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Year 2 clinical pathology > Week 4 Immunodeficiency and immunomodulation > Flashcards

Week 4 Immunodeficiency and immunomodulation Flashcards

1
Q

What are the General principles of immune response?

A

Main physiological function is to protect from infection

Multilayer defense

Network of pathogen recognition

Adaptive responses to changing pathogen

Multiple mechanisms of pathogen clearance

Effective inter-cellular communication

Limitation of host damage

Self-regulation

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2
Q

what is the importance of patern recognition receptor ?

A

structures on macrophages–> can differentiate between gram positive, negative bacteria, fungi and virus

tell you what type of pathogen the body is dealing

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3
Q

What are the Major Components of the Innate Immune System?

A

Pattern recognition receptors
(PRR

Antimicrobial peptides

Cells

Cytokins

Complement components

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4
Q

What is the function of B cells?

A

develop potential to secret antibodies: humoral immunity

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5
Q

what are the different types of T cells and there function?

A

Killer or cytotoxic T lymphocytes are able to kill. Cellular immunity

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

Suppressor T lymphocytes may damp down immune response

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6
Q

What are the different ways antibodies inactivate the antigen?

A

Neutralization, Agglutination of microbes and precipitation of dissolved antigens –> enhances phagocytosis

Activation of complement cascade –> Cell lysis

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7
Q

How does cytotoxic T cells work?

A

Cytotoxic T cell bind to the infected cell

They release perforin which damages the infected cell membrane and enzyme enteres

The infected cell is destroyed

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8
Q

What is immunodeficiency?

A

Clinical situations where the immune system is not effective enough to protect the body against infection

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9
Q

What are the causes of primary and secondary immunodeficiency?

A

Usually secondary to the effects of external factors

Some are primary immunodeficiencies caused by genetic defects in individual components of the immune system –> seen in children

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10
Q

What are the causes of SECONDARY OR ACQUIRED IMMUNODEFICIENCIES?

A

Stress
Surgery/burns
Malnutrition
Cancer – especially lymphoproliferative disease
Immunosuppressive effect of drugs inc. cancer therapy
Lymphocytes
Neutrophils

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11
Q

What are the characterstics of primary IMMUNODEFICIENCIES?

A

Very rare

Often diagnosed in early childhood but can present in
adult life

Recurrent infection often suggests immunological problem

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12
Q

How do you identify the underining cause of immunodeficiency?

A

The type of infection is a guide to underlying cause.

Laboratory tests confirm.

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13
Q

Are secondary immunodeficiency permanent?

A

No they can be transient or long lasting

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14
Q

Why is family history important to consider when considering a diagnosis of primary immunodeficiency?

A

Caused by genetic defects

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15
Q

What do you test for when examining someone with reccurent infection and are suspect of immunodeficiency?

A

You test for the levels of immunoglobulins for B cells , lymphocytes ,
neutrophils
Test of CRP if current infection to see if actually mounting an inflammatory response

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16
Q

Why would normal levels of immunoglobulins, lymphocytes and neutrophils be a indication of a problem for someone with a infection?

A

Normally these levels will be raised because of the infection. The fact that they are not means that the immune systme is not working properly

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17
Q

What is the role of IRAK?

A

is formed as part of the intracellular signalling pathway of toll like receptors (a type of PRR) when they encounter a pathogen - forms NF-kbeta which is a transcriptional factor which leads to the release of inflammatory cytokines/chemokines which leads to inflammatory and adaptive immune response

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18
Q

Why does deficiency in IRAK cause immunodeficiency?

A

Irak deficiency causes immunodeficiency because IRAK is a key component in the pathway to release of inflammatory cytokines/chemokines from the cells of the innate immune system which plays a role in the development of an adaptive and inflammatory response

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19
Q

How do you test for neutrophils?

A

Nitroblue tetrazolium test (NBT

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20
Q

What is the mechanism of phagocytosis in neutrophils?

