Humoral Arm Research Articles

An acidic microenvironment sets the humoral pattern recognition molecule PTX3 in a tissue repair mode

Pentraxin 3 (PTX3) is a fluid-phase pattern recognition molecule and a key component of the humoral arm of innate immunity. In four different models of tissue damage in mice, PTX3 deficiency was associated with increased fibrin deposition and persistence, and thicker clots, followed by increased collagen deposition, when compared with controls. Ptx3-deficient macrophages showed defective pericellular fibrinolysis in vitro. PTX3-bound fibrinogen/fibrin and plasminogen at acidic pH and increased plasmin-mediated fibrinolysis. The second exon-encoded N-terminal domain of PTX3 recapitulated the activity of the intact molecule. Thus, a prototypic component of humoral innate immunity, PTX3, plays a nonredundant role in the orchestration of tissue repair and remodeling. Tissue acidification resulting from metabolic adaptation during tissue repair sets PTX3 in a tissue remodeling and repair mode, suggesting that matrix and microbial recognition are common, ancestral features of the humoral arm of innate immunity.

APC targeted micelle for enhanced intradermal delivery of hepatitis B DNA vaccine

Chronic hepatitis B is a serious liver disease and puts people at high risk of death from cirrhosis and liver cancer. Although DNA vaccination has been emerged as a potential immunotherapeutic strategy for the treatment of chronic hepatitis B, the efficiencies were not adequate in clinical trials. Here we describe the design, synthesis, and evaluation of mannosylated phenylalanine grafted chitosan (Man-CS-Phe) as a DNA delivery vector for direct transfection of antigen presenting cells to improve cellular and humoral immunity to plasmid-coded antigen. The cationic Man-CS-Phe micelles condense plasmid DNA into nanoscale polyplexes and provide efficient protection of complexed DNA from nuclease degradation. The mannose receptor-mediated enhanced cell uptake and high in vitro transfection efficiency of the polyplexes were demonstrated in RAW 264.7 and DC 2.4 cells using GFP-expressing plasmid DNA. Furthermore, intradermal immunization of BALB/c mice indicated that hepatitis B DNA vaccine/Man-CS-Phe polyplexes not only induced multi-fold higher serum antibody titer in comparison to all other formulations including FuGENE HD, but also significantly stimulated T-cell proliferation and skewed T helper toward Th1 polarization. These results illustrate that the Man-CS-Phe can serve as a promising DNA delivery vector to harness both cellular and humoral arms of immune system.

Drosophila blood cells and their role in immune responses.

Drosophilamelanogaster has been extensively used to study the humoral arm of innate immunity because of the developmental and functional parallels with mammalian innate immunity. However, the fly cellular response to infection is far less understood. Investigative work on Drosophila haemocytes, the immunosurveillance cells of the insect, has revealed that they fulfil roles similar to mammalian monocytes and macrophages. They respond to wound signals and orchestrate the coagulation response. In addition, they phagocytose and encapsulate invading pathogens, and clear up apoptotic bodies controlling inflammation. This review briefly describes the Drosophila haematopoietic system and discusses what is currently known about the contribution of haemocytes to the immune response upon infection and wounding, during all stages of development.

Recognition of Neisseria meningitidis by the long pentraxin PTX3 and its role as an endogenous adjuvant.

Long pentraxin 3 (PTX3) is a non-redundant component of the humoral arm of innate immunity. The present study was designed to investigate the interaction of PTX3 with Neisseria meningitidis. PTX3 bound acapsular meningococcus, Neisseria-derived outer membrane vesicles (OMV) and 3 selected meningococcal antigens (GNA0667, GNA1030 and GNA2091). PTX3-recognized microbial moieties are conserved structures which fulfil essential microbial functions. Ptx3-deficient mice had a lower antibody response in vaccination protocols with OMV and co-administration of PTX3 increased the antibody response, particularly in Ptx3-deficient mice. Administration of PTX3 reduced the bacterial load in infant rats challenged with Neisseria meningitidis. These results suggest that PTX3 recognizes a set of conserved structures from Neisseria meningitidis and acts as an amplifier/endogenous adjuvant of responses to this bacterium.

