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1. Essential Medical Science > Immunopathology > Flashcards

Immunopathology Flashcards

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1
Q

What are the general principles of the immune system? (7)

A 
Multilayer defense
Network of pathogen recognition
Effective inter-cellular communication
Multiple mechanisms of pathogen clearance
Adaptive responses to changing pathogen
Self-regulation
Limitation of host damage
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2
Q

What cells come from lymphoid precursors?

A

B cells(BM), T cells (mature in thymus- CD4(TH1/2) CD8, TReg) NKcells, Plasmacytoid DC (INFa Antigen presentation)

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3
Q

What immune cells do the stem cells produce?

A

Lymphoid Precursors, Myeloid DC (IL-12 presentation) Macrophages (IL-1/IL-6, phagocytosis), Neutophillic granulocytes.

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4
Q

What is Autoimmunity?

A

Theoretical concept
Inherit to immune system (consequence of T cell maturation)
Genetically determined

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5
Q

What are Autoimmune diseases ? Who does it affect?

A

Distinct clinical entities
Breakdown of self-tolerance
Environmental factors acting on favourable genetic background
Lifelong-chronic condition
Characteristic exacerbation and remission
Traditionally divided into organ specific or systemic

Sex (hormonal influence)
women >> men
Age: autoimmunity more common in  elderly
Environmental triggers
Infection, Trauma-tissue damage, smoking
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6
Q

What are Aire genes?

A

Remove self-reactive T cells.

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7
Q

HLA and Autoimmune diseas

A

HLA us associated with many AI disease, Certain alleles= increased risk.

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8
Q

What is the significance of FOX3? How can you inherit a mutation in this gene?

A

FOX3 is important for the development of Treg cells in the thymus - normally remove self-reactive cells.
Defects in FOX3= immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.
X-linked recessive mutation

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9
Q

What is the pathophysiology of autoimmune diseases? (3)

A 
Autoreactive 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 damage
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10
Q

What are organ specific Autoimmune disorders? Give an example

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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11
Q

What are Systemic Autoimmune disorders? Give an example

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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12
Q

Hashimotos thyroiditis: what is it? Pathophysiology?

A

Hypothyroidism- CD4 cells activate B cells which produce autoantibodies to thyroglobulin and to thyroid peroxidase =necrosis and apoptosis. CD8 cells cause cytotoxic Destruction of thyroid follicles by autoimmune process

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13
Q

What are some symptoms of Hashimotos thyroiditis? (9)

A

Tiredness, difficulty concentrating, decline in memory, decreased frequency of bowel movements, increased weight gain. Feel chilled even in warm weather, decreased pulse, hair loss, delayed relaxation of deep tendon reflexes .

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14
Q

Grave’s disease: what is it? Pathophysiology?

A

CD4 T cell stimulates
a TSH reactive B cell resulting in production of a anti-TSH-autoantibody (TSI) which causes thyroid gland survival and increased thyroid hormone release= hyperthyroidism.
increased T3 and T4 and decreased TSH and TSI antibodies are diagnostic

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15
Q

What are some symptoms of Grave’s disease? (12)

A

Anxiety, weight loss, diarrhoea and palpitations, doesn’t notice cold weather, finds impossible to sleep, have an abundance of energy, swollen red eyes, rapid pulse and sweaty hands. She has rapid reflexes, Exophthalmos (bulging eyes)

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16
Q

What are Connective tissue diseases? (4)

A

SLE, Scleroderma, Polymyositis, Sjogrens syndrome

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17
Q

Diagnostics of AI diseases

A

Non specific :
Inflammatory markers
Disease specific: Autoantibody testing (anticentromere-PSS antinuclear PSS and SLE) Beware specificity and sensitivity as not 100% , HLA typing

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18
Q

What is immunosuppression?

A

Immunosuppression: a natural or artificial process which turns off the immune response, partially or fully, accidentally or on purpose.

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19
Q

What can Immunosuppression result in?

