eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

T-Cell Disorders

Author: Richard H Huggins, MD, Staff Physician, Department of Internal Medicine, State University of New York, Buffalo School of Medicine
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Aug 10, 2006

Introduction

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.

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 (ataxia telangiectasia [AT]) and Wiskott-Aldrich Syndrome (WAS), which are discussed in separate articles.

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- 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 bacterial sinopulmonary infections. 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 produce self-reactive antibodies.

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 understood better. 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.

Newly discovered mutations in the gene coding for scurfin 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 2 a receptor (IL-2R a) 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.

Pathophysiology

Critical components of T-cell antigen recognition include the CD3 complex, CD4, CD8, and the T-cell receptor heterodimers TCR a/b and TCR g/d. These molecules act in a coordinated manner to regulate intracellular pathways, which then induce or inhibit the specific immune response.

Antigen recognition through CD4 depends on antigen presentation by major histocompatibility complex (MHC) class II, while 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, functioning to regulate T-cell activation and, possibly, T-cell number. 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.

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 10,000 live births, but many of these children have minimal immune dysfunction that improves with age.

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 upon 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 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

A number of genes regulating immune function are located on the X chromosome. The gene defect in X-linked SCID (mutations in the common g chain for interleukin [IL]–2, IL-4, IL-7, IL-9, and IL-15) 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 for X-linked polyendocrinopathy and enteropathy is nearby, between bands Xp11.23 and Xq13.3.

T-cell disorders with autosomal genes include DGS at band 22q11, AT at band 11q22, and CHS at bands 1q42-43. The gene for CD3 complex is localized to chromosome band 11q23. The AIRE gene for APECED is on band 21q22.3. The gene for CD95/Fas is at band 10q23.

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 ranges. Clinical manifestations of bleeding and eczema appear within the first weeks to months before infections begin.
• AT is another T-cell disorder in which noninfectious signs (hypotonia and ataxia) often antedate infection.
• CHS, a global error in packaging of lysosomal enzymes, is associated with oculocutaneous albinism prior to the onset of recurrent cervical lymphadenopathy and the development of the accelerated phase with bleeding.

Clinical

History

Unusually severe common viral infections (eg, respiratory syncytial virus [RSV], enterovirus, rotavirus), mucocutaneous candidiasis, diarrhea, and eczematous or erythrodermatous rashes should prompt suspicion of a T-cell disorder. Failure to thrive and cachexia are late signs of a T-cell defect. Opportunistic infection develops more commonly in an infant who has become wasted, although it may be the presenting illness.

• Late diagnosis of a partial T-cell defect may occur in patients with DGS when the facial anomalies are subtle and cardiac lesions are absent. These individuals have recurrent respiratory infections consisting of sinusitis and viral infections. In addition, patients have more extensive mucocutaneous candidiasis than anticipated in a healthy host taking antibiotics.
• In patients with AT, late diagnosis is often based on the progressive loss of mobility and the appearance of telangiectasia in children aged approximately 4-5 years.
• A diagnosis of WAS may be delayed until recurrent sinopulmonary infections develop if petechiae and bloody diarrhea are minor and intermittent and if eczema is misinterpreted as common atopy. Additionally, more than 70% of patients with WAS have at least one associated autoimmune disease.
• Patients with CHS are often treated for recurrent otitis, sinusitis, and lymphadenitis caused by staphylococci and streptococci before the massive lymphadenopathy and hepatosplenomegaly of the accelerated phase make the diagnosis obvious.
• Epstein-Barr virus (EBV) infection is the predominant lethal infection in X-linked lymphoproliferative disease, and EBV infection is usually associated with development of the accelerated phase of CHS.
• The diagnosis of IDDM and diarrhea in a male infant younger than 1 year raises the possibility of IPEX syndrome. IDDM and enteropathy also are components of the autosomal recessive mutations found in patients with APECED.
• Lymphadenopathy and hepatosplenomegaly characterize mutations in the genes coding for CD3 complex and CD95/Fas.
• Patients with WAS in whom the immune system is not reconstituted using bone marrow transplantation usually die in the third decade of life from malignancies; lymphoid and CNS tumors are most common.
• Patients with AT and Nijmegen breakage syndrome (NBS) are at a higher risk for malignancies, usually lymphoid, that increases with age.
• Neurologic disorders are increasingly reported in patients with partial T-cell disorders.
  • Progressive neurologic dysfunction is well known in patients with CBSs (eg, AT, NBS) and in CHS.
  • Patients with DGS have learning and behavioral dysfunction that becomes more apparent at school age.
  • Seizure disorders frequently accompany immune dysregulation/autoimmunity syndromes such as the X-linked mutation in the gene encoding for the protein scurfin (IPEX syndrome).

Physical

The physical examination features of DGS, WAS, and AT are presented in detail in other respective articles.

• Rash often occurs in infants with a T-cell disorder, commonly as a generalized eczema or erythroderma. Urticarial rashes and cutaneous vasculitis are present in CD95/Fas and Fas ligand deficiencies. Ectodermal dystrophy characterizes APECED syndrome.
• Patients with AT have telangiectasia of the conjunctiva and pinna; these features present after the diagnosis should already have been confirmed by the presence of ataxia and infections.
• Candidiasis is a common feature of partial and complete T-cell disorders. In partial T-cell disorders (eg, DGS, WAS, APECED syndrome, IPEX syndrome) dissemination is unlikely, even when the autoimmune disease is treated with immunosuppressive agents. Disseminated invasive candidiasis suggests SCID or a phagocytic disorder.
• Patients with the classic presentation have a complete absence of T cells (ie, SCID) and lack peripheral lymphoid tissue. However, patients with partial T-cell disorders often have palpable lymph nodes.
  • Lymphadenopathy and hepatosplenomegaly may be progressive in immune dysregulation/autoimmunity syndromes, such as Fas and Fas ligand deficiencies and mutations in the gene coding for CD3 complex.
  • Lymphadenopathy suggests the possibility of lymphoma or leukemia in older patients with WAS and CBSs.
• Neurologic deterioration with hypotonia and progressive ataxia may occur before infection, raising a suspicion of immunodeficiency in patients with AT and NBS.
• Bleeding in patients with WAS is a result of decreased volume and numbers of platelets.
• In infants, the first sign of WAS is often bloody diarrhea that occurs before petechiae and epistaxis.
• In the accelerated phase, CHS is accompanied by bleeding.

Causes

Many of the exact functions of the gene products that are mutated in partial T-cell disorders have yet to be elucidated. For a more complete discussion of the genes responsible for DGS, AT, WAS, and CHS, see Pathophysiology and the specific articles for each disorder. CHS is caused by mutations in the gene encoding for the lysosomal-trafficking regulator. This mutation leads to abnormal distribution of lysosomal proteins in phagocytes (impairing bactericidal activity), in melanosomes (explaining partial albinism), and in neurologic function and to cytotoxicity by T cells and NK cells, predisposing patients to aberrant responses to EBV and leading to the accelerated phase.

• Search for CME/CE on This Topic »

• Combined B-Cell and T-Cell Disorders (Hematology)
• Hypogammaglobulinemia (Allergy and Immunology)