Primary Immune Deficiencies

Question 1

What are primary immune deficiencies?

Answer 1

PIDs; intrinsic defects in the immune sysemt (usually but not always inherited)

Question 2

What are secondary immune deficiencies?

Answer 2

Due to extrinsic factors that depress the immune response

• infections (HIV, measles)
• malnutrition
• malignancies (lymphoma, leukemia)
• metabolic (diabetes, liver disease)
• loss of lymphocytes/Abs
• immunocuppressants (corticosteroids, rituximab)
• collagen vascular disease

Question 3

When should you suspect a PID?

Answer 3

• Too many infections or infections that won’t go away
• Weird infections (e.g. P jerovecii)
• Infections in weird places (e.g. liver/lung abscesses)
• Early onset autoimmunity

Question 4

What cell expresses CD3+/CD45RA+?

Answer 4

Naive T cell

Question 5

What cell expresses CD3+?

Answer 5

All T cells

Question 6

What cell expresses CD3+/CD45RO+?

Answer 6

Memory T cell

Question 7

What cell expresses CD3+/CD4+?

Answer 7

Helper T cell

Question 8

What cell expresses CD3+/CD8+?

Answer 8

Cytotoxic T cell

Question 9

What cell expresses CD19+/CD20+?

Answer 9

All B cells

Question 10

What cell expresses CD3-/CD56+?

Answer 10

NK cell

Question 11

What are the common characteristics of neutrophil defects?

Answer 11

• Early onset (infancy/childhood)
• Severe bacterial infections and abscesses
• Poor wound healing with lack of pus

E.g. Chronic granulomatous disease, congenital/cyclic neutropenia, or leukocyte adhesion deficiency

Question 12

How do you workup a neutrophil defect?

Answer 12

1. CBC (complete blood count) with differential
   *Note ANC (absolute neutrophil count)
2. DHR (dihydrorhodamine test)
   *tests ability of PMNs to generate oxidative burst

Question 13

What are the common characteristics of complement defects?

Answer 13

• Present at any age
• Early (C2, C4) defects
  
  • autoimmune presentation most common (e.g. lupus)
  • sinopulmonary infections, sepsis
    *S. pneumoniae and H. influenzae
• Late (C5-C9) defects
  
  • increased susceptibility to Neisserial infections

Question 14

How do you workup a complement defect?

Answer 14

CH₅₀ test (functional assay for all classical complement components… CH₅₀= 0)
**If problems with complement consumption (lupus) the CH₅₀ is low

Question 15

What is the most common PID type?

Answer 15

B cell/Antibody deficiencies

Question 16

What are the common characteristics of an antibody deficiency? Examples?

Answer 16

• Recurrent sinopulmonary bacterial infections
  **encapsulated organisms (H. flu, S. pneumo, Mycoplasma)
• Chronic GI tract infections, malabsorption, failure to thrive

Examples:

1. XLA (agammaglobulinemia) *early presentation
2. CVID *presents at any age

Question 17

How do you workup an antibody deficiency?

Answer 17

1. Quantitative immunoglobulins (IgG/A/M/E)
2. Vaccine titers (diptheria, tetanus, pneumococcus)
   *If titers are low, re-immunize and remeasure after 4 weeks to double check

**Don’t forget to consider a secondary cause (immune suppressing drugs) if workup looks positive!

Question 18

What are the common characteristics of T cell defects?

Answer 18

• Recurrent, sever infections
  
  • Viruses (CMV, EBV, varicella)
  • Fungi (oral candida/thrush)
  • Bacteria
  • Opportunistic pathogens (P. jiroveci, mycobacteria)
• Poor growth/FTT
• Chronic diarrhea

**e.g. DiGeorge syndrome

Question 19

How do you workup a T cell/combined defect?

Answer 19

1. CBC with differential
   **Low ALC (absolute lymphocyte count)
2. Lymphocyte subset enumeration (flow cytometry)
   
   1. T(memory and naive)/B/NK cell numbers
   2. Quantitative Igs (G,M,A)
   3. T cell proliferation

Question 20

What is a common B/T cell combined deficiency?

Answer 20

SCID

Question 21

What are the common symptoms of SCID?

