Journal of Intellectual Disability Research, 1993, 37, 543-551

Immunological features of Down's syndrome:

a review
L. NESPOU,!* G. R. BURGIO,! A. G. UGAZIO2 & R. MACCARIOl
^Departments of Pediatrics, University ofPavia, and ^Department of Pediatrics,
University of Brescia, Italy

ABSTRACT. Young patients with Down's syndrome (DS) have high rates of
infections, malignancies and autoimmune phenomena. Therefore, DS may be
considered as a model of precocious, abnormal ageing of the thymus-dependent
system in man. In DS children less than 6 years of age, the levels of serum
immunoglobulins did not differ from healthy controls, but after that age, consid-
erable hyper-IgG and -IgA were found. Furthermore, high levels of IgGl and
IgG3 have been found, whereas a progressive decline of IgG2 and IgG4 with age
has been observed. The frequency of hepatitis B virus carriers even in the youngest
age group is much higher among DS children. It has been reported that an IgG
response was detectable in 75% of controls after HBsAg vaccination as compared
to the 16-6% of DS patients. The presence of autoantibodies against human
thyroblobulin did show a positive association with HB Virus Ag carriers, but only
in the oldest DS subjects. Natural antibodies against intestinal antigens are low,
while in the presence of cow's milk, abnormally high titres against casein and
betalactoglobulin were present. High levels of IgG antibodies against gliadin have
been observed. In spite of a normal percentage of CD3- and CD2-positive
lymphocytes, a high proportion of cells express low-avidity receptors for sheep
erythrocytes. Although the proportion of CD4+ T-lymphocyte helper-cells is
normal, a marked imbalance in the CD4+ subpopulations has been documented.
The percentage of suppressor-cytotoxic CD8+ lymphocytes is markedly in-
creased. The responses to phytoemagglutinin and concanavalin A are within the
normal range in the first decade of life and decline progressively thereafrer. A
recent study reported defective proliferative response to allo-mixed lymphocyte
culture, with decreased expression of the membrane CD25, low secretion of
interleukin 2 in the supernatant and depressed allo-specific cytotoxic activity.
Defective production of interferon alfa and gamma in DS has been described in
vivo and in vitro. Recently, it has been reported that the absolute number of TCR
alfa, beta+ cells was considerably lower for DS subjects than for controls, while
DS subjects had a markedly higher proportion of cells expressing TCR gamma
and delta. Therefore, it can be concluded that, while the primary immune defect
seems to be greatest in the cellular compartment, even the humoral immunity in
DS subjects undergoes a precocious ageing, as has already been shown for the
T-cell compartment.

*Correspondence and present address: Luigi Nespoli, Clinica Pediatrica, Ospedale de Circolo e
Fondazione Macchi, Viale Luigi Borri 57, Varese, Italy.

543
544 L. Nespoli et al.

INTRODUCTION

Down's syndrome (DS) is the most common autosomal trisomy in livebom children
and the major known genetic cause of mental retardation (Hassold & Jacobs 1984).
Congenital leukemia or leukemoid reactions, and transient polyglobulia are typically
observed in DS newboms (Weinstein 1978; Kalwinsky et al. 1990; Dewald et al.
1990). Major manifestations of DS are growth retardation, congenital heart disease
and hypotonia. Like normal elderly individuals, young patients with DS have high
rates of infections, malignancies and autoimmune phenomena (Miller 1970; Burgio
et al. 1965; Ugazio etal. 1977). These observations suggested to the present authors
that DS has some immunological features worth studying as a model of precocious,
abnormal aging of the thymus-dependent system in man (Burgio & Nespoli 1974;
Walford et al. 1981). The precocious aging of the immune system in DS seems to be
ascribed to an abnormal maturation of thymocytes into fiiUy competent cells within
the thymus (Murphy et al. 1990; Cossarizza et al. 1990). Several morphological
abnormalities such as small cortical thymocytes as well as an altered intrathymic
maturative pattern have been described (Larocca et al. 1990; Murphy et al. 1990).
Mortality and morbility from infectious diseases are still higher in DS, as com-
pared to age- and sex-matched controls living in the same environmental conditions,
in spite of the advances in chemotherapy and health care (Ugazio et al. 1990).
Derangements of humoral and cellular immune response which become more
evident in the older age group, suggest that a combined defect of the immune
functions is an integral feature of DS (Burgio et al. 1975; Cossarizza et al. 1990;
Licastro e£ a/. 1990).