A

Immunodeficiency: the lack of an efficient immune system-susceptibility to infections

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20
Q

what is primary/secondary Immunodeficiency? which is more common?

A

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.

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21
Q

What can cause secondary Immunodeficiency? (11)

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 <1 million/ml)
Irradiation (clinical or other)
AIDS
Other infections e.g. measles, TB.

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22
Q

What is primary immunodeficiency?

A

Very rare Often diagnosed in early childhood but can present in adult life
Recurrent infection often suggests immunological problem
e.g:Baby 3months, severe herpes zoster infection, hospitalised with extensive oro-pharyngeal candida , parents first cousins, sibling died at 4 mths with sepsis
(normal chicken pox is mild with small vesicles but those who are immunodeficient have a Fulminant disease with haemorrhagic lesions

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23
Q

Investigations to determine primary immunodeficiency?

A

Normal levels of IgG, no IgA and reduced IgM
Lymphocyte markers show absent/reduced T and NK cells but present B cells + diagnosis of Severe Combined Immunodeficiency syndromes (SCID)

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24
Q

What is SCID?

A

Severe Combined Immunodeficiency (SCID) syndromes

Defects in both B and T cells- BM transplant is curative, can use gene therapy if causative gene is known.

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25
Q

Defects in T cells are better or worse than B cell diseases?

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).

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26
Q

What is hypersensitivity?

A

A reaction produced by the normal immune system (directed against innocuous antigens) in a pre-sensitized (immune) host. It is undesirable, damaging, uncomfortable and sometimes fatal

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27
Q

Type 1 sensitivity: Antibody type?

A

IgE

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28
Q

Type 1 sensitivity: Antigen type?

A

exogenous

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29
Q

Type 1 sensitivity: response time?

A

15-30 minutes

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30
Q

Type 1 sensitivity: appearance?

A

weal & flare

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31
Q

Type 1 sensitivity: histology?

A

basophils & eosinophil

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32
Q

Type 1 sensitivity: Innocuous antigen?

A

pollen-hay fever

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33
Q

Type 1 sensitivity: Disease
States with
the similar
type reaction?

A

allergic asthma

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34
Q

Type 2 sensitivity: Antibody type?

A

IgG, IgM

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35
Q

Type 2 sensitivity: Antigen type?

A

cell surface

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36
Q

Type 2 sensitivity: response time?

A

minutes-hours

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37
Q

Type 2 sensitivity: appearance?

A

lysis and necrosis

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38
Q

Type 2 sensitivity: histology?

A

antibody and complement

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39
Q

Type 2 sensitivity: Innocuous antigen?

A

penicillin

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40
Q

Type 2 sensitivity: Disease
States with
the similar
type reaction?

A

Goodpasture’s nephritis

Blood Transfusion reaction

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41
Q

Type 3 sensitivity: Antibody type?

A

IgG, IgM

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42
Q

Type 3 sensitivity: Antigen type?

A

soluble

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43
Q

Type 3 sensitivity: response time?

A

3-8 hours

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44
Q

Type 3 sensitivity: histology?

A

complement andneutrophils

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45
Q

Type 3 sensitivity: Innocuous antigen?

A

mouldy hay-farmer’s lung

46
Q

Type 3 sensitivity: Disease
States with
the similar
type reaction?

A

SLE, RA, localised arthus reaction, necrotizing vasculitis, gloerulonephritis

47
Q

Type 4 sensitivity: Antibody type?

A

None as T cells

48
Q

Type 4 sensitivity: Antigen type?

A

tissues & organs

49
Q

Type 4 sensitivity: response time?

A

48-72 hours

50
Q

Type 4 sensitivity: appearance?

A

Erythema induration

51
Q

Type 4 sensitivity: histology?

A

monocytes and lymphocytes

52
Q

Type 4 sensitivity: Innocuous antigen?

A

tuberculin test, poison ivy, Metals-e.g nickel

53
Q

Type 4 sensitivity: Disease
States with
the similar
type reaction?