PTX3 Is an Extrinsic Oncosuppressor Regulating Complement-Dependent Inflammation in Cancer

PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3(-/-) mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation.

Complement activation-related pseudoallergy: insights into a stress reaction to nanomedicines in blood

The term “nanomedicine” is somewhat of a paradox. Although “nano” implies something very small, nanomedicines tend to be much larger than most medicines traditionally used in pharmacotherapy. The consequence of their larger size is that they are often mistaken by the immune system as pathogenic virus, an error that often sets off a defense reaction to eliminate the benevolent “intruder”. This unwarranted defense reaction may result not only in the loss of the medicine’s beneficial effect, but also in adverse effects on the patient. The immune reaction against intravenously applied nanomedicines may involve a rapid inflammatory-like hypersensitivity reaction, also known as infusion reaction, and/or a slow specific response manifested in antibody formation against the drug. The latter “immunogenicity” may prevent the drug from carrying out its specific and reproducible therapeutic mission, transforming it into a vaccine. Thus, immunogenicity of nanomedicines and biologicals with formation of anti-drug antibodies represents a major problem in modern pharmacotherapy. Accordingly, the phenomenon has attracted significant attention in the fields of experimental and clinical immunology and pharmacology. In contrast, the issue of infusion hypersensitivity reactions has received much less attention to date. One possible explanation for the difference is that immunogenicity prohibits the use of nanomedicines, while acute hypersensitivity reactions are in most cases preventable and manageable, their risk is accepted by the patient and the physician. Nevertheless, a small fraction of infusion reactions are not preventable, nor manageable, and cause life threatening or even fatal reactions. Due to this, hypersensitivity reactions represent a significant safety concern, for which testing in preclinical drug development is listed among the most recent regulatory recommendations. It has been increasingly recognized over the past 20 years that a major cause of acute infusion reactions to liposomeand micelle-based nanomedicines is their ability to activate the complement (C) system, which is the humoral arm of nonspecific immunity. This phenomenon was named C activation-related pseudoallergy or CARPA, a term that highlights the mechanism of the reaction. CARPA has been the subject of numerous studies and reviews to date, evolving into the broader claim that it is a manifestation of the commonly known “stress” phenomenon, wherein the body responds to external and internal noxious effects with a standard pattern of physiological changes. In the case of CARPA the noxious agents are nanoparticulate drugs mimicking viruses, the reaction proceeds via the anaphylatoxin-mast cell/macrophage axis rather than the hypothalamo-pituitary-adrenal one, and the effectors are allergy mediators rather than steroid hormones. As a reflection of growing awareness towards CARPA, the current and the 2015 July issue of the European Journal of Nanomedicine presents a series of reviews and research papers on CARPA, providing an unprecedented spectrum of old and new information on the subject. The topics addressed in the two issues include a historic account of how the concept developed from a problem in liposome research to the daring claim that CARPA is a universal stress reaction that may afflict most or all animals that have C in their blood; the types of reactogenic drugs and drug carrier nanosystems; the symptoms and mechanism of CARPA; the role of PIM cells; in vitro tests and animal models, especially pigs and rodents; prediction of CARPA in patients and approaches to prevention, as well as various other aspects of C activation and function. The guest editors of this two-part series strongly hope that the compilation of papers on CARPA in these freely accessible issues of the European Journal of Nanomedicine will significantly contribute to greater understanding of this relatively neglected subject and to its further research.

Virus-specific immune memory at peripheral sites of herpes simplex virus type 2 (HSV-2) infection in guinea pigs.

