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Test ID: ALPS    
Alpha Beta Double-Negative T Cells for Autoimmune Lymphoproliferative Syndrome

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Useful For Suggests clinical disorders or settings where the test may be helpful

Diagnosing autoimmune lymphoproliferative syndrome, primarily in patients <45 years of age

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Autoimmune lymphoproliferative syndrome (ALPS) (also known as Canale-Smith syndrome) is a complex clinical disorder of dysregulated lymphocyte homeostasis that is characterized by lymphoproliferative disease, autoimmune cytopenias, splenomegaly, and lymphadenopathy with an increased susceptibility to malignancy.(1) Typically, ALPS is diagnosed by childhood or young adulthood.

 

Genetic defects in the apoptosis (programmed cell death) pathway have been determined for most cases of ALPS. Apoptosis plays a role in normal immune homeostasis by limiting lymphocyte accumulation and autoimmune reactivity. The interaction of the surface receptor CD95 (FAS) and its ligand (CD95L;FASL) triggers the apoptotic pathway in lymphocytes.

 

The following molecular ALPS classification has been established:

 

ALPS Classification

 

Molecular/Genetic Defect in Apoptosis

Type Ia

CD95 (FAS) mutations(1)

Type Ib

Heterozygous CD95L (FASLG) mutations(1)

Type Ic

Homozygous CD95L (FASLG) mutation(2)

Type II

CASP8 or CASP10 mutations(1,3)

Type III

Unknown(1,3)

 

Patients with ALPS have an increase in a normally rare population of T cells (typically <1%) that are alpha beta T-cell receptor (TCR)-positive, as well as negative for both CD4 and CD8 coreceptors (double-negative T cells: DNT).(1) The alpha beta TCR+DNT cells from ALPS patients also express an unusual B-cell-specific CD45R isoform, called B220.(4,5) B220 expression on alpha beta TCR+DNT cells has been demonstrated to be a sensitive and specific marker for ALPS and is associated with FAS mutations.(4)

 

Several other diseases can present with an ALPS-like phenotype, including independent conditions like Evans syndrome (a combination of autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura), Rosai-Dorfman disease (massive painless cervical lymphadenopathy that may be accompanied by leukocytosis, elevated erythrocyte sedimentation rate, and hypergammaglobulinemia), and nodular lymphocyte-predominant Hodgkin disease.(1)

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Alpha beta TCR+DNT cells

2-18 years: <2% CD3 T cells

19-70+ years: <3% CD3 T cells

Reference values have not been established for patients that are less than 24 months of age.

 

Alpha beta TCR+DNT cells

2-18 years: <35 cells/mcL

19-70+ years: <35 cells/mcL

Reference values have not been established for patients that are less than 24 months of age.

 

Alpha beta TCR+DNT B220+ cells

2-18 years: <0.4% CD3 T cells

19-70+ years: <0.3% CD3 T cells

Reference values have not been established for patients that are less than 24 months of age.

 

Alpha beta TCR+DNT B220+ cells

2-18 years: <7 cells/mcL

19-70+ years: <6 cells/mcL

Reference values have not been established for patients that are less than 24 months of age.

Interpretation Provides information to assist in interpretation of the test results

The presence of increased circulating T cells (CD3+) that are negative for CD4 and CD8 (double-negative T cells: DNT) and positive for the alpha/beta T-cell receptor (TCR) is required for the diagnosis of autoimmune lymphoproliferative syndrome (ALPS).

 

The laboratory finding of increased alpha beta TCR+DNT cells is consistent with ALPS only with the appropriate clinical picture (nonmalignant lymphadenopathy, splenomegaly, and autoimmune cytopenias). Conversely, there are other immunological disorders, including common variable immunodeficiency (CVID), which have subsets for patients with this clinical picture, but no increase in alpha beta TCR+DNT cells.

 

If the percent of the absolute count of either the alpha beta TCR+DNT cells or alpha beta TCR+DNT B220+ cells is abnormal, additional testing is indicated. All abnormal alpha beta TCR+DNT cell results should be confirmed (for ALPS) with additional testing for defective in vitro lymphocyte apoptosis, followed by confirmatory genetic testing for FAS mutations (contact Mayo Medical Laboratories for test forwarding information).

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This test is typically not indicated in older adults. For questions about appropriate test selection, contact Mayo Medical Laboratories.

 

The sole presence of increased alpha beta TCR+DNT B220+ cells is not sufficient for a diagnosis of autoimmune lymphoproliferative syndrome (ALPS); additional testing is required to confirm a diagnosis of ALPS.

Clinical Reference Provides recommendations for further in-depth reading of a clinical nature

1. Worth A, Thrasher AJ, Gaspar HB: Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Brit J Hematol 2006;133:124-140

2. Del-Rey M, Ruiz-Contreras J, Bosque A, et al: A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome. Blood 2006;108:1306-1312

3. Salmena L, Hakem R: Caspase-8 deficiency in T-cells leads to a lethal lymphinfiltrative immune disorder. J Exp Med 2005;202:727-732

4. Blessing JJH, Brown MR, Dale JK, et al: TCR alpha beta+ CD4-CD8-T-cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to urine B220 and represents a marker of altered O-glycan biosynthesis. Clin Immunol 2001;100(3):314-324

5. Bleesing JJH, Janik JE, Fleisher TA: Common expression of an unusual CD45 isoform on T-cells from patients with large granular lymphocyte leukemia and autoimmune lymphoproliferative syndrome. Brit J Hematol 2003;120:93-96