheritance
Mutation

A

Episodic neutropenia every 4-6 weeks
Autosomal dominant
ELA-2

77
Q

Leukocyte adhesion deficiency

FBC changes

A

Defect of phagocyte migration. Neutrophils lack CD18 and fail to exit from blood stream
V high neutrophil in blood
Absence of pus formation

78
Q

Chronic granulomatous disease

Clinical signs

A

Failure of oxidative killing mechanism
Deficiency of component of NADPH oxidase - can’t generate oxygen radicals.

Excessive inflammation with persistent neutrophil/macrophage accumulation
without degradation of antigen

Granuloma formation
Lymphadenopathy + Hepatosplenomegaly

79
Q

Tests of chronic granulomatous disease

A 
Nitroblue tretrazolium (NBT) test - yellow to blue if interaction with HPO
Dihydrorhodoaminde test - fluorescent if oxygen free radicals

Both -ve in chronic granulomatous disease

80
Q

Il-12, Il-12 receptor, IFNg or IFNg receptor deficiency

Normal mechanism of these cytokines

Increased risk of

A

Cytokine deficiency

Infected macrophages produce Il-12.
Il-12 induces T cells to secrete IFng
IFNg feeds back to macrophages to stimulate TNFa production
- Activated NADPH oxidase and oxidative killing pathways

Mycobacterium
Salmonella

81
Q

Phagocyte deficiencies predispose to which type of infections

A

Bacterial + fungal i.e. extracellular

  • Staph, enteric bacteria
  • Candida albicans, aspergillus
82
Q

Phagocyte deficiency treatment

A

Infection tx

  • Prophylaxis: septrin (bacteria); itroconazole (fungal)
  • Oral/IV antibiotics as needed

Definitive tx
HSCT

83
Q

Chronic granulomatous disease tx

A

Definitive
Interferon gamma therapy
- Increases macrophage capacity for killing via non-oxidative pathway

84
Q

No neutrophils, Normal leukocyte adhesion markers, no pus

A

Kostmann

85
Q

High neutrophils, leukocyte adhesion markers absent, DHR normal, no pus

A

LAD

86
Q

Normal neutrophils, normal adhesion markers, abnormal NBT, pus

A

Chronic granulomatous disease

87
Q

Normal neutrophils, normal adhesion markers, normal NBT, pus

A

IL12/IFNg pathway deficiency

88
Q

NK cell deficiency predisposes to

Tx

A

Viral infection: Herpes, HSV 1+2, VZV, EMV, CMV, papillomavirus

? in trial
Prophylactic antivirals e.g. acyclovir
Cytokines?
HSCT in severe phenotypes

89
Q

Complement deficiency predisposes to

A 
Bacterial infection 
- particularly encapsulated bacteria (NHS)
Neisseria meningitides
Haemophilus influenza
Streptococcus pneumonia
90
Q

Which condition is early classical complement pathway deficiency associated with

Treatment

A

SLE
C1q, C1r, C1s, C2, C4
- C2 most common - almost all patients with C2 deficiency have SLE

local inflammation in skin, joints and kidney

Treatment:

  • Analgesia
  • Steroids
  • Cyclophosphamide
91
Q

Which complement pathways are dependent on acquired immune response (antibodies)

A

Classical pathway

92
Q

How are the 3 different complement pathways activated

A

Classical: Formation of antigen-antibody immune complexes

MBL: MBL binding to microbial cell surface carbohydrates. Directly simulates classical, involving C4 and C2

Alternative: Binding of C3 to bacterial cell wall components . Constantly at low level of activation that is negatively regulated. Involved factors B, I and P

93
Q

Components of complement that are measured

Functional complement tests and what they measure

A

C3, C4

CH50 classical: C1, C2, C4, C3, C5-9
AP50 alternative: B, D, Properidin, C3, C5-9

94
Q

Properidin deficiency

A

+C3, +C4, +CH50, -AP50

95
Q

C9 deficiency

A

+C3, +C4, -CH50, -AP50

96
Q

SLE

A

+/-C3, -C4, +/-CH50, +AP50

97
Q

C1q deficiency

A

+C3, +C4, -CH50, +AP50

98
Q

ADA deficiency
Inheritance
Phenotype

A

Type of SCID (16.5%) - Adenosine Deaminase deficiency (required for cell metabolism in lymphocytes)
Autosomal recessive

V low/absent T cells
V low/absent B cells
V low/absent NK cells

99
Q

X-linked SCID

Phenotype

A

45% of all SCID - commonest - mutation of gamma chain of Il-2 receptor –> inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells.

