Modulation and Regulation of Immune Responses

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Balance Th1/Th2

Experimental results, epidemiological studies and clinical trials strongly argue for the fact that bacterial environment plays a crucial role in the Th1/Th2 balance via different mechanisms of which cytokine synthesis by innate immune cells, especially IL-12, and IFN-g, could play a decisive role.

The prenatal period and early childhood are considered to be critical for the establishment and maintenance of a normal Th1/Th2 balance. It has been described that the immune context at birth is mainly Th2, while Th1 responses are partially suppressed, enabling non-rejection of the fetus during gestation. After birth, neonates must rapidly restore the balance by developing the potential to induce Th1-type responses (100). Various studies have shown that, in atopic infants, the switch does not occur, and the infant is in a context of an imbalance toward Th2 with a predisposition to development of IgE responses (101,102). The neonatal period is thus considered to be extremely important in enabling regulation of the Th1/Th2 balance to become operative, and the switch could occur during the first 5 years of life especially during the first year of life (103).

The Th2/Th1 switch is dependent on multiple factors whose relative importance has yet to be elucidated. Bacterial stimuli are considered to play a considerable role, and some years ago it had been claimed that infections might prevent the development of atopic diseases. This is referred to as the "hygiene hypothesis" (13), but it is now a matter of debate. From a recent study (104), authors did not find any evidence that exposure to infections in infants reduces the incidence of allergic disease, but, in contrast, exposure to antibiotics may be associated with an increased risk of developing allergic disease. Today, accumulating evidence suggests that rather than infections, alteration of the composition of the intestinal microbiota early in life may be an important determinant of atopic status (13,105). Experimental studies have supported this hypothesis. Thus, in one-week-old rats, peripheral immunization leads to a Th2-biased memory response. However, when the rats are concomitantly administered a bacterial extract by the oral route with immunization, the memory response switches to both Th1 and Th2 (106). Another study showed how, in three-week-old mice, the disturbance in intestinal bacterial equilibrium following ingestion of an antibiotic, kanamycin, promoted a shift in the Th1/Th2 balance toward a Th2-dominant immunity, while it became Th1 and Th2 in non-treated growing CV mice (107). Ingestion of intestinal bacteria such as Enterococcus faecalis five days after antibiotic treatment again permitted the shift back towards the Th1/Th2 balance (108).

From an epidemiological point of view, very interesting studies argue in favor of the important role of the bacterial environment in the first year of life in order to ensure the good orientation of immune responses preventing the short- and long-term development of atopic diseases (13,101,103,109-111). Recent comparative studies have been conducted in children living in the same allergenic environment but under different life-style conditions, urban and farming environments. Results showed that substantial protection against development of asthma, hay fever, and allergic sensitization was seen only in children exposed to stables, farm raw milk, or both in their first year of life (103). Authors also found that prenatal exposure of women had a substantial protective effect.

Bacteria that are responsible for such effects are not known. Gram-negative bacteria rich in LPS have been suggested to be important in that phenomenon (85,109,112) but it is also possible that Gram-positive bacteria, such as bifidobacteria and Lactobacillus, are involved. The comparative study between Swedish and Estonian children (105) has suggested a specific role of the intestinal microbiota, regarding its nature, diversity and changes with time. Besides genetic factors, which are known to play an important role in the development of allergic diseases, all these data suggest that the infant intestinal microbiota normally rich in Gram-negative (LPS-producing) and Gram-positive bacteria may not be well-balanced in atopic children. Depending on the microbial environment associated with the life-style, especially during the first year of life, a restoration of the normal balance could be achieved.

Clinical trials using probiotics to treat or prevent atopic eczema in infants have also generated arguments suggesting that the infantile intestinal microbiota balance plays an important role in the good orientation of immune responses. In a recent double-blind trial, Kalliomaki and coworkers (87) have shown that the supplementation of pregnant women one month before delivery followed by 6 months post-parturition (mother or baby) with a probiotic strain, Lactobacillus rhamnosus GG, lead to a significant decrease in the incidence of atopic eczema in babies with a family history of atopic disease. At two years of age, atopic eczema was diagnosed in 23% of treated babies versus 46% in the placebo group. The preventive effect of L. rhamnosus GG extends to the age of 4 years follow-up treatment (87). The mechanisms involved in such a protection are unknown. Indeed, the frequencies of positive skin-prick test reactivity (measuring the specific IgE levels) were comparable between treated and placebo groups. Further studies are necessary to elucidate the mechanisms responsible for these interesting protective effects.

On the basis of all the above data, questions arise with respect to delivery conditions, infant feeding, and antibiotic treatments to be administered during infancy in order to enable and optimally establish and maintain integrity of the intestinal microbiota. Probiotics may also be considered as good palliative agents with respect to impaired equilibrium of the intestinal microbiota. Knowledge of the immunoregulatory mechanisms driven by the intestinal microbiota of infants, as well as the bacterial components which are involved, are crucial to prevent some pathologies which are dramatically increasing today.