HUMORAL IMMUNITY
The number of lymphocytes bearing high-density membrane Ig is normal in DS
children at various ages. In DS children of less than 6 years of age, the level of serum
immunoglobulins did not differ from healthy controls. After 5 years of age, a
considerable hypergammaglobulinemia of the IgG and IgA type is found (Burgio et
al. 1975). IgG subclasses have an abnormal distribution: high levels of IgGl and
IgG3 have been found by Avanzini et al. (1988), whereas IgG2 levels were below
third centile values of age in 30% of adults DS and 9 5% of children and IgG4 was
undetectable in 30% of adults and 19% of children (Table 1).
Thefi-equencyof hepatitis B virus carriers even in the youngest age group is much
higher among DS children as compared to age- and sex-matched controls under the
same living conditions (Ugazio et al. 1977). Confiicting results have been reported
after HBsAg vaccination; Avanzini et al. (1990) have reported that the vaccine
induced an IgG response in 75% of controls, as compared to the 16-7% of DS
patients (Table 2). Furthermore, DS children showed a very low response to the
IgGl class which contains most of the antibody response in normal people (Mattila
et al. 1986). IgM levels decrease during adolescence and are lower than normal in
the majority of DS adults (Burgio et al. 1975).
 Immunological features of Down's syndrome 545
Table 1. Number of txisomic children and adults with deranged
IgG subclass levels*
Elevated Decreased
IgGl IgG3 IgG2 IgG4
(%) (%) (%) (%)
Children (21) 2(9- 5) 5 (24) 2 (9-5) 4(19)
Adults (36) 15 (41-6) 28 (77-8) 11 (30) 11(30)
P 0-02 0-0002 0-13 0-52
*ModifiedfromAvanzin er a/. (1990).
Table 2. Number of responders to hepatitis B vaccine among adults with
Down's syndrome and controls
IgGl IgG2 IgG3 IgG4
(%) (%) (%) (%)
Controls 12 (75) 4(25) 6 (37-5) 9 (56-2)
Down's syndrome 2(16-7) 2 (16-7) 2(16-7) 0
P 0-007 0-94 0-43 0-006
*Modified from Avanzini et al. (1990).

The presence of autoantibodies against human thyroglobulin showed a positive

association with HBsAg carriers in only the oldest DS subjects, suggesting that the
autoimmune phenomena primarily expressed the altered homeostatic mechanisms
of DS, rather than the rate of infection by hepatitis B virus (Ugazio et al. 1977). In
young children, thyroid autoimmunity is seldom associated with thyroid dysfunc-
tion, whereas in older subjects, autoimmunity accoimts for thyroid abnormalities
(Zori et al. 1990). It has been fovind that 8% of children under 18 years developed
hypothyroidism over a 3-year period of follow-up (Coleman & Abbassi 1984). When
studying the antibody responses against intestinal {E. coli and rabbit red blood cells)
and food antigens (cow's milk components), the present authors found low levels of
the former associated with abnormally high titres against casein and beta-lactoglobu-
lin (Nespoli et al. 1982). High levels of IgG and IgA antibodies against gliadin have
been observed in a group of 78 DS children, whereas increased incidence of coeliac
disease in the same subjects cannot be excluded (Storm 1990).

