B3.039 Immune Cell Development Flashcards
what are 3 reasons for asplenia
congenital surgical removal (trauma or disease management) autosplenectomy (sickle cell)
who has the most risk of complications due to asplenia?
younger, not yet vaccinated at increased risk of infections
older, vaccinated (have antibodies) may do better
what type of infections are of the most risk to asplenic patients?
encapsulated bacterial infections
S. pneumo, Hib, meningococcal
what is the recommendation to prevent serious infection in asplenics?
vaccination every 5 years for protection
what is AID
activation-induced cytidine deaminase
what can defects in AID lead to?
increased susceptibility to bacterial pyogenic infections only
describe the pathway which uses AID
- CD-40 and the IL-4 receptor on B cells is ligated by CD-40L
- AID is transcribed and translated to produce AID
- simultaneously, induction of transcription of the cytidine-rich regions at isotype switch sites
- AID deaminates cytidine in ssDNA only and converts the cytidine at the switch sites to uridine which is not normally there
- uracil is recognized by UNG (enzyme) removing the uracil from the nucleotide
- damaged DNA is recognized and repaired by endonucleases, excising the damaged region resulting in class switching
goal of somatic hypermutation in B cells
production of higher affinity antibodies as the immune response progresses
how does somatic hypermutation progress
during activation, point mutations are introduced into the DNA that encodes the immunoglobulin variable region affinity maturation (Selection) then occurs
positive selection
antibodies that compete for antibody binding the best receive stronger signals in the cell surface antigen receptor leading to increased proliferation
negative selection
lower affinity BCRs do not receive signals to proliferate and will undergo apoptosis
why are lymph nodes enlarged in patients with an AID deficiency?
proliferation of IgM+ B cells in the lymphoid organs (lymphoid hyperplasia)
lymphadenopathy & splenomegaly
what mutation leads to X-linked hyper IgM syndrome?
CD-40 or CD-40L gene defect
clinical result of X-linked hyper IgM syndrome?
increased susceptibility to both pyogenic and opportunistic infections
difference in inheritance between CD-40 and AID associated hyper IgM?
CD-40 is X-linked
AID is autosomal recessive
what is UNG
uracil-DNA glycosylase
what is SCID?
severe combines immune deficiency
syndrome caused by mutations in differenct genes whose products are necessary for T/B/NK cell development
SCID outcomes
early death from overwhelming infection within first year of life is not transplanted, early diagnosis is key
SCID epidemiology
1:40,000- 1:50,000 live births
50% are X-linked
why is SCID diagnosis often delayed several months?
infants look normal and maternally derived IgG provide some protection in early infancy
describe the process of fetal IgG transfer
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
how does SCID usually present
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
which organisms are SCID patient susceptible to?
opportunistic
candida, pneumocystis, VZV, adenovirus, parainfluenza, herpes, CMV, rotavirus, measles, norovirus, EBV
live viral vaccines
SCID clinical features
small thymus, less than 1 g
- fails to descend from neck
- few thymocytes
- lacks corticomedullary distinction and Hassall’s corpuscles
what are the 4 types of SCID
T-B+NK-
T-B+NK+
T-B-NK+
T-B-NK-
what is the most common form of SCID?
x-linked mutation in common gamma chain
have B cells, but they don’t work because T cells are absent
SCID lab findings
NORMAL: 70% of circulating lymphocytes are T cells
SCID infants are lymphopenic (<4000)
what lab findings constitute a strong SCID suspicion
absolute lymphocyte count <2500
T cells <20% of total lymphocytes
lymphocyte stimulation to mitogens is <10% of normal
absence of thymus on CXR
discuss the role of maternal T cells in SCID
some patients have maternal T cells cross the placenta and enter circulation
gives a normal appearance to T cell numbers (>3000)
indicator of maternal T cell engraftment
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
describe the genetic defect present in X-linked SCID
defect on X chromosome encoding the cytokine receptor subunit common gamma chain, IL2 RG
diagnosed on flow cytometry
what is the significance of the common gamma chain
receptor subunit shared by 6 difference cytokine receptor complexes: IL-2, 4, 7, 9, 15, and 21
also involved in growth hormone receptor signaling
clinical presentation of X linked SCID
male
severe infections, chronic diarrhea, failure to thrive
must be differentiated from autosomal recessive JAK3 deficiency which is also T-B+NK-
how can JAK3 deficiency and common gamma chain defect SCIDs be differentiated
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
how is SCID treated
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
epidemiology of autosomal recessive SCID
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
discuss ADA deficiency SCID
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
ADA deficiency SCID presentation
similar to all SCID cases
unique skeletal abnormalities
more profound lymphopenia (<500)
treatment for ADA deficiency SCID
cured with BM transplant
enzyme replacement with PEG-ADA (but not as good as BM transplant)
etiology of JAK3 deficiency SCID
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)
etiology of IL-7 receptor alpha chain deficiency SCID
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
etiology of RAG-1/2 SCID
T-B-NK+
involved with VDR rearrangement of T and B cell antigen receptors
fatal unless corrected with transplantation
Omenn syndrome
leaky SCID
generalized erythroderma and desquamation, diarrhea, hepatosplenomegaly, hypereosinophiia and elevated IgE
can present w/ RAG-1/2 defects
