Immune Insult Research Articles

Modulation of sexual signalling by immune challenged male mealworm beetles (Tenebrio molitor, L.): evidence for terminal investment and dishonesty

Organisms partition resources into life-history traits in order to maximise fitness over their expected lifespan. For the males of many species fitness is determined by qualitative and quantitative aspects of costly sexual signals: The notion that epigamic traits are costly forms the cornerstone of those theories that propose parasites drive sexual selection. Consequently studies examining this notion assume sexual signalling is honest (i.e. driven by cost) when they seek to identify correlations or causal links between male immune function and attractiveness. We demonstrate that immune challenged males of the mealworm beetle, Tenebrio molitor, increased their investment in epigamic pheromone signals: these males became significantly more attractive to females whilst increasing the activity of a key immune effector system. In other words males increase terminal reproductive effort (invest in attractiveness) in response to a survival threat (immune insult). Consequently the signal preferred by the female is dishonest when considering the male's condition.

3. Cytokines and chemokines

Cytokines and chemokines are secreted proteins with growth, differentiation, and activation functions that regulate the nature of immune responses. Cytokines are involved in nearly every facet of immunity and inflammation, from induction of the innate immune response to the generation of cytotoxic T cells and the development of antibodies by the humoral immune system. The combination of cytokines that are produced in response to an immune insult determines which arm of the immune system will be activated. For this update, recent advances in our understanding of cytokines will be discussed, which includes the IL-10, IL-17, and IL-27 families.

Selection on insect immunity in the wild

The strength of selection on immune function in wild populations has only been examined in a few vertebrate species. We report the results from a study measuring selection on a key insect immune enzyme, phenoloxidase (PO), in a wild population of the damselfly Calopteryx xanthostoma. We followed individually marked males from the pre-reproductive adult phase and recorded their lifetime mating success. We found positive selection on PO activity in response to an immune insult, but no selection on wing-spot quality, a trait actively displayed to females during courtship. We suggest that positive selection on PO activity in the year of study may be explained by annual fluctuations in parasite loads.

Sex and immunity in the yellow dung fly Scathophaga stercoraria

The immune system is of increasing interest to evolutionary biologists. Immunity may trade-off against other fitness components, with recent work suggesting reproduction in particular impinges on immune defence. There may also be sex differences in the immune system. Additionally, while life history traits typically have low heritability, little is known about additive genetic variance of immunity. An insect's major defence against multicellular pathogens is to encapsulate the invader. Phenoloxidase (PO) is a key enzyme in the cascade resulting in the melanized capsule, and is often used to estimate resistance to an immune insult. We examined the effects of copulation, egg laying, sex and age on PO in Scathophaga stercoraria. We also measured the heritability of PO activity. The sexes differed in haemolymph PO activity and PO was significantly affected by age, but not by copulation or egg laying. There was significant heritable variation for haemolymph PO.

COSTS OF AN INDUCED IMMUNE RESPONSE ON SEXUAL DISPLAY AND LONGEVITY IN FIELD CRICKETS

Immune system activation may benefit hosts by generating resistance to parasites. However, natural resources are usually limited, causing a trade-off between the investment in immunity and that in other life-history or sexually selected traits. Despite its importance for the evolution of host defense, state-dependent fitness costs of immunity received little attention under natural conditions. In a field experiment we manipulated the nutritional condition of male field crickets Gryllus campestris and subsequently investigated the effect of an induced immune response through inoculation of bacterial lipopolysaccharides. Immune system activation caused a condition-dependent reduction in body condition, which was proportional to the condition-gain during the preceding food-supplementation period. Independent of nutritional condition, the immune insult induced an enduring reduction in daily calling rate, whereas control-injected males fully regained their baseline level of sexual signaling following a temporary decline. Since daily calling rate affects female mate choice under natural conditions, this suggests a decline in male mating success as a cost of induced immunity. Food supplementation enhanced male life span, whereas the immune insult reduced longevity, independent of nutritional status. Thus, immune system activation ultimately curtails male fitness due to a combined decline in sexual display and life span. Our field study thus indicates a key role for fitness costs of induced immunity in the evolution of host defense. In particular, costs expressed in sexually selected traits might warrant the honest advertisement of male health status, thus representing an important mechanism in parasite-mediated sexual selection.

