Clonal predominance of CD8(+) T cells in patients with unexplained neutropenia.
OBJECTIVE
T-cell-mediated autoimmunity may be involved in some cases of idiopathic neutropenia. We hypothesized that a precise T-cell receptor repertoire analysis may uncover cytotoxic T-cell (CTL) expansions that are less pronounced than those seen in T large granular lymphocyte leukemia (T-LGL), but are pathophysiologically analogous and thus can serve as markers of a T-cell-mediated process.


METHODS
Using rational algorithms for T-cell receptor analysis and in vivo tracking of CTL responses previously established in our laboratory, we studied patients with unexplained chronic neutropenia (n = 20), T-LGL (n = 15), and healthy controls (n = 12). We further investigated the involvement of soluble inhibitory factors by coculture assays. To determine the level of immune activation, we studied interferon-gamma expression in CD8(+)cells using Taqman polymerase chain reaction.


RESULTS
Fifteen expanded (immunodominant) CTL clones were detected in 12 of 20 patients. In comparison to LGL leukemia, these clones were less immunodominant, but clearly discernible from subclinical lymphoproliferations in controls. As a surrogate of cytotoxic activity, we found markedly increased production of interferon-gamma in most of the neutropenia patients, irrespective of the presence of immunodominant CTL clones.


CONCLUSIONS
These results suggest that, while immunodominant CTL clones are detectable in a proportion of patients only, CTL-mediated pathophysiology may be a general mechanism operating in idiopathic neutropenia. Oligogoclonal CTL expansions in chronic neutropenia may indicate an ongoing autoimmune process, while highly polarized monoclonalities in a subset of neutropenic LGL patients may represent the "extreme" end of the clonal continuum.
Wlodarski
Marcin Wojciech
MW
Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center of the Cleveland Clinic, Cleveland, OH 44195, USA.
Nearman
Zachary
Z
Jiang
Ying
Y
Lichtin
Alan
A
Maciejewski
Jaroslaw Pawel
JP
D000328:Adult; D000368:Aged; D000465:Algorithms; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002908:Chronic Disease; D002999:Clone Cells / Q000276:immunology / Q000473:pathology; D015331:Cohort Studies; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D054066:Leukemia, Large Granular Lymphocytic / Q000175:diagnosis / Q000276:immunology*; D008875:Middle Aged; D009503:Neutropenia / Q000276:immunology* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma