Hepatic Immune System: Adaptations to Alcohol.

Both the innate and adaptive immune systems are critical for the maintenance of healthy liver function. Immune activity maintains the tolerogenic capacity of the liver, modulates hepatocellular response to various stresses, and orchestrates appropriate cellular repair and turnover. However, in response to heavy, chronic alcohol exposure, the finely tuned balance of pro- and anti-inflammatory functions in the liver is disrupted, leading to a state of chronic inflammation in the liver.

Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis.

Recruitment of peripheral monocytes to the liver is a key contributor to the response to injury. MIF can act as a chemokine and cytokine, regulating innate immune responses in many tissues and cell types. We hypothesized that MIF contributes to the progression of CCl4-induced hepatic fibrosis by regulating recruitment of SAM.

Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis.

Unlabelled: Macrophage migration inhibitory factor (MIF), a multipotent protein that exhibits both cytokine and chemotactic properties, is expressed by many cell types, including hepatocytes and nonparenchymal cells. We hypothesized that MIF is a key contributor to liver injury after ethanol exposure. Female C57BL/6 or MIF-/- mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 (11% total kcal;early response) or 25 (32% kcal; chronic response) days.

Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice.

Background & Aims: Complement is involved in the development of alcoholic liver disease in mice; however, the mechanisms for complement activation during ethanol exposure have not been identified. C1q, the recognition subunit of the first complement component, binds to apoptotic cells, thereby activating the classical complement pathway. Because ethanol exposure increases hepatocellular apoptosis, we hypothesized that ethanol-induced apoptosis would lead to activation of complement via the classical pathway.

An early complement-dependent and TLR-4-independent phase in the pathogenesis of ethanol-induced liver injury in mice.

Unlabelled: The innate immune system has been implicated in the pathogenesis of alcoholic liver disease. Although innate immunity is usually considered an early response to injury, previous work implicating innate immunity in ethanol-induced liver injury focuses primarily on long-term ethanol exposure. We investigated the early period of ethanol exposure to determine whether there were temporal associations between activation of innate immune responses and known correlates of liver injury.

Role of complement in ethanol-induced liver injury.

The complement cascade is a phylogenetically ancient part of our immune system and is critical to an organism's ability to ward off infection. Interest in a possible role for the complement system in the development of ethanol-induced liver injury was inspired by the large body of data implicating the complement system in the development of acute and chronic inflammatory responses to bacteria/bacterial products, as well as in response to cell injury, both hallmarks of ethanol-induced liver injury. Recent investigations have demonstrated that complement is involved in the pathogenesis of ethanol-induced liver injury.

Differential contributions of C3, C5, and decay-accelerating factor to ethanol-induced fatty liver in mice.

Background And Aims: The complement pathway is an important component of the innate and adaptive immune response. Here we tested the hypothesis that activation of complement is required for development of ethanol-induced fatty liver.

Methods: Wild-type mice and mice lacking the third (C3) or fifth (C5) components of the complement activation pathway, as well as mice lacking decay-accelerating factor (CD55/DAF), a complement regulatory protein, were fed Lieber-DeCarli ethanol-containing diets for 6 weeks or pair-fed control diets.

The innate immune response to infection, toxins and trauma evolved into networks of interactive, defensive, reparative, regulatory, injurious and pathogenic pathways.

It is hypothesized that, under selective pressure from infections, trauma and toxins, multicellular organisms evolved an innate immune response (IIR): (1) comprising neural, endocrine, biochemical and cellular pathways that restore homeostasis through pathogen clearance, repair of injury and regulation of inflammation, but also mediate injury and disease; (2) that functions independently of as well as in concert with the adaptive immune response (AIR); (3) whose functions in health and disease depend upon cross-talk and networking among these pathways. A critical review of the literature provides strong evidence to support the evolution of the IIR, Propositions 1 and 2 and partial support for Proposition 3: there are numerous interactions among the mammalian IIR pathways, but there is no direct evidence for more complex functioning networks in vivo. Some implications and questions raised by the hypothesis are presented.

Blockade of macrophage migration inhibitory factor (MIF) in Schistosoma japonicum-infected mice results in an increased adult worm burden and reduced fecundity.

Macrophage migration inhibitory factor (MIF), a cytokine produced by many cell types, modulates cellular and humoral immune responses. In schistosomiasis, ova in the portal circulation induce a delayed type hypersensitivity (DTH) that results in formation of hepatic granulomas (HG) which secrete MIF activity. Therefore, we hypothesized that endogenous MIF modulates immune responses in schistosomiasis.

