Immunodeficiencies Flashcards
What are the clinical features of immunodeficiencies?
You get recurrent infections (normal: <6-8 URI/year for the 1st 10 years; 6 otitis media and 2 gastroenteritis/year for the 1st 2-3 years), severe infections, from unusual pathogens (Aspergillus, Pneumocystis), at unusual sites (liver abscess, osteomyelitis).
The infections are from pathogens that would not normally cause disease in the individual, but because their immune system is compromised they contract them.
It could also be in unusual sites.
What are some warning signs of PID (primary immunodeficiency)?
- 8 or more new ear infections within 1 year
- 2 or more serious sinus infections within 1 year
- 2 or more months on antibiotics with little effect
- 2 or more pneumonias within 1 year
- Failure of an infant to gain weight or grow normally
- Recurrent, deep skin or organ abscesses
- Persistent thrush (mouth/elsewhere on skin) after age 1
- Need for intravenous antibiotics to clear infections
2 or more deep-seated infections - A family history of primary immunodeficiency
The symptoms are not very clear cut, so clinicians use this list of symptoms if they suspect that a patient has PID.
Generically, describe primary immunodeficiencies.
They are usually genetic.
They are infrequent but can be life-threatening.
The adaptive immune system is made up of T and B cells.
The innate immune system is made up of phagocytes, complement, etc.
Frequency: 50% antibody 30% T cell 18% phagocytes 2% complement
List some defects that can occur in adaptive immunity.
- it is a sub-classification of the primary component being affected
- e.g. B cells, T cells, combined (both B & T)
- often T cell defects impair antibody production
- defects in lymphocyte development or activation
List some major B lymphocyte disorders.
- X-linked agammaglobulinaemia (Bruton’s disease)
- Common variable immunodeficiency (CVID)
- Selective IgA deficiency
- IgG2 subclass deficiency
- Specific Ig deficiency with normal Igs
Describe X-linked Agammaglobulinaemia.
It was the first described immunodeficiency (1952); it is known as Bruton’s disease.
There is a defect in the gene that encodes a protein, Bruton’s tyrosine kinase, that is important in the development of B-lymphocytes.
The B-cells then cannot produce antibodies, and the patient will have recurrent severe bacterial infections.
It starts presenting during the 2nd half of first year of life (lung, ears, GI) – not in first half because still has maternal antibodies (IgG, then IgA via breastfeeding).
Describe the mechanism by which the Btk gene normally works, and what happens when it is defective.
It is the pre-B cell that expresses the Btk in a healthy scenario. It is downstream of the pre-B cell receptor that the pre-B cells express during this maturation stage, after they rearrange their genes.
If there is recognition of self-antigen, the receptor sends a signal via this Btk, which will rescue the cell from default apoptosis.
How would you investigate and treat X-linked Agammaglobulinaemia?
Investigations:
- B cells absent / low; plasma cells absent
- all Igs absent / very low
- T cells and T cell-mediated responses normal
Treatment:
- IVIg: 200-600mg/kg/month at 2-3 wk intervals
- or subcutaneous Ig weekly
- prompt antibiotic therapy (URI /LRI)
- do not give live vaccines
Give an example of a combined immunodeficiency.
Severe Combined ImmunoDeficiency (SCID)
Describe SCID and how it presents.
- it involves both T and B cells
- 50-60% X-linked; the rest is autosomal recessive
Presentation:
- well at birth; problems occur > 1st month
- diarrhoea; weight loss; persistent candidiasis
- severe bacterial/viral infections
- failure to clear vaccines (developing disease instead of antibodies)
- unusual infections (such as pneumocystis, CMV)
How would you investigate SCID?
- Lymphocyte subsets: T, B, NK (% and numbers) => low total lymphocyte count => SCID sign!
- Pattern: very low/absent T; normal/absent B, sometimes also absent NK (γ-chain defect affecting IL-15 receptor)
- Igs low
- T cell function ↓ (proliferation, cytokines)
How would you treat SCID?
- isolation => to prevent further infections
- do not give live vaccines !
