T-Cell Disorders Workup

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD   more...
 
Updated: May 16, 2011
 

Laboratory Studies

Partial T-cell disorders are usually difficult to identify using routine screening tests. The absolute lymphocyte count determined by the CBC count is often within reference ranges, although lymphopenia should be sought. In Chediak-Higashi syndrome (CHS), the presence of giant granules in lymphocytic and phagocytic cells confirms a definitive diagnosis by morphologic analysis. Wiskott-Aldrich syndrome (WAS) is characterized by small platelets and variable but often decreased platelet numbers.

In vivo lymphocyte function is assessed by delayed hypersensitivity skin test responses using tetanus and candidal antigens. Anergy is characteristic in patients with ataxia telangiectasia (AT), WAS, and CHS. Patients with chronic mucocutaneous candidiasis have normal responses except for anergy to candidal antigens.

Flow cytometric assessment of T-cell and B-cell populations is essential to categorize partial T-cell disorders. The markers are expanded to include TCRa/b and TCRg/d, CD45RA (ie, "naïve" T cells), CD45RO (ie, "educated" T cells), and activation markers. See Severe Combined Immunodeficiency (SCID) for a table of the lymphocyte profile characteristics for various T-cell disorders.

Patients with AT have decreased numbers of CD4+ T cells, resulting in a decreased CD4/CD8 ratio, whereas patients with WAS have an elevated ratio caused by decreased numbers of CD8 T cells. Patients with AT and CHS have an increased proportion of TCRg/d cells.

Patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome may initially present with strikingly increased levels of T-activation markers. T-cell activation may be detected in CD95/Fas and Fas ligand deficiencies. An elevated population of double-negative CD4-/CD8- T cells that express TCRa/b also characterize these mutations. They often lack intracellular expression of Foxp3.

Assessment of CD3 complex defects is particularly subtle: CD3 expression is present in a normal proportion of T cells, but the intensity (ie, mean fluorescence intensity) is decreased, and TCRa/b expression is low.

In vitro lymphocyte proliferative responses require stimulation with allogeneic lymphocytes, nonspecific mitogens including phytohemagglutinin antigen (PHA), concanavalin A (conA), pokeweed mitogen (PWM), and specific antigens including tetanus and candidal antigens. Partial T-cell defects are most likely to have decreased responses to specific antigens and variable responses to nonspecific mitogens. Mutated CD3 complex lacks lymphoproliferative responses to anti-CD3.

Humoral immunity typically shows nonspecific abnormalities in immunoglobulin class and immunoglobulin G (IgG) subclass levels with relatively preserved antibody function. Classic WAS is accompanied by low immunoglobulin M (IgM) levels, absent isohemagglutinin IgM against the A and B blood group polysaccharides, and poor IgG responses to bacterial polysaccharide antigens.

AT manifests with low-to-absent immunoglobulin A (IgA) levels in 70% of patients, low levels of IgG2 and IgG4, and diminished antibodies to antipolysaccharide antigens.

Low antipolysaccharide antibody responses also occur in patients with immune dysregulation/autoimmunity syndromes (eg, mutations in the genes of CD3, Foxp3, and FASL).

AT is usually diagnosed easily by detecting elevated a-fetoprotein levels in serum. However, patients with other chromosomal breakage syndromes (CBSs), such as NBS and Bloom syndrome, do not demonstrate increased a-fetoprotein levels. These 3 CBSs with immune deficiency (AT, Nijmegen breakage syndrome [NBS], Bloom syndrome) can be diagnosed by assessing spontaneous or induced chromosomal breakage in vitro.

Detection of infectious agents by culture and hematoxylin and eosin (H & E) staining of biopsy material is usually required. Polymerase chain reaction (PCR) techniques for viral detection have become an evaluation mainstay and are performed on body fluids and tissues.

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Imaging Studies

Cardiac studies, including echocardiography and catheterization, are appropriate in most patients with DiGeorge syndrome (DGS).

Chest radiography is useful only to confirm the absence of thymic tissue, although the thymus may be involuted in an immunologically healthy host undergoing severe stress or the thymus may be malpositioned in a patient with DGS.

The atrophy in CHS is diffuse in both the brain and the spinal cord in contrast to AT where the cerebellar area is specifically affected.

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Other Tests

Mutational analysis is available in specific laboratories for many T-cell deficiency syndromes. These tests must be made available to families to assess carrier status and to perform prenatal diagnosis.

