Immunology (Respiratory) Flashcards
What is the acronym which contains the clinical features suggestive of immunodeficiency?
SPUR
What are all the parts of the SPUR acronym?
S - serous infection (unresponsive to oral antibiotics). P - persistent infections (early structural damage, chronic infections). U - unusual infections (unusual organisms, unusual sites). R - recurrent infections (two major or one major and recurrent minor infections in one year).
What are the other features of immunodeficiencies?
Weight loss or failure to thrive, severe skin rash, chronic diarrhoea, mouth ulceration, unusual autoimmune disease, family history.
What can lead to secondary immune deficiency?
Physiological immune deficiency (extremes of age), infection (HIV, measles), treatment interventions (immunosuppressive therapy, chemotheraphy, steroids), malignancy (cancers of immune system e.g. lymphoma, leukaemia, myeloma; metastatic tumours), biochemical and nutritional disorders (malnutrition, renal insufficiency/dialysis, type 1 and 2 diabetes, specific mineral deficiencies).
What are the clinical features of phagocyte deficiencies?
Recurrent infections affecting common and unusual sites. Organisms include common (staph aureus) and unusual bacteria (burkholderia cepacian, mycobacteria, fungi).
What is reticular dysgenesis and what will happen to babies with this inherited condition?
Where the haematopoetic stem cells can’t differentiate. They will die within a few days.
What is the differentiation problem in Kostmann syndrome?
The granulocyte-monocyte progenitor can’t differentiate into neutrophils.
What autosomal recessive disorder results in severe chronic neutropenia?
Kostmann Syndrome.
What is the clinical presentation of Kostmann syndrome?
Infections usually within 2 weeks of birth (recurrent bacterial infection, systemic or localised). Non-specific: fever, irritability, oral ulceration, failure to thrive.
What are the supportive treatments that can be used to manage Kostmann syndrome?
Prophylactic antibiotics, prophylactic antifungals (mortality 70% in first year without definitive treatment).
What is the definitive treatment in Kostmann syndrome?
Stem cell transplantation with granulocyte colony stimulating factor (G-CSF, specific growth factor to assist maturation of neutrophils).
What is leukocyte adhesion deficiency?
Failure to recognise activation markers expressed on endothelial cells. Neutrophils are mobilised but cannot exit bloodstream.
What genetic defect is leukocyte adhesion deficiency caused by?
Defect in leukocyte integrins (CD18).
What is the clinical presentation of leukocyte adhesion deficiency?
Leucocytosis (increase in white blood cells) and localised bacterial infections that are difficult to detect.
What opsonins bind to receptors on the phagocyte surface in indirect recognition?
C3b, IgG and C-reactive protein.
What are the different receptors on phagocytes for antibodies bound to antigens and complement fragments bound to antigens?
Fc receptors for antibody bound to antigen, complement receptor 1 (CR1) for complement fragments bound to antigen.
What may a defect in opsonin receptors cause and why does this not generally cause significant disease?
Defective phagocytosis. Significant redundancy (think it means it is not that important a mechanism).
What other type of defect may result in decreased efficiency of opsonisation?
Any defect of complement/antibody production.
What is absent respiratory burst and what is the commonest form?
Deficiency of the intracellular killing mechanisms of phagocytes. Commonest form is deficiency of p47phox component of NADPH oxidase (X-linked), causes inability to generate oxygen free radicals (ROS/RNS).
What can failure of oxidative killing mechanisms lead to?
Excessive inflammation, failure to degrade chemoattractants and antigens so persistent accumulation of neutrophils, activated macrophages and lymphocytes, granuloma formation.
What is the disease name when there is failure of oxidative killing mechanisms?
Chronic granulomatous disease.
What are the clinical features of chronic granulomatous disease?
Recurrent deep bacterial infections (esp staph, aspergillus, pseudomonas, mycobacteria), recurrent fungal infections, failure to thrive, lymphadenopathy and hepatosplenomegaly (swelling of liver and spleen), granuloma formation.
What is the lab investigation for chronic granulomatous disease?
NBT (nitroblue tetrazolium) test (shows whether neutrophils kill through production of oxidative free radicals).
Describe the method of the NBT test.
Feed patient’s neutrophils source of E.coli, add dye sensitive to H2O2, if produced by neutrophils dye changes colour.
What are the supportive and definitive treatments for chronic granulomatous disease?
Supportive: prophylactic antibiotics and antifungals. Definitive: stem cell transplantation.
Give 3 examples of intracellular pathogens and 1 which hides within macrophages.
Salmonella, chlamydia, rickettsia. Mycobacteria.
Describe the pathway that allows defence against intracellular pathogens (specifically TB).
Infection with TB -> infected macrophages are stimulated to produce IL-12 -> IL-12 induces Th1 cells to secrete interferon gamma (INY) back to macrophages and neutrophils -> stimulates production of TNFA -> activates NADPH oxidase -> stimulates oxidative pathways.
Single gene defects in what are associated with susceptibility to intracellular bacteria?
IFNY receptor deficiency, IL-12 deficiency, IL-12 receptor deficiency.
How would you investigate how each stage of phagocyte function was occurring correctly?
Mobilisation from bone marrow (full blood count and differential), migration to site of infection (presence of pus, expression of neutrophil adhesion molecules), chemotaxis (chemotactic assays), formation of phagolysosome (phagocytosis assays), oxidative killing (NBT test).
Describe the 2 parts of treatment for phagocyte deficiencies.
Aggressive management of infection: infection prophylaxis (septrin, itraconazole [anti-fungal]), oral/IV antibiotics, surgical draining of abscesses.
Definitive therapy: bone marrow transplantation, specific treatment for CGD (gamma interferon therapy).
Describe the life cycle of a T lymphocyte.