V low/absent T cells
V low/absent NK cells
Normal or increased B cells but low Igs (will have IgM but no so much of others)

100
Q

Clinical phenotype in SCID

A

Unwell by 3 months - infections of ALL types
Failure to thrive
Unusual skin disease
- colonisation of infants empty BM by maternal lymphocytes ->GVHD
FH of early infant death

101
Q

CD8+ T cell function

Which peptides do they recognise?

Which infections are they important in providing immune response?

A

Cytotoxic - kill cells directly

  • Perforin (pore forming) and granzymes
  • Expression of Fas ligand - triggers death pathway
  • Secrete cytokines IFNg, TNFa

Peptides from intracellular proteins with HLA class 1 (A, B, C)

Viral infections and tumours

102
Q

CD4+ T cell function

Which peptides do they recognise?

Which infections are they important in providing immune response?

A

Helper cells

  • Help development of B cell response
  • Help development of some CD8+ T cell responses

Peptides from extracellular proteins presented on HLA class II molecules (DR, DQ, DP)

Extracellular pathogens

103
Q

DiGeorge syndrome

Dysmorphic features

Genetic abnormality

A

Development defect of pharyngeal pouch

High forehead, low set abnormally folded ears, cleft palate, small mouth and jaw, hypocalcaemia, oesophageal atresia, underdeveloped thymus, complex congenital heard disease

Deletion at 22q11.2

104
Q

Effect of DiGeorge syndrome on immune cells

A

Normal B cells
Reduced T cells
- Homeostatic proliferation with age

Immune function only mildly impaired and improves with age

105
Q

MHC class II deficiency

A

Selection of CD4+ T cells in thymus requires MHC class II expression. If absent, won’t get CD4+ T cells.

106
Q

Bare lymphocyte syndrome type
Defect

Clinical phenotype

A

Defect in a regulatory protein of Class II gene expression - absent expression of MHC class II molecules

Profound CD4+ cell deficiency
Normal CD8+ cells
Normal B cells - IgM normal
Low IgG/IgA due to lack of class switching

Unwell by 3 months. Failure to thrive. All types of infection. FH of early infant death

107
Q

Pneumocystis pneumonia (PCP)
Requires which cell for infection control
Occurs in which disease

A

CD4 T cells

HIV

108
Q

Investigating T cell deficiency

A 
Total WCC and differentials
Lymphocyte subsets (FACs)
Immunoglobulins
Functional tests
HIV test
109
Q

Low CD4 T cell, Low CD8 T cell, Low NK cel, low/norm B cell, low/norm IgM, low IgG

A

X-linked SCID

110
Q

Low CD4 T cell, Low CD8 T cell, norm NK cell, norm B cell, norm IgM, low/norm IgG

A

DiGeorge

111
Q

Low CD4 T cell, norm CD8 T cell, norm NK cell, norm B cell, norm IgM, low IgG

A

BLS type 2

112
Q

Management of T cell immunodeficiencies

A 
Aggressive infection tx
HSCT
- In SCID
- In BLS (replace class II deficient APCs)
Enzyme replacement therapy
- In ADA SCID
Gene therapy
Thymic transplant 
- In DiGeorge syndrome
113
Q

Structure of immunoglobulins

Specifically
IgA
IgM

A

2 heavy chains + 2 light chains

  • Antigen recognised by Fab of both heavy and light chains
  • Effector function determined by constant region of the heavy chain (Fc)
IgA = dimer
IgM = pentamer
114
Q

Antibody function and which rich parts of the antibody are involved

A

Fab mediated: Identifying pathogen/toxin

Fc mediated: Interact with other components of immune response to remove pathogens - complement, phagocytes, NK cells

115
Q

Bruton’s x linked agammaglobulinemia
Genetic abnormality

Clinical phenotype

A

Abnormal BTK gene
Pre B cells cannot mature - no mature B cells or antibodies (after 3 months)

Boys present in first few years of life
Recurrent bacterial infections espesh NHS
Viral, fungal, parastic infections
Failure to thrive

116
Q

Hyper IgM syndrome

Genetic abnormality

A

Mutation in CD40 ligand gene
X-linked

CD40 ligand expressed by activated T cells
- involved in T-B cell communication

No help by T cells for class switching of B cells

  • Normal B cell number
  • Normal T cell number but activated don’t express CD40L
  • Elevated serum IgM
  • Low IgA, IgE, IgG
117
Q

