Page 509 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Primary T-Cell Immunodeficiencies

Chaim M. Roifman

This chapter is dedicated to the diagnosis and management of The most clinically severe and studied group of patients are
inherited immune defects associated predominantly with T-cell those traditionally designated as having severe combined immu-
dysfunction. One of the central roles of T cells is the coordination nodeficiency (SCID). The clinical hallmarks of SCID include
of both the humoral and cell-mediated arms of the immune consistent clinical presentation in the first year of life, with
system; therefore T-cell deficiencies are often accompanied by repeated life-threatening bacterial, viral, or fungal infections,
1
dysfunction of other cell types, such as B and natural killer (NK) chronic diarrhea, and failure to thrive. Evaluation of the immune
cells. The focus of this chapter is on primary immunodeficiencies system typically reveals profound T-cell lymphopenia of <500
2,3
that are profound enough to require hematopoietic stem cell CD3 cells, or according to more stringent definitions, <300 T
transplantation (HSCT) or other modalities of management and cells. Invariably, in vitro responses to mitogens are severely
treatment directed at T-cell absence or dysfunction. depressed and T-cell receptor excision circle (TREC) numbers
4
are markedly reduced or below detection. The identification of
T-CELL IMMUNODEFICIENCIES these cases by TREC-based newborn screening (NBS) is the
earliest alert of T-cell deficiency. 5
KEY CONCEPTS
T-Cell Immunodeficiency COMBINED IMMUNODEFICIENCY
• A group of disorders are caused by defects in genes critical to the The second large group of disorders with significant T-cell
growth, maturation, and survival of T lymphocytes. deficiency is loosely designated as combined immunodeficiency,
• Some defects may also affect other arms of the immune system, which is arbitrarily defined by the presence of >300–500 autolo-
such as B cells, natural killer (NK) cells, or components of innate gous CD3 cells/µL in the circulation. The omission of “severe”
3,4
immunity. from this category of patients might be misleading, as many of
• The immune defects may be one feature of a multisystem these patients present with signs and symptoms indistinguish-
syndrome.
• The age of presentation and diagnosis varies widely from early infancy able from SCID. This category of heterogeneous deficiencies
(or at birth when detected through newborn screening) to adulthood. can be further subdivided into subgroups that are discussed
• The spectrum of clinical manifestations is wide and encompasses in detail in this chapter. They include T-cell deficiencies that
presentation at early infancy with extreme susceptibility to opportunistic invariably or frequently present with normal or close to normal
infections (severe combined immunodeficiency [SCID]) or disorders numbers of circulating lymphocytes, such as zeta-associated
featuring predominately autoimmunity or predisposition to cancer protein-70 (ZAP-70) deficiency. Other disorders are caused by
(combined immunodeficiency [CID]). 3
hypomorphic mutations in genes associated with SCID and
are therefore frequently referred to as “leaky SCIDs.” A third
subgroup encompasses patients with multisystem syndromes
SEVERE COMBINED IMMUNODEFICIENCY that include variable degrees of T-cell deficiency, such as cartilage
hair hypoplasia and DiGeorge syndrome. Finally, a fourth group
KEY CONCEPTS involves more selective T-cell defects, such as FOXP3 deficiency,
Severe Combined Immunodeficiency which predispose patients to a limited array of infections or are
associated with autoimmunity or lymphoid malignancies. There
• Infants present typically at 4–6 months of age with severe persistent may be a wide range of clinical manifestations, from typical
infections, oral thrush, chronic diarrhea, and failure to thrive. Siblings SCID presentation to mild or delayed presentation. Laboratory
of affected patients and cases detected through newborn screening features are also extremely variable but universally reflect T-cell
are diagnosed before symptoms occur. 6,7
• By definition, affected infants have a permanent profound T-cell dysfunction.
lymphopenia of <300–500 CD3 cells/µL, with or without reduced
numbers of circulating B cells and natural killer (NK) cells. OMENN SYNDROME
• Invariably, in vitro responses to T-cell mitogens are depressed and
+ +
T-cell receptor excision circle (TREC) levels are low or undetectable. Omenn syndrome (T B SCID; OMIM #603554) is an aberrant
• Ideally, patients with severe combined immunodeficiency (SCID) should inflammatory process associated with “leaky SCID” phenotypes,
be placed in protective isolation and offered hematopoietic stem cell
transplantation (HSCT) (or, in some cases, gene therapy). which characteristically allow for thymic escape and propagation
8
of poorly controlled T-cell clones. T-cell development is severely
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