Macrophage accumulation and renal fibrosis are independent of macrophage migration inhibitory factor in mouse obstructive nephropathy

The progression of renal injury, initiated by either an immune or non-immune insult, is closely associated with the accumulation of leucocytes and fibroblasts in the damaged kidney. Macrophage migration inhibitory factor (MIF) regulates leucocyte activation and fibroblast proliferation in vitro. Studies have identified a pathological role for MIF in immune-initiated renal injury in the rat. In this study, we examined the role of MIF in obstructive nephropathy, where renal injury is initiated by a non-immune insult. Unilateral ureteric ligation was performed on MIF wildtype (+/+) and MIF deficient (-/-) mice. Groups of five mice were killed at days 0, 1, 5 or 10 after obstruction, and kidneys were examined via immunohistochemistry and northern blotting. In MIF +/+ mice, expression of the MIF protein increased in obstructed kidneys compared to normal control kidneys. Interstitial macrophage and T cell accumulation was significantly increased in obstructed kidneys at day 5 and 10, but was unaffected by MIF deficiency. Osteopontin and macrophage colony stimulating factor (M-CSF) mRNA expression in obstructed kidneys were equally increased in both genotypes, indicating that expression of these chemokines is not influenced by MIF. No difference was detected in the development of renal fibrosis in obstructed MIF +/+ and MIF -/- kidneys, as assessed by myofibroblast accumulation and proliferation and expression of profibrotic molecules (transforming growth factor-beta 1(TGF-beta1) and collagen). These results demonstrate that MIF expression is increased in obstructive nephropathy without affecting kidney leucocyte accumulation or the development of renal fibrosis. This suggests that the progression of renal injury in obstructive nephropathy is independent of MIF.

COSTS OF AN INDUCED IMMUNE RESPONSE ON SEXUAL DISPLAY AND LONGEVITY IN FIELD CRICKETS

Immune system activation may benefit hosts by generating resistance to parasites. However, natural resources are usually limited, causing a trade-off between the investment in immunity and that in other life-history or sexually selected traits. Despite its importance for the evolution of host defense, state-dependent fitness costs of immunity received little attention under natural conditions. In a field experiment we manipulated the nutritional condition of male field crickets Gryllus campestris and subsequently investigated the effect of an induced immune response through inoculation of bacterial lipopolysaccharides. Immune system activation caused a condition-dependent reduction in body condition, which was proportional to the condition-gain during the preceding food-supplementation period. Independent of nutritional condition, the immune insult induced an enduring reduction in daily calling rate, whereas control-injected males fully regained their baseline level of sexual signaling following a temporary decline. Since daily calling rate affects female mate choice under natural conditions, this suggests a decline in male mating success as a cost of induced immunity. Food supplementation enhanced male life span, whereas the immune insult reduced longevity, independent of nutritional status. Thus, immune system activation ultimately curtails male fitness due to a combined decline in sexual display and life span. Our field study thus indicates a key role for fitness costs of induced immunity in the evolution of host defense. In particular, costs expressed in sexually selected traits might warrant the honest advertisement of male health status, thus representing an important mechanism in parasite-mediated sexual selection.

2. Cytokines and chemokines

Cytokines and chemokines are redundant secreted proteins with growth, differentiation, and activation functions that regulate and determine the nature of immune responses and control immune cell trafficking and the cellular arrangement of immune organs. Which cytokines are produced in response to an immune insult determines initially whether an immune response develops and subsequently whether that response is cytotoxic, humoral, cell-mediated, or allergic. A cascade of responses can be seen in response to cytokines, and often several cytokines are required to synergize to express optimal function. An additional confounding variable in dissecting cytokine function is that each cytokine may have a completely different function, depending on the cellular source, target, and, most important, specific phase of the immune response during which it is presented. Numerous cytokines have both proinflammatory and anti-inflammatory potential; which activity is observed depends on the immune cells present and their state of responsiveness to the cytokine. For this chapter, cytokines are grouped according to those that are mononuclear phagocytic-derived or T-lymphocytic-derived; that mediate cytotoxic (antiviral and anticancer), humoral, cell-mediated, or allergic immunity; and that are immunosuppressive. The biology of chemokines are then reviewed, grouped by family. (J Allergy Clin Immunol 2003;111:S460-75.)

