Regulation of apoptosis in germinal centre B cells

Abstract

We enjoyed reading the com- prehensive review on 'Pharma- cological inhibition of programmed lymphocyte death' by Kroemer and Martinez-A. in Immunology Today 1. Unfortunately, their coverage of apoptosis and rescue in germinal centre (GC) B-cell populations con- tained a few inaccuracies, which we would like to address: (1) anti-IgM does not drive programmed cell death (PCD) in GC cells, rather PCD is the inevitable fate of this population unless they receive a survival (rescue) signal 2. (2) We are cited as detailing the actions of antibodies to CD45 on rescue of GC cells 3, although neither we, nor to our knowledge others, have re- ported this. (3) Another paper is incorrectly quoted as describing a difference between anti-Ig and other rescue signals, in that the former failed to induce the expression of cytoplasmic Bcl-2 in GC cells; indeed, engagement of antigen receptors leads to high-level ex- pression of this survival protein in the GC-cell population 4. The major Igs expressed by freshly isolated GC cells from hu- man tonsils are IgG and IgA, and each can act as a conduit for sig- nals leading to the temporary sup- pression of apoptosis 2,s. We have recently shown that engagement of receptor of either class on GC B cells is accompanied by a sequence of in- tracellular signal transduction events similar to those observed in resting B cells following ligation of sur- face IgM. These events include: the rapid activation of protein tyrosine kinases (PTKs), the stimulation of inositol lipid hydrolysis leading to the generation of inositol (1,4,5)- trisphosphate [Ins(1,4,5)P3] , and the subsequent release of Ca 2÷ from intracellular ion stores s. The ligation of CD40 provides a more sustained rescue s~gnal than is achieved through antigen receptor, and this is also coupled to PTK in the GC-cell population, but does not engage the phosphoinositide pathway. Thus, inhibitors of PTK activity completely abolish CD40- dependent expression of Bcl-2, as well as the resultant protection from PCD (Ref. 6). In resting B cells, CD40 appears not to couple to extensive PTK activation, but is instead linked to the stimulation of serine/threonine kinases 7. This di- chotomy in signalling pathways could allow for selective targeting of CD40 function in B cells at the GC stage of differentiation. Given the potential role for CD40 in the maintenance of B-cell tumours 8,9, and perhaps also in the develop- ment of autoimmunity 1°, detailed study of the pharmacological in- hibitors of the survival pathway it engenders is clearly warranted. Kirstine A. Knox Dept of Biochemistry, University of Oxford, Oxford, UK OX1 3QW. John Gordon Dept of Immunology, The Medical School, Birmingham, UK B15 2TZ. References 1 Kroemer, G. and Martfnez-A., C. (1994) Immunol. Today 15, 235-242 2 Liu, Y-J., Joshua, D.E., Williams, G.T., Smith, C.A., Gordon, J. and MacLennan, I.C.M. (1989) Nature 342, 929-931 3 Holder, M.J., Knox, K.A. and Gordon, J. (1992) Eur. J. lmmunol. 22, 2725-2728 4 Liu, Y.J., Mason, D.Y., Johnson, G.D. et al. (1991)Eur. J. lmmunol. 21, 1905-1910 5 Knox, K.A. and Gordon, J. (1994) Cell. Immunol. 155, 62-76 6 Knox, K.A. and Gordon, J. (1993) Eur. J. Immunol. 23, 2578-2584 7 Uckun, EM., Schieven, G.L., Dibirdik, I., Chandan-Langlie, M., Tuel-Ahlgren, L. and Ledbetter, J.A. (1991) J. Biol. Chem. 266, 17478-17485 8 Holder, M.J., Wang, H., Milner, A.E. et al. (1993) Eur. J. Imrnunol. 23, 2368-2371 9 Heath, A.W., Chang, R., Harada, N. et al. (1993) Cell. Immunol. 152, 468-480 10 Gordon, J. (1993) Forum Trends Exp. Clin. Med. 3-4, 334-343