A

NADP transport H ion
H ion travels into the cell via a specific proton channel
THis reduces the Ph within the cell making it more acidic. Therefore this allows proteolytic enzymes to enter the phagasome and destroy the pathogens

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21
Q

What is the defect in CHRONIC GRANULOMATOUS DISEASE ?

A

It is a an inherited disorder of phagocytic cells resulting in an inability to phagocytose pathogenic material

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22
Q

What diseases can occur in CHRONIC GRANULOMATOUS DISEASE ?

A 
Osteomyelitis 
Pneumonia
Swollen lymph nodes 
Ginigivitis
Non-malignant granulomas
Inflammatory bowel disease
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23
Q

what type of infection can indicate the person has immunodeficiency?

A

meningococcal meningitis

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24
Q

What are the 3 activating pathways for the complement pathway?

A

Classical pathway
Alternative pathway
MB-lectin pathway

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25
Q

In CHRONIC GRANULOMATOUS DISEASE (CGD) what is the effect on neutrophils?

A

The number of neutrophils is not reduced however due to not being able to transfer Hydrogen atoms the material within the neutrophil cannot be digested.

Therefore the size of the neutrophils increase

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26
Q

What happens in CHRONIC GRANULOMATOUS DISEASE (CGD) when neutrophils are being produced?

A

Chronic inflammation occurs because the rest of the immune system becomes fustrated and response by iinflammation.

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27
Q

How do you test for terminal complement pathway?

A

Take sheep RBC’s, incubate with patient serum -

2) If complement is functioning properly all the sheep RBCs should undergo haemolysis

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28
Q

During the testing of terminal complement pathway why does sheeps RBCs undergo haemolysis but human ones don’t?

A

Human RBCs have structures on the surface which inhibit our own complement system, sheep RBCs dont have this

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29
Q

What are the key steps in terminal complement pathway?

A

Activation of C3 convertase which cleaves C5 2) Cleaving of C5 to C5b allows the rest of the complement (C6-C9) to set on the surface of the bacteria and create pores which leads to the lysis of susceptible microorganisms

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30
Q

What is X-linked agammaglobulinaemia?

A

X linked mutation where there is a defect in B cells

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31
Q

What happens in X-linked agammaglobulinaemia and what type of infection is caused by this?

A

Lead to different degrees of loss of antibody secretion.

Usually leads to recurrent bacterial infection with pyogenic organisms.

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32
Q

When is X-linked agammaglobulinaemia diagnosed and why?

A

Usually diagnosed at around 1-2 years because maternal IgG protects until this point

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33
Q

How do you treat X-linked agammaglobulinaemia?

A

Treat with antibiotics then iv IgG

Keep things under control
Need a pool of donours

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34
Q

what are 6 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

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35
Q

Why if you were hospitalized with extensive oro-pharyngeal candida would this indicate a immunodeficiency?

A

Because candida does not usually cause a serious problem in healthy people

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36
Q

Compare the characteristic of the chicken pox in a healtyh and immmunodeficient person?

A

Healthy : Mild disease

Typical vesicles

Immundeficient: Fulminant ((severe and sudden onset) disease

Haemorrhagic lesions

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37
Q

Severe combined immunodeficiency syndromes (SCID) refers to defects in what 2 kinds of cells?

A

B and T cells

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38
Q

What are the symptoms of Severe combined immunodeficiency syndromes (SCID)?

A

Symptoms are recurrent infection with opportunistic infections, bacteria, viruses, Fungi (candida), protozoa (pneumocystis).

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39
Q

Treatment for SCID?

A

Bone Marrow Transplantation curative

Gene therapy

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40
Q

GIve 4 examples of PRIMARY T- CELL DEFICIENCIES?

A

Adenosine Deaminase Deficiency

Purine Nucleoside Phosphorylase Deficiency

MHC Class II Deficiency

Wiskott-Aldrich Syndrome

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41
Q

What type of syndrome is Primary T-Cell Deficiencies?