Clinical phenotype of x-linked hyper IgM

A

Boys preesnt in first few years of life
Bacterial infections espesh NHS
Parasite infections

Subtle abnormality in T cell function predisposes to Pneumocyctitis jorevic, autoimmune disease and malignancy

118
Q

Common variable immune deficiency

Clinical presentation

A

Group of disordes where there is failure of differentiation/function of B lymphocytes

LOW IgG
Low IgA, IgE

Widespread immune dysregulation - autoimmune and inflammatory

119
Q

Selective IgA deficiency

Predisposes to which infections

A

Deficiency of mucosal barriers. IgA deficiency

Resp and GI infections in 30%

120
Q

Investigation B cell deficiencies

A

Total WCC and differential
Lymphocyte subsets
Serum immunoglobulins and protein electrophoresis
B cell function tests

121
Q

Use of protein eletrophoresis in immunology

A

Production of IgG is a surrogate marker to CD4 T cell helper function

If no gamma band - no antibodies - Brutons x-linked agammaglobulinaemia

122
Q

Management of B cell immunodeficiencies

A

Aggressive prophylaxis/tx of infection
Immunoglobulin replacement if required
Immunisation
- for selective IgA deficiency only

123
Q

Steroids mechanism of immune modulation

A
  • Glucocorticoid steroids

Actions

  • Block phospholipase A2, so there is less prostaglandin production and less inflammation
  • Blocks phagocyte recruitment and phagocytosis
  • Keeps lymphocytes sequestered in lymphoid tissue (T cells > B cells)

Effects on blood:

  • neutrophilia
  • lymphopenia
124
Q

Cyclophosphamide mechanism of action

A

Cytotoxic agent

Alkylating agent - alkylates guanine on DNA, preventing DNA replication

  • Acts on B-cells more than T-cells
  • Used in antibody-mediated disease e.g. SLE

Side-effects

  • haemorrhagic cystitis can occur due to toxic metabolite acrolein
  • Malignancy - bladder, haem
  • Anti-proliferative - hair loss, sterility, BM suppression
  • Infection: PCP
125
Q

Mycophenolate mofetil

A
  • Binds de novo guanosine analogue synthesis
  • Main use is post-transplant but also autoimmune and vasculitis

Main worry - risk of reactivated infection

  • HSV reactivation
  • JC virus + progressive multifocal leukoencephalopathy

TERATOGENIC

126
Q

Azathioprine

A

Metabolised in the liver to 6-mercaptopurine

  • This is a purine analogue, blocks de novo purine synthesis
  • Affects T-cells more than B-cells

Indications

  • Autoimmune disease e.g. SLE
  • Autoinflammatory disease e.g. Crohn’s

Side-effects

  • Some people can get complete bone marrow suppression - associated with TPMT polymorphism
  • They cannot metabolise azathioprine, so it builds up in bone marrow and causes pancytopenia
127
Q

Anti-thymocyte globulin

MOA

Uses

Side effects

A

uman thymocytes injected into rabbits

  • Rabbits produce a number of thymocyte antibodies
  • Serum containing anti-thymocyte antibodies can be injected into humans

Effects

  • T-cell depletion
  • inhibits T-cell activation
  • Inhibits T-cell migration

Uses

  • NOT SPECIFIC
  • Can be used in allograft rejection e.g. renal/heart transplant

Side-effects

  • Infusion reactions
  • Leukopenia
  • Malignancy
128
Q

Basiliximab

A

Anti-CD25 antibody

  • Targets IL-2, so IL-2 cannot acts on T-cells
  • Blocks T-cell proliferation and function

Uses
- prophylaxis for allograft rejection (given before and after transplant surgery)

Side-effects

  • Infusion reactions
  • Leukopenia
  • Malignancy
129
Q

Abatacept

A

Fusion protein of CTLA4 and human IgG Fc

  • Blocks binding of CD80 and CD86 on APCs, with T-cells
  • used in rheumatoid arthritis

Side-effects

  • Infusion reactions
  • Leukopenia
  • Malignancy
130
Q

Rituximab

A

Anti-CD20 antibody
- Depletes B-cells, but not plasma cells

Uses

  • Lymphoma
  • Rheumatoid arthritis
  • SLE

Side-effects

  • Infusion reactions
  • Infection, especially JC virus and PML
  • Exacerbation of CVD
131
Q

