Primary Immunodeficiency Flashcards
Describe the development of immune cells?
- Begins as pluripotent stem cell
- Develops into 1 off
- Premyeloid cell (precursor for neutrophils)
- Lymphocyte-committed stem cell (precursors for T cells which develop in thymus, or B cells which develop in bone marrow)
- Premonocyte (precursor of monocytes, which then becomes macrophage)
- T cell can develop into: Helper cell (Th1 and Th2), Cytotoxic cell or memory cell
- B cells produce antibodies and become plasma cell
What kind of stem cell do immune cells begin as?
Pluripotent immune cell
What is the precursor for neutrophils?
Premyeloid cell
What is the precursor for T and B cells?
Lymphocyte-committed stem cell
What is the precursor for macrophages?
Premonocyte -> monocyte -> macrophage
What are the different kinds of immunity?
- Specific immunity
- Antibodies (through B cells)
- Cellular immunity (through T cells and antigen presenting cells)
- Non-specific immunity
- Compliment system
- Phagocytes
What cells are involved in specific immunity?
- Antibodies (through B cells)
- Cellular immunity (through T cells and antigen presenting cells)
What cells are involved in non-specific immunity?
- Compliment system
- Phagocytes
When your born, where do most of your antibodies come from and what kind are they?
When born most antibodies come from mother (IgG), but then develop own
Each kind of immunity provides defence against different microorganisms, describe this?
What are the 2 categories of immunodefiency diseases?
- Primary (or congenital) immunodeficiency
- Secondary (or acquired) immunodeficiency
What are some complications of immunodeficiency diseases?
- Increased susceptibility to infection, cancer and possibly autoimmunity
What is primary immunodeficiency?
These are a collection of diseases
Describe the aetiology of primary immunodeficiency?
- Genetic, congenital disorders
- Caused by mutations or autoimmunity
- Part of the immune system is missing or functioning abnormally
- Abnormality could be
- Component of innate immune system
- Stages of lymphocyte development
- The earlier in the process of development the more profound the effect
- Responses of mature lymphocytes to antigenic stimulation
- Abnormality could be
- NOT secondary to other disease processes, toxins or drugs
Suspect immunodeficiency when infections are..?
- Recurrent
- Unusual microorganisms
- Difficult to treat
What does the type of opportunistic infection give clues about?
Degree and cause of immunodeficiency
What opportunistic infections often occur in T cell defects?
- T cells or macrophages – intracellular organisms such as protozoa, viruses and intracellular bacteria including mycobacteria
- Such as mycobacterium tuberculosis causing lung infections in immunocompetent people, but can invade body outside lungs in immunocompromised
- T cells – reactivation of latent herpesvirus, or herpesvirus-induced tumours (such as koposi sarcoma) and non-
- TH17 - candida
What opportunistic infections occur in compliment defects?
- Compliment system – meningitis caused by Neisseria meningitides
What opportunistic infections occur in B cell defects?
- Defective antibody production – encapsulated bacteria
- Pneumococcus or haemophilus spp – antibody deficiency (IgG and IgA)
What are possible causes of primary immunodeficiency?
- Mutations
- Permanent alteration in DNA sequence that affects a gene so it is no longer functional
- Rarely affect immune system, causing severe disease when they do
- Polymorphisms
- Involves one of two or more variants of a particular DNA sequence
- Commonly affects immune system, causing moderate increased risk for infection
- Polygenic disorders
- Caused by the combined action of more than one gene
- Relatively commonly affect immune system and often affect antibodies, some of these conditions caused by autoimmunity
What kind of immunodeficiency do mutations often result in?
Severe combined immunodeficiency (SCID)
What is severe combined immunodeficiency?
Group of disorders that affect both T and B cells
What does SCID stand for?
Severe combined immunodeficiency
What is the treatment for SCID?
Stem cell transplant
What are genetic polymorphisms?
Genetic polymorphisms are alleles (different forms) of the same gene occurring at a single locus in at least 1% of the population
What are examples of genetic polymorphisms?
- Human leukocyte antigen (HLA) alleles are polymorphic and affect outcome of infection
- Individuals with HLA alleles that are unable to bind viral peptides have worse outcome
- Mannan-binding lectin (MBL) binds to sugars in bacterial cell walls and activates classic complement pathway
- Polymorphisms in this affect risk of infections
What are examples of polygenic disorders?
- Common variable immunodeficiency (CVID)
- This is a group of diseases
- IgA deficiency
- Specific antibody deficiency
What does CVID stand for?
Common variable immunodeficiency
Describe the epidemiology of CVID (M:F, incidence)?
- M:F 1:1
- Incidence 1:20000 young people
- Most common immunodeficiency requiring treatment
What is seen in the biochemistry for CVID?
(levels of IgG, IgA, IgM, B and T cells)
What are possible complications of CVID?
- Recurrent respiratory tract infections
- Infections that involves gut, skin and nervous system may occur
- Autoimmunity is common
What is the presentation of specific antibody deficiency?
- Presentation with specific microorganisms despite normal total IgG
- Do not respond to polysaccharide antigens and do not respond to vaccinations
What is an example of a specific antibody deficiency?
An example is autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED)
What does APECED stand for?
Autoimmune polyendocrinopathy candidiasis ectodermal dysplasia
Describe the pathogenesis of APECED?
- Defect in central tolerance and experience many types of autoimmunity
- Some produce autoantibodies against IL-17 causing impaired responses to candida
- Others produce antibodies against IFN-γ causing recurrent mycobacterial infection
What does monogenic and polygenic mean?
Monogenic = mutation in single gene
Polygenic = mutation in many genes
Describe the typical presentation, history and lymphocyte count for SCID?
- Presentation
- Defective T and B cells so develop infections in first few weeks of life
- Unusual or recurrent infection
- Diarrhoea
- Unusual rashes
- History
- Family history of neonatal death
- Family history of consanguinity (incest)
- Lymphocyte count
- Low count (less than 1x109/L
- Measured by flow cytometry
How is lymphocyte count measured?
Flow cytometry
Describe the typical presentation and antibody levels for antibody deficiency?
- Presentation
- Later in life
- Chronic or recurrent bacterial respiratory infection
- Antibody levels
- IgG, IgA and IgM should be measured
- With low levels of immunoglobulin causes of secondary immunodeficiency should be excluded
- If total Igs are normal, specific antibodies against Hemophilus spp. And pneumococcus measured
- If these are normal, check no problems with complement or neutrophil function
Describe the treatment of a primary immunodeficiency?
Aim is to prevent infection
Treatment options:
- For mild immunodeficiency
- Prophylactic antibiotics
- For severe antibody deficiency
- Immunoglobulin replacement therapy
Describe the treatment of SCID?
- Definitive treatment should be given, but until then
- Avoid live vaccines
- Prophylaxis against opportunist infections
- Provide definitive treatment
- Stem cell transplantation (SCT)
- Most successful if done within a few weeks of birth
- Or gene therapy if SCT not option
- Stem cell transplantation (SCT)
What is gene therapy?
Gene therapy = uses recombinant technology to correct genetic defect in patients own stem cells, which can then reconstitute the immune system
What criteria must be met for gene therapy to be successful?
- Genetic mutation identified, evidence correcting this will improve condition
- Transfected gene must confer a proliferation or survival advantage
- Must not cause malignancy
