| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Gupta, Rashmi Nieto, Jennifer Stein, Joanna Stankovic, Tatjana Mongini, Patricia K. A. Allen, Steven L. Chiorazzi, Nicholas Rai, Kanti Kolitz, Jonathan E. Lee, Hyunjoo Bandovic, Jela Barrientos, Jacqueline Boyle, Erin Chu, Charles C. |
| Description |
Author Affiliation: Mongini PK ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Gupta R ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Boyle E ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Nieto J ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Lee H ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Stein J ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Bandovic J ( Department of Pathology, North Shore University Hospital-Long Island Jewish Medical Center, Manhasset, NY 11030); Stankovic T ( School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom); Barrientos J ( Department of Medicine, North Shore University Hospital-Long Island Jewish Medical Center, Manhasset, NY); Kolitz JE ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Allen SL ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Rai K ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Chu CC ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030); Chiorazzi N ( The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030) |
| Abstract |
Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) reflects the clone's Ag receptor (BCR) and involves stroma-dependent B-CLL growth within lymphoid tissue. Uniformly elevated expression of TLR-9, occasional MYD88 mutations, and BCR specificity for DNA or Ags physically linked to DNA together suggest that TLR-9 signaling is important in driving B-CLL growth in patients. Nevertheless, reports of apoptosis after B-CLL exposure to CpG oligodeoxynucleotide (ODN) raised questions about a central role for TLR-9. Because normal memory B cells proliferate vigorously to ODN+IL-15, a cytokine found in stromal cells of bone marrow, lymph nodes, and spleen, we examined whether this was true for B-CLL cells. Through a CFSE-based assay for quantitatively monitoring in vitro clonal proliferation/survival, we show that IL-15 precludes TLR-9-induced apoptosis and permits significant B-CLL clonal expansion regardless of the clone's BCR mutation status. A robust response to ODN+IL-15 was positively linked to presence of chromosomal anomalies (trisomy-12 or ataxia telangiectasia mutated anomaly + del13q14) and negatively linked to a very high proportion of CD38(+) cells within the blood-derived B-CLL population. Furthermore, a clone's intrinsic potential for in vitro growth correlated directly with doubling time in blood, in the case of B-CLL with Ig H chain V region-unmutated BCR and <30% CD38(+) cells in blood. Finally, in vitro high-proliferator status was statistically linked to diminished patient survival. These findings, together with immunohistochemical evidence of apoptotic cells and IL-15-producing cells proximal to B-CLL pseudofollicles in patient spleens, suggest that collaborative ODN and IL-15 signaling may promote in vivo B-CLL growth. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| DOI |
10.4049/jimmunol.1403189 |
| Journal |
The Journal of Immunology |
| Issue Number |
3 |
| Volume Number |
195 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2015-08-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Interleukin-15 Immunology Leukemia, Lymphocytic, Chronic, B-cell Oligodeoxyribonucleotides Pharmacology Toll-like Receptor 9 Antigens, Cd38 Metabolism Apoptosis Ataxia Telangiectasia Mutated Proteins Genetics B-lymphocytes Cell Proliferation Cells, Cultured Chromosome Aberrations Immunoglobulin Heavy Chains Mortality Membrane Glycoproteins Myeloid Differentiation Factor 88 Receptors, Antigen, B-cell Signal Transduction Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