Despite its importance in modulating HSV-2 pathogenesis, the nature of tissue-resident immune memory to HSV-2 is not completely understood. We used genital HSV-2 infection of guinea pigs to assess the type and location of HSV-specific memory cells at peripheral sites of HSV-2 infection. HSV-specific antibody-secreting cells were readily detected in the spleen, bone marrow, vagina/cervix, lumbosacral sensory ganglia, and spinal cord of previously-infected animals. Memory B cells were detected primarily in the spleen and to a lesser extent in bone marrow but not in the genital tract or neural tissues suggesting that the HSV-specific antibody-secreting cells present at peripheral sites of HSV-2 infection represented persisting populations of plasma cells. The antibody produced by these cells isolated from neural tissues of infected animals was functionally relevant and included antibodies specific for HSV-2 glycoproteins and HSV-2 neutralizing antibodies. A vigorous IFN-γ-secreting T cell response developed in the spleen as well as the sites of HSV-2 infection in the genital tract, lumbosacral ganglia and spinal cord following acute HSV-2 infection. Additionally, populations of HSV-specific tissue-resident memory T cells were maintained at these sites and were readily detected up to 150 days post HSV-2 infection. Unlike the persisting plasma cells, HSV-specific memory T cells were also detected in uterine tissue and cervicothoracic region of the spinal cord and at low levels in the cervicothoracic ganglia. Both HSV-specific CD4+ and CD8+ resident memory cell subsets were maintained long-term in the genital tract and sensory ganglia/spinal cord following HSV-2 infection. Together these data demonstrate the long-term maintenance of both humoral and cellular arms of the adaptive immune response at the sites of HSV-2 latency and virus shedding and highlight the utility of the guinea pig infection model to investigate tissue-resident memory in the setting of HSV-2 latency and spontaneous reactivation.

Extracellular pattern recognition molecules in health and diseases.

The initiation of innate immune response relies on the recognition of pathogen-associated molecular patterns by pattern recognition molecules (PRMs), including the cellular pattern recognition receptors and extracellular soluble PRMs. Pattern recognition receptors such as Toll-like receptors (TLRs), NOD-like receptors and RIG-I like receptors are well documented cell-associated PRMs that sense microbial components on the cell surface, in the cytoplasm or in the nucleus of immune or non-immune cells to initiate the innate response to eliminate the invading pathogens.1,2 However, there is limited evidence of an extracellular PRM-mediated innate response to disease. In response to pathogen invasion, humoral PRMs are rapidly produced by a variety of cells and tissues, most notably by innate immune cells such as neutrophils, dendritic cells and macrophages. Extracellular humoral PRMs can be divided into different molecular families, primarily including pentraxins,3 collectins and ficolins.4 Accumulating evidence indicates that extracellular PRMs are important components of the humoral arm of innate immunity. They are able to recognize a variety of pathogenic agents and eliminate them through shared common mechanisms including complement activation, opsonization, agglutination, neutralization and regulation of inflammation (Figure 1). Moreover, extracellular PRMs also interact with cellular TLRs and regulate their function, jointly contributing to the recognition of microbial patterns and modulation of the innate immune responses.5,6,7,8

Priming by a novel universal influenza vaccine (Multimeric-001)—A gateway for improving immune response in the elderly population