CELLULAR IMMUNITY
Decreased numbers of leucocytes and lymphocytes in DS have been repeatedly
reported and confirmed (Murphy & Epstein 1992).
Early reports on the numbers of circulating T-cells identified as rosette forming
cells with sheep red blood cells showed a reduced proportion of such lymphocytes
from the neonatal age (Burgio et al. 1975,1978). Burgio et al. (1983) postulated that
the immunologic problems associated with DS are a result of the abnormal
546 L. Nespoli et al.

maturation of thymocytes into fully competent T-cells within the thymus. Anatomi-
cal abnormalities have been demonstrated in DS thymuses even in the newborns:
these include lymphocjrte depletion, diminution of the cortex, loss of cortico-medul-
lary demarcation and enlarged cystic Hassall's corpuscles within the thymic medulla
(Benda & Strassman 1965j Levin et al. 1979; Larocca et al. 1990; Musiani et al.
1990). Murphy et al. (1990) have analysed the thymocytes for TCR alfa-beta and
CD3 fluorescence, and have been able to show that DS thymocytes always contained
fewer cells expressing high levels of TCR alfa-beta and CD3 complex as compared
to age- and sex-matched controls. However, no difference between DS and controls
was found in the total per cent of cells expressing CD3 within the thymus. Larocca
et al. (1990) have similarly noted decreased cytoplasmic TCR alfa and beta chains
in DS thymuses. A marked depletion of high-density CDl + cells and of CD3+ cells
have been documented by Musiani et al. (1990), who studied the thymuses of 15 DS
children (aged from 1 month to 4 years of age). On the contrary, the percentage of
cells bearing TCR gamma-delta was similar in DS and normal children. Recently,
Murphy & Epstein (1992) have reported that in DS peripheral blood lymphocytes
(PBLs) there is a lower proportion of cells expressing TCR alfa-beta. Moreover, their
absolute number was considerably lower for DS subjects than for controls. DS
subjects had a markedly higher proportion of PBL expressing TCR gamma, delta,
than did the controls.
Although the proportion of CD4+ lymphocytes, putative T helper-cells, is normal
or slightly reduced in DS children (Burgio et al. 1983; Murphy & Epstein 1992), a
marked imbalance in the CD4+ subpopulations has been reported. The proportion
of helper/inducer (CD4+, CDW29+) lymphocytes is significantly reduced. Study-
ing the distribution of the CD45RA antigen which distinguishes between native and
memory CD4+ T-cells, Murphy et al. (1992), have found a decreased proportion of
CD4+, CD45RA+ cells in DS PBLs. The percentage of CD8+ cells, suppressor/
cytotoxic lymphocytes, is markedly increased in most DS children. This finding is
likely to result, at least in part, from the presence in the peripheral blood of trisomie
subjects of a high percentage of natural killer (NK) cells partly expressing the CD8
antigen (Maccario et al. 1984; Montagna et al. 1988). A significant increase of the
percentage of T-cells capable of non-MHC restricted cytotoxicity, i.e. CD3+,
CD5+, has been documented.
A significantly higher proportion of NK cells, CDl 6+, has been found in DS PBL
by Murphy & Epstein (1992), whereas Cossarizza et al. (1990) demonstrated a
decrease of CDl6+ PBL and normal percentage of CD56+ cells. Significant
increases of cells possessing a low NK activity (CD57+, CD8+ and CD57+,
CD 16-), associated with a significant decrease of cells with high NK activity
(CD16+, CD57- and CD16+, CD57+), have been reported by Cossarizza et al.
(1990). Defective proliferative capacity in vitro of T-lymphocytes from subjects with
DS has been reported in several studies, using different experimental designs.
The response to phytohemagglutinin (PHA) and concanavalin A (Con A) are
within the normal range in the first decade of life and decline progressively thereafrer.
As shown in Fig. 1, the response to PHA by peripheral blood lymphocytes showed
a progressive decline which was highly correlated to the age of the DS subjects. In
 Immunological features of Down's syndrome 547

