Another prominent and important factor in the suppression of lymphocyte and monocyte function and thus the occurrence of opportunistic infections is the use of corticosteroids. Early trials showed no benefit to their use with alkylating agents, and trials of their addition to purine analogues were halted because of a higher incidence of infection, but they remain the drug of choice in treating the autoimmune complications of CLL. Corticosteroids are also used almost without the knowledge of the physician directing therapy to suppress transfusion reactions and reactions to infusions of rituximab. More recently high dose steroids have found favour in the treatment of bulky and drug resistant disease.
One further piece of evidence of immunodeficiency should be mentioned. It has long been believed that second malignancies are commoner in CLL than in the general population and this has been attributed to a defect of immune surveillance. A recent review  goes into painstaking detail of all reported studies. The risk is particularly great for skin cancers and virally induced cancers but less convincing for other tumours. There are difficulties in assembling accurate statistics, since CLL frequently goes unreported or undiagnosed in old people. Patients with cancer are more likely to have blood tests than normal individuals so that asymptomatic CLL is more likely to be diagnosed. Similarly, patients with CLL are more likely to be seen by doctors than individuals without it, and other cancers, especially skin cancers are thus more likely to be diagnosed. Nevertheless, there almost certainly is an increase in some cancers which might be attributed to a defect in cell mediated immunity.
The causes of the immune defect.
The immune defect in CLL is mediated by the presence of the tumour cell in the midst of the lymphoid organs and by the attempts of the physician to remove them. In the normal immune response T-cell activation is involves interactions with antigen presenting cells (APCs) – dendritic cells and B-cells. T-cells encounter antigen as APC-processed peptides requiring cell-cell contact via low affinity interaction between CD11a and CD54 (LFA-1 and ICAM-1) which facilitates antigen recognition between the T-cell receptor/CD3 complex and MHC class II and CD4. This signals the upregulation of certain surface markers and the secretion of certain cytokines. The activation of helper T-cells in an immune response may have a defined polarity depending on what cytokines are produced. Th-1 polarity with secretion of gamma-interferon favours cell mediated immunity; Th-2 polarity with secretion of IL-4 favours antibody production. In a Th-2 response the activated T cells are able to ‘help’ activate normal B cells and induce them to mature and secrete antibody. The upregulated activation marker CD28 interacts with the CD80/CD86 receptors on B cells and the increased expression of CD154 on T cells binds to its ligand CD40 on B cells. The cytokine interleukin-2 (IL-2) is produced, which facilitates proliferation and clonal expansion of T cells. Activation of the T-cell has a built in ‘off switch’. A late activation molecule on the T-cell surface is CTLA-4 (CD152) which on engaging with the CD80/CD86 complex on the B cells inactivates the T-cell response .
CTLA-4 is also present on a subpopulation of regulatory T cells that suppress antigen-specific T-cell immune responses. These naturally occurring cells play a central role in the maintenance of peripheral tolerance by suppressing autoreactive T-cell populations.
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