Lecture 26 Flashcards
What are the two sates of immunodeficiency?
Congenital where the immunodeficiency is due to a genetic defect, these are quite rare conditions
Acquired of secondary when another disease or treatment causes immunodeficiency
What are the 7 common causes of acquired immunodeficiency?
HIV via destruction of CD4 lymphocytes Drug therapy systemic disease malnutrition or alcoholism stress or depression advanced age over exercise
What is severe combined immunodeficiency?
Genetic disorder which affects both the B and T lymphocytes of the immune system, babies typically only survive for a year with these conditions
What are the examples of sever combined immunodeficiency studied in class?
Adenosine deaminase deficiency
Purine nucleoside phosphorylase deficiency
X linked SCID
RAG-1, RAG-2 gene mutations
What is adenosine deaminase deficiency?
A primary immune deficiency which leads to a build of toxic products from cell metabolism as purines are unable to be broken down leading to adenosine and adenine accumulation in plamsa, and ADP, GTP, ATP accumulation in lymphocytes
Deoxy-ATP can become toxic inhibiting synthesis of DNA precursors preventing lymphocyte proliferation and therefore reducing the number of circulating lymphocytes
What is the potential treatment for adenosine deaminase deficiency?
Gene therapy has been trialled via infusion of T lymphocytes that have been manipulated to induce ADA expression
What is purine nucleoside phosphorylase deficiency?
Defects in the gene prevents metabolization of purines inosine and guanosine, their accumulation can be toxic resulting in a loss of T cells and a suppression of B cell responses as they lack T cell help
What are the treatments for ADA and PNP deficiencies?
Bone marrow transplantation, stem cell treatment, enzyme replacement therapy and gene therapy
What is X linked SCID?
Most common SCID, mutation of gamma chain for IL-2 and receptors for IL-4,7,9,15 leading to widespread immune system affects as it does not develop or function correctly there are low T and NK cells as well as non-functional B cells
What is X linked SCID also known as?
Bubble Boy disease
What is the only chance of a permanent cure for X linked SCID?
A compatible bone marrow transplant
What occurs in RAG-1 and RAG-2 mutations?
Inability to form the typical hetero-dimer resulting in an inability to undergo the initiation step in B and T cell antigen receptor gene segment assembly causing the cell to be unable to undergo recombination of antigen receptor genes causing Band T cells to have reduced or no function resulting in the patient suffering from opportunistic pathogens
What is X-linked agammaglobulinemia or Bruton agammaglobulinaemia?
First described Immunodeficiency,
Presents in childhood with recurrent pyogenic infections
Caused by a mutation of the tyrosine kinase enzyme which has a key role in cell development, this results in loss of B cells and therefore a loss of antibodies
How is X-linked agammaglobulinemia/ Bruton agammaglobulinaemia treated?
Infusion of human antibodies every 3-4 weeks for life
What is leukocyte adhesion deficiency 1?
Defect in the beta2 sub unit of integrin cell adhesion molecules (alphaLbeta2, alphaMbeta2, alphaXbeta2) which results in leukocytes and neutrophils cannot adhere to endothelial cells and therefore cannot reach the inflammed/infected sites
What is leukocyte adhesion deficiency 2?
Defect in the glycosyltransferases required to decorate selectin ligands with sugar moieties resutling in leukocytes not being able to migrate from the blood
How are LAD-1 and LAD-2 treated?
Bone marrow transplantation
What is Hyper IgM syndrome?
Very high expression o IgM antibodies, but low IgG and IgA levels causing susceptibility to upper respiratory tract bacterial infections and intracellular parasites
This is caused by B cells neing unable to make the switch from production of IgM to other antibody types typically due to a mutation in CD40 or CD40L
What is selective IgA deficiency?
A common immune deficiency with only mild disease where the IgA which protects the mucous membranes of the body is absent
What is complement deficiency syndrome?
Deficiency of components of the complement cascade making the patient more susceptible to neisserial infections, particularly if C5-C8 are the missing components
Pateints are susceptible to recurrant pyogenic infections and have a higher risk of developing systemic lupus erythematosus
What is chronic granulomatous disease?
Diverse group of hereditary diseases where the enzyme NADPH oxidase is defected resulting in an inability to form reactive oxygen species making ingested pathogens much hard to kill
What mediates each of the 4 types of hypersensitivity?
