Prof. Alfred Hässig, Prof. Liang Wen-Xi and Dr. Kurt Stampfli
Continuum vol.3 no.5
Jan./Feb. 1996
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A characteristic for the transition from asymptomatic HIV infection to AIDS-related complex and to full-blown AIDS is the continual reduction in the number of CD4-lymphocytes in the blood while the CD8-lymphocyte count remains practically constant. According to current wisdom, this is because of the increasing destruction of CD4-cells by HIV.
Last year however, Carbonari et al showed that apoptotic (apoptosis = programmed cell death) lymphocytes in AIDS patients consist for the most part of CD8 T-cells and CD19
B-cells.(1) They concluded from this that the phenomenon of in-vitro apoptosis might not be related to the depletion of CD4 T-cells in AIDS. Finkel et al recently showed that apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes.(2) In their commentary, Pantaleo and Fauci did not wish to give any conclusive answer to this.(3)
In order to clarify the question of the cause of the increasing depletion of CD4-cells in the transition from healthy ‘HIV’-carrier to AIDS patient it seems to us to be useful to make a critical review of the studies of this phenomenon which appeared before the first description of AIDS in 1981.
In the mid-’70s Fauci and his working group showed that after the administration of cortisol (a hormone produced by the adrenal glands in response to stress) the body appeared to respond with a selective reduction in the number of CD4-cells. This was found to be because most of this sub-group of white blood cells migrated from the blood circulating in the blood vessels into other areas of the body outside the vascular system.(4,5,6) After the withdrawal of cortisol, the CD4-cells return to the circulating blood and CD4/CD8 ratio returns to normal.
With regard to where the CD4-cells migrate under the influence of cortisol, it has been shown in animal experiments that they are sequestered mainly into the bone marrow.(4,7,8) Following these studies Antonacci and Calvano, from the working group of Shires, showed that a similar depletion of CD4-cells is also seen in burn patients.(9) Calvano also demonstrated that in cases of burns the body’s own bioactive cortisol level rises sharply.(10) These investigators concluded from their findings that the sequestration of CD4-cells to bone marrow may be considered as a general phenomenon in any severe and persistent hypercortisolism (an excess of cortisol in the blood) in acute-phase inflammatory reactions in which the whole body responds to an inflammation or injury.
With regard to the direct effect of hypercortisolism on the lymphocytes, it has to be considered that immature CD4+/CD8+ cells which are produced in the thymus (thymocytes) represent the most cortisol-sensitive element of the lymphatic tissue. They are reduced by increased apoptosis so that the number of these immature CD4/CD8 cells decreases noticeably. Peripheral mature CD4+/CD8- and CD4-/CD8+ lymphocytes are relatively cortisol resistant.(11)
One could now ask whether the temporary sequestration of CD4-cells to the bone marrow during acute-phase reactions can be incorporated into the general concept of the neuroendocrinal control of the immune system. Mosmann and Coffman showed in 1986 that the CD4-lymphocytes can be divided into two cell-groups, known as Th-1 and Th-2 cells (Th is an abbreviation for T-helper cell).(12) The Th-1 cells secrete mainly Interleukin(IL)-2, IL-12 and Interferon(IFN)-gamma, which are chemical messengers which stimulate cellular immune reactions. The Th-2 cells secrete mainly IL-4, IL-6 and IL-10 which stimulate the humoral immune reactions.
The significant step towards clarification of the mechanisms behind production of these chemical messengers known as cytokines was made by the study group around Daynes.(13,14) This group revealed first of all that regulation of the cytokine production of activated lymphocytes takes place in the periphery. Mitogen (a substance which activates cells to divide)- or antigen-stimulated lymphocytes from lymphoid organs of the mucus membranes produce mainly IL-4. Lymphocytes from internal organs produce mainly IL-2.
The decisive factor for the type of peripheral regulation of lymphocyte cytokine production is the production of steroid hormones which are produced locally from inactive precursors. In this process the dehydroepiandrostosterone (DHEA) produced in the cortex of the adrenal glands plays an important role as an antagonist to cortisol. DHEA is the adrenocortical hormone contained in the blood in the highest concentration of all the steroid hormones.
In its sulphated form, DHEAS, it is inactive. By means of steroid sulphatase, DHEAS is desulphated in the periphery and thus transformed into DHEA, the active form. In the lymphocytes the active DHEA causes increased production of IL-2 and IFN-gamma, but not of IL-4. These findings have revealed that the varying concentration of steroid sulphatase in different tissues during the transformation of the pre-hormone DHEAS into active DHEA plays a central role in the production of Th-1 and/or Th-2 CD4-lymphocytes.
In the lymphatic tissue the macrophages are the only cells that have an appreciable quantity of DHEAS sulphatase. Moreover the high concentration of circulating DHEAS is used for the production of androgenic (male sex) and secondarily of oestrogenic (female sex) hormones.
After what has been said it seems plausible to us to consider the sequestration of CD4-lymphocytes to the bone marrow as a significant component of a stress-induced Th-2 profile of CD4-lymphocytes, because in the Th-2 profile in the bone marrow CD4-cells actively stimulate the B-cells, present there in large numbers, to increase the formation of antibodies.