A

Severe Combined Immunodeficiency syndromes

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42
Q

The presence of Mycobacterium who indicate a defect in ?

A

Defects in cytokines

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43
Q

If there was a defect in complement what infection would this present?

A

Meningococcus

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44
Q

Presence of Pneumococcus and HSV would indicate the defect in what?

A

Defect in PRR

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45
Q

A defect in B cells would present with what infection?

A

Recurrent sino-pulmonary infections

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46
Q

A defect in T cells would present with what infection?

A

SCID, opportunistic infections

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47
Q

The presence of ) Staphylococcus 2) Aspergillus would indicate a defect in what part of the immune system?

A

Defects in neutrophils and macrophages

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48
Q

What is the defintion of immunodulation

A

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

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49
Q

What are the 3 different types of immunodulation caused by therapeutic effect?

A

immunopotentiation,
immunosuppression,
induction of immunological tolerance

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50
Q

What are the mechanisms of immunodulation?

A 
Immunization
Replacement therapy
Immune stimulants
Immune suppressants
Anti-inflammatory agents
Allergen immunotherapy (desentization)
Adoptive immunotherapy
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51
Q

Define Biologics- Immunomodulators

A

Medicinal products produced using molecular biology techniques including recombinant DNA technology

52
Q

What are the 3 classes of biological immunomodulator?

A

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

53
Q

What are fusion proteins?

A

attach proteins with different biological function –> to reach a certain site

54
Q

What is Adalimumab?

A

Is a Human IgG anti-TNF monoclonal Antibody

55
Q

What is the structure of Adalimumab?

A

Human Fc portion and Human Fab portion that binds to TNF

56
Q

What is Etanercept?

A

Is a fusion protein anti-TNF monoclonal

57
Q

What is TNF?

A

An important pro-inflammatory cytokine

58
Q

What is the structure Etanercept?

A

The Human Fc portion bound to a human TNFR2 (TNF receptor) which in the body serves to mop up extra TNF)

59
Q

What is Cetrolizumab?

A

Is a humanized monovalent Fab-PEG anti-TNF monoclonal

60
Q

What is the structure of Cetrolizumab?

A

Human Fab region bound to a polyethylene glycol - this makes the Fab region more stable and less digestible

61
Q

What is Infliximab?

A

Is a chimeric mouse-human anti-TNF monoclonal Ab

62
Q

What is the structure of Infliximab?

A

Mouse Fab portion Human Fc portion Mice

63
Q

What is the function of Infliximab?

A

Produce a human Fc portion and are given TNF so produce an Ab against TNF with a mouse Fab portion and a human Fc portion

64
Q

What are the different ways of Immunopotentiation?

A

Immunization –> Passive and Active
Replacement therapies
Immune stimulants

65
Q

what is the definition of Passive immunization? What type of protection does it provide

A

transfer of specific, high-concentration antibody from donor to recipient.
Provides immediate but transient protection –> short lived

66
Q

What are the problems of Passive immunization?

A

Risk of transmission of viruses –> as it is blood products

Serum sickness

67
Q

What are the types of passive immunization and the uses of it?

A

Types
Pooled specific human immunoglobulin  from human plasma
Animal sera (antitoxins and antivenins)

Uses
Hep B prophylaxis and treatment
Botulism, VZV (pregnancy), diphtheria, snake bites

68
Q

What is active immunization?

A

To stimulate the development of a protective immune response and immunological memory

69
Q

What immunological material is used in active immunization?

A

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

70
Q

What are the problems with active immmunization?

A

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

71
Q

What are the different Replacement therapies and immune stimulation and what are they used for?

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

72
Q

what are the 5 ways of Immunosuppression?

A

Cortocosteroids

Cytotoxic/ agents

Anti-proliferative/activation agents

DMARD’s

Biologic DMARD’s

73
Q

What are the actions of Corticosteroids?

