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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 91, Num. 3, 1996, pp. 363-366
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Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 91(1), May/June
1996
Gastrointestinal Immune Responses in HIV
Infected Subjects
LRR Castello-Branco^+, DJM Lewis*, MB Ortig o-de-Sampaio, GE
Griffin*
Departamento de Imunologia, Instituto Oswaldo Cruz, Av. Brasil
4365, 21045-900 Rio de Janeiro, RJ, Brasil *Division of
Infectious Diseases, St. George's Hospital Medical School,
London, UK
Code Number: OC96072
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The gut associated lymphoid tissue is responsible for
specific responses to intestinal antigens. During HIV infection,
mucosal immune deficiency may account for the gastrointestinal
infections. In this review we describe the humoral and cellular
mucosal immune responses in normal and HIV-infected subjects.
Key words: gastrointestinal tract - HIV - mucosal immunology -
immunity to HIV
GASTROINTESTINAL IMMUNOLOGY
Intestinal mucosal defence is dependent on a number of non
specific factors, including gastric acidity, normal bowel flora,
intraluminal proteases, peristalsis, goblet cell mucus and a
normal enterocyte membrane composition. Changes or disruption of
any of these normal non specific defence mechanisms may influence
the uptake of intestinal macromolecules and antigens. The gut
associated lymphoid tissue (GALT) provides a second line of
protection in which cells and antibodies are specifically
directed against mucosal pathogens and antigens. GALT is
responsible for specific responses to antigens, through its
components: secretory IgA, interstitial IgA, IgG, IgM and cell-
mediated immunity (Castello-Branco 1993).
GALT is composed of organized lymphoid follicles (Peyer s
patches in the distal ileum and lymphoid aggregates in the
colon), antigen presenting cells and lymphocytes within the
lamina propria, intraepithelial lymphocytes and mesenteric lymph
nodes. Such lymphoid tissue within the lamina propria constitutes
the most important mediator organ of specific humoral immunity
in the intestine. There are about 10^10 immunoglobulin producing
cells per metre of human small bowel (Brandtzaeg et al. 1987),
this is four fold the total amount of such cells determined for
bone marrow, spleen, and lymph nodes.
Peyer's patches in the intestinal mucosa are a major source of
precursor IgA-producing cells and Peyer's patch T cells have a
specialized role in regulating the production of IgA by Peyer's
patches B cells. The intraepithelial T lymphocyte population is
predominantly CD8 positive in contrast with the lamina propria
where the majority of lymphocytes are CD4 positive (Doe 1989).
Peyer s patches and colonic lymphoid aggregates have a
specialized epithelium which facilitates controlled uptake of
antigens for induction of mucosal immune responses. The
epithelium above Peyer's patches is characterized by a decrease
in epithelial cell and brush border height, lack of goblet cells,
decrease in surface mucus coat, absence of secretory component
and the presence of M cells (Wolf 1988). M cells (membranous or
microfold) are specialized epithelial cells which provide
physiological portal of entry for luminal antigens, which are
non-selectively endocytosed and transported to adjacent
lymphocytes, macrophages and dendritic cells. M cells are
relatively rare and fail to express HLA-DR, secretory component,
or lysosomes (Brandtzaeg & Bjerke 1990).
Mucosal lymphocytes stimulated by antigen presentation, and T
cell cytokines, migrate to the circulation and return, after
maturation, to the mucosal immune system (Castello-Branco 1993).
Antigen-stimulated lymphocytes migrate first to mesenteric lymph
nodes and then to the systemic circulation via the thoracic duct,
following which they home to disseminated mucosal surfaces
(McDermott et al. 1986). This homing mechanism is mediated by
interaction between an adhesion molecule on the surface of the
lymphocyte and a surface molecule at high endothelial venules.
The principal determinant of humoral immunology in humans is
secretory IgA. Human IgA exists in two subclasses, IgA1 and IgA2,
which occur in different proportions in serum (80-90% IgA1) and
secretions (30-50% IgA2) (Mestecky & Russel 1986).
