Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PATH30001 > lecture 11 > Flashcards

lecture 11 Flashcards

Immune System-induced diseases 1 Overview of the immune system - innate and adaptive immunity - cells and molecules involved When the immune system fails - primary immunodeficiency (PID) - e.g. CVID, SAD

1
Q

What is the primary purpose of the immune system?

A
  • to protect the host from disease
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

By what mechanisms does our immune system protect us?

A

Non-specific mechanisms

  • physical/chemical barriers
  • innate immunity

Specific mechanisms
- adpative immunity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the key physical and chemical barriers?

A
  • skin
  • pH
  • antimicrobials
  • commensals (beneficial bacteria)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the three ‘lines of defense’?

A 
Innate (nonspecific immunity) 
1st line of defence 
- intact skin
- mucous membranes and their secretions 
- normal microbiota 
2nd line 
- natural killer cells and phagocytic white blood cells 
- inflammation 
- fever 
- antimicrobial substances

Adaptive (acquired) immunity
3rd line
- specialised lymphocytes: T cells and B cells
- antibodies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is innate immunity?

A
  • first line of defence
  • non-specific but rapid
  • does not have capacity to ‘remember’
  • key cells involved:
    • monocytes/macrophages (APCs)
    • NK cells
    • Dendritic cells
  • involve cytokines, complement, antimicrobials
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are dendritic cells?

A
  • central role in generating immune responses
  • act as sentinels
  • interface between innate and adaptive immunity
  • functions include:
    • recognition of microbial patterns (PRRs/TLRs)
    • costimulation for T lymphocytes
    • response determined by environment (e.g. cytokines)

‘master manipulators’

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the adaptive immune system?

A
  • highly specific but slower
  • able to eliminate foreign antigens
  • has a critical memory function
  • cells/molecules involved:
    • T lymphocytes: secrete cytokines/chemokines
    • B lymphocytes: secrete antibodies
  • involved in self/non-self discrimination
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are some of the main lymphocytes?

A

T lymphocyte: produce cytokines

  • helper T lymphocytes (Th)
  • cytotoxic T lymphocytes (Tc)
  • regulatory T lymphocytes (Treg)

B lymphocytes - produce antibodies

  • B-1/B-2
  • marginal zone B cells (MZB) (CD27 marker)
  • follicular B cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the kinetics of immune protection?

A
  • primary response: IgM, low (e.g. vaccination)

- exposure to infection, massive response (greater magnitude), class switched IgG, IgA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the sizes of the different antibodies?

A

IgM - secreted as pentamer - 950kD

  • IgD - 175
  • IgG - 150
  • IgA - 160 - 400
  • IgE - 190
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the functions of the different Igs?

A

IgM: first response, pentamer, low affinity, high avidity
IgD: less known, potentially involved in development, function not well described
IgG: complement activating, placental transport
IgA: mucosal
IgE: mast sensitising

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How might an immune response be carried out?

A
  • antigen presented to an immune cell (APC)
  • maybe cytotoxic pathway (T cells)
  • can directly interact with B cell
  • memory cells and plasma cells that secrete antibodies
  • after T cell help B cells undergo class switching and affinity maturation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are T-independent antigens?

A
  • include polysaccharides (pneumoccocal PS)

- B cells produce short lived plasma cells without the help of T cells (can’t recognise PS)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are T-dependent antigens?

A
  • typically proteins

- B cells produce long lived plasma cells and memory cells with the help of T cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

How are Regulatory T cells important in the control of immunity?

A
  • involved in controlling a number of the inflammatory responses
  • e.g. suppression of effector Th17 cells
  • lots of suppression: inhibition of allergic type cells
  • IL10 - unwanted or unwarranted allergy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are regulatory T cells (Treg)?