A

Contact dermatitis
Tubercular lesions
Graft rejection

54
Q

Type 3 sensitivity: appearance?

A

Erythema,edema, necrosis

55
Q

Type 1 Hypersensitivity: Immunopathogenesis

A

IgE antibody mediated mast cell and basophil degranulation

Release of preformed and de novo synthesized inflammatory mediators

56
Q

Type 1 Hypersensitivity: clinical features

A 
Fast onset (15-30 min)
Weal and flare
57
Q

Type 1 Hypersensitivity: Primary response

A

Primary response
Degranulates and releases;
Histamine, Proteases, Chemotactic factors

58
Q

Type 1 Hypersensitivity: Late phase response

A

Eosinophils
Central role for Th2 T cell
Secondary/late phase response (lipid mediators)
Releases;Prostaglandin and Leukotrienes

59
Q

Effects of histamine release? (8)

A

Blood clots, gastric acid secretion, BV dilation, Bronchoconstriction, Increases capillary permeability, adrenaline release, swelling and inflammation.

60
Q

Type 1 Hypersensitivity: Mild reaction features (10)

A

Itchy eyes or nose
Cutaneous pruritus
Flushing, Urticaria (like hives) , Oral tingling/pruritus, Abdo pain/nausea/ vomiting, Runny nose, sneezing

61
Q

Type 1 Hypersensitivity: Moderate-severe reaction features (14)

A

Diffuse urticaria and angioedema, Severe abdominal pain, vomiting diarrhoea, Hoarseness, cough , Shortness of breath
Wheezing and cyanosis, Respiratory arrest, Hypotension, Dizziness, loss of consciousness
May not have all of these symptoms together

62
Q

Type 1 Hypersensitivity: Anaphylaxis

A

Medical emergency
Anaphylaxis- An acute, potentially life-threatening, IgE mediated systemic hypersensitivity reaction
]
swelling behind teeth (tongue in throat), hypotension, difficulty breathing, dizziness and collapse.

63
Q

Why do we get allergies?

A

Components of the immune system responding to parasitic infection are also involved in allergic responses
The system has developed to produce a rapid tissue-based response to re-infection
The lack of infectious drive is a contributory factor in allergic disease
Combination of genetic and environmental factors

64
Q

How are we sensitised?

A

Allergen seen by dendritic cell/ÁPC and presented to naïve T cell
T cell differentiates into a Th2 cell
Secretes cytokines IL-4 and IL-13 which act as signals to Naïve B cells
Naïve B cells become memory B cells which have specific IgE that will recognise the allergen on further exposure

65
Q

What is the Dual allergen exposure hypothesis?

A

This theory suggests that early cutaneous exposure to food protein through a disrupted skin barrier leads to allergic sensitisation.
Whereas early oral exposure to food allergen induces tolerance.
(LEAP study: peanut avoidance group developed more peanut allergies than the peanut consumption group)
Additional theories relate to other environmental factors such as vitamin D which might be required for regulatory immunologic mechanisms that are important in preventing FA and establishing oral tolerance.

66
Q

Genetic influences on the ‘allergic’ immune response

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

NOT sufficient for disease
ONLY susceptibility

67
Q

Diagnosis of allergies

A 
History
Specific IgE (>0.35 KuA/L)
Skin prick test (>3mm wheal) 
Intra-dermal test
Oral challenge test – Gold standard
Component resolved diagnostics
68
Q

Skin prick test

A

Allergen solution is placed on arm with the +ve control-histamine (will produce a wheal) and a -ve control saline. Put allergen into a scratch and wait 15min if wheal is >3mm bigger than the -ve control = allergic

69
Q

What is the Atopic triad?

A

Asthma, Rhinitis, Eczema
Food allergy, eczema and asthma have high prevalence in childhood but decrease over time whereas rhinitis increases in incidence over time.

