Primary Immunodeficiency 31/01/23 Flashcards
What is the definition of an immunodeficiency?
Immunodeficiency is defined as disease characterised by absence or failure of any part of the immune system.
What is the definition of a primary immunodeficiency?
Immunodeficiencies that are caused by genetic defects that disable parts of the immune network (a failure within the immune system itself).
What is the basis of the immune system?
Pluripotent haematopoietic stem cells in the bone marrow differentiate via the myeloid or lymphoid pathway into the various immune cells. Immune cells migrate from blood circulation into the tissues, using cell adhesion molecules, chemotactic factors and complement proteins that regulate the inflammatory response. After entering tissues, phagocytic cells, part of the innate immune response, engulf pathogens by phagocytosis and destroy them with lots of different microbicidal agents.
What is the function of natural killer cells?
Natural Killer cells deal with intracellular infections (phagocytes, complement, and antibodies cannot access pathogens once inside the cell). NK cells are also part of the innate immune response. NK cell are large granular leukocyte that does not rearrange nor express either Ig or T cell receptor genes. It recognizes virally infected cells and tumour cells in an major histocompatibility complex and antibody dependent manner. NK cells can also mediate antibody-dependent cellular cytotoxicity.
What is the adaptive immune system?
Adaptive immunity (antibody producing B cells, helper, cytotoxic and regulatory T cells) provides back-up to the innate response such as natural killer cells. The adaptive immunity takes a while to develop (much quicker secondary responses than initial encounter with a pathogen). Antibodies have neutralizing function as well as function as opsonin. Cytotoxic T cells destroy infected/abnormal cells by specific binding to the major histocompatibility complex and fragmenting.
What risk does a immunodeficiency disease cause to the individual?
They are at risk of opportunistic infections which are caused by microorganisms that healthy individuals can easily get rid of but that cause disease and even death in those with significantly impaired immune function.
When was the first immunodeficiency disease discovered?
Before antibiotics were used in the 1950s most patients with immunodeficiencies died during infancy or early childhood. Since so many infants died before antibiotics were used death caused by immunodeficiencies did not become apparent until the introduction of antibiotics so this was when the first primary immunodeficiency was diagnosed.
What causes an immunodeficiency disease?
Genetic or developmental defects such as a missing enzyme, cell type, or non-functioning component can cause immunodeficiency.
Who is affected by immunodeficiency and what genes are involved?
Defects of virtually any gene involved in immune development or function can cause these diseases. Mutant alleles have been found in most genes encoding components of the immune system and immunologists have learnt a lot about the functions of genes from looking at the types of infections patients with defective alleles have-in a similar manner to mouse knock-out models.
Those effected at birth have a congenital (defect present at birth) disease. Possible for disease to not manifest until later in life.
How severe are immunodeficiencies?
Depending upon which component is failing determines the type of immunodeficiency and the severity. Some immunodeficiency disorders are relatively minor requiring little or no treatment, whereas others are life threatening and require major intervention.
How many people do immunodeficiencies affect?
1 in 10,000 births. They can be recessive, dominant, or x-linked. Most are x-linked therefore they are more common in males than females.
How can the type of recurrent infection inform which immune cell is affected?
-Bacteria indicate defects of antibody, complement, phagocytic defects
-Viral suggest T-cell defects
-Fungal suggest T-cell defects
-Autoimmunity can be main symptom
How many immunodeficiencies are there?
Over 350.
What is a IgA deficiency?
IgA deficiency is a relatively common disorder due to failure IgA bearing lymphocytes to differentiate into plasma cells. Many individuals with IgA deficiency are clinically asymptomatic but those with symptoms have sinopulmonary and gastrointestinal infections. These individuals are at risk of developing anti-IgA antibodies when given blood products. Occurs in 1 in 700 Caucasians but rare in other ethnic groups.
What is a IFN-γ deficiency?
IFN-γ is the main cytokine that activates macrophages. Macrophages are important for defence against intravascular bacteria such as mycobacteria. IFN-γ is secreted by NK cells (innate immunity) and TH1 CD4+ and cytotoxic CD8+ cells (adaptive immunity). When IFN-γ binds to IFN-γ Receptor it causes increased phagocytosis and bacterial killing by activating JAK1 and JAK2 pathways. Patients with IFN-γ receptor deficiency due to recessive mutations of IFN-γ R1 genes have no R1 polypeptides on the cell surface, so cannot respond to IFN-γ .
What do dominant IFN-γ deficiency cause?
Dominant mutations of IFN-γ R1 cause truncated cytoplasmic tails so they are unable to bind and activate JAK1 signalling (but can still bind IFN-γ). Because only need one mutant allele for a dominant condition 25% of receptors are normal so blood monocytes still response to IFN-γ (but less than healthy people). This form of disease is less severe and usually diagnosed later than those resulting from recessive mutations.
What affect do antibody deficiencies cause?
Encapsulated pyogenic bacteria (e.g. Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus) are not recognized by phagocytic receptors of macrophages and neutrophils, so need to bound by specific antibody and complement first, then ingested and killed by phagocytes. Patients with antibody deficiency have lasting, recurrent pyogenic infections until given antibiotics.
What is x-linked agammaglobulinaemia?
A rare disease where the body is unable to produce immunoglobulins. It produces a susceptibility to opportunistic infection due to the failure of humoral antibodies (cell-mediated immunity is unaffected). XLA was the 1st immunodeficiency identified (also known as Bruton’s disease). Bruton’s tyrosine kinase (Btk) is involved in intracellular signalling from the B-cell receptor, causing maturation of pre-B cells. Mutant Btk causes the B-cells to be arrested at the pre-B-cell stage and the production of Ig is grossly depressed (All classes of Ab affected). B-cells are reduced or absent in the peripheral blood and there are few lymphoid follicles or plasma cells in the lymph nodes.
What does x-linked agammaglobulinaemia result in?
-Unable to produce functional B cells in males
-Females are carriers but healthy
-Ig production is grossly reduced
-Affected boys initially protected by passive immunity for first few months life due to transfer of maternal antibodies via placenta
-Recurrent pyogenic bacterial infections
-Cell-mediated immunity is normal so viral infections are dealt with
How is x-linked agammaglobulinaemia treated?
-Antibiotics
-Intravenous Ig administration (passive immunity) against all common pathogens every 3-4 weeks to maintain adequate concentrations of circulating Ig to prevent tissue damage caused by the excessive release of proteases from both the infecting bacteria and defending phagocytes. This is particularly problematic in the lungs and can cause chronic inflammation known as bronchiectasis.