Arise from haematopoetic stem cells in bone marrow -> undergo selection in thymus (10% survive) -> mature T lymphocytes enter circulation and reside in lymph nodes and secondary lymphoid follicles (approximately 10^7-10^9 clones).
Describe the development of a B lymphocyte.
Stem cells -> lymphoid progenitors -> pro B cells (IgM antibody) -> pre B cells (IgM and IgD) -> IgM B cells -> can differentiate into IgM plasma cells or other Ig producing cells which can then go on to form plasma cells.
When B cells are undergoing highly complex genetic rearrangements in the germinal centres, what is the Ig isotype switch influenced by?
Cytokines derived from Th1 and Th2 effector cells.
What are the functions of antibodies?
Identification of pathogens, recruitment of other components of immune response to remove pathogens (complement, phagocytes, NK cells), neutralisation of toxins, particularly important in defence against bacteria of all kinds.
What does defects of lymphoid precursors cause?
Severe combined immunodeficiency and failure of production of lymphocytes.
What is the clinical presentation of severe combined immunodeficiency?`
Unwell by 3 months of age, persistent diarrhoea, failure to thrive, infections of all types, unusual skin disease (graft versus host disease - colonisation of infant;s empty bone marrow by maternal lymphocytes), family history of early infant death.
What are some of the causes of severe combined immunodeficiency?
Deficiency of cytokine receptors, deficiency of signalling molecules, metabolic defects, defective receptor rearrangements.
What is the commonest form of severe combined immunodeficiency?
X-linked SCID (severe combined immunodeficiency).
What is the mutation in X-linked SCID and what does it cause?
Mutation of a component of IL-2 receptor. Results in inability to respond to cytokines so failure of T and NK cell development and production of immature B cells.
What is the clinical phenotype of X-linked SCID?
Very low or absent T cells, normal or increased B cells, poorly developed lymphoid tissues and thymus.
Describe the prophylactic and definitive treatment of SCID.
Prophylactic: avoid infections (prophylactic antibiotics/antifungals, no live attenuated vaccines), aggressive treatment of existing infections, antibody-replacement (IV immunoglobulin).
Definitive: stem cell transplant from HLA identical sibling if possible; other sibling or parent, or from matched unrelated donor.
What is the potential gene therapy for SCID?
Stem cells can be treated ex vivo to express the missing component, these cells have a survival advantage in vivo.
What syndrome is a developmental defect of the 3rd/4th pharyngeal pouch?
DiGeorge syndrome.
What does DiGeorge syndrome cause?
Low set ears that are abnormally folded, high forehead, cleft palate, small mouth and jaw, hypocalcaemia, oesophageal atresia (absence or closure), T cell lymphopenia and complex congenital heart disease.
What kind of infections do people with DiGeorge syndrome get and why?
Recurrent viral infections (CD8+ T cells are essential in killing virally-infected host cells), recurrent bacterial infections (effector CD4+ Tfh cells are essential for helping B cells make antibodies), frequent fungal infections (effector CD4+ Th cells are essential for defence against fungal pathogens).
What would the white cell count look like in Di George syndrome?
Absent or decreased number of T cells, normal or increased B cells, normal NK cell numbers.
Are recurrent bacterial or viral infections more common in immune deficiencies affecting B lymphocytes?
Bacterial.
What is the B cell maturation defect in Bruton’s X-linked hypogammaglobulinaemia?
Pro B cells do not differentiate into pre B cells, so no circulating B cells.
What can a selective IgA deficiency cause?
1/3rd of people get recurrent respiratory tract infections.
What types of antibodies are low in common variable immune deficiency?
IgG, IgA and IgE.
What are the clinical features of common variable immune deficiency?
Recurrent bacterial infection (often with severe end-organ damage e.g. bronchiectasis, persistent sinusitis, recurrent GI infection), autoimmune disease, granulomatous disease.
What is the genetic defect in X-linked hyper IgM syndrome (HIGM syndrome)?
Defective CD40 signalling via B cells affecting Ig class switch recombination (CSR) and somatic hypermutation.
What co-stimulatory signal is essential for full B cell activation/differentiation and the germinal centre reaction?
Interaction between CD40 ligand (antigen-activated B cells) and CD40 (effector Tfh cells).
What are the clinical features of B cell deficiencies?
Recurrent infections (often very common bacteria), opportunistic infections, antibody-mediated autoimmune disease.
What are the first line investigations of B cell deficiencies?
Total white cell count and differential, serum/urine immunoglobulins.
What are the second line investigations of B cell deficiencies?
Quantitation of B and T lymphocytes, specific antibody responses to host pathogens (measure IgG antibodies against pathogens, if low immunise with killed vaccine then test again 6-8 weeks later to see if antibody response has been mounted).
What are the management options for B cell deficiencies?
Aggressive treatment of infection, Ig replacement, stem cell transplantation in some situations.
What is hypersensitivity reaction?
Immune response that results in bystander damage to the self. Usually exaggeration of normal immune mechanisms.
What are Gel and Coomb’s classification of hypersensitivity reactions?
Type I - immediate hypersensitivity. Type II - direct cell killing. Type III - immune complex mediated. Type IV - delayed type hypersensitivity.
.What is an allergy?
IgE mediated response to external antigen (allergen).
Describe the hygiene hypothesis.
Changes in microbial stimuli influences the maturation of the immune response e.g. general decrease in infectious burden in early life (resp infections in particular), variations in GI flora, results in increased predisposition to allergic conditions during early childhood.
Describe some Th1 differentiation stimuli.
Older siblings, early daycare oxposure, rural environment, childhood infections, microbial exposure.
Describe some lack of Th1 stimuli.
Only child, widespread use of antibiotics, urban environment with allergen sensitisation e.g. dust mites, cockroaches.