BackgroundA new vaccine, “Multimeric-001” (M-001) has been recently developed, containing conserved, common linear influenza epitopes that activate both cellular and humoral arms of the immune system against a wide variety of influenza A and B strains. Apart from its direct action, M-001 is an attractive candidate for priming immune responses to seasonal influenza vaccine for the elderly population. The current clinical study was designed to assess M-001's standalone and priming action in participants over 65 years old. Evaluation of standalone action is based on induction of cell mediated immunity (CMI), since M-001 alone does not induce hemagglutinin inhibition (HAI) antibodies. MethodsThis was a two-center, randomized, placebo-controlled study. 120 participants were randomized 1:1:1:1 into four groups to receive either two sequential non-adjuvanted or a single non-adjuvanted or a single adjuvanted intramuscular injection of 500mcg M-001 (treatment), or one placebo (saline) injection, before receiving the trivalent inactivated influenza vaccine (TIV). Due to visual differences between placebo and treatment the study was partially blinded. HAI was evaluated at baseline and 3 weeks after standard TIV vaccination as a measure of M-001's efficacy. CMI responses were evaluated in a subset (10/group) of the participants. Participants were monitored for safety throughout the study. ResultsOverall the treatment was well-tolerated and safe, though sample sizes allowed only limited statistical analysis. M-001 priming resulted in enhanced seroconversion towards all three TIV strains, compared to priming with placebo. Significant elevation of influenza-specific CMI was observed following immunization with M-001 alone. ConclusionsThe standalone and priming actions of M-001 were demonstrated in elderly participants despite the limitations of small population size and pre-existing HAI antibody titers in some participants. As a standalone vaccine, M-001 induced significant CMI to multiple strains and as a primer, M-001 enhanced HAI responses. Larger scale studies are warranted. ClinicalTrials.gov registry numberNCT01419925.

Intracellular immunity: finding the enemy within--how cells recognize and respond to intracellular pathogens.

Historically, once a cell became infected, it was considered to be beyond all help. By this stage, the invading pathogen had breached the innate defenses and was beyond the reach of the humoral arm of the adaptive immune response. The pathogen could still be removed by cell-mediated immunity (e.g., by NK cells or cytotoxic T lymphocytes), but these mechanisms necessitated the destruction of the infected cell. However, in recent years, it has become increasingly clear that many cells possess sensor and effector mechanisms for dealing with intracellular pathogens. Most of these mechanisms are not restricted to professional immune cells nor do they all necessitate the destruction of the host. In this review, we examine the strategies that cells use to detect and destroy pathogens once the cell membrane has been penetrated.

Vaccination with Toxoplasma lysate antigen and CpG oligodeoxynucleotides: comparison of immune responses in intranasal versus intramuscular administrations.

Toxoplasma gondii (T. gondii) is one of the most successful intracellular protozoan parasites on earth and highly prevalent in most warm-blooded vertebrates. There are no drugs that target the chronic cyst stage of this infection; therefore, development of an effective vaccine would be an important advance in disease control. Oligodeoxynucleotides (ODN) which contain immunostimulatory CG motifs (CpG ODN) can promote T-helper 1 (Th1) responses, an adjuvant activity that is desirable for vaccination against intracellular pathogen. In this study, we compare the immune responses of Toxoplasma susceptible C57BL/6 mice following intranasal and intramuscular vaccination with Toxoplasma lysate antigen (TLA) with or without CpG ODN as adjuvant. Immunized and control non-immunized mice were challenged with 85 cyst of the moderately virulent Beverley strain of T. gondii. Intranasal vaccination gave significantly a higher protection compared to other groups as indicated by prolonged survival and significantly reduced brain cyst burden (P < 0.01). Intranasal vaccination stimulated cellular immunity towards Th1 response characterized by significant INF-γ production (P < 0.01). Furthermore, fecal IgA antibody levels as an indicator of mucosal immune responses were significantly higher (P < 0.05) in intranasal vaccinated group before the challenge compared to all other groups. Intranasal vaccination was not able to upgrade the Th1 humoral arm. In contrast, intramuscular vaccination enhanced humoral immunity towards a type Th1 pattern characterized by a significant increase of specific IgG and Ig2a. Our results suggest that intranasal administration of CpG/TLA would provide a stable, pronounced, and effective vaccine against toxoplasmosis through stimulation of Th1 cellular immunity and mucosal IgA.