In the past, subtle T-cell dysfunction has been confirmed by delayed rejection of skin grafts in disorders such as AT.

Research studies of autoimmune phenomenon in partial T-cell defects have shown failure to delete T cells that recognize self-antigens. Fas and Fas ligand defects caused by mutations are the prototypic T-cell disorders of this type.

Analysis of additional T-cell functions, such as cytotoxicity in patients with CHS, is only available from specific research laboratories. Such tests are rarely needed to establish the diagnosis.

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Procedures

As in complete T-cell defects, obtaining appropriate culture material to identify infectious agents is critical. The most common procedures are bronchoscopy, culture of the sinuses, and biopsies performed in lymph nodes and the liver.

Biopsies of lymphoid tissue are necessary to distinguish lymphoproliferative states from malignancy.

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Histologic Findings

The thymus has been studied histologically in patients with DGS and AT. In patients with DGS, the thymus has a wide spectrum of morphology, ranging from apparently intact thymic size and structure to disruption of the medulla and absent Hassall corpuscles to complete thymic absence. Patients with AT have a small thymus, are markedly deficient in thymocytes and Hassall corpuscles, and have poor corticomedullary demarcation. CD3 complex deficiencies show thymic defects similar to those in AT. Histologic analysis has not been available for many partial T-cell disorders until chronic disease and corticosteroid therapy have altered the histologic findings.

Lymphoid hyperplasia is present in Fas and Fas ligand deficiencies and in other immune dysregulation/autoimmunity syndromes. In situ T-cell markers may show excessive CD4+ T cells, a high proportion of CD4-/CD8- T cells, or an imbalance of TCR α/β and TCR γ/δ T cells. The histologic appearance may resemble immunoblastic lymphoma.

The accelerated phase of CHS may be confused with lymphoma or erythrophagocytic lymphohistiocytosis.

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Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Robert Y Lin, MD  Professor, Department of Medicine, New York Medical College; Chief, Allergy and Immunology, and Director of Utilization Review, Department Medicine, New York Downtown Hospital

Robert Y Lin, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology and American Federation for Medical Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Terry W Chin, MD, PhD  Associate Director, Pediatric Allergy/Immunology/Pulmonology, Miller Children's Hospital, Long Beach Memorial Medical Center; Associate Professor, Department of Pediatrics, University of California, Irvine, School of Medicine

Terry W Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David J Valacer, MD  Consulting Staff, Hoffman La Roche Pharmaceuticals

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

David Pallares, MD  Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville

David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD  Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

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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.
Malformation of the pinna
Giant lysosomes.
Table. Immune Globulin, Intravenous[16, 17, 18, 19]
Brand(Manufacturer)Manufacturing ProcesspHAdditives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].) Parenteral Form and Final ConcentrationsIgA Content mcg/mL
Carimune NF



(CSL Behring)



Kistler-Nitschmann fractionation; pH 4 nanofiltration6.4-6.86% solution: 10% sucrose, < 20 mg NaCl/g proteinLyophilized powder 3%, 6%, 9%, 12%720
Flebogamma



(Grifols USA)



Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization5.1-6Sucrose free, contains 5% D-sorbitolLiquid 5%< 50
Gammagard Liquid 10%



(Baxter Bioscience)



Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation 4.6-5.10.25M glycineReady-for-use liquid 10%37
Gamunex



(Talecris Biotherapeutics)



Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation4-4.5Does not contain carbohydrate stabilizers (eg, sucrose, maltose), contains glycineLiquid 10%46
Iveegam EN



(Baxter Bioscience)



Cohn-Oncley fraction II/III; ultrafiltration; pasteurization6.4-7.25% solution: 5% glucose, 0.3% NaClLyophilized powder 5%< 10
Polygam S/D



Gammagard S/D



(Baxter Bioscience for the American Red Cross)



Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated 6.4-7.25% solution: 0.3% albumin, 2.25% glycine, 2% glucoseLyophilized powder 5%, 10%< 1.6 (5% solution)
Octagam



(Octapharma USA)



9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events



Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization5.1-610% maltoseLiquid 5%200
Panglobulin



(Swiss Red Cross for the American Red Cross)



Kistler-Nitschmann fractionation; pH 4 incubation; trace pepsin; nanofiltration6.6Per gram of IgG: 1.67 g sucrose, < 20 mg NaClLyophilized powder 3%, 6%, 9%, 12%720
Privigen Liquid 10%



(CSL Behring)



Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration4.6-5L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)Ready-for use liquid 10%< 25
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