If one looks into this question further one finds four studies by Fauci et al who, during 1976 and 1977, drew attention to the fact that in the case of cortisol-induced sequestration of CD4-cells into the bone marrow, these stimulate the B-cells to increase antibody production. In these studies they anticipated many findings regarding the Th-1 and Th-2 cytokine profiles of CD4-lymphocytes.(15-18)
In order to support our still hypothetical notions it seems to us to be useful to analyse the course of the CD4/CD8 ratio in the transition phase from HIV infection to the development of AIDS together with other parameters for this acute phase reaction, e.g. the body’s own bioactive cortisol content or the C-reactive protein content. Following a suggestion by Cottier, in these patients we recommend that the size of the thymus be measured regularly by means of an imaging procedure such as nuclear magnetic resonance.(19)
In conclusion we would point out that studies of sequestration of CD4-cells in bone marrow can provide a clue to the question of long-term survival of individuals judged to be infected with HIV. They may have overcome HIV infection not exclusively by cellular immune reactions as in immunologically healthy persons, but with an additional humoral response in which the production of anti-HIV antibodies has occurred. They then remain in the neuroendocrine Th-1 state and do not induce the transformation into the Th-2 state along with the hypercortisolism required for the development of AIDS, thus sparing the patients this disease. *
References
M. Carbonari, et al.: Detection and Characterization of Apoptotic Peripheral Blood Lymphocytes in Human Immunodeficiency Infection and Cancer Chemotherapy by a Novel flow Immunocytometric Method. Blood, 83:1268-1277 (1994).
T.H. Finkel, et al.: Apoptosis occurs predominantly in Bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nature Medicine, 1:129-134 (1995).
G. Pantaleo & A.S. Fauci: Apoptosis in HIV infection. Nature Medicine, 1:118-120 (1995).
A.S. Fauci & D.C. Dale: The effect of in vivo hydrocortisone on sub-populations of human lymphocytes. J. Clin. Invest., 53:240-246 (1974).
A.S. Fauci & D.C. Dale: The effect of hydrocortisone on the kinetics of normal human lymphocytes. Blood, 46:235 (1975).
B.F. Haynes & A.S. Fauci: The differential effect of in vivo hydrocortisone on the kinetics of sub-populations of human peripheral blood thymus-derived lymphocytes. J. Clin. Invest., 61:703-707 (1978).
J.J. Cohen: Thymus-derived lymphocytes sequestered in the bone marrow of hydrocortisone-treated mice. J. Immunol., 107:841-844 (1972).
M.A. Levine & H.N. Claman: Bone marrow and spleen: dissociation of immunologic properties by cortisone. Science, 167:1515 (1970).
A.C. Antonacci, et al.: Flow cytometric analysis of lymphocyte sub-populations after thermal injury in human beings. Surg. Gynaecol. Obstet., 159:1-8 (1984).
S.E. Calvano, et al.: Changes in free and total levels of plasma cortisol and thyroxine following thermal injury in man. J. Burn Care Rehab., 5:143-151 (1984).
J. Gruber, et al.: Thymocyte apoptosis induced by elevated endogenous corticosterone levels. Euopr. J. Immunol., 24:1115-1121 (1994).
T.R. Mosmann & R.L. Coffman: Th-1 and Th-2 Cells: Different Patterns of lymphokine Secretion Lead to Different Functional Properties. Ann. Rev. Immunol., 7:145-173 (1989).
R.A. Daynes, et al.:Regulation of murine lymphokine production in vivo. III. The Lymphoid Tissue Microenvironment Exerts Regulatory Influences over T-Helper Cell Functions. J. Exp. Med., 171:9790996 (1990).
J.D. Hennebold & R,A, Daynes: Regulation of Macrophage Dehydroepiandrosterone Sulfate Metabolism by Inflammatory Cytokines. Endocrinology, 135:67-75 (1994).
A.S. Fauci & K.R. Pratt: Activation of human B Lymphocytes. I. Direct Plaque-Forming Cell Assay for the Measurement of Polyclonal Activation and Antigenic Stimulation of Human B Lymphocytes. J. exp. Med., 144:674-684 (1976).
A.S. Fauci, K.R. Pratt & G. Whalen: Activation of human B Lymphocytes II. Cellular Interactions in the PFC Response of Human Tonsillar and Peripheral Blood B Lymphocytes to Polyclonal Activation by Pokeweed Mitogen. J. Immunol., 117:2100-2104 (1976).
B.F. Haynes & A.S. Fauci: Activation of human B Lymphocytes III. Concanavalin A-Induced Generation of Suppressor Cells of the Plaque-Forming Cell Response of Normal Human B Lymphocytes. J. Immunol., 118:2281-2287 (1977).
A.S. Fauci, K.R. Pratt & G. Whalen: Activation of human B Lymphocytes. IV. Regulating Effects of Corticosteroid on the Triggering Signal in the Plaque-Forming Cell Response of Human Peripheral B Lymphocytes to Polyclonal Activation. J. Immunol., 119:598-6063 (1977).
H. Cottier: personal communication.
This paper was offered to Nature Medicine, but after some deliberation they refused to publish it.