Expression and regulation of complement receptors by human natural killer cells

Integration of cellular and humoral arms of the innate immune response is fundamental to the development of powerful effector functions in host defence as well as aberrant immune responses. Here, we provide evidence in support of the relationship between complement activation and NK cell functional modulation. We demonstrate that human NK cells and both CD56brightCD16− and CD56dimCD16+ populations express receptors known to detect the biologically active peptides C3a and C5a (i.e. C3aR, C5aR, C5L2) and the covalently-bound fragments C3b and metabolites iC3b and C3d which serve in immune adhesion (e.g. CR3, CR4). We also show that several pathogen- or tumour/inflammation-related stimuli differentially regulated those complement receptor expression. Furthermore, our results suggest that C3 fragments (C3a, iC3b) have a negative regulatory effect on IFN-γ production in NK cells. This work provides extensive information of human complement receptors relevant to the integrated actions of complement and NK cells which has been suggested by animal studies. The observations may act as a resource that allows further understanding and exploitation of role of complement in human health and immune mediated diseases.

The Humoral Pattern Recognition Molecule PTX3 Is a Key Component of Innate Immunity against Urinary Tract Infection

Immunity in the urinary tract has distinct and poorly understood pathophysiological characteristics and urinary tract infections (UTIs) are important causes of morbidity and mortality. We investigated the role of the soluble pattern recognition molecule pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, in UTIs. PTX3-deficient mice showed defective control of UTIs and exacerbated inflammation. Expression of PTX3 was induced in uroepithelial cells by uropathogenic Escherichia coli (UPEC) in a Toll-like receptor 4 (TLR4)- and MyD88-dependent manner. PTX3 enhanced UPEC phagocytosis and phagosome maturation by neutrophils. PTX3 was detected in urine of UTI patients and amounts correlated with disease severity. In cohorts of UTI-prone patients, PTX3 gene polymorphisms correlated with susceptibility to acute pyelonephritis and cystitis. These results suggest that PTX3 is an essential component of innate resistance against UTIs. Thus, the cellular and humoral arms of innate immunity exert complementary functions in mediating resistance against UTIs.

Current views of haemolytic streptococcal pathogenesis

Increasing disease caused by beta-haemolytic streptococci indicates the need for improved understanding of pathogenesis. Streptococcus pyogenes, or group A Streptococcus (GAS), causes significant disease worldwide. The closely related Streptococcus dysgalactiae subspecies equisimilis (SDSE) is increasingly recognized as causing a similar disease spectrum. Whole-genome sequencing applied to the study of outbreaks may reveal factors that contribute to pathogenesis and changes in epidemiology. The role of quorum sensing in biofilm formation, and interspecies communication with other streptococci, is discussed. GAS has evolved multiple mechanisms to evade the humoral arm of innate immunity, including complement, which is well known in protecting the host from bacteria, and the coagulation-fibrinolytic system, which is increasingly recognized as an innate immune effector. Molecular biology has enhanced our understanding of the intricate balance of host-pathogen interactions that result in clearance or establishment of invasive streptococcal infection. Although the skin and oropharynx remain the usual ecological niche of GAS and SDSE, occasionally the bacteria find themselves within deeper tissues and blood. Recent research has armed us with better knowledge of bacterial adaptations to this alternative environment. However, the challenge is to translate this knowledge into clinical practice, through the development of novel therapeutic options and ultimately a vaccine against GAS.

Sensitized Patients, Transplant, and Management

Sensitization to human leukocyte antigens (HLA) creates significant barriers for renal transplant candidates, reducing access to transplantation by limiting donor availability and increasing the risk of rejection. Sensitized patients also endure longer wait-times on dialysis. Desensitization protocols, kidney-paired donation, and a combination of both of these modalities have been used to remove or circumvent the clinically deleterious anti-HLA antibodies. Technical advances in antibody characterization methods and therapies targeting the humoral arm of the immune system have facilitated successful transplantation for these immunologically challenging patients. However, antibody-mediated rejection and transplant glomerulopathy resulting from injury to the vascular endothelium are major impediments to further improvement in outcomes. This review describes the assessment protocols, antibody monitoring techniques, and therapeutic strategies that have been used effectively to overcome HLA incompatibility.

