Primary Immune Deficiencies Flashcards
What are primary immune deficiencies?
PIDs; intrinsic defects in the immune sysemt (usually but not always inherited)
What are secondary immune deficiencies?
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
When should you suspect a PID?
- 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
What cell expresses CD3+/CD45RA+?
Naive T cell
What cell expresses CD3+?
All T cells
What cell expresses CD3+/CD45RO+?
Memory T cell
What cell expresses CD3+/CD4+?
Helper T cell
What cell expresses CD3+/CD8+?
Cytotoxic T cell
What cell expresses CD19+/CD20+?
All B cells
What cell expresses CD3-/CD56+?
NK cell
What are the common characteristics of neutrophil defects?
- 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
How do you workup a neutrophil defect?
- CBC (complete blood count) with differential
*Note ANC (absolute neutrophil count) - DHR (dihydrorhodamine test)
*tests ability of PMNs to generate oxidative burst
What are the common characteristics of complement defects?
- 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
How do you workup a complement defect?
CH50 test (functional assay for all classical complement components… CH50= 0)
**If problems with complement consumption (lupus) the CH50 is low
What is the most common PID type?
B cell/Antibody deficiencies
What are the common characteristics of an antibody deficiency? Examples?
- Recurrent sinopulmonary bacterial infections
**encapsulated organisms (H. flu, S. pneumo, Mycoplasma) - Chronic GI tract infections, malabsorption, failure to thrive
Examples:
- XLA (agammaglobulinemia) *early presentation
- CVID *presents at any age
How do you workup an antibody deficiency?
- Quantitative immunoglobulins (IgG/A/M/E)
- 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!
What are the common characteristics of T cell defects?
- 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
How do you workup a T cell/combined defect?
- CBC with differential
**Low ALC (absolute lymphocyte count) - Lymphocyte subset enumeration (flow cytometry)
- T(memory and naive)/B/NK cell numbers
- Quantitative Igs (G,M,A)
- T cell proliferation
What is a common B/T cell combined deficiency?
SCID
What are the common symptoms of SCID?
- 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
What is the screening test for SCID?
- 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
What does the CATCH22 mnemonic stand for?
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
Describe DeGeorge syndrome
TBX1 gene deletion from chromosome 22q11.2
*T cell abnormalities also lead to Ab deficiency
**results in field defects of pharyngeal pouches 1-6:
- tubotympanic anomalies
(1st arch: facial anomalies… maxillary/mandible) - tonsil/thyroid anomalies
- inferior parathyroid/thymus deficiencies
- superious parathyroid
Describe XLA symptoms… what mutation causes it?
(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
What lab results would point towards XLA?
No B cells present (normal T cells)
Hypogammaglobulinemia
Diffuse bronchiectasis (widening of airway)
What lab results would point towards CVID?
Bronchiectasis (widening of airway)
Opacification of sinuses/mucosal thickening
Normal T and B cells
Low IgG and no IgA (usually, or low IgA/IgM)
Describe CVID
**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)
What is the most common Ab deficiency? What are the characteristics/symptoms?
**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
Describe CGD
**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)
What is the cause of CGD?
- Functional absence of respiratory burst in neutrophils and monocytes- impair bactericidal killing
- Defect in NADPH oxidase (most common= x linked)
How does a DHR test work? What is it used for?
- 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
**used to diagnose neutrophil disorders (e.g. CGD)
Describe late complement deficiency
- Cannot form MAC (lack C5-9)
- First infection usually ~17 yo
- Recurrent meningitis (but lower fatality from it)
*susceptible to all neisseria including gonorrhea
Describe early complement deficiency
- C2= most common deficiency (autosomal recessive)
- Associated with collagen vascular diseases
- Recurrent bacteremia (pnemo, flu, enteric, staph)
