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Flashcards in lecture 11 Deck (39):
1

What is the primary purpose of the immune system?

- to protect the host from disease

2

By what mechanisms does our immune system protect us?

Non-specific mechanisms
- physical/chemical barriers
- innate immunity

Specific mechanisms
- adpative immunity

3

What are the key physical and chemical barriers?

- skin
- pH
- antimicrobials
- commensals (beneficial bacteria)

4

What are the three 'lines of defense'?

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

What is innate immunity?

- 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

What are dendritic cells?

- 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

What is the adaptive immune system?

- 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

What are some of the main lymphocytes?

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

What are the kinetics of immune protection?

- primary response: IgM, low (e.g. vaccination)
- exposure to infection, massive response (greater magnitude), class switched IgG, IgA

10

What are the sizes of the different antibodies?

IgM - secreted as pentamer - 950kD
- IgD - 175
- IgG - 150
- IgA - 160 - 400
- IgE - 190

11

What are the functions of the different Igs?

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

How might an immune response be carried out?

- 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

What are T-independent antigens?

- include polysaccharides (pneumoccocal PS)
- B cells produce short lived plasma cells without the help of T cells (can't recognise PS)

14

What are T-dependent antigens?

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

15

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

- 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

What are regulatory T cells (Treg)?

- 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

How is the immune system imperfect?

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

18

What is immunodeficiency?

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

19

What are Primary Immunodeficiencies?

- 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

What are the types of primary immunodeficiency?

- antibody deficiencies (majority)
- complement deficiency
- phagocytic
- cellular deficiency
- combined immunodeficiency

21

How do we classify PIDs?

- classified in terms of the response and the cells involved
(8 classes as defined by IUIS)

22

What are examples of PIDs?

- 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

What are clinical signs of PIDs?

- >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

What are pathological features of PIDs?

- 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