Natalizumab

A

Anti-alpha 4 integrin antibody

  • Alpha-4 is part of an integrin complex with B1/B7
  • The integrin complex is involved in leukocyte arrest, adhesion and migration
  • Natalizumab block leukocyte migration to tissue

Uses

  • Highly active relapse-remitting MS
  • Crohn’s disease (in the past, not anymore)

Side-effects

  • Infusion reactions
  • Infection - HIGH RISK of JC virus and PML
  • hepatotoxic
  • Malignancy
132
Q

Toclizumab

A

IL-6 antibody
- Wide immunosuppressive effect, as IL-6 is involved in macrophages, T-cells, B-cells and neutrophils

Uses

  • Castleman’s disease (IL-6 producing tumour)
  • Rheumatoid arthritis - very effective

Side-effects

  • infection
  • hepatotoxic
  • dyslipidaemia
  • malignancy
133
Q

Cytokine therapy

A

IFN-alpha - Hep B, Hep C, Kaposi Sarcoma, CML

IFN-beta - Bechet’s disease

IFN-gamma - chronic granulomatous disease

134
Q

What is immunopathology

Examples

A

Damage to host caused by immune response

  • EBV = Pathogen - adaptive response via cytokines
  • Abscess = Pathogen - innate response via neutrophils
  • Ankylosing spondylitis = No obvious pathogens - innate response via cytokines
  • Anaemia due to haemolysis secondary to ant-RBC antibodies = adaptive response via antibodies
135
Q

Monogenic autoinflammatory disease

A

Mutations in a gene encoding a protein involved in a pathway associated with innate function (abnormal signalling that involves Il-1 and TNF-alpha)

Gain of function in Cryopyrin (NALP3)

  • Muckle wells
  • Familial cold-autoinflammatory syndrome
  • Chronic infantile neurological articular syndrome

Loss of function in Pyrin marenostrin (MEFV)
- Familial mediterranean fever

Both lead to Increased activation and inflammation
- ASC -> procaspase 1 -> IL-1, NFkB (->TNFa) , Apoptosis

136
Q

Familial mediterranean fever

A

Monogenic autoinflammatory disease
Loss of function in Pyrin marenostrin (MEFV)

Periodic fevers for 48-96h
Peritonitis
Pericarditis
Arthritis
Rash

Long term risk of amyloidosis, nephrotic syndrome and renal failure

Rx: Colchicine
Otherwise:
- Anakinra (anti IL-1)
- Etanercept (TNFa inhibitor)

137
Q

Monogenic autoimmune diseases

A

Mutation in a gene that encodes a protein involved in a pathway associated with adaptive immune cell function

APECED

  • Autosomal recessive mutation in AIRE
  • Autoimmune T cells
  • Candida, hypoparathyroid, Addison

IPEX

  • X linked defect in Fox P3 (needed for TReg)
  • Autoantibodies
  • Diarrhoea, dermatitis, diabetes, death
    • Hypothyroid

ALPS

  • Mutations in fas pathway (TNFRS56) = no T cell death
  • Autoimmune cytopenia
  • Splenomegaly, lymphadenopathy, lymphoma
138
Q

Polygenic autoimmune disease HLA associations

A 
Goodpastures - HLA DR15
T1DM - HLA DR3/4
RA - HLA DR4/1
Graves disease - HLA DR3
SLE - HLA DR3
139
Q

Polygenic autoimmune disease T cell activation associations

A

PTPN22 (suppresses T cell activation)
- Without -> more T active T cells -> SLE, T1DM, RA

CTLA4 (negative regulator of T cells)
- Without –> SLE, T1DM, RA, Thyroid

140
Q

Chron’s polygenic auto-inflammatory associations

Treatment

A

IBD1 gene on Chr16 = NOD2/CARD15
- In 30% of Chron’s patients

NOD2 = microbial sensor that stimulates NFkB and inflammatory response. Presnet in cytoplasm of myeloid cells.