Luteotropic roles of prolactin in early pregnant hamsters.

Prolactin (PRL) has long been regarded as a luteotropin maintaining early pregnancy in rodents. To delineate luteotropic roles of PRL in terms of luteal vascularization and immune privilege, luteal expression of Thy-1 differentiation protein, Fas, and Fas ligand (FasL) in early pregnancy was studied in hamsters on Day 4 of pregnancy (P4 group). Release of pituitary PRL was blocked by daily treatment with bromocriptine (1 mg s.c. given at 1000 h) on Days 1-4 of pregnancy (PB group). PRL withdrawal induced functional luteolysis, as evidenced by a precipitous drop in serum progesterone to background levels. In situ 3' end-labeling of fragmented DNA (TUNEL method) also clearly showed that many apoptotic nuclei accumulated in the disintegrated luteal vessels in the corpus luteum in the PB group. Immunohistochemical studies showed that luteal Thy-1-positive vascular pericytes were abundant in the P4 group but rare in the PB group. Thus, PRL is essential for luteal vascularization in early pregnancy. Western blotting and quantitative real-time reverse transcription-polymerase chain reaction data showed that Fas protein and mRNA levels increased, whereas those of FasL decreased after PRL withdrawal. Accordingly, apoptosis initiated by Fas-FasL interaction is involved in the bromocriptine-induced luteolysis. Therefore, luteotropic roles of PRL are to support Thy-1 positive pericytes in maintaining proper luteal vascularization and to prevent immune insult by preserving a balance between luteal Fas and FasL expression in early pregnancy.

Investment in immune function under chronic and acute immune challenge in an insect

Summary In this paper we investigate the relationship between the chronic burden of mid-gut parasites (eugregarine trophozooites) and the effect of an acute haemolymph challenge (a nylon insert) on two important insect immune effector systems (phenol oxidase (PO) and the encapsulation response) in a field-population of damselflies. PO levels in the haemolymph, and the magnitude of the encapsulation response were maintained, regardless of chronic and subsequent acute experimental immune challenges. The maintenance of these effector systems is therefore probably an important life-history requirement in these damselflies. Investment in mid-gut PO levels was significantly negatively related to the animal's chronic parasite burden after an acute experimental challenge in the haemolymph, suggesting that maintaining PO levels across two physiological compartments (haemolymph and mid-gut) is costly. The results suggest that the immune effector system activity in different physiological compartments in an insect's body is affected by chronic parasite burdens in the face of the demands imposed by an acute immune insult.

Investment in immune function under chronic and acute immune challenge in an insect

SummaryIn this paper we investigate the relationship between the chronic burden of mid‐gut parasites (eugregarine trophozooites) and the effect of an acute haemolymph challenge (a nylon insert) on two important insect immune effector systems (phenol oxidase (PO) and the encapsulation response) in a field‐population of damselflies. PO levels in the haemolymph, and the magnitude of the encapsulation response were maintained, regardless of chronic and subsequent acute experimental immune challenges. The maintenance of these effector systems is therefore probably an important life‐history requirement in these damselflies. Investment in mid‐gut PO levels was significantly negatively related to the animal's chronic parasite burden after an acute experimental challenge in the haemolymph, suggesting that maintaining PO levels across two physiological compartments (haemolymph and mid‐gut) is costly. The results suggest that the immune effector system activity in different physiological compartments in an insect's body is affected by chronic parasite burdens in the face of the demands imposed by an acute immune insult.

Research on renal endothelin in proteinuric nephropathies dictates novel strategies to prevent progression.