In vitro and in vivo regulation by macrophage migration inhibitory factor (MIF) of expression of MHC-II, costimulatory, adhesion, receptor, and cytokine molecules.

The secretion of macrophage migration inhibitory factor (MIF) is enhanced by inflammatory and other stimuli. MIF regulates innate and adaptive immune responses, but the mechanisms of this regulation are poorly understood. Our hypothesis was that MIF generated by these stimuli regulates these responses by modulating key molecular expression.

Upregulation of DAF (CD55) on orbital fibroblasts by cytokines. Differential effects of TNF-beta and TNF-alpha.

Purpose: Decay accelerating factor (DAF) and membrane cofactor protein (MCP) are membrane complement regulators that protect self cells from deposition of autologous C3b on their surfaces. CD59, a third downstream regulator of the cascade, prevents the assembly on self cells of autologous membrane-attack complexes. All three proteins are highly expressed on corneal and conjunctival epithelia, and are present in lower levels on multiple intraocular and adnexal cell types.

In vivo blockade of macrophage migration inhibitory factor prevents skin graft destruction after indirect allorecognition.

Background: The effector mechanisms that ultimately destroy transplanted tissues are poorly understood. In particular, it is not clear how CD4+ T cells primed to donor-derived determinants expressed on recipient MHC molecules (the indirect pathway) can mediate graft destruction in the absence of cognate recognition of peptide: MHC on the graft cells themselves. Macrophage migration inhibitory factor (MIF) inhibits macrophage movement and is a proinflammatory and regulatory cytokine known to be essential for development of delayed-type hypersensitivity reactions.

Murine schistosomiasis mansoni: coordinate cytokine regulation and differences in cellular immune responses of granuloma cells and splenocytes to endogenous and exogenous schistosome egg antigens.

To better understand the cellular immune mechanisms that regulate granulomatous inflammation to Schistosoma mansoni ova, we examined the dynamics of lymphocyte proliferation and cytokine expression by granuloma cells and splenocytes to endogenous and exogenous schistosome egg antigen (SEA) 6-19 weeks postinfection. Compared to splenocytes, granuloma cells (partially CD4+ cells) which are at the site of antigen release were highly activated by endogenous SEA and terminally differentiated as indicated by the more than 10-fold greater frequency of ex vivo interleukin (IL)-4, IL-5 and interferon (IFN)-gamma -secreting cells, greater levels of constitutive cytokine production and failure to proliferate to either endogenous or exogenous SEA. Endogenous cytokine production by granuloma cells was coordinately regulated, enhanced little by exogenous SEA, and temporally correlated with granulomatous inflammation.

Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes.

We recently described a novel population of blood-borne cells, termed fibrocytes, that display a distinct cell surface phenotype (collagen+/CD13+/CD34+/CD45+), rapidly enter sites of tissue injury, and contribute to scar formation. To further characterize the role of these cells in vivo, we examined the expression of type I collagen and cytokine mRNAs by cells isolated from wound chambers implanted into mice. Five days after chamber implantation, CD34+ fibrocytes but not CD14+ monocytes or CD90+ T cells expressed mRNA for type I collagen.

Deficiency of interleukin-2 production upon addition of soluble egg antigen to cultures of isolated hepatic granulomas or hepatic granuloma cells from mice infected with Schistosoma japonicum.

Schistosoma japonicum-infected C57BL/6 mice show similar dynamics of hepatic granulomatous inflammation and delayed hypersensitivity elicited by soluble egg antigens (SEA) which reach peak levels at 9 weeks of infection and then spontaneously regress. In an attempt to link the level of interleukin 2 (IL-2) production to the spontaneous regression of hepatic granulomatous inflammation, the study determined the dynamics of IL-2 production by SEA-challenged isolated hepatic granulomas (HG) and cells isolated enzymatically from the HG. The production of IL-2 by SEA-stimulated HG or HG cells reached its peak when these preparations from 9-week-infected mice were stimulated and fell thereafter.

Deficiency of interleukin-2 activity upon addition of soluble egg antigen to cultures of spleen cells from mice infected with Schistosoma japonicum.

Schistosoma japonicum-infected C57BL/6 mice show similar dynamics of hepatic granulomatous inflammation (HGI) and delayed hypersensitivity (DH) elicited by soluble egg antigens (SEA) which reach peak levels at 9 weeks of infection and then spontaneously regress. The in vitro SEA-induced proliferation of spleen cells (SC) from infected animals attained its high point and then declined when SC from 5-week-infected mice were used. The present study determined the dynamics of interleukin-2 (IL-2) production by SEA-challenged SC from infected mice in an attempt to link the level of IL-2 production to the spontaneous regression of the aforementioned T-cell-mediated immune responses.

