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B-CLL IS A CONDITION OF AGING:
AN EDITORIAL COMMENT
WH ADLER
My proposal is simply that B-cell Chronic Lymphocytic
Leukemia is not a disease, it is a condition, and specifically it is a
condition of aging. My reasons for proposing this are that all that I heard
at the meeting about the Cells, the Patients, the Disease, and the Risk
Factors brought me back to things which we consider to be part of normal
human aging. The major difference between a “condition” and a “disease”
is going to be the incidence and I'll get to that in a moment.
With aging the following features are well documented
(see Ref. 1 for a general review of aging and immune function in humans):
A limitation in the use of the Variable Heavy Chain Genes by B-cells. A
loss of heterogeneity in the immune response with a limitation in the avidity
and specificity of the antibody (2). A decrease in the proliferative ability
of the lymphocyte with more cells residing in the G0 and G2 parts of the
cell cycle (3,4).
A marked increase in the synthesis and release of
TGF-b is noted with aging (5). This is seen in humans and mice, in vivo
and in vitro. It occurs in the absence of any added stimulant such as endotoxin
LPS but can be boosted with LPS and ConA. It may be linked to abnormalities
in receptor expression but can be shown to be an inhibitor of proliferation
by interacting with the
p21 protein that controls the cdc kinase system.
Benign monoclonal gammopathies appear in the elderly
(6), as do autoimmune antibodies (7). About 10% of people over age 70 will
have Rheumatoid Factor. Disruptions in the pattern of lymphokine synthesis
occurs with a decrease in the T cell growth factors such as IL-2, and an
increase in the amounts of IL-6, TNF, TGF, IFNg, and IL-4 which can encourage
B-cell growth
(8). There are also gender differences in the types of B-cells in the
circulation (9).
B-CLL is not a fatal disease in many people. Risk
factor analysis points to age as the most important variable. In fact with
age factored out or corrected for, no other major risk factor appears.
Loss of B-cell function and all the various B-cell abnormalities listed
above occur without an identifiable B-cell defect(s). All the B-cell problems
seen in aging seem to be related to a loss of T cell control. Thymic involution
and loss of T cell function is age related. Most individuals over
age 60 have marginal T cell function.
Therefore it would seem to me that you are not dealing
with a disease. There are many features of aging that are “conditions”
rather than “diseases”. Hair loss, wrinkles, menopause, weight gain,
thymic involution, loss of T cell mediated immunity, and glucose metabolic
abnormalities are not considered to be diseases. A major difference between
a condition and a disease is going to be the incidence. Based on the assumption
that B-CLL is a condition of aging I would predict that you will find a
lot more “abnormal” B-cells in a larger part of the elderly population
than you might expect. It may well be a relatively common finding, far
in excess of the reported disease incidence rate for B-CLL. This will make
patient population selection very important, and comparisons of young versus
old patients may be instructive.
REFERENCES
1. Adler WH, Nagel JE: Clinical Immunology and Aging. In Principles
of Geriatric Medicine,
and Gerontology Third Edition, WR Hazzard,
EL Bierman, JP Blass, WH Ettinger, JB
Halter, and R Andres Eds., McGraw-Hill,
New York 1994; 61-75.
2. Schulze DH; Goidl EA Age-associated changes in antibody-forming
cells (B-cells).Proc Soc
Exp Biol Med 1991; Mar;196(3):253-9
3. Adler WH, Nagel JE. Studies of Immune Function in a Human
Population. In
Immunological Aspects of Aging, D Segre,
L Smith Eds., Marcel Dekker, Inc., New York
and Basel, 1988, p. 295-330.
4. Song LJ, Kim Y, Chopra RK, Proust JJ, Nagel JE, Nordin AA,
Adler WH. Age related
effects in T cell activation and proliferation.
Exp Gerontol 1993; 28: 313-321.
5. Zhou D, Chrest FJ, Adler WH, Munster A, Winchurch R. Increased
production of TGF beta
and Il-6 by aged spleen cells. Immunol
Lett 1993;36:7-12.
6. Radl J. Age-related monoclonal gammopathies: Clinical lessons
from the aging C58Bl mouse.
Immunology Today 1990; 11: 234.
7. Silvestris F. et al. Discrepancy in the expression of autoantibodies
in healthy aged individuals.
Clinical Immunology and Immunopathology
1985; 35: 234
8. Adler WH, Song LJ, Chopra RK, Winchurch RA, Waggie KS, Nagel
JE. Immune
Deficiency of Aging. In Aging, Immunity,
and Infection, DC Powers, JE Morley and RM Coe
Eds., Springer Publishing Co. New York
1994; 66-81.
9. Chrest FJ, Pyle RS, Schoonmaker MM, Nagel JE, Adler WH. Age
and gender differences
in human CD19+ and CD19+/CD 23+ peripheral
blood B lymphocytes. Aging Immunol Inf
Dis 1993; 4: 231-244.
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