Proteinuria is one of the major risk factors for renal disease progression in patients with chronic nephropathies. Studies in disease models have helped to delineate mechanisms leading to renal structural damage as a result of persistent dysfunction of the glomerular barrier to proteins, even when the primary immune or non-immune insult to the kidney has ceased. From these preclinical studies, a role for endothelin in proteinuric chronic renal diseases has been suggested, thus providing the rationale for novel therapeutic approaches with endothelin receptor antagonists to maximize renoprotection so far achieved with blockade of the renin-angiotensin system by angiotensin-converting enzyme inhibition or angiotensin II receptor antagonism. Trials are needed to explore this potential area of clinical interest.

Assessment of bone marrow stem cell reserve and function and stromal cell function in patients with autoimmune cytopenias

To investigate whether bone marrow (BM) stem cell compartment and/or BM microenvironment are affected by the immune insult in autoimmune cytopenias (AICs), BM stem cell reserve and function and BM stromal function were studied in 15 AIC patients. Stem cells were evaluated by means of flow cytometry, clonogenic progenitor cell assays, long-term BM cultures (LTBMCs), and limiting dilution assay for quantification of long-term–culture initiating cells (LTC-ICs). Stromal cell function was assessed with the use of preformed irradiated LTBMCs from patients and normal controls, recharged with normal CD34+ cells. AIC patients exhibited a high number of CD34+, CD34+/CD38+, and CD34+/CD38− cells; high frequency of granulocyte-macrophage colony forming units in the BM mononuclear cell fraction; high colony recovery in LTBMCs; and normal LTC-IC frequency. Patient BM stromal layers displayed normal hematopoietic-supporting capacity and increased production of granulocyte-colony stimulating factor. Data from this study support the concept that AIC patients with severe, resistant disease might be appropriate candidates for autologous stem cell transplantation.

Pathogenic principles in giant cell arteritis

In giant cell arteritis, an immune insult in the vascular wall initiates a reaction in the artery that leads to structural changes, intimal hyperplasia, and luminal occlusion. The mechanisms triggering the immune stimulation are unknown; however, the process is strictly dependent on T cells that are found in the vicinity of the vasa vasorum in the adventitia and that produce interferon-γ. The major effector cells in the artery are macrophages and giant cells that are ultimately under T-cell control but assume different functions depending on their location in the arterial wall. The response of the artery to the injury is maladaptive and includes mobilization and proliferation of smooth muscle cells in conjunction with matrix production and neoangionesis, resulting in the formation of a lumen-obstructive neointima. Heterogeneity in the immune insult and the resulting arterial response patterns correlate with variations in clinical disease.

Inducible (type II) nitric oxide synthase in human placental villous tissue of normotensive, pre-eclamptic and intrauterine growth-restricted pregnancies

We have utilized two distinct monospecific antibodies against the type II (macrophage or inducible) nitric oxide synthase (NOS) isoform to localize the distribution of the enzyme within the human placenta in tissues from normotensive pregnancies and those complicated by pre-eclampsia and/or intrauterine growth restriction. Both antibodies immunolocalize to cells in the villous stroma on frozen sections of villous tissue. Colocalization studies with anti-CD14 or anti-CD45 antibodies that recognize cells of leucocyte or monocyte/macrophage lineage indicate that Hofbauer cells are expressing type II NOS. This is in contrast to expression of type III (endothelial) NOS which is seen in syncytiotrophoblast and in villous vascular endothelium. In some, but not all, normotensive and pathologic placental tissue, some type II NOS immunostaining could be seen in syncytiotrophoblast and vascular endothelium; however, no differences could be discerned between groups of tissues. Expression of type II NOS by Hofbauer cells may indicate they are involved in surveillance against maternal immune insult or maternal pathogens whereby they secrete nitric oxide to exert a cytostatic/cytotoxic effect.

MOLECULAR BIOLOGY OF CYTOKINES IN ALLERGIC DISEASES AND ASTHMA

The repertoire of cytokines produced in response to an immune insult determines whether an immune response develops and whether the response will be humoral, cell-mediated, or allergic. Several cytokines particularly important in generating the allergic phenotype include those responsible for the IgE isotope switch (interleukin [IL]-4 and [IL]-13) ; eosinophil proliferation, recruitment, and activation (IL-5, IL-3, GM-CSF, RANTES, and MIP-1), and mast cell proliferation and activation (IL-3, IL-9, stem cell factor, RANTES, and MCP-1). Cytokines mediate cellular activation through a unique superfamily of receptors. These receptors transduce the biologic activity of their respective cytokines through a unique activation cascade termed the Jak-STAT pathway. Recognition of the importance of cytokines in allergic inflammation has led to the development of pharmacologic agents that modulate cytokine function and show promise in the treatment of allergic diseases.

