T-Cell Disorders

Updated: Jan 12, 2016
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD  more...
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Overview

Background

This article discusses partial T-cell disorders. For reviews of complete T-cell deficiencies, see the articles titled Severe Combined Immunodeficiency (SCID), Omenn Syndrome, and Cartilage-Hair Hypoplasia. Much remains to be understood about the association of partial T-cell immunodeficiency and immune dysregulation. [1] These heterogeneous disorders are characterized by an incomplete reduction in T-cell number or activity, autoimmunity, inflammatory diseases, and elevated immunoglobulin E (IgE) production.

The nomenclature for T lymphocytes is based on the role of the thymus in the differentiation and maturation of T lymphocytes. The prototypic T-cell disorder in which the thymus is absent, small, or in an aberrant location is DiGeorge syndrome (DGS). Other well-known partial deficiencies in T-cell function include the chromosomal breakage syndromes (CBSs), B-cell and T-cell combined disorders (eg, ataxia telangiectasia [AT]) and Wiskott-Aldrich Syndrome (WAS), which are discussed in separate articles. Similarly, pityriasis lichenoides et varioliformis acuta [2] and other entities linked with or part of T-cell lymphoma spectrum are covered elsewhere.

Partial T-cell disorders typically have limited T-cell defects that predispose patients to more frequent or extensive infections; these disorders often include immune dysregulation that allows autoimmune phenomena, lymphoproliferation, and malignancies. For example, patients with partial DGS rarely lack T-cell function as measured by in vitro T-cell proliferation to nonspecific mitogens. When T-cell function is absent in T-cell disorders, the disorder can be lethal. Conventional clinical management for absent T-cell function consists of immune reconstitution using stem cell or bone marrow transplantation.

Partial T-cell defects commonly cause abnormalities of immune regulation. Thus, T-cell to B-cell communication is defective, with partial defects in antibody production and increased incidence of atopy and autoimmune disorders. Inadequate antibody responses directed against bacterial polysaccharide antigens cause an increased risk for sinopulmonary infections caused by encapsulated organisms. The increased risk for reactive airway disease and thyroiditis in patients with DGS and the high incidence of autoimmune hemolytic anemia in patients with WAS are examples of defective T-cell/B-cell interactions that result in self-reactivity.

T-cell disorders in which autoimmunity and polyendocrinopathy predominate have recently been elucidated, and more will certainly be discovered as pathways for T-cell signal transduction are better understood. Mutations in the CD3+ T-cell complex are associated with autoimmune cytopenias, autoimmune enteropathy, and recurrent sinopulmonary infections. Defects in CD95/Fas and Fas ligand lead to autoimmune cytopenias, lymphadenopathy, and hepatosplenomegaly. A syndrome of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the AIRE gene coding for autoimmune regulator.

Mutations in the gene coding for Foxp3 at chromosome band Xp11.22 are manifested as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (also termed X-linked syndrome with polyendocrinopathy, immune dysfunction, and diarrhea [XPID]). Mutations in the gene coding for interleukin 2a receptor (IL-2Ra) have similarly caused diarrhea, candidiasis, and lymphoproliferation.

Knockout and transgenic mice have been developed for specific T-cell disorders and are recognized to have helped predict human genetic disorders.

Partial T-cell immunodeficiencies constitute a heterogeneous cluster of disorders characterized by an incomplete reduction in T-cell number or activity. The immune deficiency component of these diseases is less severe than that of the severe T-cell immunodeficiencies and therefore some ability to respond to infectious organisms is retained. Unlike severe T-cell immunodeficiencies, however, partial immunodeficiencies are commonly associated with hyper-immune dysregulation, including autoimmunity, inflammatory diseases, and elevated IgE production. This causative association is counter intuitive. Immune deficiencies are caused by loss-of-function changes to the T-cell component, whereas the coincident autoimmune symptoms are the consequence of gain-of-function changes or loss of regulatory functions.

Partial T-cell immunodeficiencies may also be evident in primary cutaneous γδ T-cell lymphoma, a rare and aggressive cutaneous lymphoma. [3, 4] These cutaneous lymphomas should be distinguished from γδ T-cell–rich variants of pityriasis lichenoides and lymphomatoid papulosis, both of which are benign. [5]

This article details the genetic basis of partial T-cell immunodeficiencies and draws on recent advances in mouse models to propose mechanisms by which a reduction in T-cell numbers or function may disturb the population-dependent balance between activation and tolerance.

One may view immune function as a double-edged sword, with components such as Th17 cells preventing repeated infections yet facilitating autoimmune disorders when dysregulated. [6]

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Pathophysiology

That partial T-cell disorders are associated with immunodeficiency is clear. However, as many as half of patients with these diseases that result in reduced functioning or quantities of T-cells develop autoimmune diseases. [7] The reduction in T-cell quantity or activity in patients with partial T-cell disorders may result in inefficient tolerance mechanisms, which, in turn, predisposes these individuals for the development of autoimmune diseases. [1]

Mature functional T cells undergo differentiation and maturation in the thymus; therefore, the thymus is critical for intact cell-mediated immunity. The thymus also regulates central tolerance by deleting T cells that recognize self-antigens. Thus, defects in the thymic microenvironment, as in DGS, result in poor T-cell function. The ability of T cells to recognize and respond appropriately to antigen depends on a complex pathway of surface glycoproteins and transmembrane molecules involved in signal transduction, many of which can be ascertained by flow cytometry using monoclonal antibodies directed against these antigens.