- Blood products from CMV-negative donors
- IVIg replacement
- Treat infections
- Bone marrow/ haematopoietic stem cell transplant
- Gene therapy (for ADA and γ-chain genes)
What would be the outcome of SCID?
- dependent on promptness of diagnosis
- Survival >80% (early diagnosis, good donor match, no infections pre-transplant)
- Survival <40% (late diagnosis, chronic infections, poorly matched donors)
- Regular monitoring post BMT => engraftment
List some major T Lymphocyte disorders.
- DiGeorge syndrome
- Wiskott-Aldrich syndrome
- Ataxia-telagiectasia
Describe DiGeorge Syndrome.
It is thymic hypoplasia.
There is a 22q11 deletion, so we get failure of developmental 3+4th pharyngeal pouches.
It leads to:
- complex array of developmental defects
- dysmorphic face: cleft palate, low-set ears, fish-shaped mouth
- hypocalcaemia, cardiac abnormalities
- variable immunodeficiency (absent/reduced thymus => affects T cell development)
Describe Wiskott-Aldrich syndrome (WAS).
- it’s an X-linked disorder
- there is a defect in WASP (protein involved in actin polymerisation => defect in signalling)
- we get thrombocytopaenia, eczema, infections
- there is also progressive immunodeficiency (T cell loss)
- progressive ↓ T cells; ↓ T cell proliferation
- Ab production (↓ IgM, IgG; high IgE, IgA)
Describe Ataxia-Telengiectasia (AT).
- it is autosomal recessive
- there is a defect in cell cycle checkpoint gene (ATM) => sensor of DNA damage => activates p53 => apoptosis of cells with damaged DNA
- the ATM gene stabilises DNA double strand break complexes during V(D)J recombination => defect in generation of lymphocyte antigen receptors & lymphocyte development
- it is combined immunodeficiency (B & T)
- defects in production of switched Abs (IgA/G2)
- T cell defects (less pronounced) <= thymic hypoplasia
- upper & lower respiratory tract infections
- autoimmune phenomena, cancer
Symptoms:
- progressive cerebellar ataxia (abnormal gait)
- typical telangiectasia (ear lobes, conjunctivae)
- immunodeficiency
- increased incidence of tumours later in life
What are the two types of defects in innate immunity?
- phagocyte defects
- complement defects
Describe phagocyte defects, and give some examples.
They can be quantitative (where you get a ↓ in number), or qualitative (where we get a decrease in quality).
Examples would be:
- Chronic granulomatous disease
- Chediak-Higashi syndrome
- Leucocyte adhesion defects (LADs)
Describe Chronic Granulomatous Disease.
The defect is in the killing of the microbe, and it is to do with the generation of the oxidative species that are critical for the killing of certain pathogens.
This comes about as a mutation of the phagocyte oxidase (NADPH) components.
They can’t eliminate the pathogen, so the body form granulomas to try to prevent the spread of the infection to the rest of the body.
Describe the oxygen-dependent killing of pathogens.
After the microbe is taken up by the phagocyte, then you have the assembly of the NADPH complex by recruitment of subunits from the cytosol. This converts oxygen into the superoxide anion that can be used to generate the reactive oxygen species.
In the chronic granulomatous disease, there are defects in various components that lead to the formation of the complex, so it cannot create the superoxide anion, so it cannot generate reactive oxygen species.
How would you diagnose CGD?
You would use tests that measure oxidative burst:
- NBT test (nitroblue tetrazolium reduction)
- Flow cytometry assay dihydrorhodamine
Describe the NBT reduction test.
You take neutrophils (from the patient and control) and incubate them with the nitroblue tetrazolium reduction, then activate them using cytokines or microbes to see if they can produce reactive oxygen species.
If they can, they will cleave the dye, generating the blue colour. If they can’t, we won’t see the blue colour.
Describe the dihydrorhodamine assay.
Again, you will take neutrophils from the patient and control and activate them. If they can make reactive oxygen species, they will cleave the dihydrorhodamine and make it fluorescent If they can’t, it will remain dull.