MicroRNA-224 regulates Pentraxin 3, a component of the humoral arm of innate immunity, in inner ear inflammation

microRNAs (miRNAs) are regulators of differentiation and development of inner ear cells. Mutations in miRNAs lead to deafness in humans and mice. Among inner ear pathologies, inflammation may lead to structural and neuronal defects and eventually to hearing loss and vestibular dysfunction. While the genetic factors of these pathways have not been defined, autoimmunity participates in these processes. We report that inflammatory stimuli in the inner ear induce activation of the innate immune system via miR-224 and pentraxin 3 (Ptx3). miR-224 is a transcriptional target of nuclear factor κB, a key mediator of innate immunity. Ptx3 is a regulator of the immune response. It is released in response to inflammation and regulated by nuclear factor κB. We show that miR-224 and Ptx3 are expressed in the inner ear and we demonstrate that miR-224 targets Ptx3. As a model of the innate immune response, we injected lipopolysaccharide into the scala tympani of mouse inner ears. This resulted in changes in the levels of miR-224 and Ptx3, in addition to activation of the complement system, as measured by immune cell infiltration and activated C3. This suggests that while miR-224 regulates Ptx3 under normal conditions, upon inflammation, both are recruited to offer a front line of defense in acting as responders to inflammation in the inner ear. miR-224 diminishes the innate immune response by down-regulating Ptx3 expression, while Ptx3 stimulates the innate immune response. An understanding of the molecular components of the inflammatory pathway may help develop therapeutics for reducing inflammation associated with inner ear injury.

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

There is a need to develop a single and highly effective vaccine against the emerging chikungunya virus (CHIKV), which causes a severe disease in humans. Here, we have generated and characterized the immunogenicity profile and the efficacy of a novel CHIKV vaccine candidate based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). MVA-CHIKV was stable in cell culture, expressed the CHIKV structural proteins, and triggered the cytoplasmic accumulation of Golgi apparatus-derived membranes in infected human cells. Furthermore, MVA-CHIKV elicited robust innate immune responses in human macrophages and monocyte-derived dendritic cells, with production of beta interferon (IFN-β), proinflammatory cytokines, and chemokines. After immunization of C57BL/6 mice with a homologous protocol (MVA-CHIKV/MVA-CHIKV), strong, broad, polyfunctional, and durable CHIKV-specific CD8(+) T cell responses were elicited. The CHIKV-specific CD8(+) T cells were preferentially directed against E1 and E2 proteins and, to a lesser extent, against C protein. CHIKV-specific CD8(+) memory T cells of a mainly effector memory phenotype were also induced. The humoral arm of the immune system was significantly induced, as MVA-CHIKV elicited high titers of neutralizing antibodies against CHIKV. Remarkably, a single dose of MVA-CHIKV protected all mice after a high-dose challenge with CHIKV. In summary, MVA-CHIKV is an effective vaccine against chikungunya virus infection that induced strong, broad, highly polyfunctional, and long-lasting CHIKV-specific CD8(+) T cell responses, together with neutralizing antibodies against CHIKV. These results support the consideration of MVA-CHIKV as a potential vaccine candidate against CHIKV. We have developed a novel vaccine candidate against chikungunya virus (CHIKV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). Our findings revealed that MVA-CHIKV is a highly effective vaccine against chikungunya virus, with a single dose of the vaccine protecting all mice after a high-dose challenge with CHIKV. Furthermore, MVA-CHIKV is highly immunogenic, inducing strong innate responses: high, broad, polyfunctional, and long-lasting CHIKV-specific CD8(+) T cell responses, together with neutralizing antibodies against CHIKV. This work provides a potential vaccine candidate against CHIKV.