Critical components of T-cell antigen recognition include the CD3 complex, CD4, CD8, and the T-cell receptor heterodimers TCRα/ß or TCRg/σ. These molecules act in a coordinated manner to regulate intracellular signaling pathways, which then induce or inhibit the specific immune response. One study generated mice with decreased quantities of immunoreceptor tyrosinase–based activation motifs (ITAMs) in the TCR-CD3 complex. Mice with as little as a 50% reduction in immune-signaling capacity exhibited both partial immunodeficiency and autoimmunity. [8]

Antigen recognition through CD4 depends on antigen presentation by major histocompatibility complex (MHC) class II, whereas CD8 requires antigen presentation by MHC class I. Additional molecules, such as Fas and Fas ligand, mediate apoptosis of T cells that recognize self-antigens. The scurfin protein is a newly identified transcription factor encoded by the FOXP3 gene that is expressed both in the thymus and in peripheral T cells. Foxp3 protein is expressed by regulatory T cells that inhibit proliferation and functions of effector T cells and is thought to be crucial for maintenance of peripheral tolerance. Immune regulation occurs centrally in the thymus and in peripheral T cells, lymphoid tissues, and nonlymphoid tissues (eg, gut, skin).

Defects in cytotoxicity by T cells and natural killer (NK) cells in Chediak-Higashi syndrome (CHS) reflect a global error in packaging of lysosomal enzymes caused by a mutation in the gene coding for lysosomal-trafficking regulator.

For a more detailed discussion of the intricate pathways of T-cell signaling, see the articles on specific T-cell deficiency syndromes listed in Differentials.

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Epidemiology

Frequency

United States

Overall frequency of T-cell disorders has been estimated at 1 case per 70,000 people. Specific T-cell disorders are even more infrequent. DGS has an estimated incidence of 1 case per 5,000 live births, but many of these children have minimal immune dysfunction that improves with age. A recent study concluded that the incidence of primary immunodeficiency dramatically increased between 1976-2006. [9] DGS is increasing in incidence due to affected parents bearing their own affected children. [10]

Cutaneous T-cell lymphoma incidence had been increasing steadily in the past quarter century, but it seems to be stabilizing. [11]

International

Partial T-cell defects are seen in persons of all ethnic backgrounds. This is well established for specific syndromes such as DGS and WAS. Some autosomal recessive disorders are seen more frequently in inbred populations. As mutation analysis becomes more routine, heterozygous mutations have been frequently defined in some disorders, such as AT.

Mortality/Morbidity

Patients with partial T-cell disorders usually have chronic illness from sinopulmonary infections, autoimmune cytopenias, diarrhea, and polyendocrinopathies, especially insulin-dependent diabetes mellitus (IDDM). Depending on the specific mutation, severe disease may cause death in infancy or the patient may survive into middle childhood. Lymphoproliferative disease and malignancy are features of WAS, AT, and immune dysregulation/autoimmunity syndromes.

DGS (partial) is the single T-cell disorder in which the incidence of respiratory and candidal infections often decreases in patients older than 2 years. However, the incidence of hypothyroidism and other autoimmune complications increases in mid childhood. Bone marrow transplantation is the best treatment in patients with WAS and CHS younger than 2 years because outcome studies show higher rates of cure at earlier ages. CHS is difficult to treat once it enters the accelerated phase. Progressive neurologic deterioration is a feature of AT and CHS.

Race

T-cell disorders affect all ethnic populations. Isolated inbred populations in Europe and the Middle East have been identified with a number of rare partial T-cell disorders that were subsequently found to occur sporadically in the United States. Studies of unique large extended families with rare immunodeficiencies have been an important source in documenting clinical manifestations, and these detailed genetic studies have improved understanding of specific gene function.

Sex

Numerous genes regulating immune function are located on the X chromosome. The gene defect in X-linked SCID (mutations in the common γ chain for interleukin [IL]–2, IL-4, IL-7, IL-9, IL-15, and IL-21) is located at chromosome band Xq13. The BTK gene for X-linked agammaglobulinemia is at band Xq21.3. X-linked hyperimmunoglobulin M (XHIM; CD40 ligand deficiency) is caused by mutations at band Xq26.2. X-linked lymphoproliferative disease is caused by mutations in the gene for signaling lymphocyte activation molecule (SLAM)–associated protein at band Xq25. The gene responsible for WAS is located at band Xp11.22, and the gene coding for scurfin (Foxp3), the defect of which causes X-linked polyendocrinopathy and enteropathy (IPEX), is located nearby, between bands Xp11.23 and Xq13.3. In these disorders, only males are affected and females are asymptomatic carriers.

T-cell disorders associated with autosomal chromosomes include DGS at band 22q11 (microdeletion), AT at band 11q22, and CHS at bands 1q42-43. The gene for CD3 complex is localized to chromosome band 11q23. The AIRE gene is on band 21q22.3; AIRE mutation causes APECED. The gene for CD95/Fas is at band 10q23; CD95 deficiency causes one type of autoimmune lymphoproliferative syndrome (ALPS). Targeted next-generation sequencing is a rapid cost-effective method that identified five variants causing five ataxia-telangiectasia in three Chinese probands in one study. [12]

Age

Most T-cell disorders present in early infancy with unusually severe or frequent infections. A search for nonimmunologic features of specific syndromes may aid in the diagnosis of specific syndromes.

DGS can be recognized by facial features and cardiac anomalies at birth. WAS can be diagnosed at birth by the small size of platelets, although the platelet count is within reference range. Clinical manifestations of bleeding and eczema appear within the first weeks to months before infections begin. Clinical phenotypes of WAS widely vary depending on mutations of WAS gene, and a mild form of WAS can present as a chronic thrombocytopenia without features of T-cell immunodeficiency. AT is another T-cell disorder in which noninfectious signs (hypotonia and ataxia) often predate infection. CHS, a global error in intracellular protein transport, is associated with oculocutaneous albinism prior to the onset of recurrent cervical lymphadenopathy and the development of the accelerated phase with bleeding.

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