In most patients with CLL T cell numbers are increased. This increase mainly affects CD8+ cells, but CD4+ cells are also increased, though the CD4/CD8 ratio is reversed [16]. Analysis of the expanded CD8+ cell population demonstrates that they are also positive for CD45RA and CD57, and negative for CD27 [16, 17] indicating that they have a cytotoxic function. Moreover, both CD4+ and CD8+ T cells appear to have restricted clonality when examined for T-cell receptor V gene usage and length of the CDR3 [16, 18-21], and display an activated phenotype with upregulation of CD69, VD16, CD56, CD71 and HLA-DR with loss of CD62L and CD28 [22]. These finding was originally interpreted as evidence that there is an autologous T-cell response against the tumour [23], but convincing evidence of such a response is still lacking [17, 22].
A T cell lymphocytosis with a similar marker profile is seen during viral infections, and in patients latently infected with CMV, increased senescence of the immune system with age is associated not with a falling away of CMV-reactive T cells, but with a marked increase of such cells, which tend to be oligoclonal and have the same immunophenotype as those seen in CLL [24, 25]. In elderly individuals CMV-specific cytotoxic T cells may comprise more than half the CD8+ repertoire [25] and the figure is similar in CLL [17]. Indeed in patients with CLL who are seronegative for CMV there is no increase in T cell numbers and the CD4/CD8 ration is not reversed [17].
There are other changes in T cell function, many of which will be explored with the discussion of interactions between the CLL cells and the host T cells, but it seems clear that many of the changes observed in the T cells population in CLL are a consequence of the immune system having to ‘work harder’ to control latent herpes virus infections, especially CMV.
It has not escaped the notice of investigators that the anti-CMV response might be harnessed and redirected to attack the CLL itself [26].
Apart from viruses, some patients are susceptible to other opportunistic infections in the same way as other haematological patients treated with cytotoxic drugs. Infections with Listeria, Nocardia, Candida, Aspergillus, Pneumocystis, Histoplasmosis, Cryptococcus and atypical mycobacteria, seldom occur in untreated patients and in my estimation represent a failure of effector function in the immune system. Neutropenia may be a consequence of any cytotoxic therapy, though it is usually short-lived. Autoimmune neutropenia is exceedingly rare [27], but patients with stage C disease frequently have severe and prolonged neutropenia to accompany their anaemia and thrombocytopenia. Because the often very high lymphocyte counts in such patients interfere with automatic differential counting, the neutropenia is often not observed. Prolonged neutropenia also occurs sometimes after treatment with fludarabine based regimens. The reason for this is not clear, although unexpected cases of secondary myelodysplastic syndrome following treatment with purine analogue and alkylating agent combinations are being reported [28, 29].
Early papers identified defects in phagocytic function and cytotoxic activity of neutrophils, monocytes and NK cells [30, 31]. Although early authors were seeking to establish a common lineage between the CLL cells and other blood elements, just as exists for chronic myeloid leukaemia, the fact that features like deficient levels of -glucuronidase, myeloperoxidase and lysozyme in neutrophils and monocytes were corrected after treatment removed most of the CLL cells [30] from the circulation strongly suggests that the tumour cells affect effector cell function either by their secretions or cellular contact. NK cells function is similarly restored by removal of the CLL cells [32] and indeed it has been shown that treatment with fludarabine spares NK cells and may actually enhance their activity [33]. More recent papers have identified defects in the production of pro-inflammatory cytokines by CLL monocytes [34] and of chemotaxis, but not phagocytosis or intracellular killing in CLL granulocytes [35].
Early studies suggested that deficiency of the complement components C1 and C4 was a regular occurrence in CLL [36]. Although this has not always been confirmed [37] there is undoubtedly an abnormality of complement function in many patients, resulting in an inability to coat bacteria with C3b, and perhaps most frequently involving the alternative pathway {37, 38].
References
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17. Mackus WJ, Frakking FN, Grummels A, Gamadia LE, De Bree GJ, Hamann D, Van Lier RA, Van Oers MH. Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia. Blood. 2003;102:1057-63.