A
  • Identification of CD25 by Shimon Sakaguchi in 1995 led to advances in Treg biology
  • Also referred to as ‘suppressor’ T cells:
  • Two types:
    • naturally-occurring: CD4+, CD25+, FoxP3+
    • inducible: CD4+CD25-FoxP3- (Tr1;IL-10) and CD4+CD25+/-FoxP3+ (Th3; TGF-beta)
  • controls inflammation, allergy and autoimmunity
  • Foxp3 transcription factor is key marker
17
Q

How is the immune system imperfect?

A
  • defects in the immune system can happen
  • can be genetically pre-determined or a consequence of aberrant regulation
  • outcomes include:
    • immunodeficiency
    • autoimmunity
    • allergy
18
Q

What is immunodeficiency?

A
  • a group of disorders where part of the immune system is missing or defective
  • two classifications:
    • primary immunodeficiency (genetic)
    • secondary immunodeficiency (HIV)
19
Q

What are Primary Immunodeficiencies?

A
  • approx 150 different conditions; most rare
  • inherited (present at birth)
  • defect in one or more components of the immune system (innate and adaptive)
  • symptoms may not appear until adulthood
20
Q

What are the types of primary immunodeficiency?

A
  • antibody deficiencies (majority)
  • complement deficiency
  • phagocytic
  • cellular deficiency
  • combined immunodeficiency
21
Q

How do we classify PIDs?

A
  • classified in terms of the response and the cells involved
    (8 classes as defined by IUIS)
22
Q

What are examples of PIDs?

A
  • combined B and T lymphocyte immunodeficiencies
  • MHC Class I/II deficiency
  • Hyper IgM syndrome (CD40-CD40L deficiency)
  • Agammaglobunemias (Ab deficiency)
  • Common Variable Immunodeficiency (CVID)
  • Selective IgG, IgM or IgA (and subclass) deficiencies
  • Wiskott-Aldrich disease
  • DiGeorge Syndrome
  • Chronic granulomatous deficiency (phagocytes)
  • NK deficiencies, Complement deficiencies
23
Q

What are clinical signs of PIDs?

A
  • > 10 episodes acute otitis media per year (infants and children)
  • > 2 episodes consolidated pneumonia per ear
  • > 2 life-threatening infections per lifetime
  • two or more serious sinus infections within 1 year
  • abnormal response to microbes

Diagnosis is a combination of clinical history and laboratory evaluation of immune system

24
Q

What are pathological features of PIDs?

A
  • recurrent deep skin or organ abscesses
  • two or more deep-seated infections such as meningitis, osteomyelitis, cellulitis or sepsis
  • persistent oral thrush or candida infection elsewhere on the skin (>1yr age)
  • recurrent autoimmune phenomena
  • dysmorphic features associated with recurrent infection
  • infections that worsen chronic disorders (e.g. asthma)
  • infections with pathogen despite vaccine (e.g. pneumococcal)
25
Q

What is CVID?

A
  • common variable immune deficiency
  • one of the most common PIDs: 1:50,000 affected
  • characterised by low levels of serum Igs - hypogammaglobulinaemia
  • increased susceptibility to infections (mainly bacterial)
  • genetic causes unknown (10-25% inherited e.g. TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor)
  • nature and type of deficiency varies with patient
  • affects multiple organs: Lungs, GIT, spleen, blood, ears (middle, predominantly)
26
Q

To what is CVID normally due?

A
  • normal B cell numbers
  • B cells fail to differentiate into plasma cells
  • Lack of Ab production (IgG mainly, also IgA, IgM)
  • deficient memory B cells
  • poor response to vaccines
  • also lack of T cell help
27
Q

What are the pathological outcomes of CVID?

A
  • no physical abnormality
  • recurrent and severe lung infections: bacteria such as pneumococcus, H. influenzae type b
  • enlarged lymph node, spleen
  • polyarthritis
28
Q

What are infections associated with CVID?

A
  • sinusitis
  • pneumonia (biggest killer of children under 5)
  • bronchitis
  • otitis
  • abscess
  • rec herpes zoster
  • sepsis
  • meningitis
  • cellulitis
  • osteomyelitis
29
Q

How is CVID treated?