Pentraxin 3 as a Prognostic Biomarker in Patients with Systemic Inflammation or Infection

Purpose. The long pentraxin 3 (PTX3) is a key component of the humoral arm of the innate immune system. PTX3 is produced locally in response to proinflammatory stimuli. We reviewed the usefulness of systemic levels of PTX3 in critically ill patients with systemic inflammatory response syndrome (SIRS), sepsis, and bacteremia, focusing on its diagnostic and prognostic value. Methods. A PubMed search on PTX3 was conducted. The list of papers was narrowed to original studies of critically ill patients. Eleven papers on original studies of critically ill patients that report on PTX3 in SIRS, sepsis, or bacteremia were identified. Results. Systematic levels of PTX3 have little diagnostic value in critically ill patients with SIRS, sepsis, or bacteremia. Systemic levels of PTX3, however, have superior prognostic power over other commonly used biological markers in these patients. Systemic levels of PTX3 correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Finally, systemic levels of PTX3 remain elevated in the acute phase and decreased on recovery. Notably, the age of the patients and underlying disease affect systemic levels of PTX3. Conclusions. The diagnostic value of PTX3 is low in patients with sepsis. Systemic levels of PTX3 have prognostic value and may add to prognostication of patients with SIRS or sepsis, complementing severity-of-disease classification systems and other biological markers.

Regulatory B Cells: An Exciting Target for Future Therapeutics in Transplantation

Transplantation is the preferred treatment for most end-stage solid organ diseases. Despite potent immunosuppressive agents, chronic rejection remains a real problem in transplantation. For many years, the predominant immunological focus of research into transplant rejection has been T cells. The pillar of immunotherapy in clinical practice is T cell-directed, which efficiently prevents acute T cell-mediated allograft rejection. However, the root of late allograft failure is chronic rejection and the humoral arm of the immune response now emerges as an important factor in transplantation. Thus, the potential effects of Abs and B cell infiltrate on transplants have cast B cells as major actors in late graft rejection. Consequently, a number of recent drugs target either B cells or plasma cells. However, immunotherapies, such as the anti-CD20 B cell-depleting antibody, can generate deleterious effects on the transplant, likely due to the deletion of beneficial population. The positive contribution of regulatory B (Breg) cells or B10 cells has been reported in the case of transplantation, mainly in mice models and highlights the primordial role that some populations of B cells can play in graft tolerance. Yet, this regulatory aspect remains poorly characterized in clinical transplantation. Thus, total B cell depletion treatments should be avoided and novel approaches should be considered that manipulate the different B cell subsets. This article provides an overview of the current knowledge on the link between Breg cells and grafts, and reports a number of data advising Breg cells as a new target for future therapeutic approaches.

Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers

Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector function and biophysical features of HIV-specific antibodies in a cohort of controllers with and without protective HLA-B alleles in order to investigate whether there was evidence for multiple paths to HIV-1 control, or whether cellular and humoral arms of immunity might exhibit coordinated profiles. However, with the exception of IgG2 antibodies to gp41, HLA status was not associated with divergent humoral responses. This finding did not result from uniform antibody responses across subjects, as controllers could be regrouped according to strong differences in their HIV-specific antibody subclass specificity profiles. These divergent antibody profiles were further associated with significant differences in nonneutralizing antibody effector function, with levels of HIV-specific IgG1 acting as the major distinguishing factor. Thus, while HLA background among controllers was associated with minimal differences in humoral function, antibody subclass and specificity profiles were associated with divergent effector function, suggesting that these features could be used to make functional predictions. Because these nonneutralizing antibody activities have been associated with spontaneous viral control, reduced viral load, and nonprogression in infected subjects and protection in vaccinated subjects, understanding the specific features of IgGs with potentiated effector function may be critical to vaccine and therapeutic antibody development. In this study, we investigated whether the humoral and cellular arms of adaptive immunity exhibit coordinated or compensatory activity by studying the antibody response among HIV-1 controllers with different genetic backgrounds.