70
Q

What is rhinitis? Symptoms, allergens, treatment

A

Allergic/non-allergic. Perennial or seasonal
Blocked nose, runny nose - often with eye symptoms
House Dust mite, Animal danders, Pollen
Treatment – nasal steroids and antihistamines

71
Q

What is Asthma? Symptoms, allergens, treatment

A

Disease of inflammation and hyperactivity of the small airways
In childhood - aero-allergic stimuli - house dust mite key pathogenic importance
Damage to airways due to late phase response
Immediate symptoms are IgE-mediated

72
Q

What is Atopic Dermatitis? Symptoms, allergens, treatment

A

Many different types
Atopic/ Contact – allergic/non-allergic
CLINICALLY - Intense itching, blistering/weeping, cracking of skin
HOUSE DUST MITE now thought to be MAJOR TRIGGER in atopic disease
Treatment:Topical steroids and moisturisers

73
Q

Type II- Cytotoxic Hypersensitivity: Mechanism

A

IgG/IgM Ab response against combined self/foreign antigen at the CELL SURFACE
complement activation/phagocytosis/ADCC

74
Q

Type II- Cytotoxic Hypersensitivity: Clinical features

A

Onset minutes to hours

Cell lysis and necrosis

75
Q

Blood Transfusion reaction : What type of hypersensitivity is it? What happens?

A

If incorrectly matched blood
Patient’s APC/DC/macrophage) detect the foreign antigen,
present it to Bcells which will make antibodies.
This activate complements= =cytotoxic action-MAC attack complex (classical pathway)
Takes hours to a day

76
Q

Type III hypersensitivity- Mechanism

A

IgG/IgM Ab against SOLUBLE antigen-IMMUNE COMPLEX DEPOSITION

77
Q

Type III hypersensitivity- Clinical features

A

Onset 3-8h
Vasculitis
Traditional cause- serum sickness

78
Q

SLE pathophysiology

A

Type III hypersensitivity
You should have tolerance i.e. self recognising T and B cells should be excluded in the secondary lymphoid organs.
If a Bcell recognises self as foreign- autoimmunity results. Thinks this DNA is foreign. Clonal B cell expansion.Small immune complexes result. C1 from the complement system binds the antibody and C1-9 follow with increased permeability of vessels
C3 and 4 used is large amounts- key blood test

Don’t get cleared as easily from the system and stick to blood vessel wall
anaphylatocins C5a/Ć4a/Ć3a increase vascular permeability=vasculitis
Fluid can also leak out=edema

79
Q

Type IV hypersensitivity: Mechanism

A

Antigen specific T-cell mediated cytotoxicity

therefore no antibodies involved as T cell mediated

80
Q

Type IV hypersensitivity: Clinical features

A 
Delayed onset 48-72h
Erythema induration (thick and hard skin)
81
Q

Poison ivy reaction:

A

Poison Ivy makes the antigen urushiol this activated APCs in skin/Langerhans DC cell in dermis this activates T cells- TH1 which releases IFNy which increases inflammation and macrophage recruitment. TH1 also releases IL-2 which increases Tc cell proliferation.

82
Q

What is the Tuberculin Test?

A

Mycobacterium tuberculosis is placed on the skin to see if T cells react.

83
Q

What is Urticaria?

A

Urticaria is a dermatological manifestation characterized by the sudden appearance of itchy hives (wheals), angioedema or both

84
Q

What are the features of hives? (3)

A

A hive consists of three typical features:
Central swelling of variable size, usually surrounded by a reflex erythema
Associated itching (pruritus), or sometimes a burning sensation
Usually resolves within a few hours and always by 24 hours

85
Q

What are the features of angioedema? (4)

A

Angioedema is typically characterized by:
Sudden, pronounced swelling of the lower dermis and subcutis
Sometimes pain rather than itching
Frequent involvement below mucous membranes
Up to 72 hours for resolution

86
Q

What are Mast Cells? Where are they located?

