T-Cell Deficiency Disorders, Inherited

Diagnostic Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

  Human Immunodeficiency Virus in Infants Testing Algorithm

Clinical Background

Cell-mediated immunity is mediated by T-lymphocytes (T-cells) and their effector response and interactions with other immune cells. Several inherited T-cell disorders have been identified.

T-cell immunodeficiency diseases include

• Ataxia telangiectasia
• Chronic mucocutaneous candidiasis
• DiGeorge syndrome
• Severe combined immunodeficiencies (SCID)
• Wiskott-Aldrich syndrome (WAS)
• Adenosine deaminase deficiency
• Purine nucleoside phosphorylase deficiency

Epidemiology

• Incidence – rare disorders <1/1,000,000
• Age – most common during neonatal period and infancy
  •  Adult onset rare
• Sex – M:F, equal, except X-linked diseases
  • M>F, for X-linked SCID and WAS

Inheritance

• Autosomal recessive for all diseases except X-linked SCID and WAS

Pathophysiology

• Defective lymphocyte responses may occur to stimulants
  • Nonspecific mitogens (PHA, Con A and PWM)
  • Specific antigens, such as Candida or tetanus
• Characterized by increased susceptibility to infections from opportunistic organisms
  • Cytomegalovirus (CMV)
  • Candida albicans
  • Pneumocystis carinii

Clinical Presentation

• SCID
  • Early onset of severe infections (intracellular bacterial, viral, fungal, Pneumocystis)
  • Growth failure
  • Persistent diarrhea
  • Occurrence of graft-versus-host disease upon exposure to maternal lymphocytes or blood transfusions
  • Earliest onset in X-linked SCID, adenosine deaminase (ADA) deficiency, purine nucleoside phosphorylase deficiency (PNP), ZAP70 defects, and T- and B-cell variants

    T- and B-cell Variants of SCID
    Variant	T-cell	B-cell	NK-cell	Comment
    IL2RG	–	+	–
    JAK3	–	+	–
    IL7R2	–	+	+	T-cell growth IL7
    ADA	–	–	–	Adenosine is toxic to all cells; depresses all cells
    PNP	–	+	–
    RAG1 and RAG2	–	–	+	Recombinant of T- and B-cell receptors
    ARTEMIS	–	–	+	Recombinant of T- and B-cell receptors
    CD3D or CD3E	–	+	+	T-cell receptors only
    CD45	–	+	+	T-cell receptors only
    ZAP70	CD4 (-) CD8 (+) Lymphocytes	–	+

• DiGeorge syndrome
  • Recurrent infections – fungal, viral, bacterial, Pneumocystis
  • Congenital heart disease
  • Hypocalcemic tetany
  • Abnormal facies
  • Palatal abnormalities
  • Thymic hypoplasia
• WAS
  • Recurrent infections – viral, pneumococcal
  • Eczema
  • Associated autoimmune disease common
• Ataxia telangiectasia
  • Recurrent infections – sinopulmonary are most common
  • Progressive cerebellar dysfunction
  • Oculocutaneous telangiectasia
• Chronic mucocutaneous candidiasis
  • Persistent or recurrent Candida infections of the skin, nails and mucous membranes
  • Often have an associated autoimmune disease
  • May be associated with multiple endocrinopathies

Treatment

• Patients with severe T-cell defects, such as SCID, may be appropriate candidates for bone marrow or stem cell transplants and possibly gene therapy
• Evaluation in the first 2-3 months of life treatment may decrease morbidity and mortality

Diagnosis

• Indications for testing – recurrent infections, particularly with opportunistic organisms
• Laboratory testing
  • Initial testing
    • HIV testing – PCR qualitative or quantitative for infants ≤15 months
    • CBC with differential – profound thrombocytopenia with small, non-functioning platelets suggests WAS
    • Total absolute lymphocyte count
    • Immunoglobulin quantitative – if low, proceed with B-cell immunodeficiency testing
    • Sweat chloride – if positive, proceed with cystic fibrosis genetic testing
  • Cell-mediated immune screen – lymphocyte mitogen stimulated ATP production (LMPS); rapid overnight test
  • Lymphocyte subset – if low, proceed with lymphocyte antigen and mitogen test
  • Lymphocyte antigen and mitogen proliferation test
    • Measures tritiated thymidine (³H-TdR) uptake by lymphocytes in response to stimulus (requires 5-7 days)
    • Low with low T-cells confirms T-cell disorder
  • Lymphocyte antigen and mitogen stimulation with cytokines
  • Further specific genetic testing based on the results of the above testing

Differential Diagnosis

• HIV
• Immunoglobulin disorders
• Complement deficiencies
• Chronic granulomatous disease (CGD)
• Neutrophil disorders

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, Monokines 0051587 Method: Cell Culture/Multi-Analyte Fluorescence Detection
Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, TH2 Cytokines 0051586 Method: Cell Culture/Multi-Analyte Fluorescence Detection
Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, TH1 Cytokines 0051585 Method: Cell Culture/Multi-Analyte Fluorescence Detection

General References

References from the ARUP Institute for Clinical and Experimental Pathology®