A
  • effective treatment allows patients to lead a normal life
    • immunoglobulin replacement therapy (IVIg)
    • antibiotics for chronic infections
30
Q

What is specific antibody deficiency (SAD)?

A
  • Patients have normal Ig levels and normal Ig subclasses: lacking IgG2
  • responses to protein antigens/vaccines normal
  • failure to produce protective antibody levels in response to polysaccharide antigens
    • streptococcus pneumoniae (pneumococcus)
  • IgG2: detects polysaccharide antigen
  • susceptible to infections with encapsulated bacteria
  • may also have IgG4 and IgA deficiency
31
Q

What is a major complication of SAD?

A
  • pneumococcal disease
  • S. pneumoniae (pneumococcus): important pathogen globally (1-2 million children die each year)
  • affects young children, older adults and immunocompromised
  • often described as a commensal organism (carrier = asymptomatic)
  • can cause bacterial meningitis and acute otitis media (middle ear infection)
32
Q

What is pneumococcal disease?

A
  • gram + diplococci
  • encapsulated bacteria - the capsule is a T-independent antigen (no T cell help)
  • many types: more than 90 different serotypes, different PS
  • significant pathogen causing pneumonia, otitis media (can lead to long term hearing impairment) and sinusitis
  • also more serious invasive diseases such as meningitis and sepsis
  • therefore diagnosis and management of SAD is critical
33
Q

How do you diagnose SAD in the lab?

A
  • evaluate response to pneumococcal polysaccharide vaccine - 23 serotypes
  • respond to at least half the serotypes - 4-fold rise in IgG or >1/3µg/mL
  • memory B cell numbers indicative of SAD
  • treated with IVIg and/or antibiotics
34
Q

What is severe combined immunodeficiency (SCID)?

A
  • rare, potentially fatal (bubble boy)
  • lack of T and B cell function (also NK)
  • several genetic defects identified (12 so far)
    • most common is X-linked (45%) - c-gamma mutation
  • IL7-alpha, Jak3, CD3, CD45
  • extreme susceptibility to infections
    • cytomegalovirus (CMV), HSC, EBV
    • implications for live virus vaccines
35
Q

What is IPEX syndrome?

A
  • immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
  • very rare condition caused by mutation in FoxP3
  • lack of functional Treg cells
  • multiple autoimmune disorders
    • diabetes, thyroiditis, haemolytic anaemia
  • allergic phenotypes also occur
  • mainly resulting in unwanted infection, malnutrition etc
36
Q

What is the pathology of IPEX?

A
  • absence of small bowel mucosa
  • inflammatory infiltrate in many organs
  • Liver: fatty change
  • Kidney: nephritis
  • Skin: eczematous
  • duodenal villous atrophy
  • no goblet cells
  • inflammatory cell infiltrate
37
Q

What is chronic granulomatous disease?

A
  • X-linked disorder, incidence 1:500,000
  • defect in intracellular bacterial killing by neutrophils and monocytes due to mutations in NADPH oxidase (>400 known)
  • increased susceptibility to infections by ‘catalase’ organisms
38
Q

What is IRAK-4 deficiency?

A
  • interleukin-1 receptor-associated kinase-4
  • extremely rare condition (48 worldwide as at 2010)
  • essential role in TLR and IL-1 receptor signalling
    • innate immune receptors for pathogen binding
    • affects NFkB signalling
    • inability to activate T cells
  • susceptible to pyogenic bacteria, not viruses, fungi
    • predominantly S. pneumoniae
  • vaccination can be beneficial
  • much fewer numbers of CD4 and CD8
39
Q

How do we diagnose PIDs in the lab?

A

Antibody deficiency

  • IgG, IgM, IgA (and subclasses)
  • total and specific antibody (post vaccine)
  • B cell analysis (total, memory)

Cellular deficiency

  • blood counts (total white blood cells)
  • lymphocyte proliferation assays (antigen stimulation)
  • oxidative burst (neutrophil function)

Can only be done with reference to appropriate controls

PATH30001 (34 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions