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
2
Q
By what mechanisms does our immune system protect us?
A
Non-specific mechanisms
- physical/chemical barriers
- innate immunity
Specific mechanisms
- adpative immunity
3
Q
What are the key physical and chemical barriers?
A
- skin
- pH
- antimicrobials
- commensals (beneficial bacteria)
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
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
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’
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
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
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
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
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
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
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)
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
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
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
What is CVID?
- 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
To what is CVID normally due?
- 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
What are the pathological outcomes of CVID?
- no physical abnormality
- recurrent and severe lung infections: bacteria such as pneumococcus, H. influenzae type b
- enlarged lymph node, spleen
- polyarthritis
28
What are infections associated with CVID?
- sinusitis
- pneumonia (biggest killer of children under 5)
- bronchitis
- otitis
- abscess
- rec herpes zoster
- sepsis
- meningitis
- cellulitis
- osteomyelitis
29
How is CVID treated?
- effective treatment allows patients to lead a normal life
- - immunoglobulin replacement therapy (IVIg)
- - antibiotics for chronic infections
30
What is specific antibody deficiency (SAD)?
- 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
What is a major complication of SAD?
- 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
What is pneumococcal disease?
- 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
How do you diagnose SAD in the lab?
- 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
What is severe combined immunodeficiency (SCID)?
- 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
What is IPEX syndrome?
- 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
What is the pathology of IPEX?
- 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
What is chronic granulomatous disease?
- 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
What is IRAK-4 deficiency?
- 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
How do we diagnose PIDs in the lab?
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
