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Severe Combined Immunodeficiency: a Review for Neonatal Clinicians Thomas F

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Severe Combined Immunodeficiency: a Review for Neonatal Clinicians Thomas F Severe Combined Immunodeficiency: A Review for Neonatal Clinicians Thomas F. Michniacki, MD,* Divya Seth, MD,† Elizabeth Secord, MD† *Pediatrics and Communicable Diseases, Division of Pediatric Hematology/Oncology, University of Michigan, Ann Arbor, MI †Department of Pediatrics, Division of Allergy, Asthma, & Immunology, Wayne State University, Detroit, MI Education Gaps 1. Pediatric clinicians should be able to describe the normal development and function of lymphocytes along with how neonatal immunity varies from that of adults and older children. 2. Neonatal clinicians should be proficient in the diagnosis and initial management of infants suspected of having a severe combined immunodeficiency. Abstract The proper development and function of T cells is imperative in the creation of adequate cell-mediated and humoral immunity. Healthy term newborns have baseline immune immaturity, increasing their risk of infections, but significant immunologic consequences can occur, because of abnormal T-cell maturation. Combined immunodeficiencies can result, because B cells and natural killer cells rely on successful interactions with T cells to ensure their proper performance and survival. Severe combined immunodeficiency (SCID) is the most noteworthy of these conditions, leading to considerable early morbidity and often death by the age of 1 year if left untreated. Newborn screening for SCID is effective and allows for early implementation of lifesaving supportive measures, including protective isolation, initiation of prophylactic antimicrobials, caution with blood product transfusions, and avoidance of live vaccinations. Once a definitive diagnosis of AUTHOR DISCLOSURE Drs Michniacki, Seth, and Secord have disclosed no financial SCID has been established, treatment frequently involves bone marrow or stem relationships relevant to this article. This cell transplantation; however, enzyme replacement and gene therapy are also commentary does not contain a discussion of an unapproved/investigative use of a becoming options in those with SCID due to adenosine deaminase deficiency and commercial product/device. other forms of SCID. Neonatal clinicians should understand the screening and diagnostic approach to SCID along with the initial management approaches for ABBREVIATIONS ADA adenosine deaminase these extremely high-risk patients. APC antigen-presenting cell HSCT hematopoietic stem cell transplantation MHC major histocompatibility complex After completing this article, readers should be able to: Objectives NBS newborn screening 1. Explain the normal development and function of lymphocytes and describe NK natural killer SCID severe combined how they interact to successfully enable innate and adaptive immunity. immunodeficiency TRECs T-cell receptor excision circles e326 NeoReviews Downloaded from http://neoreviews.aappublications.org/ by guest on June 10, 2019 2. Describe newborn immunity with an emphasis on neonatal cell-mediated and humoral immunity. 3. Explain the pathophysiology, clinical presentation, and diagnosis of severe combined immunodeficiency and related conditions. 4. Recognize the benefits and limitations of newborn screening for severe combined immunodeficiency. 5. Successfully implement the initial management strategies in an infant suspected to have severe combined immunodeficiency. 6. List the various treatment modalities for a patient with severe combined immunodeficiency and related conditions. INTRODUCTION minimal plasma cell differentiation and a lack of significant immunoglobulin isotype class switching. Fortunately, term In this review, we provide a summary of severe combined infants are afforded some assistance with immunity via the immunodeficiency (SCID) and related conditions with addi- placental transfer of maternal IgG that begins around 32 tional education on the normal development and function of weeks’ gestation. Premature infants born before 32 weeks’ lymphocytes, with an emphasis on neonatal immunology. gestation thus have profound IgG deficiency. Maternal IgG Educating neonatal clinicians about screening, confirma- will allow for sufficient humoral protection in the term tory diagnostic, and initial management approaches for infant until approximately 6 months of age. Specific anti- newborns with disorders of cellular immunity, including body production becomes adequate for some protein anti- SCID, is imperative to ensuring optimal outcomes for these high-risk patients. gens by 2 months of age and is delayed for polysaccharide antigens until approximately 24 months of age. (2) Commitment of the common lymphoid progenitor to a T NORMAL DEVELOPMENT AND FUNCTION OF lineage and proper development and