A

Decreased neutrophil margination to the tissue

Reduced production of inflammatory cytokines

Inhibition phospholipase A2 (reduced arachidonic acid
metabolites production)

Lymphopenia

Decreased T cells proliferation at high doses as they are
toxic

Reduced immunoglobulins production

74
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

75
Q

What are the uses of corticosteroids?

A

Autoimmune diseases –> Connective tissue disease,
vasculitis, RA

Inflammatory diseases–> Crohn’s, sarcoid, GCA/polymyalgia rheumatica

Malignancies –> Lymphoma

Allograft rejection –> used in transplant

76
Q

What are the 4 types of drugs that target lymphocytes

A

Antimetabolites
Calcineurin inhibitors
M-TOR inhibitors
IL-2 receptor mABs

77
Q

Give example of Antimetabolites?

A 
Azathioprine (AZA)
Mycophenolate mofetil (MMF)
78
Q

what is the action of Antimetabolites? What effect does this have on B and T cells?

A

Inhibit nucleotide (purine) synthesis

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

79
Q

What is the action of Azathioprine (AZA) ?

A

Guanine anti-metabolite

Rapidly converted into 6-mercaptopurine

80
Q

What is the action of Mycophenolate mofetil (MMF)?

A

Non-competitive inhibitor of IMPDH

Prevents production of guanosine triphosphate

81
Q

Give two examples of Calcineurin inhibitors?

A 
Ciclosporin A (CyA)
Tacrolimus (FK506)
82
Q

What is the mode of action of Calcineurin inhibitors? What effect does this have on T cells?

A

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

83
Q

What does Ciclosporin A bind to?

A

Binds to intracellular protein cyclophilin

84
Q

What does Tacrolimus (FK506) bind to?

A

Binds to intracellular protein FKBP-12

85
Q

Give me a example of M-TOR inhibitors?

A

Sirolimus (rapamycin)

86
Q

What does Sirolimus (rapamycin) bind to and therefore what does it inhibit?

A

Also binds to FKBP12 but different effects

Inhibits mammalian target of rapamycin (mTOR)

87
Q

What is the mode of action of Sirolimus and therefore its effect on T cells ?

A

Inhibits response to IL-2 by the MTOR pathway.

This causes the T cell to arrest at G1-S phase which prevents it from proliferating

88
Q

What are the side effect of Calcineurin/Sirolimus side-effects

A 
Hypertension
Hirsutism
Nephrotoxicity
Hepatotoxicity
Lymphomas
Opportunistic infections
Neurotoxicity
Multiple drug interactions (induce P450
89
Q

What is the Calcineurin/mTOR inhibition clinical use?

A

Transplantation -> Allograft rejection

Autoimmune diseases

90
Q

What is the action of Methotrexate (MTX)?

A

Folate antagonists

91
Q

What is the action of Cyclophosphamide

A

Cross-link DNA

92
Q

What is the two step process of once a T cell is presented with a antigen by a APC?

A

1) Activation occurs by autocrine cytokine IL-2
2) Proliferation - IL2 stimulates signalling pathway involving mTOR which allows cells to go into the cell cycle and proliferate

93
Q

Give 2 examples of IL-2 receptor mABs

A

Basiliximab

Daclizumab

94
Q

What are the side effect of all cytotoxic drugs?

A

Bone marrow suppression
Gastric upset
Hepatitis
Susceptibility to infections

95
Q

What is the specific side effect of Cylophosphamide?

A

Cystitis

96
Q

What is the specific side effect of Methotrexate ?

A

pneumonitis –> inflammation of the walls of the alveoli (air sacs) in the lungs

97
Q

What is the clinical use of methotrexate?

A

RA, Psoriatic Arthritis, Polymyositis, vasculitis

Graft-versus-host disease in bone marrow transplant

98
Q

What is the clinical use of Cyclophosphamide?

