B3.039 Immune Cell Development

Question 1

what are 3 reasons for asplenia

Answer 1

congenital
surgical removal (trauma or disease management)
autosplenectomy (sickle cell)

Question 2

who has the most risk of complications due to asplenia?

Answer 2

younger, not yet vaccinated at increased risk of infections

older, vaccinated (have antibodies) may do better

Question 3

what type of infections are of the most risk to asplenic patients?

Answer 3

encapsulated bacterial infections

S. pneumo, Hib, meningococcal

Question 4

what is the recommendation to prevent serious infection in asplenics?

Answer 4

vaccination every 5 years for protection

Question 5

what is AID

Answer 5

activation-induced cytidine deaminase

Question 6

what can defects in AID lead to?

Answer 6

increased susceptibility to bacterial pyogenic infections only

Question 7

describe the pathway which uses AID

Answer 7

1. CD-40 and the IL-4 receptor on B cells is ligated by CD-40L
2. AID is transcribed and translated to produce AID
3. simultaneously, induction of transcription of the cytidine-rich regions at isotype switch sites
4. AID deaminates cytidine in ssDNA only and converts the cytidine at the switch sites to uridine which is not normally there
5. uracil is recognized by UNG (enzyme) removing the uracil from the nucleotide
6. damaged DNA is recognized and repaired by endonucleases, excising the damaged region resulting in class switching

Question 8

goal of somatic hypermutation in B cells

Answer 8

production of higher affinity antibodies as the immune response progresses

Question 9

how does somatic hypermutation progress

Answer 9

during activation, point mutations are introduced into the DNA that encodes the immunoglobulin variable region
affinity maturation (Selection) then occurs

Question 10

positive selection

Answer 10

antibodies that compete for antibody binding the best receive stronger signals in the cell surface antigen receptor leading to increased proliferation

Question 11

negative selection

Answer 11

lower affinity BCRs do not receive signals to proliferate and will undergo apoptosis

Question 12

why are lymph nodes enlarged in patients with an AID deficiency?

Answer 12

proliferation of IgM+ B cells in the lymphoid organs (lymphoid hyperplasia)
lymphadenopathy & splenomegaly

Question 13

what mutation leads to X-linked hyper IgM syndrome?

Answer 13

CD-40 or CD-40L gene defect

Question 14

clinical result of X-linked hyper IgM syndrome?

Answer 14

increased susceptibility to both pyogenic and opportunistic infections

Question 15

difference in inheritance between CD-40 and AID associated hyper IgM?

Answer 15

CD-40 is X-linked

AID is autosomal recessive

Question 16

what is UNG

Answer 16

uracil-DNA glycosylase

Question 17

what is SCID?

Answer 17

severe combines immune deficiency

syndrome caused by mutations in differenct genes whose products are necessary for T/B/NK cell development

Question 18

SCID outcomes

Answer 18

early death from overwhelming infection within first year of life is not transplanted, early diagnosis is key

Question 19

SCID epidemiology

Answer 19

1:40,000- 1:50,000 live births

50% are X-linked

Question 20

why is SCID diagnosis often delayed several months?

Answer 20

infants look normal and maternally derived IgG provide some protection in early infancy

Question 21

describe the process of fetal IgG transfer

Answer 21

IgG crosses the placenta
takes 6 months for the infant to reach its lowest IgG level before picking up on its own production
igA and IgM are low as well in normal infants

Question 22

how does SCID usually present

Answer 22

recurrent diarrhea, pneumonia, otitis, sepsis, and cutaneous infections within first few months of life
growth is initially normal, but slows and failure to thrive ensues after infections and diarrhea begin

Question 23

which organisms are SCID patient susceptible to?

Answer 23

opportunistic
candida, pneumocystis, VZV, adenovirus, parainfluenza, herpes, CMV, rotavirus, measles, norovirus, EBV
live viral vaccines

Question 24

SCID clinical features

Answer 24

small thymus, less than 1 g

• fails to descend from neck
• few thymocytes
• lacks corticomedullary distinction and Hassall’s corpuscles

Question 25

what are the 4 types of SCID

Answer 25

T-B+NK- T-B+NK+ T-B-NK+ T-B-NK-

Question 26

what is the most common form of SCID?