The majority of gastrointestinal immunocytes form J chain
containing dimers or larger polymers of IgA. Such polymeric IgA
(pIgA) can be transported through glandular epithelium with a
polymeric Ig receptor called secretory component. Secretory
component is a glycolipid molecule synthesized by epithelial
cells in secretory glandular tissue and mucosal surfaces. The
daily output of SIgA exceeds that of all other immunoglobulins
combined, and IgA is the major immunoglobulin class in the
intestinal secretions. Serum IgA is synthesized largely in the
bone marrow, whereas SIgA is produced by plasma cells resident
in the sub-mucosa of secretory epithelia and in the glandular
stroma (Russel & Mestecky 1988). B lymphocytes that are primed
by gut antigens in Peyer's patches subsequently migrate to the
intestinal lamina propria and differentiate into IgA-secreting
cells (Kagnoff 1987).
HIV AND THE GASTROINTESTINAL TRACT
That a mucosal immune deficit occurs during HIV infection is
manifest by the frequency and extent of associated - especially
gastrointestinal - mucosal infections. Whereas acute weight loss
in AIDS is more often associated with non gastrointestinal
infections such pneumonia, opportunistic infection of the small
intestine characteristically causes chronic disease with
diarrhoea and malabsorption, and around 70% of chronic weight
loss is associated with gastrointestinal infection and diarrhoea
(Macallan et al. 1993). Opportunistic parasitic gut infections
cause severe diarrhoea and profoundly compromised small bowel
absorptive function (Kapembwa et al. 1990) and cause significant
mortality in AIDS both in Western (Levine et al. 1991) and
developing countries (Gilks et al. 1990). A frequent absence of
pathogens and small bowel villous atrophy (Miller et al. 1988)
resembling graft-versus-host disease suggest that immune-mediated
responses within the mucosa may also be involved.
GASTROINTESTINAL IMMUNE RESPONSES TO HIV
The intestinal and respiratory mucosal are the major portal of
entry for pathogens and it is therefore not surprising that in
immunodeficiency states such pathogens cause significant disease.
Specific defects in mucosal immunity are now beginning to be
apparent in discrete models of immunodeficiency. In this respect,
HIV infection has proved to be important in providing insights
into mucosal immunity (Mestecky & Jackson 1994). For example,
intestinal infection with Cryptosporidium sp. is
a major cause of morbidity in clinically advanced HIV infection;
a recent study (Benhamou et al. 1995) has demonstrated an
inefficacy of intestinal secretory immune response to this
enteropathogen in AIDS, even though there were detectable
specific serum antibodies to this enteropathogen. A paradox of
clinical infection has been the demonstration of hypergamma-
globulinaemia in the face of advanced disease and deteriorating
immune function which is inversely correlated to peripheral blood
CD4 count. Both IgA1 and IgA2 subclass concentrations have been
demonstrated to be elevated and the presence of IgA from gut
mucosal origin has been detected in serum (Quesnel et al. 1994a).
This study probably represents a generalized B-cell stimulation
secondary to Il-6 drive since this cytokine is thought to be
constitutively expressed in advanced HIV infection. Cytokine
production has been shown to be disregulated in intestinal mucosa
of patients with HIV infection with the tendency towards the
production of proinflammatory cytokines (McGowan et al. 1994).
The failure of intestinal immunity has previously received
attention in adults (Eriksson et al. 1993, Lewis et al. 1994).
A recent study has now shed important light on the development
of impaired gut mucosal immunity in children (Quesnel et al.
1994b). Impaired intestinal immunity was evident very early in
the course of paediatric HIV infection as demonstrated by serum
parameters, but local mucosal antibody production or response to
enteral vaccines was not investigated.
The production of mucosal antibodies against HIV is likely to
be crucial in the protection induced by vaccines against HIV,
both in the intestinal and genital tracts. The mucosal immune
response to HIV per se is of great pathophysiological
significance in the course of HIV infection and a recent study
in Zambian patients (Mathewson et al. 1995) has focused on
secretory IgA response to p24 during acute and chronic diarrhoea.