Type 1= IgE
Type 2= Antibody mediated
Type 3= Immune-complex mediated
Type 4= Cell mediated
What triggers a type 1 hypersensitivity?
Response is provoked by exposure via ingestion, inhalation. injection or direct contact of a specific allergen
This leads to overproduction of IgE and TH2 cytokines resulting in excessive activation of mast cells and basophils
What is the key cellular interactions in Type 1 hypersensitivity?
Allergen bound B cells react with TH2 cells turning on IgE production
IgE binds to Fc receptors of mast cells
A divalent allergen can cross link two IgE molecules when bound to mast cells to trigger release of cellular mediators
What are the immediate and late affects of a type 1 hypersensitivity reaction?
Immediate= Vasodilation, vascular leakiness, pruritis and smooth muscle contraction
Late response is cellular involving leukocyte infiltration causing damage and remodelling of tissues
What are the mast cell mediators released in a type 1 hypersensitivity reaction?
Histamine, heparin, chemokimes, leukotrienes and prostaglandins which trigger inflammation
What is the hygiene hypothesis?
The suggestion that a lack of childhood exposure to infectious agents and lack of helminth exposure as adults increases allergic susceptibility, as exposure is required to activate Tregs
What are the different forms of type 2 hypersensitivity?
Complement fixation
Antibody dependant cell mediated cytotoxicity
Frustrated phagocytosis
What do all the different types of type 2 hypersensitivity have in common?
Antibody-antigen complexes form on the patients own cell surface, these can be either self or non self antigens this results in killing of the cell to which the antibody is bound
What occurs in complement fixation?
IgG and IgM form complexes to activate the complement system causing cell death
What occurs in antibody dependant cell-mediated cytotoxicity?
IgG or IgM form complexes, which recruit NK and macrophages via the FcgammaRIII receptor, these cells kill the Ig bearing cells
What is frustrated phagocytosis?
When neutrophils are unable to completely engulf their target resulting in release of digestive enzymes into the the extracellular space where they mat cause cellular damage
What are examples of type 2 hypersensitivity diseases?
Autoimmune haemolytic disease
Hemolytic disease of the newborn
Goodpastures syndrome
What occurs in autoimmune haemolytic disease?
IgG and IgA attach to red blood cells causing damage to these in the spleen
What occurs in haemolytic disease of the newborn?
An Rh-ve mother will reject her second Rh+ve child as she will have antibodies to the blood type
What occurs in goodpasture’s syndrome?
Antibodies attack the good pasture antigen on type IV collagen found in the kidney and lung
What is sometimes referred to as type V hypersensitivity?
Antibodies bind to cellular receptors resulting on blocking or stimulating their function
What are examples of an antibody blocking a receptors activity?
Hashimotos thyroiditis
Pernicious anemia
What occurs in Hashimotos thyroiditis?
Antibodies bind to thyroid peroxidase/thyroidglobulin causing gradual destruction of thyroid follicles causing hypothyroidism
What occurs in pernicious anemia?
Antibodies against intrinsic factor are produced prevent B12 absorption
What is an example of an antibody stimulating a receptor? and what occurs in this condition?
Grave’s disease where autoantibodies bind to the thyrid stimulating hormone resulting in increased levels of this hormone
What is the difference between type II and III hypersensitivity reactions?
Type II is made from antibody/antigen complexes on cells while Type III is induced by soluble complexes which then deposit themselves around different regions of the body
The effector/damage causing mechanisms are the SAME
What is an example of type III hypersensitivity?
Immune complexes formed after infection,
Systemic lupus erythematosus where the immune system attacks the body’s cells and tissues,
Farmers lung where allergic alveolitis is caused by inhalation of actinmycete fungi causing complement activation and inflammatory cell recruitment
What is type IV hypersensitivity?
Reaction which is cell mediated rather than antibody mediated which means it consequently takes longer to develop. Caused specific T lymphocytes (TH1) recruting macrophages which induce cellular damage
How does granulomatus function as a type 4 hypersensitivity reaction?
Persistance of phagocytozed bacteria leads to chronic stimulation of T cells this leads to formation of a granuloma
This causes damage due to the mass affect of the granulomas on the anatomy
