Clonal predominance of CD8+ T cells in patients with unexplained neutropenia

Abstract

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. Materials and Methods-Using rational algorithms for T-cell receptor analysis and in vivotracking 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-g 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-γ 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.Drugs, hereditary factors, infections, and intrinsic bone marrow diseases explain the etiology of most neutropenias. The inability to detect an immune-mediated process or other obvious cause often leads to diagnosis of chronic idiopathic neutropenia (CIN) [1][2][3][4][5][6]. Similarly, secondary autoimmune neutropenia (AIN), usually associated with collagen vascular diseases, lymphoproliferative disorders and viruses, is typically diagnosed by exclusion and thus relies on the quality of clinical and laboratory workups [6][7][8][9]. Lineage-restricted cytopenias, including neutropenia, have been associated with T-cell large granular lymphocyte leukemia It is likely that patients with AIN/CIN may belong to a heterogeneous group of diseases combining various autoimmune etiologies. Appearance of the bone marrow may reveal some clues as to the cellular targets of the autoimmune process; left shift could indicate that more mature cells are targets, while pure white cell aplasia suggests that very early myeloid precursors are affected. The similar target spectrum in AIN/CIN and T-LGL suggests that cytotoxic T-cell (CTL)-mediated autoimmunity can also operate in AIN/CIN. Consequently, detection of highly polarized CTL expansions in some cases of neutropenia patients may be consistent wi...

Severe chronic primary neutropenia in adults: report on a series of 108 patients

“…Wlodarski et al previously noted this overlap in the first report of the association between CPN and CD8 clonal T-cell expansions. 8 In our study, the specificity of the neutrophil antibody was identified in only 10 patients (43.5%). Detection of granulocyte-specific antibodies is highly variable and depends on studies, contexts, and methods.…”

“…8 To better understand their clinical impact, we compared these subgroups of patients with others CPN patients of our cohort. Only 6 of the 47 patients who were tested had a T-cell clone.…”

“…4,5,7,8,14,16 Moreover, primary and secondary neutropenia were often pooled in small and mostly unicentric studies. We report here the clinical, biological, and long-term outcome of the largest severe CPN cohort in adults followed for a median of 8.3 years.…”

“…1 Severe chronic primary neutropenia (CPN) in adults includes true idiopathic neutropenia (CIN), primary autoimmune neutropenia defined by the presence of neutrophil autoantibodies, and CPN associated with a T-cell clone (excluding large granular lymphocyte leukemia). [2][3][4][5][6][7][8][9][10] So far, there is no evidence based on clinical characteristics and outcome to consider these entities as different.…”

Advances in diagnosis and treatment of large granular lymphocyte syndrome

“…Differentiation between leukemia and chronic LGL oligo/monoclonal lymphocytosis is sometimes impossible due to similar clinicopathological features [39]. It has been shown that neutropenia may occur in the spectrum of clonal LGL proliferations from oligoclonal to leukemia [43]. Kreutzman et al [44] showed that elevated counts of mono/oligoclonal LGLs frequently occur in chronic myeloid leukemia (CML) patients at the time of diagnosis and during imatinib therapy.…”