In this study, a secretory IgA to HIV antigens was demonstrated,
but its functional role in enteropathy or the nature of the
response was not clearly elucidated. The response may represent
an anamnestic response in the face of mucosal stimulation by a
secondary enteropathogen. A correlation of specific
enteropathogen secretory IgA production with HIV disease
progression will be an interesting development of this study. A
parallel study (Janoff et al. 1994) examined antibody levels in
intestinal fluids from HIV infected individuals and demonstrated
aberrant mucosal antibody responses and decreased integrity of
the mucosal barrier.
The course of HIV is accompanied by weight loss, malnutrition
and trace-element deficiency, particularly in the later stages
of the disease. It is therefore often impossible to ascribe
primary or secondary aetiological roles to immunodeficiency
caused by HIV per se or to accompanying malnutrition. The
profound role of nutrition in relation to intestinal tract has
recently been summarized (Ferguson 1994) and the specific
importance of intraluminal nutrition in the maintenance of
intestinal mucosal immunity demonstrated in an animal model
(Serizawa et al. 1994).
To exploit fully the potential of the gut for the induction and
the dissemination of mucosal and systemic immunity, and better
to treat pathological gut inflammatory responses or
immunodeficiency states will require a detailed knowledge of the
cellular cytokine control mechanisms unique to the mucosal immune
system. This is gradually being elicited for the rodent model,
but extrapolation to humans may not always be valid; further
studies in humans are mandatory.
MUCOSAL IMMUNE RESPONSES FOLLOWING ORAL IMMUNIZATION IN HIV-
INFECTED SUBJECTS
We have studied mucosal immune responses using the potent
cholera toxin B subunit (CTB) (Holmgren et al. 1987), initially
defining kinetics and antibody class/subclass of circulating B-
cell and antibody responses, and kinetics and phenotype of
circulating T-cell responses in healthy volunteers after primary
and booster oral immunization. A boostable IgG (mainly IgG1) and
IgA (mainly IgA1) circulating B cell response occurs, peaking on
day 7 after primary and day 5 after booster oral immunization
(Lewis et al. 1991, 1993a), as well as a serum IgG and IgA
response (to conformational epitopes on the B subunit pentamer)
(Lewis et al. 1993b). A circulating CD4+T-cell response
(Castello-Branco et al. 1994, 1995) peaking on days 10-25 but
detected up to year later, is also seen. Thus oral CTB, a potent,
non-living oral immunogen is a good model to investigate mucosal
immune responses in HIV.
We studied British HIV positive homosexual men (with advanced -
mean CD4 counts 52/mm^3), and HIV-infected and uninfected female
workers in Nairobi, Kenya (Lewis et al. 1994), at all stages of
disease, divided into two groups (CD4 count < 400/mm^3 and
>400/mm^3) with mean CD4 counts of 186 and 752/mm^3,
respectively. After oral immunization with CTB, the African high
CD4 group had primary and booster serum IgG and IgA responses
equivalent to those of healthy English HIV negative subjects. In
contrast, the African low CD4 group had a poor primary response,
but booster oral immunization gave equivalent IgG and IgA
antibody levels to healthy English subjects. Unlike the English
subjects, Africans are exposed to LT of enteropathogenic
Escherichia coli, and probably have a recall response. The
immunodeficient English HIV positive homosexual men had no
significant response to primary or booster oral immunization.
Circulating spontaneously secreting anti-CTB IgG and IgA
plasmablasts were detected in African HIV infected subjects, and
numbers correlated with surrogate markers of disease beta2-
microglobulin and CD4 cell count. Early data suggests that a
preserved IgM plasmablast response may occur, but this requires
confirmation with more subjects. Although mucosal
immunodeficiency does develop, the mucosal system seems able to
respond well to oral immunogens until relatively late in HIV
disease. We are now characterizing in Brazilian patients the
clinical stage at which mucosal immunodeficiency occurs and
studying T cell responses and the mucosal level more directly in
terms of T cell subsets and secretory IgA responses.
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^+Corresponding author. Fax: 55-21-280.1589
Received 7 December 1995
Accepted 10 January 1996
Copyright 1996 Fundacao Oswaldo Cruz
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