A

Primary effector cells in urticaria and angioedema

Widely distributed in skin, mucosa and other areas of the body

87
Q

What receptors do Mast Cells have?

A

Have high-affinity IgE receptors

88
Q

What does Mast Cell degranulation cause?

A

Rapid release of inflammatory mediators, e.g. histamine, leukotrienes and prostaglandins
Vasodilation and leakage of plasma in/below skin
Delayed (4-8 hour) secretion of inflammatory cytokines, e.g. tumor necrosis factor, interleukin 4/5
Further inflammatory responses, longer lasting lesions

89
Q

Mechanism of mast cell activation

A

Antigen binds to igE ehich does 3 things:
activates Primary mediators by: Causing mast cell degranulation (histamine, proteases, chemotactic factors-ECF NCF
Activates secondary mediators by:
Stimulates cytokine secretion
Activates phospholipase kinase A2 which activates membrane PL’s-PAF and Arachdonic acid (leukotrines B4,C4,D4 and prostaglandin D2)

90
Q

Acute urticaria types? (2)

A

IgE-mediated urticaria and Non-IgE-mediated urticaria

91
Q

Causes of IgE-mediated urticarial?

A

Food allergy, Drug allergy , Insect toxin allergy , Aeroallergies

92
Q

Causes of Non- IgE-mediated urticarial?

A

Infection, Medications (NSAID’s), Stress (exercise) , Idiopathic

93
Q

What is Chronic spontaneous urticaria (CSU)

A

Chronic spontaneous urticaria (CSU) can be defined as the spontaneous daily, or almost daily, occurrence of itchy hives, angioedema or both, lasting for 6 weeks or more
known(inc AI) or unknown causes

94
Q

Acute vs chronic urticaria

A

Acute: Symptoms for <6 weeks
Chronic:Symptoms daily or almost daily for ≥6 weeks

95
Q

Spontaneous vs Inducible

urticaria

A

Spontaneous: No obvious external specific trigger
Inducible: Symptoms induced by a specific trigger, e.g. temperature, pressure, cholinergic

96
Q

Chronic Ideopathic urticarial definition

A

Skin lesions persistent/recurring for >6weeks (with/without angioedema) Persistent symptoms may be daily/episodic . Have to exclude underlying aetiologies

97
Q

Chronic spontaneous urticarial- Diagnosis

A

A routine patient evaluation should comprise a thorough history and physical examination
Most CSU patients present with both hives and angioedema (a lot with hives only, some angioedema only)
Timing, frequency, duration of attacks, Shape, size, distribution and associated symptoms of lesions, Family and medical history, including allergies, Correlation to any triggers, Work, hobbies, smoking habits and stress, Drugs/treatments used

98
Q

CSU epidemiolgy

A

CSU affects up to 1% of the population at any given time, accounting for approximately two-thirds of cases of CU
Female: male ratio is 2:1
All age groups can be affected, but peak incidence is between 20–40 years of age
No apparent relationship between urticaria prevalence and education, income, occupation, place of residence or ethnic background
Evidence suggests that the prevalence of CU may be increasing
CSU is a chronic disease whose duration is estimated to be 1–5 years in most cases (50%have it after 6m, 30%after 3yrs, 10%after 5 yrs, 8%after 25yrs)

99
Q

Prognostic factors for CSU duration

A

Studies suggest that although the duration of CSU is generally 1–5 years, it is likely to be longer in patients with more severe disease, Concurrent angioedema, Concurrent inducible urticarial, A positive autologous serum skin test

100
Q

What is the affect of CSU on quality-of-life

A

Many aspects of QoL are found to be reduced in patients with CSU with the presence of angioedema further impairing QoL scores. Treatment-induced restrictions/daily living/ impact socially/ impaired mental status etc
In addition to the classical symptoms associated with CSU, factors of major importance to patients that contribute to a reduced QoL include:Unpredictability of attacks, Persistent lack of sleep, Fatigue, Disfigurement
Patients with CSU may also have comorbidities such as depression and anxiety

