Overview of Severe Combined Immunodeficiencies (SCID) in...
Transcript of Overview of Severe Combined Immunodeficiencies (SCID) in...
Overview of Severe Combined Immunodeficiencies (SCID) in Plain Communities During the Era of
Newborn SCID Screening
Christine Seroogy MD Associate Professor
Department of Pediatrics Division of Allergy, Immunology & Rheumatology
Funding Source:
Objectives • Newborn Screening for SCID successfully
detects many forms of SCID • Awareness of SCID forms and T cell
lymphopenias in Plain communities and approach to evaluation (emphasis on RAG1)
• Curative treatment for SCID early and infection-free leads to better outcomes
• Ongoing challenges associated with treatment of SCID in newborns/Plain communities
Severe Combined Immunodeficiency (SCID)
CLINICAL: • Infections in first year of life • Failure to thrive
LABORATORY: • T cells markedly decreased or absent & don’t function • B cells absent or non-functional • To date, 20+ genetic mutations associated with SCID
phenotype.
Fatal without immune reconstitution in the first year of life
Common Theme in ALL forms of SCID: Impaired Thymopoiesis
T Cell Receptor Excision Circle (TREC): biomarker of thymic function
Generation of T cell receptor excision circles (TRECs) occur in >70% of all new (naïve) T
cells and can be detected by PCR Ponchel et al. BMC Biotechnology 2003
TREC Assay Platform in Newborn Screening Laboratory
Slide courtesy of Dr. Mei Baker
Population Cumulative 2008-2013 birth number SCID SCID
Prevalence
Total WI population 404,836 (average 67,473/year) 9 1 in 44,982
WI Plain Communities 5,280 (average 880/year) 5 1 in 1,056
(estimated)
Wisconsin SCID Statistics Since NBS SCID Screening
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Es>mated using vital records and unique methodology, Drs. Angela Rohan and Murray Katcher, unpublished data
Includes one Amish newborn
Genetic Mutations Associated with T cell Lymphopenia & NBS SCID Screening in the Plain Communities
Immunologic Diseases Associated with T cell Lymphopenia
CSC (Lancaster Co, PA)
DDC (Northeast
OH) Indiana WI Other
Detected by NBS
SCID Screen
Plain Community
RAG1 SCID/Omenn Syndrome X X X YES Amish
ADA SCID X X YES Amish
IL7Ra SCID X X YES Mennonite
CD3delta SCID X YES Mexican/Low German-Mennonite
Cartilage Hair Hypoplasia X X X Variable Amish
ZAP70 CID X Variable Amish
Ataxia Telangiectasia X Variable Amish/Mennonite
22q11.2 microdeletion X X Variable Amish
Wiskott Aldrich Syndrome X NO Amish
RAG1 CID X Unknown Mennonite
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* Direct experience, personal communications, expert opinion, and review of medical literature
Initial Management NBS SCID Positive Screen
• Confirmatory testing and continued diagnostic testing for SCID • Protective isolation: where is safest environment? • Antimicrobial prophylaxis • Intravenous gamma globulin • No live vaccines • Irradiated, CMV- blood products • Safety of breastfeeding? • Cure?
Railey et al J. of Ped 2009
Bone Marrow Transplant in the First 3.5 Months Of Life Has Best Outcome in SCID (Dr. Buckley’s data—no conditioning)
Overall survival 77%, survival for BMT in first 3.5 months is 94%
Primary Immunodeficiency Treatment Consortium (PIDTC, 25 centers), 240 Infants with Classical Severe Combined
Immunodeficiency Retrospective 2000-2009:
Pai S et al. N Engl J Med 2014;371:434-‐446.
Age & Infection Status at the time of Bone Marrow Transplant (BMT) Impact Survival
Primary Immunodeficiency Treatment Consortium (PIDTC, 25 centers), 240 Infants with Classical Severe Combined
Immunodeficiency Retrospective 2000-2009:
Pai S et al. N Engl J Med 2014;371:434-‐446.
Survival is Highest with Matched Sibling Donor and Reduced in Recipients with Conditioning Regimens
Conclusions
• Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection.
• All available graft sources are expected to lead to excellent survival among asymptomatic infants.
• Questions:
When does conditioning need to be used? What is the minimal amount of conditioning that is required for acceptable engraftment? Is this a one-size fits all or does SCID genotype matter?
PIDTC MultiCenter Classical SCID BMT Conclusions
• RAG (recombination-activating gene) 1/2 proteins critical for T and B cell development by initiating VDJ recombination process. This leads to a block in early thymopoiesis.
• Mutations in RAG1/2 initially associated with SCID. More recent studies have demonstrated RAG 1/2 mutations in patients with combined immune deficiencies, autoimmune disease, and granulomatous disease.
Nature Structural & Molecular Biology 2009
RAG1
J Allergy Clin Immunol. 2014 Apr;133(4):1099-‐108. doi: 10.1016/j.jaci.2013.10.007. Epub 2013 Nov 28
T-‐B-‐NK+SCID Omenn Syndrome γδ-‐T SCID Leaky SCID CID Unknown
Muta>on found
in Amish
Muta>on found in Amish
RAG Recombination Activity Tends to Correlate with Clinical Phenotype
Omenn Syndrome (OMIM no. 603554)
• Clinical features: early in life diffuse erythrodermia, hepatosplenomegaly, lymphadenopathy, alopecia, failure to thrive, recurrent infections.
• Laboratory features: Absence of circulating B cells, infiltration of skin and intestine by activated oligoclonal T lymphocytes, high serum IgE levels, peripheral blood eosinophilia, increased numbers of poorly functional activated circulating T cells.
Clinical Immunology, Volume 128, Issue 1, 2008, 31 - 38
Omenn Syndrome • To date, many SCID-associated genes have been
associated with OS. Mutations in RAG1 is the prototype and most studied.
• Some hypomorphic mutations, including RAG1, can cause either SCID or OS. Thus, suggesting other gene modifiers or environmental triggers necessary for OS phenotype.
T Cell Number & T Cell Function
Classical SCID
Leaky SCID
Omenn Syndrome
Unique Challenges in Plain Communities:
• Decreased rates of newborn screening • Increased population prevalence of
hypomorphic RAG1 mutations • Curative approaches for SCID are expensive • Opposition to chemotherapy • Opposition to prolonged hospitalizations • Poor access to tertiary care centers • Refusal of therapy for fatal, but curative
disease
General Challenges • The use of conditioning for bone marrow
transplantation in newborns (1-2 months) is an extremely difficult decision – Tandem transplant? – Antibody depleting regimens (CD45 not
readily available and anti-c-kit in development)
– Lower dose conditioning? (PIDTC trial) – Serotherapy and αβ-‐T cell depletion?
Conclusion • Newborn screening for SCID successfully
detects all forms of SCID (and other clinically actionable T cell lymphopenias).
• Early screening leads to early treatment in healthy infants resulting is better outcomes.
• All forms of SCID and some T cell lymphopenias found in Plain Communities are easily amenable to NBS SCID screening (but not all).