Natural IgG

In the absence of immunization, there is a natural level of immunoglobulins (Ig) in serum named "natural Ig" or "natural Abs." The roles of those Abs in the immune responses have yet to be completely elucidated but it is known that they play important regulatory roles in humoral immune responses, especially in immune responses to self-Ag (113). It has also been demonstrated in mice that they intervene with the development of the B repertoire at peripheral level (spleen), enabling expansion of the Ab response towards thymo-dependant Ags (114,115). In man, the role of these natural Abs is under investigation in the context of research on certain autoimmune disease (116).

Intrinsic and extrinsic factors, especially the intestinal microbiota, act on the natural Ig levels, depending on isotypes and sub-classes. Thus, GF mice had normal serum IgM levels, but IgG, and IgA levels are approximately 5% of conventionally reared littermates (114). It has been established in mice that one of the roles of the natural IgG is to expand B cell repertoire. The latter can be evaluated through the expression of some genes coding for the variable part of the heavy chain of Ig (VH gene) using probes. Analysis of a VH gene expression has provided a quantitative tool for the global assessment of Ab repertoire, and a preferential use of the gene means that the repertoire is poorly diversified.

Early in ontogeny, a high frequency of B cells could bind to multiple Ags, among which auto-Ags are found, in neonatal CV mice. This fact has been correlated with preferential use of VH gene family, namely VH7183. In CV adult mice these multi-reactive B cells are much less frequent coinciding with a random usage of VH genes, as seen by the decreased utilization of VH7173 gene family, showing a diversified repertoire. Thus, there is a maturation of the immune system of adult CV mice. This fact is not present in adult GF mice where a high percentage of B cells expressing VH 7138 genes is found as in neonatal CV mice (115). The injection of purified natural IgG Ig from serum adult CV mice into GF mice reduced the use of the VH7183 gene family in the peripheral B-cells, as in CV mice (115). From these data authors concluded that if a genetic program leading to non-random position-dependent preference of rearrangement and expression initially controls the establishment of the VH repertoire, a broader utilization of the B-cell repertoire is thereafter stimulated by environmental Ags and Igs. The finding that GF mice maintain a "fetal-like" VH repertoire that can be modified by the administration of pooled Igs from normal unimmunized CV mice establishes the crucial role of the intestinal microbiota in this function.

This data may have clinical relevance. Many reports have described the beneficial results of intravenous injection of normal human IgG in treatment of autoimmune disease (116).

The mechanism by which exogenous antigenic stimulation can influence the expression of VH gene remains unclear. Exogenous Ags may play an important role in the final modulation of the expressed repertoires either by direct stimulation of Ag-specific clones or indirectly by idiotype interactions mediated by the Abs produced in those responses (113-115).

Autoimmune Diseases

One example of the regulatory effect exerted by intestinal microbiota on an autoimmune disease has been reported by Van der Broek and co-workers (117). Streptococcal cell wall (SCW)-induced arthritis is a chronic erosive polyarthritis, which can be induced in susceptible rats by a single intra-peritonal injection of a sterile aqueous suspension of SCW. The acute phase of the disease develops within a few days, the second, chronic phase, which mainly involves peripheral joint inflammation, develops from 10 days after. The second phase is dependent on functional T lymphocytes. F344 rats are genetically described as resistant to the second chronic phase, while in contrast another strain of rats, Lewis rats, are described as susceptible. These data suggest that a T-cell unresponsiveness due to immune tolerance to SCW may be the mechanism underlying resistance to SCW-induced arthritis of F344 rats, while Lewis rats are defective in their tolerance. When F344 rats are reared in GF conditions, they become susceptible to SCW-induced arthritis as are Lewis rats. There was a correlation between the susceptibility of the disease and the

T cell proliferation response to SCW measured in vitro. In CV Lewis and GF-F344 rats, a proliferation was measured while it was not present in CV F-344 rats. This concept that disease might result from a similarity between naturally occurring cell surface Ags of the host and those expressed on some commensal or pathogenic micro-organisms have been referred to as the "molecular mimicry hypothesis." Mono-association of GF F344 rats with E. coli resulted in resistance, which equaled that in CV F344 rats whereas mono-association with a Lactobacillus strain did not really affect susceptibility. Thus, in CV F-344 rats, a state of tolerance to arthritogenic epitopes is induced during the neonatal period of life and maintained through life by the bacterial microbiota, resulting in resistance to SCW-induced arthritis. In Lewis rats, this tolerant state is deficient and/or easily broken.

Bacterial effects have been suggested in other autoimmune diseases. Thus, oral antibiotic treatment after adjuvant-induced arthritis (AIA) induction in rats significantly decreased clinical symptoms of AIA while, concomitantly, E. coli levels increased in the distal ileum of antibiotic-treated rats (118). In addition, it has been described that Mycobacterial infections profoundly inhibit the development of diabetes in non-obese diabetic (NOD) mice (119).

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