Answer 21

• Onset in infancy (otitis media, thrush, diarrhea, FTT)
• Opportunistic pathogen infection (e.g. P. jiroveci)
  **Lack T/NK cells, B cells present but don’t function
• Most commonly X-linked (mutation in gamma chain of IL2 receptor)

**100% mortality without bone marrow transplant

Question 22

What is the screening test for SCID?

Answer 22

• TRECs (T cell Receptor Excision Circles; nonreplicating circular pieces of DNA in naive T cells generated in the process of making a TCR)
• TREC number (measured by RT-PCR) is a surrogate marker for the number of normal naive T cells
• T cells/TRECs low in all forms of SCID and T cell lymphopenias

Question 23

What does the CATCH22 mnemonic stand for?

Answer 23

The wide clinical spectrum of DeGeorge syndrome:

• Cardiac defects
• Abnormal facies
• Thymic hypoplasia
• Cleft palate
• Hypocalcemia
• 22nd chromosome

**many cases undiagnosed until late childhood/adulthood

Question 24

Describe DeGeorge syndrome

Answer 24

TBX1 gene deletion from chromosome 22q11.2

*T cell abnormalities also lead to Ab deficiency

**results in field defects of pharyngeal pouches 1-6:

1. tubotympanic anomalies
   (1st arch: facial anomalies… maxillary/mandible)
2. tonsil/thyroid anomalies
3. inferior parathyroid/thymus deficiencies
4. superious parathyroid

Question 25

Describe XLA symptoms... what mutation causes it?

Answer 25

(X-linked Agammaglobulinemia) Commonly observe: * onset in infancy/early childhood * recurrent otitis, sinusitic, pneumonia * encapsulated bacteria (S. pneumo, H. infl) and mycoplasma sp * severe enteroviral infections; vaccine related polio \*\*Caused by mutations in Bruton's Tyrosine Kinase Gene (Btk) which results in the failure of B cells to differentiate... can diagnose with flow cytometry

Question 26

What lab results would point towards XLA?

Answer 26

No B cells present (normal T cells) Hypogammaglobulinemia Diffuse bronchiectasis (widening of airway)

Question 27

What lab results would point towards CVID?

Answer 27

Bronchiectasis (widening of airway) Opacification of sinuses/mucosal thickening Normal T and B cells Low IgG and no IgA (usually, or low IgA/IgM)

Question 28

Describe CVID

Answer 28

\*\*Common variable immunodeficiency * Most common PID * Onset at ANY AGE with variable clinical course * Infections common * GI/liver disease (Inflammatory bowel disease) * Pulmonary disease **(bronchiextasis, interstitial lung disease)** * **​**Autoimmunity (cytopenias)

Question 29

What is the most common Ab deficiency? What are the characteristics/symptoms?

Answer 29

\*\*IgA deficiency * Extremely low IgA, normal IgG and IgM * Normal T cell function * Usually **no phenotype** * Some have increased sinopulmonary/GI infections * Increased incidence of atopic, celiac and autoimmune disease \*\*\***Do not treat with IVIG**

Question 30

Describe CGD

Answer 30

\*\*Chronic Granulomatous Disease * onset usually by 2 yo * hepative abscess without obvious source in young child is CGD until proven otherwise * pneumonia * sepsis * osteomyelitis * infection with catalase + bacteria (burkholderia, nocardia)

Question 31

What is the cause of CGD?

Answer 31

* Functional absence of respiratory burst in **neutrophils** and monocytes- impair bactericidal killing * Defect in **NADPH oxidase** (most common= x linked)

Question 32

How does a DHR test work? What is it used for?

Answer 32

* Dihydrorhodamine is oxidized when PMNs are stimulated to undergo oxidative burst (by PMA/phorbol ester) * The oxidized form of DHR exhibits increased fluorescence which is seen as a right-shifted peak on flow cytometry post-burst * **Carriers** will have two peaks (one normal, one shifted pos-burst) -\> at risk for autoimmune disease ## Footnote **\*\*used to diagnose neutrophil disorders (e.g. CGD)**

Question 33

Describe late complement deficiency

Answer 33

* Cannot form MAC (lack C5-9) * First infection usually ~17 yo * Recurrent meningitis (but lower fatality from it) \*susceptible to all neisseria including gonorrhea

Question 34

Describe early complement deficiency

Answer 34

* C2= most common deficiency (autosomal recessive) * Associated with collagen vascular diseases * Recurrent bacteremia (pnemo, flu, enteric, staph)