Immunodeficiences Flashcards
what should a well-functioning immune system be able to?
- recognize and destroy self and non-self entities that are causing harm (i.e pathogens or tumours)
- ignore entities that are harmless (i.e consumed food)
barriers of the body that interact with the environment are important for this
–> lungs, GI tract, skin
what is immunodeficiency?
- is when a part of the immune system is weakened or impaired immune system that makes the body more susceptible to infections, certain vaccines may be less effective, and there is an increased risk of tumors
- there are two types: primary and secondary
what is primary and secondary immunodeficiency?
- primary = caused by a genetic or developmental defect, such as mutations in genes responsible for the immune response
- secondary = caused by external agents, such as drugs, radiation, infectious agents
what are the characteristics of primary immunodeficiencies?
- leads to increased infections and/or increase risk of tumour development
- present at birth, but may not be detected until later in life when they cause symptoms
- may manifest as an autoimmune disease
- can affect innate or adaptive immune responses
- typically are very rare
What are the main factors that determine the consequences of a genetic mutation in primary immunodeficiency disorders (PIDs)?
- most PIDs are caused by a single gene defect
- the consequence of the immune gene mutation depends on:
1) the role of the affected protein
2) the nature of the mutation (prevent expression or protein function) - mutations that occur early stages of hematopoiesis (the process of blood cell formation) can disrupt every downstream step of immune cell development, leading to broad immune deficiencies
what is combined immunodeficiencies (CIDs)?
- CIDs are diseases that result in the absence of T cells or significant T cell function impairment combined with some impairment of the B
cell response
–> T cell mutations often lead to B cell impairment because TFH cells help B cells
with activation, antibody production, class switching and affinity maturation
what is severe combined immunodeficiency (SCID)?
- severe, life-limiting condition
- characterized by a lack of functional lymphocytes (T and B cells) causing severe impairment to immune system
- This disease presents in early childhood with the following symptoms:
1) Repeated viral infection from 2-3 months of age
2) Susceptible to bacterial and fungal infections
3) Diarrhea, failure to thrive, lung failure
how is SCID treated?
- aggressive, immediate treatment with bone marrow or hematopoietic stem cell transplant
- Without treatment, infants with SCID usually die from infections within the first two years of life
–> With an early bone marrow transplant, frequent follow-up and prompt treatment for infections, survival rates are very good
what are the 5 categories of defects causing SCID in humans?
- reticular dysgenesis (RD) = defective differentiation of hematopoietic stem cells into myeloid and lymphoid cells
- defective purine metabolism = leads to build up of toxic metabolites in B and T cells (impairs, weakens, kills lymphocytes)
- defects in receptor rearrangement (RAG mutation) = leading to no VDJ recombination of TCRs and BCRs so no functional t-cells and b-cells develop
- mutations in cytokine receptor signalling = failure of developing t-cells to receive survival signals
- defects in t-cell signalling = lead to inability to signal through TCRs
all have different outcomes and spectrum of severity, but bone marrow transplant is the treatment
what is agammaglobulinaemias?
- a group of inherited immune disorders that cause severe antibody deficiencies in the blood
- caused by defects in b-lymphocytes
- have similar presentation to SCID and require a bone marrow transplant for treatment
what is X-linked hyper-IgM syndrome?
- a rare, inherited immune deficiency disease that affects mostly males
- individuals have a defective CD40L or CD40
- this results in no CD40/CD40L interaction = there is no co-stimulation signal (Signal 2) between T cells and B cells.
what are the consequences of X-linked hyper-IgM syndrome?
1) impaired antibody production
- no class switching can occur so only IgM antibodies are produced in high amounts
- lack of IgG, IgA and IgE antibodies
2) no germinal centers
- B cells cannot form germinal centers, preventing efficient antibody affinity maturation
3) no memory b-cells
- Impaired production of memory B cells, leading to poor long-term immunity.
4) recurrent infections
- increased susceptibility to bacterial infections, as IgG (critical for opsonization and complement activation) is absent.
*IgM antibodies are still produced at high levels = B cell activation to T cell-independent antigens is unaffected
what are other antibody-related deficiencies?
- selective IgA Deficiency is the most common antibody-related deficiency
- caused by IgA-expressing B cells failling to differentiate into plasma cells = leading to reduced or absent IgA production.
- individuals may exhibit greater than normal susceptibilities to infections in the respiratory, intestinal and genitourinary tracts
- it affects around 1 in 700 individuals but 70% are asymptomatic
- symptoms can include: intestinal malabsorption, allergic disease and autoimmune disorders
what are innate immune deficiencies?
conditions that occur when the body’s innate immune response to infection is delayed or impaired, primarily affecting phagocytes or the complement system
- phagocytic defects can result from:
(1) reduced number of phagocytes = less monocytes in the blood and macrophages in tissues
(2) defects in the phagocytic process = cell motility, binding to pathogen, failure in phagocytic process, defective intracellular killing mechanism
what is chronic graulomatous disease (CGD)?
- defect in NADPH oxidase, an enzyme required by phagocytes to produce reactive oxygen species (ROS)
- this means they cannot effectively kill pathogens
–> No NAPDH oxidase = no ROS/RNS = less effective pathogen killing
