Primary immunodef Flashcards

Question

What is chronic granulomatous disease? What is the defect in, how does it present?

Answer 1

Certain step of phagosome mechanism - they have a mutation in NADH components- defective oxidative killing of phagocytosed microbes- mutation in the phagocyte oxidase components - various genes can be defect There is an inability to do intracellular killing- ingested bacteria survive and proliferate in intracellular enviroemtn free from AB and most antibiotics. Here there is a failure to produce high concetrations of ROS ``` Clinical features: · Present with granulomas on the skin (wall of pathogens) Infections are recurrent and prolonged Clinical features may be minimal despite severe infection Infections are: • poorly responsive to antibiotics • commonly staphylococcal • involve skin and mucous membranes • complicated by lymphadenopathy ``` Diagnosis: · NBT test (nitroblue tetrazolium reduction)- uses phagosomes of the blood then compare with control- treat with NBT- if they produce ROS-t if they do it produces blue but in CGD remain blue Flow cytometry assay dihydrohodamines - activate neutrophils if they produce ROS- the molecule is cleared 'Treatment: prophylaxis AB (usually co-trimoxazole) and antifungal agents Some studies show IFNy reduces infections, allogenic BM transplant offer only long term hope

Answer 2

· Rare genetic disease Autosomal recessive · Defect in LYST gene (regulates lysosome traffic) - enzymes to do with lysosomes not fuses · Defetc in phagosome- lysosome fusion- defective killing of phaogyctosed microbes- leading to recurrent infections · Therefore can only use ROS · Neutrophils have defective phagocytosis · Repetitive severe infections Diagnosis: · Decreased number neutrophils · Neutrophils have giant granules b/c lysosomes fuse with each other as they cannot fuse with phagosomes