18. Goolsby CL, Kuchnio M, Finn WG, Peterson L. Expansions of clonal and oligoclonal T cells in B-cell chronic lymphocytic leukemia are primarily restricted to the CD3(+)CD8(+) T-cell population. Cytometry. 2000;42:188-95.
19. Farace F, Orlanducci F, Dietrich PY, Gaudin C, Angevin E, Courtier MH, Bayle C, Hercend T, Triebel F. T cell repertoire in patients with B chronic lymphocytic leukemia. Evidence for multiple in vivo T cell clonal expansions. J Immunol. 1994;153:4281-90.
20. Rezvany MR, Jeddi-Tehrani M, Osterborg A, Kimby E, Wigzell H, Mellstedt H. Oligoclonal TCRBV gene usage in B-cell chronic lymphocytic leukemia: major perturbations are preferentially seen within the CD4 T-cell subset. Blood. 1999;94:1063-9.
21. Wen T, Mellstedt H, Jondal M. Presence of clonal T cell populations in chronic B lymphocytic leukemia and smoldering myeloma. J Exp Med. 1990;171:659-66.
22. Van den Hove LE, Vandenberghe P, Van Gool SW, Ceuppens JL, Demuynck H, Verhoef GE, Boogaerts MA. Peripheral blood lymphocyte subset shifts in patients with untreated hematological tumors: evidence for systemic activation of the T cell compartment. Leuk Res. 1998;22:175-84.
23. Rezvany MR, Jeddi-Tehrani M, Rabbani H, Rudén U, Hammarström L, Osterborg A, Wigzell H, Mellstedt H. Autologous T lymphocytes recognize the tumour-derived immunoglobulin VH-CDR3 region in patients with B-cell chronic lymphocytic leukaemia. Br J Haematol. 2000;111:230-8.
24. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 2002;169:1984-1992.
25. Pourgheysari B, Khan N, Best D, Bruton R, Nayak L, Moss PA. The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire. J Virol. 2007;81:7759-65.
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What is the normal CD4/CD8 Ratio.
ReplyDeleteI had slowly rising ALC & WBC until # years ago when I had a case of the shingles I was given an anti viral to deal with the shingles. It also cleared up some warts i had been getting. Since that time my ALC has stopped increasing and stayed around 20K. My WBC has stayed around the low 20Ks. I've always wondered if this had something to do with the anti-viral controling the warts.
ReplyDeleteJohn Liston
The CD4/CD8 ration is nomally at least 2:1 and often higher. aciclovir should not benefit the warts virus, but it is a strange virus that remits for no very good reason.
ReplyDeleteThis is an interesting area of research. Personally, I know very little about T lymphocytes other than the basics, because most of the treatments I've researched have been directed at the CLL B lymphocytes themselves.
ReplyDeleteIt is indeed a provocative notion that T cells are also dysregulated.
I've not encountered the interesting finding that a 'similar marker profile' to CLL has been found in T cells in CMV.
I would conclude that perhaps CMV may be one of the antigens that may explain the minimally-diverse nature of CLL clones (only a limited variety of clones are found in CLL).
Unfortunately, we cannot conclude that CLL forms only in CMV experienced patients, though the T cell ratio 'flip' doesn't occur.
1. Do CMV-negative patients have a different disease course than CMV-experienced CLL patients?
2. Would clearing the body of CMV affect the natural history of CLL?
3. Is the complement disarrangement in CLL correctable with frozen complement, which has already been used in treating patients with rituximab?
The idea that CLL has a limited repertoire of CDR3s is specious. The stereotypic CDR3s comprise about 20% of CLLs, but if you think of CLL as a malignant outgrowth of dividing lymphocytes, you would almost expect to find this as dividing lymphocytes are those responding to infection. Most infections are with common becteria such as pneumococcus, E.coli, streptococcus, staphylococcus etc so you would expect there to be a fairly restructed set of antibody responses. The idea that these cross react with DNA, LPS and other similar antigens is also misleading since IgM antibodies are notoriously sticky and bind fairly non specifiaccly to theses sorts of molecules.
ReplyDeleteThe increase in T cells directed against CMV is simply a matter of teh immune system failing so that more B cells are infected with it and these require more T cells to control them.
About 85-90% of people carry CMV.