function of T lympho- LYMPHOCYTES AND IMMUNITY IN THE NEONATE cytes requires stem cell passage through the thymus. It is in the thymus that the T-cell receptor is first expressed on the Hematopoietic stem cells give rise to all cellular blood cell surface. Initially, the double-negative (CD4À CD8À) components, including lymphocytes, which develop after thymocytes upregulate both CD4 and CD8 to become a pluripotent stem cell’s transition to the common lymphoid double-positive (CD4þ CD8þ) cells. (1) During the process progenitor. This progenitor may then progress to 1 of 3 lineages: B cells, T cells, or natural killer (NK) cells. T cells of positive and negative selection, either CD4 or CD8 is and B cells are involved in the body’s adaptive immune suppressed, creating helper or cytotoxic T cells, respectively. þ þ response through cell-mediated immunity (facilitated by T CD8 cells are involved in cell lysis whereas CD4 cells þ cells) and humoral immunity (mediated by B cells). NK cells assist CD8 cells in the cellular lytic process and also act as a major component of innate immunity. (1) interact with B cells via soluble factors and direct cell-to- Precursor B cells initially develop predominantly in the cell communication to produce antibodies. (1) As a result of bone marrow before transition to the spleen and lymph this B-cell functional dependence on T cells, qualitative or node germinal centers. It is in the germinal centers that quantitative T-lymphocyte defects will often cause B-cell mature B cells (expressing CD19, CD20, IgM, and IgD deficiency or poor humoral immunity. (3) In addition to surface markers) either become plasma cells that secrete the helper and cytotoxic varieties, T cells eventually develop protective immunoglobulins or memory B cells (expressing into effector, memory, and regulatory subtypes to complete IgG, IgA, or IgE surface markers) that assist in the second- the impressive functionality of T lymphocytes. Antigen ary immune response. By recognizing and binding to specificity and effective adaptive immunity is created specific antigens, immunoglobulins assist in the eventual through somatic rearrangements of T-cell receptor genes to destruction of harmful pathogens. (1) Immunoglobulin create a diverse population of T lymphocytes. Successful production, especially IgG, in the fetus is poor, given adaptive immunity also requires the activation of naïve T Vol. 20 No. 6 JUNE 2019 e327 Downloaded from http://neoreviews.aappublications.org/ by guest on June 10, 2019 cells, which involves not only an interaction between the T- assessment. Patients may also show low B-cell and NK-cell cell receptor and major histocompatibility complex (MHC) absolute values and decreased quantitative immunoglobulin on antigen-presenting cells (APCs) but also the binding of levels, though these findings are not required for diagnosis. various T-cell surface molecules to additional ligands pre- Leaky SCID refers to a combined immunodeficiency caused sent on APCs (costimulation). Cytokines play a crucial role by a hypomorphic mutation in a recognized SCID-causing in T-cell activation, with interleukin 2 leading to a sustained gene, leading to the production of some Tcells (typical levels proliferation of lymphocytes. (1) of 300–1,500 cells/mL) that are poorly functioning (mitogen Fetuses and newborns have an increased vulnerability to stimulation of 10%–30% of normal controls). (5)(8) Mater- pathogens that require T cells for optimal control, such as nal engraftment of T cells can occur in infants with SCID, viruses, fungi, parasites, and mycobacteria. Unlike humoral given a lack of autologously produced fetal T cells to elim- immunity, infants do not receive passive maternal T-cell inate placentally transferred lymphocytes. These cells typi- immunity assistance during gestation and thus must rely on cally will fail to respond to mitogen stimulation but may their own autologous T cells for protection. It is hypothe- cause graft-versus-host disease in the neonate, manifesting sized that this elevated infectious sensitivity found in neo- as cutaneous and hepatic abnormalities. (1)(5)(9) Clinicians nates is partially secondary to decreased differentiation of should be aware of the phenomenon of Omenn syndrome neonatal naïve CD4 T cells and relative APC immaturity, in those with leaky SCID. The syndrome is thought to result especially dendritic cells. (2) from the clonal proliferation of a population of T lympho- NK cells are considered innate lymphoid cells that func- cytes present in the patient with leaky SCID. These infants tion as cytotoxic cells with a primary role of destroying cells may present with normal lymphocyte numbers and a infected with viruses and intracellular bacteria. Cytokines response to mitogen stimulation but continue to have poor and antibodies (via coating of pathogen-inflicted cells) immunologic function,
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