Mar27 M2-The immune work up

Question 1

types of diseases of errors of immunity

Answer 1

• immunodeficiencies (primary and secondary. primary = single gene disorders. secondary = acquired)
• immune dysregulation syndromes
• auto-inflammatory syndromes

Question 2

different arms of the immune system + how related to disease

Answer 2

• humoral (B cells)
• cellular (T cells)
• combined (B and T)
• phagocytic arm (neutrophils, macrophages)
• complement system
• each disease = one or many arms defective

Question 3

examples of diseases where an arm of the immune system is compromised

Answer 3

• defect in IFN gamma prod (interferonopathies)
• inflammasome related problems
• immunity related to non-hematopoietic tissues (spleen, osteoclasts, epidermis, fibroblasts, neurons)

Question 4

causes of secondary immunodeficiencies

Answer 4

HIV, neoplasia, transplant, splenectomy, chemo, radiation, diabetes

Question 5

how many genes involved in immunity

Answer 5

2150 (approx 10% of our 20 000 protein coding genes)

Question 6

how many PIs

Answer 6

350 (344 genes). hypo or hypermorphic mutations. symptoms differ from patient to patient, even within same gene mutated

Question 7

at what age do PIs appear

Answer 7

any age!! even age 50. so don’t assume it’s a secondary one

Question 8

incidence of PIs

Answer 8

1 in 2500 persons

Question 9

important PI to know about and why

Answer 9

SCID (1 in 50 000 affected)

• 95% survival if detected
• 100% death before age 1 if not detected

Question 10

10 reasons to investigate for IEI (inborn error of immunity)

Answer 10

1. 8+ ear infections in 1 yr
2. 2+ sinus infections in 1 yr
3. 2+ months on Abx with no effect
4. 2+ pneumonias in 1 yr
5. failure to gain weight or grow normally
6. recurrent deep skin or organ abscesses
7. persistent oral candidal infection mouth (thrush) or skin after age 1
8. Need IV Abx to clear infections
9. 2+ deep-seated infections
10. FHx of PI

Question 11

specific things that should make us think of inverstigating PI

Answer 11

• unusual infections (opportunistic)
• very mild inflammatory signs in pretty bad infections
• sick after vaccine
• recurrent autoimmune phenemona

Question 12

IEI: most to least common defective arms

Answer 12

• humoral (B) (most common)
• combined (B and T)
• cellular (T)
• phagocytic
• complement (very rare)

Question 13

important think that can hint us towards what arm is defective in an IEI

Answer 13

• finding the bugs that cause the recurrent infections (send to culture)
• each defective arm = get specific infections

Question 14

bugs found in culture depending on defective immune arm

Answer 14

• B deficit AND complement deficits = EC organisms, enterovirus, giardia lamblia.
• T deficit: viruses, IC organisms, opportunistic organisms like candida
• phagocytic deficit: atypical bacteria, mycobacteria, fungi, protozoa
• complement deficit = often Neisseria

Question 15

when to suspect B cell deficit

Answer 15

• many bacterial infections
• resp infections (strep, haemophilis)
• seen after 6 months of age (when lose mom Ab)

Question 16

example of phagocytic deficits

Answer 16

• LAD (leukocyte adhesion deficiency)

- chronic granulomatous disease (CGD): neutrophils can’t produce oxygen radicals to kill pathogens after engulf them

Question 17

phagocytic deficits when to suspect

Answer 17

• skin, liver, GI infections
• no detachment of umb cord
• abscesses
• gingivitis, periodontitis

Question 18

2 types of complement deficits and what you see

Answer 18

C1-C4 deficiency = rheumatic disorders, pyogenic (means produce pus) infections
C5-C9 deficiency = susceptibility to encapsulated organisms (pneumococcus, meningococcus, H. flu), recurrent sinopulmonary infections

Question 19

1st lab done when suspect IEI

Answer 19

CBC (want nbr and fct of the immune cells)

Question 20

how to check B cell fct (things you can do)

Answer 20

• qt of all the Igs in the blood
• serology before and after vaccination
• DNA sequencing for known defects

Question 21

good vaccine serology (good resp after vaccine shows what)

Answer 21

functional B AND T cells

Question 22

how to check T cell fct

Answer 22

• vaccine serology
• T cell stimulation or proliferation assay
• PPD (type IV delayed HS test). response = T cells working
• DNA sequencing for known defects

Question 23

T cell prolif assay how it works

Answer 23

put in mitogenic milieu (specific substances known to make T cells replicate) with radioactive thymidine. measure if T cells proliferate (functional) or not (non functional) with how much radioactivity from cells

Question 24

how to check phagocytic fct

Answer 24

• CBC, ANC
• for LAD, measure adhesion molecules at neutrophils surface with flow cytometry
• DHR (dihydrorhodamine) test for CGD. if cells CAN make ROS, will reduce DHR to strongly fluorescent rhodamine
• DNA seq for known defects

Question 25

3 complement pathways

Answer 25

1. classical pathway (Ag-Ab complexes). CRP for ex
2. lectin pathway (microbial surfaces like mannose and others (like IgA)
3. alternative pathway (spontaneous and foreign substances like LPS)

Question 26

end effect of complement pathway

Answer 26

MAC (membrane attack complexes) formed

Question 27

complement molecules easily measured

Answer 27

C3 and C4

Question 28

how to check complement system fct

Answer 28

• measure C3 and C4
• ELISA (enzyme immunoassay) to stimulate the 3 complement pathways and measure how much MAC proteins are formed (C5b to C9)
• CH50 (classical pathway testing)
• AH50 (MBL, mannose-binding lectin, and alternative pathways testing)