eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

T-Cell Disorders

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Robert Y Lin, MD, Professor, Department of Medicine, Medical Advisor, Department of Case Management/Utilization Review, New York Medical College; Chief, Allergy and Immunology Section, St Vincent's Catholic Medical Centers, St Vincent's of Manhattan
Contributor Information and Disclosures

Updated: Jul 10, 2009

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. 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.

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.

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.

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.² 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.³

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.

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 1976-2006.⁴

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 g 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).

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.

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 DiGeorge syndrome (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 ataxia telangiectasia (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 Wiskott-Aldrich syndrome (WAS) may be delayed until recurrent sinopulmonary infections develop if petechiae and bloody diarrhea are minor and intermittent and if eczema is misinterpreted as severe atopic dermatitis. Additionally, more than 70% of patients with WAS have at least one autoimmune complication.
• Patients with Chediak-Higashi syndrome (CHS) are often treated for recurrent otitis, sinusitis, and lymphadenitis caused by staphylococci and streptococci before the massive lymphadenopathy and hepatosplenomegaly make the diagnosis obvious in the accelerated phase.
• Epstein-Barr virus (EBV) infection is the predominant lethal infection in X-linked lymphoproliferative disease (XLP), and EBV infection is usually associated with development of the accelerated phase of CHS.
• The diagnosis of insulin-dependent diabetes mellitus (IDDM) and diarrhea in a male infant younger than 1 year raises the possibility of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. IDDM and enteropathy are also components of the clinical features in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (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 by hematopoietic stem cell transplantation usually die by the third-fourth 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 chromosomal breakage syndromes (CBSs), such as 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 IPEX caused by FoxP3 gene mutation . 

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 as well as caspase 10 defects. 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.
  
  

  

  This patient was diagnosed with ataxia telangiectasia (AT) when she presented at age 6 years. The family was concerned about the increased frequency of sinusitis during the past winter, and she was noted to have poor balance. Findings in her eyes had been explained as conjunctivitis since age 4 years.

  [ CLOSE WINDOW ]

  

  This patient was diagnosed with ataxia telangiectasia (AT) when she presented at age 6 years. The family was concerned about the increased frequency of sinusitis during the past winter, and she was noted to have poor balance. Findings in her eyes had been explained as conjunctivitis since age 4 years.

  
  
  

  

  A prominent site for telangiectasia in classic ataxia telangiectasia is the pinna.

  [ CLOSE WINDOW ]

  

  A prominent site for telangiectasia in classic ataxia telangiectasia is the pinna.

  
  
  

  

  Malformation of the pinna

  [ CLOSE WINDOW ]

  

  Malformation of the pinna

• 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 severe combined immunodeficiency (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 impaired platelet aggregation with smaller platelet size and numbers of platelets.
• In infants, the first sign of WAS is often bloody diarrhea that occurs before petechiae and epistaxis following introduction of solid food.
• 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 natural killer (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)