The role of the complement system in innate immunity

Complement is a major component of innate immune system involved in defending against all the foreign pathogens through complement fragments that participate in opsonization, chemotaxis, and activation of leukocytes and through cytolysis by C5b-9 membrane attack complex. Bacterias and viruses have adapted in various ways to escape the complement activation, and they take advantage of the complement system by using the host complement receptors to infect various cells. Complement activation also participates in clearance of apoptotic cells and immune, complexes. Moreover at sublytic dose, C5b-9 was shown to promote cell survival. Recently it was also recognized that complement plays a key role in adaptive immunity by modulating and modifying the T cell responses. All these data suggest that complement activation constitutes a critical link between the innate and acquired immune responses.     

Protective immunity against the gastrointestinal nematode Nippostrongylus brasiliensis requires a broad T-cell receptor repertoire

The parasitic gastrointestinal nematode Nippostrongylus brasiliensis induces massive expansion of T helper type 2 (Th2) cells in the lung and small intestine. Th2 cells are a major source of interleukin-4 and interleukin-13, two cytokines that appear essential for rapid worm expulsion. It is unclear whether all Th2 cells induced during infection are pathogen-specific because Th2 cells might also be induced by parasite-derived superantigens or cytokine-mediated bystander activation. Bystander Th2 polarization could explain the largely unspecific B-cell response during primary infection. Furthermore, it is not known whether protective immunity depends on a polyclonal repertoire of T-cell receptor (TCR) specificities. To address these unresolved issues, we performed adoptive transfer experiments and analysed the TCR-Vβ repertoire before and after infection of mice with the helminth N. brasiliensis. The results demonstrate that all Th2 cells were generated by antigen-specific rather than superantigen-driven or cytokine-driven activation. Furthermore, we show that worm expulsion was impaired in mice with a limited repertoire of TCR specificities, indicating that a polyclonal T-cell response is required for protective immunity.     

The role of chemokines in linking innate and adaptive immunity.

It is becoming clear that chemokine function is necessary to translate an innate-immune response into an acquired response. Dendritic cells activated by innate stimuli and loaded with foreign antigen travel to regional lymph nodes to activate the acquired-immune system. Subsequently, the activated acquired-immune cells move into tissue, where the innate immune system sets-off the danger signal. The chemokine system has emerged as an essential regulator of this dendritic cell and lymphocyte trafficking, which is necessary to turn an innate immune response into an adaptive response.     

Protective immunity to Nippostrongylus brasiliensis in the rat: central role of the lymphocyte in worm expulsion

Evidence is presented to show that the expulsion of adult Nippostrongylus brasiliensis worms from the intestine of the rat requires the presence of functional lymphocytes. It has been established by previous workers that expulsion involves two steps, the first involving antibody action on the worms, and the present work shows that the second step requires the participation of lymphocytes. This conclusion comes from experiments in which the expulsion of worms already affected by step 1 (damaged worms) was examined in rats which were depleted of or restored with lymphocytes, as follows:

Expulsion of worms was inhibited in young rats and in irradiated adult rats (confirming previous work) and inhibited in adult, neonatally thymectomized rats treated with antithymocyte antiserum. The expulsion mechanism was restored in irradiated adult rats and in young rats by giving them syngeneic mesenteric lymph node cells from uninfected adult donors. Macrophage enriched peritoneal exudate cells did not restore the expulsion mechanism either in young or in irradiated adult recipients. Mesenteric lymph node cells subjected to 5000 r prior to injection of the recipients also failed to restore the expulsion mechanism in adult rats.

     

The effect of host immunity on the metabolism of Nippostrongylus brasiliensis

Measurements were made, at different stages of infection, of the uptake by N. brasiliensis of labelled inorganic phosphate from the host. It was found that uptake declined rapidly from day 7 of the infection onward. Worms showing lowered phosphate uptake could however `recover' when transferred surgically to a fresh rat, the extent of recovery depending on the length of sojourn in the primary host. The relevance of these results to the mechanism of immune expulsion of N. brasiliensis is discussed.     