101
Q

Treatment options in CSU

A

Symptomatic treatment aims to reduce the effect of mast cell/basophil (effector cell) mediators, e.g. histamine, on target organs leading to the symptoms of urticaria

102
Q

Exacerbating factors in CSU

A

Physical and emotional stress
Tight clothing and shoes
NSAID’s
Opiates
Acute and chronic infection
Pseudoallergens
e.g. colours, preservatives & aspirin
Natural salicytates found in fresh food & drinks (fruit, beer, cider)Biogenic amines (tuna, banana, avocado, walnut, well-matured cheeses, alcohol)
Also present in tomato extract, white wine and herbs

103
Q

What are the 4 stages of treatment of chronic urticaria and angiodema?

A

1) Standard dose non-sedating H1 antihistamine
2)Higher dose of H1-antihistamine (up to 4x) or add second antihistamine
3)Consider a second line agent, anti-leukotriene or, if angioedema is present, use tranexamic acid*
4)Consider an immunomodulant (e.g. omalizumab, cyclosporine)
“A short course of corticosteroids may be appropriate in severe episodes at any stage (e.g. prednisolone up to 40 mg daily for 7 days)”

  • Not licensed for treatment in CSU
104
Q

H1-antihistamines effectiveness

A

Modern (second generation) H1-antihistamines are well tolerated by most patients, are non-sedating or minimally‑sedating and are free of anticholinergic effect
they are effective against a placebo, however they fail to control symptoms in up to 50% of CSU patients at licensed doses even if 4-fold dose is given one third of patients remain symptomatic.

It has been suggested that the increase in dose not only blocks histamine mediated effects but also reduces mast cell activation and has an impact on various cytokine and endothelial adhesion molecules5

105
Q

Classical antihistamines advantages and disadvantages

A 
Advantages
Trusted (in use >50yrs) 
Parenteral formulation
Cheap
Additional properties (anticholinergic etc) 
Disadvantages  
Sedating (impairs REM sleep)
Harmful in overdose)
Not recommended in CSU
106
Q

2nd and 3th antihistamines advantages and disadvantages

A 
Advantages 
Licenced and recommended in CSU
Trusted (in use for 10-25yrs)
Non-sedating
Very safe
Disadvantages 
Restricted use in young children
107
Q

What is Omalizumab?

A

Omalizumab is a humanized monoclonal IgG antibody against IgE, with low immunogenicity
Portions of the murine CDRs were grafted onto a human IgG1 kappa framework. Omalizumab consists of 95% IgG1 kappa human framework and 5% mouse sequence, which is hidden from the immune system when omalizumab binds to IgE to reduce potential for human anti-mouse antibody (HAMA) response.

108
Q

Why does Omalizumab target IgE?

A

The high-affinity IgE receptor (FcεRI) on mast cells plays a key role in activation of these cells and in the pathophysiology of CSU resulting in the symptoms of hives/ itch/ angioedema /reflex erythema
Total IgE levels in patients with CSU are typically higher than in healthy individuals

109
Q

How does Omalizumab work?

A

Omalizumab binds to the Ce3 domain of IgE, forming trimers or hexamers and preventing it from binding to FceRI on the surface of mast cells and basophils
However Omalizumab cannot bind to receptor-bound IgE
Omalizumab binds to IgE and reduces free IgE levels, leading to down-regulation of FcRI on mast cells and basophils

110
Q

Omalizumab Dosage

A

Omalizumab (Xolair) is indicated as add-on therapy CSU treatment in those 12 years and above with inadequate response to H1 antihistamine treatment
Omalizumab (Xolair) is indicated as add-on therapy for the treatment of chronic spontaneous urticaria in adult and adolescent (12 years and above) patients with inadequate response to H1 antihistamine treatmen(multiple treatment courses may be required)
resulted in improvement of itch and QoL score

1. Essential Medical Science (8 decks)

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