Lecture 11 - Immunodeficiencies Flashcards
What is innate immunity made up of?
First line:
• Physical barriers
• pH
• Secretions
Second line:
• Innate immune cells
Describe the role of DC’s
- ‘Sentinels’
- Link between innate and adaptive immunity
- PAMP recognition with PRRs
- T-lymphocyte co-stimulation
- Nature of their function dependent on cytokine signalling
What are the critical features of adaptive immunity?
- Slower to be induced
- Memory function
- Recognises specific antigen
What are the different type of B cells?
- B-1
- B-2
- Marginal zone B cells (MZB)
- Follicular B cells
Describe the kinetics of immune protection after vaccination
→ Vaccination
- Induction of the primary immune response; IgM
- Response dies back, pool of memory cells present
→ Exposure to antigen from environment
3. Induction of immune response more quickly and to a greater magnitude; IgG, IgA
What are the main difference between the primary and secondary immune responses?
Secondary:
• greater magnitude
• more quickly induced
• class switched Ig (e.g. IgG, IgA)
Can IgA or IgM be monomers?
IgM: no
IgA: yes
What is the structure and function of memory B cells?
- Surface bound immunoglobulins
* hang around after the immune response has been resolved, waiting for the next exposure to the antigen
Compare T-dep. and T-independent antigen, and the respective immune responses
T-dependent:
• usually protein
• T cell help available to B cells
→ longer lived, more robust response
T-independent: • polysaccharide • no T cell help available to B cells → short lived response • no SHM or CSR
Describe the role and function of Treg
Suppressive effects on: • granulocytes • DC's • B cells • Th2 • Th1 • Th17 • T cell migration to tissues Under normal conditions, control allergy, autoimmunity and inflammation
What are the markers of Treg?
Why is this important?
- CD25
- CD4
• FoxP3 (transcription factor)
Deficiency in FoxP3 leads to deficiency of Treg.
This is called IPEX syndrome
What are the generalised outcomes of immune system defects?
- Autoimmunity
- Allergy
- Immunodeficiency
Define Immunodeficiency
A group of disorders where part of the immune system is missing or defective
What are the two categories of immunodeficiency?
Give examples for each
Primary: inherited (HIGM)
Secondary: acquired (HIV/AIDS)
What is PID?
Describe some features.
When is the onset?
What are the various classes?
Primary immune deficiency
• 150 different conditions
• most are rare
• inherited
Onset is usually in childhood, but can in adulthood
Classes in order of prevalence: • Antibody • Combined • Phagocytic • Cellular • Complement
What are clinical signs of PID used for diagnosis?
Combination of patient history w/ lab tests
Patient history: • >10 cases of otitis media per year • >2 cases of pneumonia • >2 life threatening infections per lifetime • >2 sinus infections per year
Lab tests:
• Low Ig levels (in general, or of specific classes)
• Cellular deficiencies
What are the pathological features of PID?
• Recurrent deep skin or organ abscesses
• >2 deep-seated infections such as meningitis,
osteomyelitis, cellulitis or sepsis
- oral thrush or Candida infection
- Autoimmune phenomena
- Dysmorphic features associated with recurrent infection
- Infections that worsen chronic disorders (eg. asthma)
- Infections with pathogen despite vaccine (eg pneumococcal)
Give some specific examples of PID
- T cell
• IPEX
• SCID - B cells
• CVID
• SAD - Innate deficiency
• Chronic granulomatous disease
• IRAK-4
What are some Antibody deficiencies?
- CVID
- SAD
(HIGM, agammaglobulinaemia; but these aren’t death with in this lecture)
What are some T-cell deficiencies?
- SCID (severe combined immune deficiency)
* IPEX syndrome
Describe the general features CVID
What is the cause?
Normal numbers of B cells, but they do not develop properly in plasma cells to produce Ab
- One of the most common PID’s
- V. low levels of serum Ig
- Increased susceptibility to infection due to this Ab deficiency
• Affects multiple organs (lungs, GIT, spleen, ears, blood)
Causes: Mutations in: • TACI • ICOS • CD19
What are the pathological outcomes of CVID seen around the body?
1. Frequent lung infections • Sinusitis • Pneumonia • Bronchitis • Otisis
- Enlarged lymph nodes & spleen
- Polyarthritis
What are the treatment options for CVID?
What about SAD?
- Intragam (IVIg)
- Antibiotics for the infections
Same for SAD
What is the main features of SAD?
What is lacking?
What isn’t?
(Specific antibody deficiency)
• Failure to produce normal Ab levels against specific polysaccharide antigens
(IgG2?)
NB
• Normal general Ig levels, and normal Ig subclasses, and normal response to protein antigens
• It is only Ig against very specific antigens that are absent
What is the main complication of SAD?
Why?
Pneumococcal infection
Antigen that is normally recognised by the immune system is polysaccharide
In SAD, there is failure to produce antibody against polysaccharide antigens
Which people are most commonly affected by Pneumococcal disease and why?
Who:
Children, elderly, SAD patients
Reason:
• The antigen is T-cell independent
• Children are yet to develop the required response
• Immunocompromised individuals lack the response
• Elderly has lost the required response
What is an important structural feature of S. pneumoniae?
Polysaccharide capsule
Describe how SAD is diagnosed in the lab
- Response to pneumococcal polysaccharide antigens
• Patient exposed to 23 different p.p. antigens
• If the patient responds to less than half, we diagnose with SAD
(NB respond indicates IgG specific for the antigen produced) - No memory B cells
• Using flow cytometry
What’s wrong with ‘Bubble boy’?
SCID: severe combined immune deficiency
Describe the features of SCID, as well as the cause(s)
Immune system lacks:
• T cells
• B cells
• NK cells
• Severe susceptibility to infection
Cause: • Many genetic causes identified to date e.g.; • cγ mutation • IL-7α • JAK3
What is IPEX syndrome?
Describe some features including pathogenesis
(Immunodysregulation polyendocrinopathy enteropathy X- linked syndrome)
• Very rare
Pathogenesis:
• Mutation in FoxP3 (marker of Tregs)
• Lack of functional Treg
→ multiple autoimmune disorders and allergies
Describe the pathology of IPEX
- Absence of small bowel mucosa
- Inflammatory infiltrate in many organs
- Steatosis in liver
- Nephritis
- Eczematous skin
- No goblet cells
- Atrophy of villi in duodenum
What is Chronic granulomatous disease?
What is the cause?
- Innate immune deficiency
- Neutrophils / macrophages cannot produce superoxide
- Cannot kill phagocytosed bacteria
Cause:
• Mutations in NAPDH oxidase
What are some examples of innate immune deficiency?
- IRAK-4 deficiency
* Chronic granulomatous disease
What is IRAK-4?
Interleukin-1 receptor associated kinase-4
It is a protein kinase involved in the intracellular transduction pathway after TLRs and Interleukin signalling
Describe the pathogenesis of IRAK-4 deficiency
Which infections will one be susceptible to?
- Lack of IRAK-4
- Impaired IL-1 and TLR signalling
- Impaired T-cell activation
Infection:
• Susceptible to pyogenic bacteria
• Not susceptible to viruses or fungi
Which disorders can probiotics help?
Some success seen in allergies
Which ‘helper’ T cell is usually induced in an immune response?
Th1
What is the function of Th2?
Helminth immunity
Allergy
What is the function of Th17?
Immunity against extracellular bacteria
Which classes of Ig can be transported across the mucosa?
Only IgA1 and IgA2
What is CVID also known as?
Hypogammaglobulinaemia