Agaricus brasiliensis mycelium and its polysaccharide modulate the parameters of innate and adaptive immunity

The biological properties of Agaricus brasiliensis mainly include immunostimulating and antitumour activities. This study evaluated the immunomodulating effect of A. brasiliensis mycelium (LPB) and its exopolysaccharides (EPS) on immunological parameters, such as phagocytosis of Candida albicans and nitric oxide (NO) production by infected macrophages, splenocytes proliferation in response to C. albicans. It also assessed the effects of the intake of LPB on the number of lymphocytes in the lymph node and spleen of treated animals and the TNF-α production. It was showed that the LPB and EPS had opposite effects; LPB had antiproliferative action and also reduced the NO levels produced by macrophages. However, the EPS showed an immune-stimulating effect potentiating the splenocytes proliferation and NO production from macrophages after stimulation with C. albicans. In addition, it also protected the macrophages from death induced by yeast. These data confirmed the immunomodulatory properties of LPB and its polysaccharides.     

Evolution of complement as an effector system in innate and adaptive immunity

For a long time, the complement system in mammals has been regarded as a biological system that plays an essential role in innate immunity. More recently, it has been recognized that the complement system contributes heavily to the generation and development of an acquired immune response. In fact, this ancient mechanism of defense has evolved from a primitive mechanism of innate immune recognition in invertebrate species to that of an effector system that bridges the innate with the adaptive immune response in vertebrate species. When and how did complement evolve into a shared effector system between innate and adaptive immunity? To answer this question, our group is interested in understanding the role of complement in innate and adaptive immune responses in an evolutionary relevant species: the teleost fish. The attractiveness of this species as an animal model is based on two important facts. First, teleost fish are one of the oldest animal species to have developed an adaptive immune response. Second, the complement system of teleost fish offers a unique feature, which is the structural and functional diversity of its main effector protein, C3, the third component of the complement system.     

A regulatory role for complement in innate immunity and autoimmunity

The complement system comprises a strong defense against various pathogens and is a major component of our innate immune system. While earlier studies have established a crucial role of complement in recognition, opsonization and enhanced phagocytosis of microorganisms by professional phagocytes such as polymorphonuclear leukocytes and macrophages, recent studies delineate an additional role of complement in initiation and maintenance of the acquired immune response. In addition, it seems that opsonization of apoptotic cells by complement may lead to polarization of the response of professional antigen-presenting cells to a more inflammatory or tolerogenic response. The present review summarizes these different contributions of complement to the shaping of the immune balance.     

Reagin-like antibodies in rats infected with the nematode parasite Nippostrongylus brasiliensis

The immune response to Nippostrongylus brasiliensis in rats is closely associated with the formation of antibodies resembling human reagins. These are detected in some rats immediately after acquiring resistance to the parasite after an initial infection and in all rats 1 week later. Further infections stimulate an anamnestic rise in `reagin' production. `Reagin' formation is due to the living worms, primarily the adult stage. `Reagins' were detected by passive cutaneous anaphylaxis in the rat (homologous passive cutaneous anaphylaxis=PCA) with a 72-hour interval between intradermal injection of antibody and intravenous injection of antigen, which was a saline extract of adult worms.

`Reagin' production in rats vaccinated with worm extracts contrasts sharply with `reagin' production in rats infected with living worms. Vaccination with worm extracts stimulates `reagin' production in only some rats during the primary response only; after second and later vaccinations, `reagins' were not detected in any rats. Prolonged vaccination induces the formation of `blocking' antibodies and a further type of antibody capable of inducing 6-hour PCA, but not 72-hour PCA in rats. Even after prolonged vaccination, however, a subsequent infection stimulates an anamnestic rise in `reagin' production in some rats. Vaccination did not induce resistance to infection in any rats.

Rats recovered from an initial infection become increasingly susceptible to anaphylactic shock when challenged with worm antigen, but the sensitivity of rats to systemic anaphylaxis is not closely correlated to the level of circulating `reagins'. Heterologous anaphylactic reactions did not induce expulsion of worms from the intestine and anaphylaxis is not directly related to the ability of rats to resist infection.

     

Mast cell responses in mesenteric lymph nodes to infection of rats with the nematode, Nippostrongylus brasiliensis

The number of mast cells and their distribution in rat mesentery lymph nodes were assessed after a primary infection and after several successive infections with the nematode, Nippostrongylus brasiliensis. Following primary infection with N. brasiliensis, two peaks in total mast cell counts were observed. An initial small increase was restricted to day 5 and to the region of entrance to the lymph node. During the second peak, a marked increase in the number of mast cells occurred after day 15, the majority of cells is migrating through the afferent lymphatics, and then advancing from the cortical to the medullary region. The number of cells found in the hilus always remained low, indicating that mast cells accumulate and degranulate within the lymphoid organ.

