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Update on Cellular Immunodeficiencies

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Update on Cellular Immunodeficiencies Francisco A. Bonilla Children s Hospital Boston Harvard Medical School MA SCID NBS Laboratory Testing Algorithm Overview (All ... – PowerPoint PPT presentation

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Title: Update on Cellular Immunodeficiencies


1
Update on Cellular Immunodeficiencies
  • Francisco A. Bonilla
  • Childrens Hospital Boston
  • Harvard Medical School

2
WHO / IUIS classification
3
IUIS-I Combined immunodeficiencies
  • T-B SCID
  • Gamma c IL2RG
  • JAK3 JAK3
  • IL-7 R alpha IL7RA
  • CD45 PTP1C
  • CD3 delta CD3D
  • CD3 epsilon CD3E
  • CD3 zeta CD3Z
  • Coronin1a CORO1A
  • T-B- SCID
  • RAG1/2 RAG1/2
  • Artemis DCLRE1C
  • DNA-PK DNAPK
  • ADA ADA
  • Adenylate kinase 2 (reticular dysgenesis) AK2

4
IUIS-I Combined immunodeficiencies
  • DNA ligase 4 LIG4
  • Cernunnos NHEJ1
  • Hyper-IgM syndrome
  • CD40L TNFSF5
  • CD40 TNFRSF5
  • PNP NP
  • CD3 gamma CD3G
  • CD8 alpha CD8A
  • ZAP-70 ZAP70
  • Calcium channel defects
  • Orai-1 ORAI1
  • Stim-1 STIM1
  • MHC class I
  • TAP1/2 TAP1/2
  • TAP BP TAPBP
  • MHC class II
  • CIITA MHC2TA
  • RFXANK RFXANK
  • RFX5 RFX5
  • RFXAP RFXAP
  • WHN WHN
  • STAT5b STAT5B
  • Itk ITK
  • DOCK8 DOCK8

5
SCID due to Coronin 1a deficiency
  • 15 month old girl
  • OM x 2, URIs, pneumonia x 1, GERD, oral thrush
  • Severe chicken pox after varicella immunization,
    required IV acyclovir for resolution
  • Cognitive impairment
  • No parental consanguinity
  • No family history of PIDD
  • Started IVIG age 2, still had pansinusitis,
    frequent abx, severe viral illnesses
  • Underwent BMT

6
SCID due to Coronin 1a deficiency
Shiow et al. Clin Immunol 2009 13124
7
SCID due to Coronin 1a deficiency
Shiow et al. Clin Immunol 2009 13124
8
SCID due to Coronin 1a deficiency
Thymus present Pansinusitis
Shiow et al. Clin Immunol 2009 13124
9
SCID due to Coronin 1a deficiency
  • Phenotype concordant with Coronin 1a knockout
    mouse model
  • Father had 2 bp deletion in CORO1A
  • Child had large deletion spanning CORO1A on other
    chromosome

10
Reticular dysgenesis
  • Pannicke
  • Bertrand

11
Reticular dysgenesis
  • One of the oldest known forms of SCID (described
    1959)
  • Severe T B lymphopenia and agranulocytosis
  • Bacterial and fungal sepsis, pneumonia,
    enteritis, maternal T cell engraftment and GVHD
  • Sensorineural deafness
  • Uniformly fatal within months

12
Reticular dysgenesis
  • Genome-wide SNP array for regions of homozygosity
    in 6 individuals with RD
  • Region 1p34.3-36.11 homozygous in all
  • 185 genes, 80 expressed in bone marrow
  • Tested expression of all 80 genes in BM cells of
    one pt., found abnormal mRNA for adenylate kinase
    2 (AK2)
  • Sequenced AK2 gene and found mutations in
    all

Pannicke et al., Nat Genet 2009 41101.
13
Reticular dysgenesis
  • Adenylate kinase 2, mitochondrial enzyme that
    generates ADP, required for normal oxidative
    metabolism in lymphoid and myeloid precursors and
    neurons in the inner ear (other tissues use AK1).
  • In the absence of adequate ATP, mitochondria
    activate apoptosis

14
Reticular dysgenesis
Apoptosis in fibroblasts
Pannicke et al., Nat Genet 2009 41101.
15
STAT5b deficiency
  • Growth failure with GH insensitivity
  • Severe infections (hemorrhagic varicella)
  • Chronic lung disease (fibrosis, LIP)
  • Atopy (eczema)
  • Autoimmunity (ITP, juvenile arthritis)

16
STAT5b deficiency
Nadeau et al., J Pediatr 2011 158 701.
17
STAT5b deficiency
  • IgG elevated
  • CD3 low (both CD4 CD8)
  • Treg low
  • NK low
  • B cells normal or low
  • Antibody formation normal
  • T cell proliferation low

18
Nadeau et al., J Pediatr 2011 158 701.
19
ITK deficiency
  • Sister A
  • Aphthous stomatitis and thrush age 5
  • EBV-associated lymphoproliferative disease age 6
  • Died of PCP age 10
  • Sister B
  • Healthy until EBV-associated lymphoproliferative
    disease age 5
  • Died during BMT

Huck et al, J Clin Invest 2009 1191350
20
ITK deficiency
  • Screening evaluation of T cell, B cell, and NK
    cell function essentially normal
  • Absent NKT cells (characteristic of XLP due to
    SH2D1A or XIAP defects

