Immunodeficiencies Flashcards
How can immunodeficiencies be classified?
Primary (congenital) = Immunodeficiency caused by defect in the component of the immune system
Secondary (acquired) = Immunodeficiency caused by another disease e.g infection (viral, bacterial), malignancy (myeloma, lymphoma, leukaemia), extremes of age, nutrition (anorexia, iron def), splenectomy
What are the two basic clinical features of immunodeficiencies?
- Recurrent infections
- Severe infections, unusual pathogens (Aspergillus, Pneumocystis), infections will be in unusual sites for example liver abscesses or osteomyelitis (bone)
What are warning signs of primary immunodeficiencies?
2 or more of the following symptoms can identify a 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
Provide a general description of primary immunodeficiencies
- Usually genetic
- Infrequent but can be life threatening
- Adaptive IS = Made up of B and T cells
- Innate IS = Made up of phagocytes, complement, etc
- Frequency
- 50% antibody; 30% T cell; 18% phagocytes, 2% complement
List some defects in adaptive immunity
- Sub-classification; primary component affected
- E.g. B cells, T cells, combined (both B and T)
- Often T cell defects will impair antibody production!!
- This is because B-cells will require T-cell activation in order to undergo class switching and affinity maturation
- Defects in T or B-cells can be either in lymphocyte development or in the activation stage later on
- This is because B-cells will require T-cell activation in order to undergo class switching and affinity maturation
- Often T cell defects will impair antibody production!!
What are 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
- First described primary immunodeficiency (Bruton’s disease)
- Defect in btk gene
- Encodes Bruton tyrosine kinase important for B-lymphocyte development
- Block in B-cell development (stop at pre-B cells)
- Subsequent stages are missing and no Ab production
- Leads to recurrent severe bacterial infections
- Presents in 2nd half of first year, as children have some immunity in first half from passive transfer of maternal IgG and IgA via breastfeeding
- Leads to recurrent severe bacterial infections
How do we 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 disorder that affects both B and T cells (SCID)
Severe Combined ImmunoDeficiency (SCID)
Describe the presentation and inheritance of SCID?
- Presentation = 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 Abs)
- Unusual infections (such as pneumocystis, CMV)
- Presentation
What are the causes of severe combined immunodeficiency?
-
Causes (syndrome as the causes can be different)
- Common cytokines receptor γ-chain defect (signal transducing component of receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, IL-21); IL-7 needed for survival T cell precursors → Defective T cell development → Lack in B cell help (low Ab)
- RAG-1/RAG-2 defect = No T and B cells
- ADA (adenosine deaminase deficiency); = accumulation of deoxyadenosine and deoxy-ATP à toxic for rapidly dividing thymocytes
How would be investigate for severe combined immunodeficiency syndrome?
- Low total lymphocyte count
- Pattern: very low/ absent T; normal/ absent B, sometimes also absent NK (γ-chain defect affecting IL-15 receptor)
- Igs low
- Decrease in T cell function (proliferation, cytokines)
How can you treat severe combined immunodeficiency syndrome?
- 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 is the outcome of SCID?
- Dependant 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 -à engraftment
Give examples of predominant T-cell disorders that can lead to immunodeficiency?
- DiGeorge Syndrome
- Wiskott Aldrich Syndrome
- Ataxia Telangiectasia
Describe Wiskott-Aldrich Syndrome
- X-linked
- Also known as eczema thrombocytopenia immunodeficiency syndrome
- Defect in WASP protein (involved in actin polymerisation of cytoskeleton) = defect in signalling
- (T cells will form psuedopods + immunological synapses with other cells so they can interact)
- Progressive immunodeficiency (T cell loss)
- Progressive decreased T cells, decreased T cell proliferation
- Ab production (low IgM, IgG, high IgE, IgA)
- Will produce high IgE and IgA which contributes to the development of eczema
- Will produce high IgE and IgA which contributes to the development of eczema
- (T cells will form psuedopods + immunological synapses with other cells so they can interact)
Describe DiGeorge Syndrome (22q11 deletion)
- Thymic hypoplasia
-
22q 11 deletion = failure development of 3+4th pharyngeal pouches
- 3rd pharyngeal pouch goes on to develop into the thymus hence underdevloped = thymic hypoplasia
- Complex array of developmental defects
- Dysmorphic face: cleft palate, low-set ears, fish-shaped mouth
- Hypocalcaemia (as it also affects parathyroid gland),cardiac abnormalities
- Variable immunodeficiency (absent/ reduced thymus à affects T cell development)
- 3rd pharyngeal pouch goes on to develop into the thymus hence underdevloped = thymic hypoplasia
Describe ataxia telangiectasia
- Autosomal recessive
- Defect in cell cycle checkpoint (ATM) à sensor of DNA damage = activates p53 = apoptosis of cells with damaged DNA
- ATM gene stabilises DNA double break complexes during V(D)J recombination = defect in generation of lymphocyte antigen receptors and lymphocyte development
What are symptoms of ataxia telangiectasia?
- Progressive cerebellar ataxia (abnormal gait(walking)
- Typical telangiectasia (ear lobes, conjunctivae)
- Immunodeficiency
- Increased incidence of tumours later in life
Describe chronic granulomatous disease
- Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidative (NADPH) components
- This means pathogens cant be eliminated properly
- There will be granuloma formation preventing the spreading of the infection to other areas.
Describe the oxygen dependant 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 will convert oxygen into the superoxide anion that is used to generate the ROS
- In chronic granulomatous disease = defects in various components that lead to the formation of the complex, cannot create the superoxide anion and generate ROS
How can you diagnose chronic granulomatous disease?
- Use tests that measure the oxidative burst
- NBT test (nitroblue tetrazolium reduction)
- Flow cytometry assay dihyrorhodamine
Describe Chediak Higashi syndrome
- Rare genetic disease
- Defect in the LYST gene (involved in trafficking of lysosomes)
- Phagosome is unable to fuse with the lysosome; enzymes cannot access the pathogen to break it down
- Neutrophils have defective phagocytosis killing
- Repetitive, severe infections
What is the diagnosis for chediak higashi syndrome
- Decreased number of neutrophils
- Neutrophils have giant granules
Describe leukocyte adhesion deficiency, how it presents and how you would investigate?
- Defect in β2-chain integrins (LFA-1, Mac-1)
- Defect in sialyl-Lewis X (selectin ligand)
- Delayed umbilical cord separation à Diagnosis defect in β2-chain integrins (LFA-1, Mac-1)
- Presentation
- Skin infections, intestinal + perianal ulcers
- Investigations
- Decreased neutrophil chemotaxis
- Decreased integrins on phagocytes (flow cytometry)
- Presentation
