T-Cell Deficiency Disorders, Inherited

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Recurrent infections, particularly with opportunistic organisms

Laboratory Testing

  • Initial testing
    • HIV testing
      • Infants ≤15 months – PCR qualitative or quantitative
      • Adults – screen for antibodies; confirm positive results with Western blot
    • CBC with differential – profound thrombocytopenia with small, nonfunctioning platelets suggests Wiskott-Aldrich syndrome
    • Immunoglobulin (quantitative) – if low, proceed with B-cell immunodeficiency testing

    • Sweat chloride – if positive, proceed with cystic fibrosis  genetic testing
    • T-cell immunodeficiency profile testing
      • T-cell testing at minimum should include CD4, CD45RA, CD45RO, CD8, CD4:8 ratio, CD3, CD19, and NK-cell
      • If abnormal, proceed with lymphocyte antigen and mitogen test
  • Cell-mediated immune screen – lymphocyte mitogen stimulated ATP production (LMPS); rapid overnight 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

Human Immunodeficiency Virus in Infants Testing Algorithm

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Cell-mediated immunity is accomplished by T-lymphocytes (T-cells) and their effector response and interactions with other immune cells.

T-cell immunodeficiency diseases include 

  • Severe combined immunodeficiencies (SCID)
  • Wiskott-Aldrich syndrome (WAS)
  • Ataxia telangiectasia
  • DiGeorge syndrome
  • Immuno-osseous dysplasias
  • Dyskeratosis congenta
  • Chronic mucocutaneous candidiasis

Epidemiology

  • Incidence – rare (<1/1,000,000)
  • Age – most commonly discovered during neonatal period and infancy
    •  Adult onset rare
  • Sex – M:F, equal, except for 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 to stimulants may occur
    • Nonspecific mitogens (phytohemagglutinin, concanavalin A and pokeweed mitogen)
    • Specific antigens, such as Candida or tetanus
  • Characterized by increased susceptibility to infections from opportunistic organisms

Clinical Presentation

  • Ataxia telangiectasia
    • Recurrent infections – sinopulmonary are most common
    • Progressive cerebellar dysfunction
    • Oculocutaneous telangiectasia
    • Cancer risk 35-40% in affected individuals
      • Increased risk of solid tumors in older population
      • Leukemia and lymphoma in children
      • Risk ~4 times greater than general population, especially for breast cancer
  • 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
  • DiGeorge syndrome
    • Recurrent infections – fungal, viral, bacterial, Pneumocystis
    • Congenital heart disease
    • Hypocalcemic tetany (due to hypoparathyroidism)
    • Abnormal facies
    • Palatal abnormalities
    • Thymic hypoplasia
  • SCID
    • Early onset of severe infections (intracellular bacterial, viral, fungal, Pneumocystis)
    • Growth failure
    • Persistent diarrhea
    • 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
    • Refer to T- and B-cell Variants of SCID table in the SCID ARUP Consult topic
  • WAS
    • Recurrent infections – viral, pneumococcal
    • Eczema
    • Associated autoimmune disease common
    • Increased risk for malignancy
    • IgA nephropathy

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

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

Human Immunodeficiency Virus 1 (HIV-1) by Qualitative PCR 0093061
Method: Qualitative Polymerase Chain Reaction

Human Immunodeficiency Virus 1 by Quantitative PCR 0055598
Method: Quantitative Polymerase Chain Reaction

Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies by CIA with Reflex to HIV-1 Antibody Confirmation by Western Blot 2005377
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Follow Up

If results low, proceed to B-cell immunodeficiency testing

CD4+ T-Cell Recent Thymic Emigrants (RTEs) 2010179
Method: Quantitative Flow Cytometry

Lymphocyte Subset Panel 6 - Total Lymphocyte Enumeration with CD45RA and CD45RO 0095862
Method: Quantitative Flow Cytometry

Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899
Method: Quantitative Flow Cytometry

Follow Up

Severe deficiencies in T cells should initiate differential workup based on deficiency

Lymphocyte Antigen and Mitogen Proliferation Panel 0096056
Method: Cell Culture

Limitations

Bacterial or endotoxin contamination of sample profoundly affects test results

Follow Up

T-cell immunodeficiency profile (short and extended)