Immune regulation in schistosomiasis japonica.

In schistosomiasis caused by the blood fluke, Schistosoma japonicum, the major lesion responsible for clinical disease is the granuloma formed in the liver as an immune response to the eggs deposited there. In this review Abram Stavitsky discusses the most recent evidence for the mechanisms involved in the formation and spontaneous regression of the granulomas and presents a working hypothesis to guide future research.

Inhibition of immediate and Arthus responses to schistosome egg antigens by T cells from Schistosoma japonicum-infected mice.

Schistosoma japonicum-infected mice develop hepatic granulomas, immediate hypersensitivity (IH), and delayed hypersensitivity (DH) to soluble egg antigens (SEA) released by parasite eggs trapped in liver sinusoids. All of these responses spontaneously regress after 7 to 9 weeks of infection. This study aimed to develop an in vivo system for the further dissection of cellular and humoral immune responses to SEA.

Mechanisms of in vivo modulation of granulomatous inflammation in murine schistosomiasis japonicum.

In schistosomiasis japonicum, the major pathologic lesion is the granulomatous inflammation that occurs around parasite eggs trapped in the liver. The size of these granulomas and their major sequela, a rise in portal pressure, both peak between 8 and 10 weeks after infection and then spontaneously decrease. We have shown that the adoptive transfer of the serum, but not lymphoid cells, of 30-week-infected mice caused decreases in both the size of the hepatic granulomas and the portal pressure of acutely infected recipient mice.

Regulation of egg antigen-induced in vitro proliferative response by splenic suppressor T cells in murine Schistosoma japonicum infection.

Beginning about 5 weeks after infection, C57BL/6J mice infected with Schistosoma japonicum developed granulomas around parasite eggs trapped in the liver. These granulomas attained peak size about 9 weeks after infection and then spontaneously regressed. This regression was also induced by the injection of serum immunoglobulin G1 but not lymphoid cells from chronically infected mice, but it was conceivable that lymphoid cells from mice infected for 10 weeks could also induce regression.

Mitogen-induced phosphorylation of cytosolic proteins in rabbit T- and B-lymphocytes.

The addition of anti-immunoglobulin (anti-Ig) to purified rabbit B-cells or concanavalin A (Con A) to purified rabbit T-cells within minutes resulted in the phosphorylation of a number of cytosolic proteins. Two-dimensional (2-D) electrophoresis and autoradiography of 32P-labeled cell sonicates was used to identify proteins whose phosphorylation was enhanced by these mitogens. Two proteins, pp58 and pp90, were phosphorylated 1.

Spontaneous and egg antigen-induced syntheses of immunoglobulin and antibody by spleen cells and hepatic granulomas of mice infected with Schistosoma japonicum.

In the absence of egg antigen (SEA), spleen cells from C57BL/6 mice infected for 22 weeks with Schistosoma japonicum were spontaneously induced in vitro to synthesize total immunoglobulin and antibody to SEA. Hepatic granulomas from mice infected for 12 weeks, but not for 22 weeks, also showed spontaneous syntheses of total immunoglobulin and antibody to SEA, but these syntheses were not enhanced upon the addition of SEA. Total immunoglobulin production was enhanced when SEA was added to spleen cells from mice infected for 4 to 7 weeks but not at any other time point.

Effects of trifluoperazine, a calmodulin antagonist, on rabbit T- and B-cell responses to mitogens and antigen.

Trifluoperazine (TFP), an inhibitor of the calcium-binding protein, calmodulin (CaM), was used to assess the role of calmodulin in the responses of rabbit lymphoid cells to stimulation with mitogen and antigen. After binding goat anti-rabbit Fab antibody, rabbit B cells lose their surface immunoglobulin (Ig) through endocytosis and then reexpress this protein during the next 24 hr. This reexpression was markedly inhibited by TFP.

Depressed in vitro and in vivo antibody response and adoptive transfer of delayed hypersensitivity to myoglobin with spleen cells of mice chronically infected with Schistosoma japonicum and injected with myoglobin.

Spleen cells from C57BL/6J mice infected for 21 weeks with Schistosoma japonicum did not show an in vitro secondary antibody response upon challenge with sperm whale myoglobin. Mice infected for 13 weeks showed almost no in vivo secondary antibody response to this antigen. Spleen cells from mice infected for 12 to 21 weeks did not adoptively transfer delayed hypersensitivity to this antigen.