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Update on Cellular Immunodeficiencies

Update on Cellular Immunodeficiencies. Francisco A. Bonilla Children’s Hospital Boston Harvard Medical School. WHO / IUIS classification. 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

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Update on Cellular Immunodeficiencies

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  1. Update on Cellular Immunodeficiencies Francisco A. Bonilla Children’s 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 duetoCoronin 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 duetoCoronin 1a deficiency Shiow et al. Clin Immunol 2009; 131:24

  7. SCID duetoCoronin 1a deficiency Shiow et al. Clin Immunol 2009; 131:24

  8. SCID duetoCoronin 1a deficiency Thymus present Pansinusitis Shiow et al. Clin Immunol 2009; 131:24

  9. SCID duetoCoronin 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 adenylatekinase 2 (AK2) • Sequenced AK2 gene and found mutations in all Pannicke et al., Nat Genet 2009; 41:101.

  13. Reticular dysgenesis • Adenylatekinase 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; 41:101.

  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 • Aphthousstomatitis 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; 119:1350

  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; 119:1350

  21. ITK deficiency Huck et al, J Clin Invest 2009; 119:1350

  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%20and%20TCR%20Signaling.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; 124:1289

  26. Comparative genomic hybridization http://www.nature.com/scitable/content/ 41020/arrayCGH_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; 124:1289

  28. DOCK8 mutations in HIE-2 Engelhardt et al., J Allergy Clin Immunol 2009; 124:1289

  29. DOCK8 mutations in HIE-2

  30. The Massachusetts SCID NBS WorkgroupRepresentatives from Newborn Screening, Immunology, Infectious Disease, Public Health and Transplantation Dr. Barbara Stechenberg Dr. Alicia Johnston Dr. Ellen Rae Cooper Dr. Alfred DeMaria Dr. Francisco Bonilla Dr. Luigi Notarangelo Dr. Sung-Yun Pai Dr. Cody Meissner Dr. Mark Pasternak Dr. Paul Hesterberg Dr. Jolan Walter Dr. Beverly Hay Dr. John Sullivan 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 < 503 RNaseP < 4032 Prompts retest in duplicate of same specimen SCREEN NEGATIVE Two or Three tests with RNaseP < 4032 Two or Three tests with RNaseP ≥ 4032 and TREC ≥ 252 Two or Three tests with RNaseP ≥ 4032 and TREC < 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 (<252 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 <2,500 cells-mm3 Naïve T cells (CD4 or CD8)% <50% 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 1:50,000

  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 1:4,851 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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