In addition, evaluate chronic infection based on clinical history and in conjunction with other tests

Severe Combined Immunodeficiency (SCID) Panel, Sequencing and Deletion/Duplication, 19 Genes 2010219
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations

Not determined or evaluated mutations in genes not included on the panel, deep intronic and regulatory region mutations, breakpoints for large deletions/duplications

Deletions/duplications will not be detected in exon 1 in ADA gene, exon 11 in CORO1A gene, exons 4, 6, and 8 in DCLRE1C gene, and exons 3, 6, and 9 in JAK3 gene

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of SCID

Chromosome Analysis - Breakage, Ataxia Telangiectasia, Whole Blood 2005749
Method: Giemsa Band

Limitations

Carriers are not detected by this test

Additional Tests Available

Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, 12 Cytokines (INACTIVE as of 04/04/16: Refer to February 2016 Hot Line for Replacement Test: 2013117, ACTIVE 04/04/16) 0051584
Method: Cell Culture/Multiplex Bead Assay

Comments

Test for lymphocyte cytokine responses to

  • Phytohemagglutinin
  • Concanavalin A
  • Pokeweed mitogen
  • Candida antigen
  • Tetanus antigens 

Use to evaluate chronic infections

Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, Monokines (INACTIVE as of 04/04/16) 0051587
Method: Cell Culture/Multiplex Bead Assay

Comments

Test for lymphocyte cytokine responses to interleukin 1 beta, interleukin 6, interleukin 8, and tumor necrosis factor alpha

Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, TH2 Cytokines (INACTIVE as of 04/04/16) 0051586
Method: Cell Culture/Multiplex Bead Assay

Comments

Test for lymphocyte cytokine responses to interleukin 4, 5, 10, 13

Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, TH1 Cytokines (INACTIVE as of 04/04/16) 0051585
Method: Cell Culture/Multiplex Bead Assay

Comments

Test for lymphocyte cytokine responses to interleukin 2; interleukin 2 receptor (CD25), soluble

Lymphocyte Antigen Proliferation  0096055
Method: Cell Culture

Comments

Rapid test for Candida and tetanus antigens

Use to evaluate chronic infections

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chapel H, Conley M, Cunningham-Rundles C, Etzioni A, Fischer A, Franco J, Geha R, Hammarström L, Nonoyama S, Notarangelo L, Ochs H, Puck J, Roifman C, Seger R, Tang M. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011; 2: 54. PubMed

General References

Filipovich A, Johnson J, Zhang K. WAS-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews. University of Washington, 1993-2015. Seattle, WA [Last updated Mar 2014; Accessed: Nov 2015]

Gatti R. Ataxia-Telangiectasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Mar 2010; Accessed: Nov 2015]

Hershfield M. Adenosine Deaminase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Jun 2014; Accessed: Nov 2015]

Immune Deficiency Foundation. Towson, MD [Accessed: Nov 2015]

Kirkpatrick C. Chronic mucocutaneous candidiasis. Pediatr Infect Dis J. 2001; 20(2): 197-206. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Augustine N, Pasi B, Hill H. Comparison of ATP production in whole blood and lymphocyte proliferation in response to phytohemagglutinin. J Clin Lab Anal. 2007; 21(5): 265-70. PubMed

Efimova O, Kelley T. Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway. BMC Immunol. 2009; 10: 59. PubMed

Shyur S, Hill H. Immunodeficiency in the 1990s. Pediatr Infect Dis J. 1991; 10(8): 595-611. PubMed

Shyur S, Hill H. Recent advances in the genetics of primary immunodeficiency syndromes. J Pediatr. 1996; 129(1): 8-24. PubMed

Wang S, Delgado J, Ravkov E, Eckels D, Georgelas A, Pavlov I, Cusick M, Sebastian K, Gleich G, Wagner L. Penaeus monodon tropomyosin induces CD4 T-cell proliferation in shrimp-allergic patients. Hum Immunol. 2012; 73(4): 426-31. PubMed

Medical Reviewers

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Last Update: December 2015