Increased PGE 2 from human monocytes isolated in the luteal phase of the menstrual cycle. Implications for immunity?

The reproductive hormones are implicated in the well documented sexual dimorphism in cellular and immune responses. Prostaglandins (PGs) are mediators of the immune response with their concentration and relative amounts being pivotal to their impact. In resident peritoneal macrophages isolated from mice we had previously noted that the cells from females synthesized significantly more PG than males. In these experiments we investigated whether PG metabolism in the human monocyte was influenced by gender and by stage of the menstrual cycle. Monocytes isolated from the female and activated in vitro with LPS produced on average significantly more PG into the medium than the males. Among females, significantly more PG was found in the medium from cells isolated during the luteal phase of the cycle than during the early follicular phase. It was also in this luteal phase in which the female differed substantially from males. We suggest that the in vivo hormonal changes associated with the menstrual cycle modulate monocyte synthesis of PG and other immune modulators such as interleukin-1 (IL-1). This could be a key to understanding differences in vulnerability between males and females as well as within phases of the cycle, to immune and inflammatory insult.

Increased PGE 2 from human monocytes isolated in the luteal phase of the menstrual cycle. Implications for immunity?

The reproductive hormones are implicated in the well documented sexual dimorphism in cellular and immune responses. Prostaglandins (PGs) are mediators of the immune response with their concentration and relative amounts being pivotal to their impact. In resident peritoneal macrophages isolated from mice we had previously noted that the cells from females synthesized significantly more PG than males. In these experiments we investigated whether PG metabolism in the human monocyte was influenced by gender and by stage of the menstrual cycle. Monocytes isolated from the female and activated in vitro with LPS produced on average significantly more PG into the medium than the males. Among females, significantly more PG was found in the medium from cells isolated during the luteal phase of the cycle than during the early follicular phase. It was also in this luteal phase in which the female differed substantially from males. We suggest that the in vivo hormonal changes associated with the menstrual cycle modulate monocyte synthesis of PG and other immune modulators such as IL-1. This could be a key to understanding differences in vulnerability between males and females as well as within phases of the cycle, to immune and inflammatory insult.

Autoimmunity Causing Thyroid Dysfunction

Considerable evidence for a genetically induced antigen-specific defect in suppressor T lymphocytes as the basis for AITD has been derived from several laboratories and via different types of experimental techniques. This defect may result from abnormal antigen presentation to T lymphocytes via an aberrant antigen-specific HLA-related gene. In addition, there is now evidence for additive effects on reducing generalized suppressor T lymphocyte numbers and function by environmental factors as well as hyperthyroidism itself. These effects would be superimposed on the organ-specific defect. Such effects on generalized suppressor T lymphocyte numbers may act as precipitating and self-perpetuating factors. Presentation of the antigen by the thyroid cell via HLA-DR expression on its cell membrane does occur as a result of IFN-gamma production by T lymphocytes. This appears to be secondary to the initial specific immune assault and is not a primary inductive step. Although it may be important as an amplifying intermediate factor, antigen presentation cannot perpetuate the process in the absence of the underlying immune disorder. There is, indeed, no evidence for an underlying antigenic abnormality or stimulus in human autoimmune thyroid disease, and the initiating event would appear to be due to perturbation of the generalized immune system superimposed on the organ-specific immunoregulatory abnormality. Variations in the serologic and clinical expression of AITD would appear to depend on the severity of the original organ-specific disturbance in suppressor T lymphocyte function, plus the added factor of environmental influences playing on generalized suppressor T lymphocyte function and numbers. Remissions in Graves' disease brought about by antithyroid drugs may well be via their effect on modulating thyroid cell activity; this then reduces thyrocyte-immunocyte signaling, allowing remission to occur in those patients with a partial organ-specific defect in suppressor T lymphocytes.