In rats infected several times with the nematode parasite, mast cell numbers were markedly increased and the distribution pattern was similar to that found on day 21 after a primary infection. The observation that the percentage of cells found in the capsule was rather low in these animals indicates that local proliferation might have contributed to the high mast cell counts.

     

The role of CD94/NKG2 in innate and adaptive immunity

CD94/NKG2 is a heterodimer expressed on natural killer (NK) and a small subset of T cells. This receptor varies in function as an inhibitor or activator depending on which isoform of NKG2 is expressed. The ligand for CD94/NKG2 is HLA-E in human and its homolog, Qa1 in mouse, which are both nonclassical class I molecules that bind leader peptides from other class I molecules. Although <5% of CD8 T cells express the receptor in a naïve mouse, its expression is upregulated upon specific recognition of antigen. Similar to NK cells, most CD8 T cells that express high levels of CD94 co-express NKG2A, the inhibitory isoform. The engagement of this receptor can lead to a blocking of cytotoxicity. However, these receptors have also been implicated in the cell survival of both NK and CD8T cells. The level of CD94 expression is inversely correlated with the level of apoptosis in culture. Thus, CD94/NKG2 receptors may regulate effector functions and cell survival of NK cells and CD8 T cells, thereby playing a crucial role in the innate and adaptive immune response to a pathogen.     

Dendritic cells and complement: at the cross road of innate and adaptive immunity

The interaction between different components of the immune system plays a pivotal role in the overall development of immune responses. Dendritic cells (DCs) and complement are essential components of innate immunity. They have been shown to be relevant both in the induction of adaptive immune responses and in maintenance of tolerance. However, hyperactivity of these systems has also been demonstrated to be detrimental in various disease states. Despite increased insight into dendritic cell biology, relatively little is known about possible interactions between dendritic cells and complement. This review focuses on novel findings, which have started to shed light on these intriguing components of the innate immune system.     

The circulating immunoglobulins involved in protective immunity to the intestinal stage of Nippostrongylus brasiliensis in the rat

Antisera taken from rats after one, two or three larval infections with Nippostrongylus brasiliensis or after one infection of adult worms were separated by chromatography and the fractions were tested for passive protective activity.

Irrespective of the number or type of infections given, protection against the parasite was most frequently obtained with fractions of antisera containing predominantly 7Sγ₁-globulin. γM- and γA-globulins sometimes appeared to contribute to protective activity, but γM-globulin was not the major source of protective antibodies in antisera taken after a primary infection either of adult worms or of larvae. 7Sγ₂-protective antibodies were found only in a pool of antiserum taken after three infections.

Rats were passively protected with antiserum or fractions of antiserum, which were free of reagins and of other identifiable anaphylactic antibodies. It appears that rats can be passively immunized with antisera which do not have anaphylactic activity.

     

The interface between innate and adaptive immunity

This focus analyzes some of the ways the innate immune system influences adaptive immune responses. Here the main principles and themes that govern this intricate relationship are discussed.     

Neutrophils in innate and adaptive immunity

Neutrophils have long been viewed as short-lived cells crucial for the elimination of extracellular pathogens, possessing a limited role in the orchestration of the immune response. This dogma has been challenged by recent lines of evidence demonstrating the expression of an increasing number of cytokines and effector molecules by neutrophils. Moreover, in analogy with their “big brother” macrophages, neutrophils integrate the environmental signals and can be polarized towards an antitumoural or protumoural phenotype. Neutrophils are a major source of humoral fluid phase pattern recognition molecules and thus contribute to the humoral arm of innate immunity. Neutrophils cross talk and shape the maturation and effector functions of other leukocytes in a direct or indirect manner, through cell–cell contact or cytokine production, respectively. Therefore, neutrophils are integrated in the activation and regulation of the innate and adaptive immune system and play an important role in the resolution or exacerbation of diverse pathologies, including infections, chronic inflammation, autoimmunity and cancer.     

Cytokines in innate and adaptive immunity

Cytokines and chemokines are hormone-like messengers which act to regulate the development and expression of the broad array of immune responses that are mounted against a variety of pathogens. As such, they are critical determinants of the types of cells which will regulate and participate in innate and adaptive immune responses, they may act both in highly localised environments but also in a systemic manner, and they may, themselves, directly mediate antimicrobial effector activities. In this article, we will outline current concepts of the activities of cytokines and chemokines in the immune response and discuss the various cell types, including dendritic cells and other antigen-presenting cells, T cells and B cells, which both produce and respond to these potent regulatory molecules.