A

Vasculitis (Wagner’s, CSS)

SLE

99
Q

What is the clinical use of Azathioprine, Mycophenolate mofetil ?

A 
Autoimmune diseases (SLE, vasulitis, IBD)
Allograft rejection
100
Q

What are Disease-modifying antirheumatic drugs (DMARDs)?

A

Disease-modifying antirheumatic drugs (DMARDs) are a group of medications commonly used in patients with rheumatoid arthritis.

101
Q

What catogerios do Biologic DMARD’s fall into?

A 
Anti-cytokines (TNF, IL-6 and IL-1)
Anti-B cell therapies
Anti-T cell activation
Anti-adhesion molecules 
Complement inhibitors
102
Q

What are the three types of Anti-cytokines?

A

Anti-IL-1
Anti-IL-6 (Tocilizumab
Anti-TNF

103
Q

What is Anti TNF used for?

A

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)

104
Q

What does Anti TNF increae the risk of?

A

TB

105
Q

What is Anti-IL-6 (Tocilizumab) used for?

A

Blocks IL-6 receptor

Used in therapy of RA and Adult-onset Still’s disease (AOSD) –> rare form of arthritis

106
Q

What problems can be caused by the use of Anti-IL-6

A

May cause problems with control of serum lipids

107
Q

What are the 3 different agents of Anti-IL-1?

A

anakinra, rilonacept and canakinumab

108
Q

What is Anti-IL-1 used for?

A

Used in treatment of AOSD and autoinflammatory syndromes

109
Q

What is the action of Rituximab?

A

Chimeric mAb against CD20- B cell surface

110
Q

What was the initial use of Rituximab?

A

For treatment of chemotherapy resistant DLCL

111
Q

What is the current use of Rituximab?

A

Lymphomas, leukaemias
Transplant rejection
Autoimmune disorders

112
Q

What are the two forms of adoptive immunity?

A

Bone marrow transplant (BMT)

Stem cell transplant (SCT)

113
Q

What are the uses of adoptive immunity?

A

Immunodeficiencies (SCID)
Lymphomas and leukemias
Inherited metabolic disorders (osteopetrosis)
Autoimmune diseases

114
Q

What are the different types of Immunomodulators against allergy?

A

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

115
Q

What is Allergen specific immunotherapy?

A

People are given doses of an allergen in a controlled manner to inducer tolerance to that allergen, may be give subcutaneously or sublingually

116
Q

What is the mechanisms of allergen specific immunotherapy?

A

Switching of immune response from Th2 (allergic) to Th1 (non-allergic)

Development of T reg cells and tolerance

117
Q

What are the routes of allergen specific immunotherpay?

A

Subcutaneous injection or sublingual for aero-allergens

118
Q

What are the side effects of allergen specific immunotherapy?

A

Localised and systemic allergic reactions

119
Q

Give 2 uses of allergen specific immunotherpay?

A

Allergic rhinoconjutivitis not controlled on maximum medical therapy
Anaphylaxis to insect venom

120
Q

What is monclonal antibodies?

A

Are monospecific antibodies that are made by identical immune cells that are all clones of a unique parent cell, in contrast to polyclonal antibodies which are made from several different immune cells.

121
Q

What is Omalizumab? What does it act against?

A

It is a mAb against IgE

122
Q

What is the use of Omalizumab?

A

Used in Rx of asthma

Also useful in Rx of chronic urticaria and angioedema

123
Q

What is a side affect of omalizumab?

A

May cause severe systemic anaphylaxis

124
Q

What is Mepolizumab? What does it act against?

A

It is a mAb against IL-5

125
Q

What is the use of Mepolizumab?

A

Prevents eosinophil recruitment and activation

126
Q

What syndromes does Mepolizumab have little or no effect against?

A

Limited effect on asthma

No clinical efficacy in hypereosinophilic syndrome

Year 2 clinical pathology (21 decks)

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