Answer 3

``` · One of the class of the molecules that is important for the movement of neutrophils rom blood into the tissue- intergrins and selectins ligands are impaired- therefore neutrophils cannot leave · Defect in B2 chain integrins (LFA-1, Mac1) · Defect in sialyl lewis X (Selectin ligand) · Delayed umbilical cord separation- the stump takes longer to fall off- need phagocytes to clear the debris- diagnosis defect in B2 chain integrins (LFA-1, Mac1) ``` Clinical presentation: · Skin infection, intestinal and perianal ulcers, and ginigivitis Deep abscesses, peritonitis, osteomyelitis Investigations: · Decreased neutrophils chemotaxis - can do this in vitro · Reduced integrins on phagocytosis (flow cytometry)

Answer 4

Depending on the component that is affected- affects the symptoms- either lyse them or promote inflammatory response · Recurrent infections Neisseria group- deficiency terminal complex (MAC- membrane attack complex): C5-C9 · Severe fatal pyrogenic infections (C3 deficiency) which is Key in all activation of complement · SLE like syndrome (C1q, C2, C4 deficiency) this is involved in activation of vesicle forming pathway - milder presentation ·Hereditary angioneurotic odema: failure to inactive complement (deficiency in C1 inhibitor) intermittent acute odema skin/mucosa- vomiting, diarrhoea, airway obstruction to investigate: CH50 complete function Measure individual components

Answer 5

Deficiency of the inhibitor of the first component of complement (Cī inhibitor) (Cī INH) It is the commonest known deficiency of a complement component. Patients suffer from recurrentattacks of skin, laryngeal or intestinal oedema. In contrast to urticaria, localized oedema of the face, limbs and trunk is neither painful nor itchy. Sometimes, however, oedema occurs in the intestinal tract, causing severe abdominal pain and vomiting when the jejunum is involved, or watery diarrhoea if the colon is affected. Laryngeal oedema may be fatal because of airways obstruction. The attacks develop over a few hours and subside spontaneously over 1–2 days · Measure individual components · Complement function: CH50 (haemolysis) · A total complement measurement, also known as a total hemolytic complement or a CH50 measurement, checks how well the complement system is functioning. · Screening tests: C3 & C4 · Typically the C4 is low, C3 is normal (low C4 and low C3 is seen in immune complex disease due to complement consumption) · Confirm diagnosis by C1 esterase inhibitor: low level confirms HAE type 1 which makes up 85% · 15% have normal C1 esterase inhibitor level, but it is non functional (type ii HAE) Treatment: replace C1est. inhibitor by infusions and/or bradykinin receptor blocker (subcutaneous injection (as the angioedema/sweeling is mediated by bradykinin not histamine · Cannot to turn off- use up all of the complement in their blood therefore do not have any left for infection- too much inflammation · We have various inhibitors which stop this Complications: laryngeal odema

Answer 6

Aims: · Minimise/control infection · Replace defective/absent component of IS · Prompt treatment of infection · Prevention of infection: isolation, AB prophylaxis, vaccination (not live) Nutrition

Answer 7

Important to find out: • How much of a component of the immune system is present/deficient (quantitative tests)? • How well do the components of the immune system function (functional tests)?

Answer 8

Serological tests: These tests measure serum proteins (e.g. antibodies, complement) 1. Quantitative tests: Immunoglobulins: • The three main immunoglobulin classes IgG, IgA, and IgM are measured • Deficiency raises suspicion of immunodeficiency and needs further investigation. IgG subclasses: • IgG can be subdivided into IgG1, IgG2, IgG3, and IgG4, all of which have slightly different functions, so deficiency can cause susceptibility to certain infections. • It’s possible to be deficient in an IgG subclass and still have a normal total IgG level. Complement: • Any complement component including mannose binding lectin (MBL), may be deficient • Deficiency in terminal complement components may result in an increased susceptibility to meningococcal infection, MBL deficiency may result in increased frequency of chest infections and C2 deficiency is associated with autoimmunity. • Deficiency in C1 esterase inhibitor results in hereditary angioedema. 2. Functional Tests. Specific antibody responses. This measures specific IgG antibodies directed against: 1. Common pathogens/environmental microbes e.g. E.coli, isohaemagglutinin. • Absence of these specific antibodies may suggest a more general failure to respond appropriately to infection. 2. Tetanus, H. influenza type B and pneumococcus (“functional antibodies”). • A pre and post vaccination level can be measured. Failure to respond to vaccination (i.e. a less that four-fold increase in titres) can be found in immunodeficiency. Total haemolytic complement: This measures the function of the classical pathway (CH50 test) or alternative pathway (AP50 test). Opsonisation (heat inactivated serum): Detects deficient antibody function to a certain organism.

Answer 9

Quantitative tests: The white cell count and differential will identify deficiency of lymphocytes and neutrophils. A “lymphocyte subsets” test (done by flow cytometry) will count numbers of CD4, CD8, NK and B cells. T lymphocyte functional tests: stimulating cultured T lymphocytes with a variety of antigens (e.g. candida, PHA, MLR) can help to identify exact functional defects. Phagocyte functional tests: 1. Dihydrorhodamine test (DHR) or nitro blue test (NBT). This identifies failure of the neutrophil oxidative burst/intracellular killing mechanism 2. Mobility tests identify cells which are unable to move properly/transmigrate from the blood stream to tissues 3. Opsonisation tests detect abnormal phagocytosis 4. Cell surface markers: it is known that abnormal phagocytes lack certain cell surface markers (CD18, CD11a etc). This can be measured by flow cytometry.

Answer 10

Discuss the likely causes of his recurrent infections B cells or complement List the relevant points in the above history that may help make a diagnosis LN NOT enlarged: not responding to infection!!!!! Candida would suggest T cells Could be X linked! Antibody deficiency • X linked agammaglobulinemia (male, fx) • Transient hypogammaglobulinemia of infancy (when the period when the material IGG goes down, and infant starts to make own antibodies) (male or female, prematurity) Complement deficiency is rare What investigations may help arrive at a diagnosis? • Serum immunoglobulins are very low • Lymphocyte genotyping: absent B cells and normal T cells • BTK gene mutations- this helps makes the firm diagnosis Diagnosis: X linked agammaglobulinaemia confirmed by tyrosine kinase gene mutations (BRUTONS)

Answer 11

Discuss the likely causes of his recurrent infections Chest infections- B cells Fungal infection and antibiotics not working - T cells Faltering growth Parents consanguineous Infection suggests combined T and B cell defect Primary: combined B and T cells e.g SCID Secondary: HIV and AIDs What investigations may help arrive at a diagnosis? • Lymphocyte count low • Lymphocyte phenotyping: T and B cells are low • Immunoglobulins low (due to B cell and T cell being low) ○ There is a bit of IGG- they still have the mothers Severe combined immunodeficiency Types of SCID- present similarly within the first 6 months of life (infections, faltering growth) Learning: • Lymphopenia <2 x 109 in baby <6 months SCID until proven otherwise • Suspected SCID should be referred urgently • AVOID LIVE VACCINES • Iridate all cell products to avoid engraftment of donor lymphocyte

Answer 12

What are the likely causes for her symptoms? Complement deficiency- C1 esterase inhibitor Anaphylaxis is she reacting to anaesthetic Ask if there itching with the swelling Drug induced (analgesics, ACE i) What investigations may help arrive at a diagnosis? • C3 is normal • C4 is low • C1 esterase inhibitor LEVEL: is low • C1 esterase inhibitor function Is low Diagnosis: HAE- swelling is deeper therefore do not get itching

Answer 13

Discuss the possible causes of his symptoms and signs • Chronic granulomatous disease--> neutrophils are affected! • Antibody deficiency (B cells) What investigations may help arrive at a diagnosis? • Full FBC/DC ○ Low HB, normal lymphocyte, elevated neutrophil, elevated ESR (showing inflammation) • Serum immunoglobulins elevated ○ IGG is high trying to fight infection • CRP is high • Neutrophil phagocytosis: normal - they are encapsulated and then they get respiratory burst to kill • Neutrophil respiratory burst (DHR): absent Encapsulated bacteria Delayed healing- neutrophils re not performingwell Chronic granulamatous disease Chronic granulomatous disease (CGD) Fx, consanguityy (X linked, AR) HX of bacterial/fungal infections Review of systems: deep seated infections (live abscess, lymphadenopathy, osteomyelitis), granuloma in bowel (malabsorption) Diagnosis is missed unless test for respiratory burst is asked for

Primary immunodef Flashcards

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