60 r

50

40

o-
T-
X

50

20
P<0001
P<0001

10 15 20 25 30
Age (years)
Figure 1. PHA responsiveness of PBL from patients with DS of different ages ( • • ) as
compared with karyotypically normal controls ( • • ) . Data are expressed as mean±SD.
The niimber of subjects in each age group is given in parentheses.

particular, PBL from DS subjects less than 11 years old responded normally to the
mitogen, while after this age, PHA responsiveness rapidly declined (Burgio et al.
1975; Gershwin et al. 1977; Melman et al. 1970; Philip et al. 1986; Scheckter et al.
1977; Whittingham et al. 1977). A defective response of T-lymphocjrtes to other
T-cell mitogens such as monoclonal antibodies specific for the CD3 and CD2
antigens, and a normal proliferative response to some polyclonal activators such as
phorbol ester and calcium ionophore A23187 have also been reported (Bertotto et
al. 1989). Conflicting results have been reported concerning T-cell proliferation
induced in allogeneic MLC (allo MLC). Some groups have foxind an abnormally
high proliferation (Franceschi et al. 1980; Gupta et al. 1983; Sasaki & Yoshitaka
1969), while others have shown depressed response (Raziuddin & Elawad 1990;
Walford etal. 1981). In a recent study, our group has reported defective proliferative
response to allo MLC (Ugazio et al. 1990) with decreased expression of the mem-
brane receptor (CD25) for interleukin-2, the lymphokine necessary to promote
antigen- and mitogen-induced T-cell growth. Low secretion of interleukin-2 in the
supernatant and depressed allo-specific cytotoxic activity have also been reported in
the same study. Analysis of the in vitro proliferative response of lymphocytes fi:om
subjects with DS to antigenic stimuli has given different results depending on the
antigen used. Production and secretion of lymphokines by T-lymphocytes has been
investigated by several authors: some have reported defective production of inter-
leukin-2 in response to PHA (Ugazio et al. 1990), anti-CD3 or anti-CD2 and
548 L. Nespoli et al.

Table 3. In vivo and in vitro evaluation of T-cell

functions in Down's syndrome
Function Activity
Mitogen-induced proliferation
Phytohemoagglutinin Low/normal
Concanavalin A. alfa-CD3, alfa-CD2 Lxjw
Phorbol ester +A23187 Normal
Allogeneic mixed lymphocyte
culture (MLC):
proliferation Low/high
cytotoxic activity Low
Antigen-induced proliferation
Staph. strept. Sendai IV. Normal
TT, influenza v. Low
Interleukin-2 production
Mitogen-induced Low/normal
Allo-MLC-induced Low/normal
Antigen-induced Low/normal

allogeneic stimuli, while in other studies, interleukin-2 production induced by PHA

or in the MLC has been normal (Table 3). Recently, a severe impairment of
interleukin-2 gene expression has been reported in DS (Gerez et al. 1991). Defective
production of interferon alfa and gamma in DS was first described in vivo at the onset
of viral infections and then confirmed in vitro in different experiments involving
measurement of both (Levin etal. 1979).

CONCLUSION

Since the begirming of the nineteen-seventies, DS has been considered a primary

immune defect due to the higher incidence of leukemias and lymphomas observed.
Histological studies of the thymic gland as well as the altered ratios between different
T-cell subsets have confirmed that the majority of these immune disorders might be
ascribed to an altered thymic function. The homeostatic control of T-cells on B-cell
functions and differentiation cannotfinelyregulate the antibody and Ig productions.
Exaggerated response to food antigens and to autoantigens associated with a poor
production of natural antibodies is present since the first years of life in DS. These
abnormalities become more severe in adult life, as shown by the high incidence of
dysgammaglobulinemia and by the defective antibody response to HBV vaccine.
Therefore, it can be concluded that, while the primary immvine defect seems to be
greatest in the cellular compartment, even the humoral immunity in DS subjects
undergoes a precocious ageing, as already shown for the T-cell compartment.
 Immunological features of Down's syndrome 549

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Received 16 July 1992; revised 5 July 1993