Corticosteroids
Azathioprine
Anti-TNF
Anti IL12/23

141
Q

Ankylosing spondylitis mixed pattern disease

A

HLA B27
accounts for <50% of genetic risk

Inflammation at sites of high tensile forces

  • Sacroiliac joints
  • Achiles tendon
  • Low back pain and stiffness
  • Uveitis
  • Enthesitis (sites where tendons/ligaments insert into bone)

Treatment

  • Anti-TNFa
  • Anti-IL17
  • Anti IL12/23
142
Q

Gel and coombs classification of hypersensitivity

A

T1: Immediate IgE mediated

T2: Antibody reacts with cellular antigen

  • Rh haemolytic anaemia
  • Goodpastures (GBM)
  • Pemphigus vulgaris (epidermal cadherin)
  • Graves (TSH receptor)
  • Myasthenia gravis (Ach receptor)
  • Pernicious anaemia (parietal cells)
  • RA? (CCP)

T3: Antibody reacts with soluble antigen to form an immune complex

  • SLE
  • RA (RF and anti-CCP)
  • Cyroglobinaemia

T4: Delayed hypersensitivity - T-cell mediated

  • RA
  • T1DM (pancreatic beta cell antigen)
  • MS (myelin basic protein/ proteolipid protein)
143
Q

Anti-nuclear antibody (ANA) disorders

A

dsDNA
- SLE. ANA stain is homogenous

ENA+ve (extractable nuclear antigen): SPECKLED

  • Ro, La, Sm, RNP = SLE
  • Ro, La = Sjogren’s
  • Scl 70 = Diffuse systemic sclerosis. ANA stain is nucleolar
  • Centromere = Limited sclerosis. Ana stain is centromere

Cytoplasmic
- Jo1 = Myositis, Dermatomyositis

144
Q

Acute urticaria

A

Causes

  • 50% idiopathic
  • 50% due to food, drugs, latex, viral, febrile illness

IgE mediated reaction with wheals. Completely resolves in 6 weeks

Dx is clinical. Can do skin prick test

Treatment
AVOID allergen
GIVE antihistamines

145
Q

Allergic rhinitis

A

SEASONAL (tree, pollen, fungal, spores);
Perennial aka all the time (pets, houst dust, mites)
Occupational

Nasal itch + obstruction
Sneezing
Anosmia
Eye symptoms

Dx: Pale blue swollen nasal mucosa
- Skin prick test and RAST

Treatment

  • Allergen avoidance
  • Antihistamines
  • Steroid nasal spray
  • Eye drops
  • Oral steroids
  • Ipatropium nasal spray
  • Grass pollen desensitisation
146
Q

Oral allergy syndrome

A

Birch pollen, fruits, melon, celery (cross reactivity)

Symptoms LIMITED to mouth. 2% get anaphylaxis

Dx

  • Clinical
  • ? Skin prick

Management

  • Avoid food
  • Wash mouth if ingested
  • Anti-histamine
147
Q

Secukinumab

A
  • Antibody to IL-17A

Uses

  • Psoriasis - very effective
  • Psoriatic arthritis - very effective (as effective as TNFa)
  • Ankylosing spondylitis

Side-effects
- Infection (TB)

148
Q

Denosumab

A

Antibody binds to the RANK ligand

  • RANK-L usually binds to RANK on osteoclasts to stimulate bone resorption
  • Denosumab reduces bone resorption

Uses
- Effective 2nd line treatment for osteoporosis (After alendronate)

Side effects

  • Injection site reactions
  • Infection - mildly immunosuppressive
  • AVN of jaw
  • Long-term increased risk of atypical femoral fractures
149
Q

Ustekinumab

A
  • Antibody that binds to p40, a subunit shared by IL-12 and IL-23
  • Depleted IL-12 and IL-23
  • This blocks IL-17 expression by T-cells

Uses

  • Psoriasis (very effective)
  • Psoriatic arthritis
  • Crohn’s disease

NOT useful in Rheumatoid arthritis

Side-effects

  • Injection site reactions
  • Infections (TB)
150
Q

Anti-TNF alpha antibodies

A

Infliximab
Adalimumab
Certolizumab
Golimumab

These bind to circulating TNFa, so TNFa cannot bind to target cells

Uses:

  • Crohn’s disease
  • Rheumatoid arthritis
  • V. effective in reducing pain in ankylosing spondylitis
  • Psoriasis

Side-effects

  • Injection site reactions (given IV or SC)
  • Infections (HBV, HCV, TB)
  • T-cell depletion leading to lupus-like conditions
  • Increased risk of skin cancer (but not solid tumours)
151
Q

Etanercept

A
  • Fusion of TNFa receptor p75, with human IgG antibody
  • This acts as a decoy receptor so that TNFa cannot bind to its target receptor
Uses 
- Same as TNFa receptor, but not used in Crohn's 
e
Side-effects 
- Same as above

Path (6 decks)

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