Huck et al, J Clin Invest 2009 1191350
21
ITK deficiency
Huck et al, J Clin Invest 2009 1191350
22
ITK deficiency
  • Genome-wide linkage analysis in 8 family members
    indicated ITK as candidate gene

23
ITK signaling
http//www.biolegend.com/media_assets/pathways/ITK
20and20TCR20Signaling.jpg
24
Hyper-IgE syndrome type 2
  • Eczema, recurrent skin viral (molluscum, herpes)
    and bacterial (Staph), and fungal (Candida)
    infections, CNS vasculopathy
  • Normal facies, teeth and bones
  • Elevated IgE, eosinophilia
  • Autosomal recessive

25
Hyper-IgE syndrome type 2
  • Comparative genomic hybridization
  • Affected individuals and obligate carriers from
    20 kindreds

Engelhardt et al., J Allergy Clin Immunol 2009
1241289
26
Comparative genomic hybridization
http//www.nature.com/scitable/content/ 41020/arra
yCGH_Theisen_large_2.jpg
27
Hyper-IgE syndrome type 2
  • Decreased copy number seen in region of
    chromosome 9 encompassing DOCK8 locus

Engelhardt et al., J Allergy Clin Immunol 2009
1241289
28
DOCK8 mutations in HIE-2
Engelhardt et al., J Allergy Clin Immunol 2009
1241289
29
DOCK8 mutations in HIE-2
30
The Massachusetts SCID NBS Workgroup
Representatives from Newborn Screening,
Immunology, Infectious Disease, Public Health and
Transplantation
Dr. Anne Marie Comeau Dr. Roger Eaton Dr.
Inderneel Sahai
31
Severe Combined Immunodeficiency (SCID)
  • 15 genetic causes
  • Common characteristic severe defect of T cell
    development
  • Incidence in general US population
  • Clinically presenting and diagnosed
  • About 1/100,000
  • Estimates 1/10,000-1/50,000
  • (Native American Navajo nation 1/ 2,000)

32
SCID
  • Uniformly fatal if not treated
  • Bone marrow (stem cell) transplantation
  • Curative if successful
  • Key to success
  • EARLY TRANSPLANT
  • Before infection
  • Before further deterioration of thymus

33
www.biomedcentral.com/.../1472-6750-3-18-1-l.jpg
34
MA SCID NBS Laboratory Testing Algorithm Overview
(All TREC RNaseP Values are copies/ul)
Dried Blood Spot Specimen
Multiplex PCR assay for TREC and RNaseP
TREC 503 and RNaseP 4032
TREC lt 503
RNaseP lt 4032
Prompts retest in duplicate of same specimen
SCREEN NEGATIVE
Two or Three tests with RNaseP lt 4032
Two or Three tests with RNaseP 4032 and TREC
252
Two or Three tests with RNaseP 4032 and TREC
lt 252
SCID SCREEN UNSATISFACTORY
SCREEN NEGATIVE
SCREEN POSITIVE
Phone call to PCP office to Request Repeat NBS
specimen
PHONE CONSULT with PCP and recommendation for
repeat NBS and/or Flow Cytometry followed by fax
of Screen Positive report packet
35
SCID NBS Notification Algorithm Overview

SCREEN POSITIVE RESULT
Request repeat NBS specimen
REPEAT SCREEN POSITIVE
REPEAT SCREEN NEGATIVE
Was any previous specimen above cutoff?
Yes
No
PHONE CONSULT with PCP and recommendation for
Flow Cytometry
36
Prompts for Referral to Flow Cytometry
  • Undetectable TREC on initial NBS specimen
  • Two out of range TREC results (lt252 copies/ul)
    from two independent NBS specimens in the absence
    of a normal TREC result
  • In NICU infants if a subsequent normal TREC
    result is obtained prior to flow cytometry being
    done then the recommendation for flow cytometry
    will be withdrawn in the absence of clinical
    concerns
  • Persistent SCID unsat due to failed amplification
    of RNaseP

37
Current Work-up Algorithm
Flow Cytometry CD3, CD4, CD8, CD16/56,
CD19 Naïve T cell determination Clinic Referral
for Possible SCID and functional T cell tests
if Total T cell number lt2,500 cells-mm3 Naïve
T cells (CD4 or CD8) lt50 Clinic referral for
possible other PIDD if any other abnormality on
flow cytometry Referral to Transplant Center for
SCID if T cell functional tests are indicative
38
DATA and Experience in MA
Through Guthrie date 9/15/2011
194,056 infants screened for SCID 4
SCID Incidence 150,000
39
194,056 infants screened for SCID
  • 619 infants with positive SCID NBS result on any
    specimen (0.3)
  • 40 infants referred to Flow Cytometry
  • 14,851 newborns screened (0.021)

40
Status of 40 Infants with Out Of Range SCID NBS
Prompting Flow Cytometry
41
Summary of MA SCID cases detected by NBS
42
US PILOT STUDIES INTERIM FINDINGS Combined data
from CDC and NICHD-funded pilots (through April
2011)
  • Increased incidence extent?
  • 48 10 X-linked?
  • 6 65 Hispanic?
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