Answer 26

x-linked mutation in common gamma chain | have B cells, but they don't work because T cells are absent

Question 27

SCID lab findings

Answer 27

NORMAL: 70% of circulating lymphocytes are T cells | SCID infants are lymphopenic (<4000)

Question 28

what lab findings constitute a strong SCID suspicion

Answer 28

absolute lymphocyte count <2500 T cells <20% of total lymphocytes lymphocyte stimulation to mitogens is <10% of normal absence of thymus on CXR

Question 29

discuss the role of maternal T cells in SCID

Answer 29

some patients have maternal T cells cross the placenta and enter circulation gives a normal appearance to T cell numbers (>3000)

Question 30

indicator of maternal T cell engraftment

Answer 30

greater predominance of either CD4 or CD8 | maternally engrafted cells have memory phenotype and are CD45RO, whereas normal infant T cells are naïve and CD45RA

Question 31

describe the genetic defect present in X-linked SCID

Answer 31

defect on X chromosome encoding the cytokine receptor subunit common gamma chain, IL2 RG diagnosed on flow cytometry

Question 32

what is the significance of the common gamma chain

Answer 32

receptor subunit shared by 6 difference cytokine receptor complexes: IL-2, 4, 7, 9, 15, and 21 also involved in growth hormone receptor signaling

Question 33

clinical presentation of X linked SCID

Answer 33

male severe infections, chronic diarrhea, failure to thrive must be differentiated from autosomal recessive JAK3 deficiency which is also T-B+NK-

Question 34

how can JAK3 deficiency and common gamma chain defect SCIDs be differentiated

Answer 34

functional STAT5 tyrosine phosphorylation assay presence of tyrosine-phosphorylated STAT5 by flow cytometry after IL-2 stimulation indicates a functional IL-2/JAK-3 signal transduction pathway

Question 35

how is SCID treated

Answer 35

pediatric emergency HLA-identical or haploidentical donor bone marrow transplantation within first 3.5 mo of life provides 94% chance of 20 yr survival IVIg often needed after curative BM transplant

Question 36

epidemiology of autosomal recessive SCID

Answer 36

more common in Europe 12 genetic types: ADA< JAK2, IL-17 receptor alpha, RAG1/2, Artemis, ligase 4 deficiency, DNA-PKcs, CD3 and CD45 deficiencies

Question 37

discuss ADA deficiency SCID

Answer 37

T-B-NK- 16% of SCID accumulation of adenosine, 2'-deoxyadenosine and 2'-O-methyladenosine latter 2 lead directly or indirectly to apoptosis of thymocytes and circulating lymphocytes

Question 38

ADA deficiency SCID presentation

Answer 38

similar to all SCID cases unique skeletal abnormalities more profound lymphopenia (<500)

Question 39

treatment for ADA deficiency SCID

Answer 39

cured with BM transplant | enzyme replacement with PEG-ADA (but not as good as BM transplant)

Question 40

etiology of JAK3 deficiency SCID

Answer 40

T-B+NK- 30 patients reported low or absent NK cell activity downstream cytokine signaling issue, not a problem with TCR activation abnormal B cell function despite high number unless they have donor B cell engraftment (require lifelong Ig replacement therapy)

Question 41

etiology of IL-7 receptor alpha chain deficiency SCID

Answer 41

``` T-B+NK+ 3rd most common SCID phenotype IL-7 receptor alpha chain = CD127 specific ONLY for T cell development patients acquire normal B cell function after BM transplant without donor B cells ```

Question 42

etiology of RAG-1/2 SCID

Answer 42

T-B-NK+ involved with VDR rearrangement of T and B cell antigen receptors fatal unless corrected with transplantation

Question 43

Omenn syndrome

Answer 43

leaky SCID generalized erythroderma and desquamation, diarrhea, hepatosplenomegaly, hypereosinophiia and elevated IgE can present w/ RAG-1/2 defects