SummaryInterleukin-33 (IL-33) is a member of the IL-1 cytokine family. It predominantly induces type 2 immune responses and thus is protective against atherosclerosis and nematode infections but contributes to allergic airway inflammation. Interleukin-33 also plays a pivotal role in the development of many autoimmune diseases through mechanisms that are still not fully understood. In this review, we focus on the recent advances in understanding of the expression and function of IL-33 in some autoimmune disorders, aiming to provide insight into its potential role in disease development.

Interleukin-33 (IL-33) is a well-recognized immunomodulatory cytokine which plays critical roles in tissue function and immune-mediated diseases. The abundant expression of IL-33 in brain and spinal cord prompted many scientists to explore its unique role in the central nervous system (CNS) under physiological and pathological conditions. Indeed emerging evidence from over a decade's research suggests that IL-33 acts as one of the key molecular signaling cues coordinating the network between the immune and CNS systems, particularly during the development of neurological diseases. Here, we highlight the recent advances in our knowledge regarding the distribution and cellular localization of IL-33 and its receptor ST2 in specific CNS regions, and more importantly the key roles IL-33/ST2 signaling pathway play in CNS function under normal and diseased conditions.

Recent research findings have provided convincing evidence indicating a role for Interleukin-33 (IL-33) signalling pathway in a number of central nervous system (CNS) diseases including multiple sclerosis (MS) and Alzheimer’s disease. However, the exact function of IL-33 molecule within the CNS under normal and pathological conditions is currently unknown. In this study, we have mapped cellular expression of IL-33 and its receptor ST2 by immunohistochemistry in the brain tissues of MS patients and appropriate controls; and investigated the functional significance of these findings in vitro using a myelinating culture system. Our results demonstrate that IL-33 is expressed by neurons, astrocytes and microglia as well as oligodendrocytes, while ST2 is expressed in the lesions by oligodendrocytes and within and around axons. Furthermore, the expression levels and patterns of IL-33 and ST2 in the lesions of acute and chronic MS patient brain samples are enhanced compared with the healthy brain tissues. Finally, our data using rat myelinating co-cultures suggest that IL-33 may play an important role in MS development by inhibiting CNS myelination.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0344-1) contains supplementary material, which is available to authorized users.

BackgroundLarvae of several common species of parasitic nematodes obligately migrate through, and often damage, host lungs. The larvae induce strong pulmonary Type 2 immune responses, including T-helper (Th)2 cells as well as alternatively activated macrophages (AAMφ) and associated chitinase and Fizz/resistin family members (ChaFFs), which are thought to promote tissue repair processes. Given the prevalence of systemic or lung-resident Type 1-inducing pathogens in geographical areas in which nematodes are endemic, we wished to investigate the impact of concurrent Type 1 responses on the development of these Type 2 responses to nematode larval migration. We therefore infected BALB/c mice with the nematode Nippostrongylus brasiliensis, in the presence or absence of Plasmodium chabaudi chabaudi malaria parasites. Co-infected animals received both infections on the same day, and disease was assessed daily before immunological measurements were taken at 3, 5, 7 or 20 days post-infection.ResultsWe observed that the nematodes themselves caused transient loss of body mass and red blood cell density, but co-infection then slightly ameliorated the severity of malarial anaemia. We also tracked the development of immune responses in the lung and thoracic lymph node. By the time of onset of the adaptive immune response around 7 days post-infection, malaria co-infection had reduced pulmonary expression of ChaFFs. Assessment of the T cell response demonstrated that the Th2 response to the nematode was also significantly impaired by malaria co-infection.ConclusionP. c. chabaudi co-infection altered both local and lymph node Type 2 immune activation due to migration of N. brasiliensis larvae. Given recent work from other laboratories showing that N. brasiliensis-induced ChaFFs correlate to the extent of long-term lung damage, our results raise the possibility that co-infection with malaria might alter pulmonary repair processes following nematode migration. Further experimentation in the co-infection model developed here will reveal the longer-term consequences of the presence of both malaria and helminths in the lung.

BackgroundAntibody isotype responses can be useful as indicators of immune bias during infection. In studies of parasite co-infection however, interpretation of immune bias is complicated by the occurrence of cross-reactive antibodies. To confidently attribute shifts in immune bias to the presence of a co-infecting parasite, we suggest practical approaches to account for antibody cross-reactivity. The potential for cross-reactive antibodies to influence disease outcome is also discussed.ResultsUtilising two murine models of malaria-helminth co-infection we analysed antibody responses of mice singly- or co-infected with Plasmodium chabaudi chabaudi and Nippostrongylus brasiliensis or Litomosoides sigmodontis. We observed cross-reactive antibody responses that recognised antigens from both pathogens irrespective of whether crude parasite antigen preparations or purified recombinant proteins were used in ELISA. These responses were not apparent in control mice. The relative strength of cross-reactive versus antigen-specific responses was determined by calculating antibody titre. In addition, we analysed antibody binding to periodate-treated antigens, to distinguish responses targeted to protein versus carbohydrate moieties. Periodate treatment affected both antigen-specific and cross-reactive responses. For example, malaria-induced cross-reactive IgG1 responses were found to target the carbohydrate component of the helminth antigen, as they were not detected following periodate treatment. Interestingly, periodate treatment of recombinant malaria antigen Merozoite Surface Protein-119 (MSP-119) resulted in increased detection of antigen-specific IgG2a responses in malaria-infected mice. This suggests that glycosylation may have been masking protein epitopes and that periodate-treated MSP-119 may more closely reflect the natural non-glycosylated antigen seen during infection.ConclusionsIn order to utilize antibody isotypes as a measure of immune bias during co-infection studies, it is important to dissect antigen-specific from cross-reactive antibody responses. Calculating antibody titre, rather than using a single dilution of serum, as a measure of the relative strength of the response, largely accomplished this. Elimination of the carbohydrate moiety of an antigen that can often be the target of cross-reactive antibodies also proved useful.

When and how populations are regulated by bottom up vs. top down processes, and how those processes are affected by co‐occurring species, are poorly characterised across much of ecology. We are especially interested in the community ecology of parasites that must share a host. Here, we quantify how resources and immunity affect parasite propagation in experiments in near‐replicate ‘mesocosms’’ – i.e. mice infected with malaria (Plasmodium chabaudi) and nematodes (Nippostrongylus brasiliensis). Nematodes suppressed immune responses against malaria, and yet malaria populations were smaller in co‐infected hosts. Further analyses of within‐host epidemiology revealed that nematode co‐infection altered malaria propagation by suppressing target cell availability. This is the first demonstration that bottom‐up resource regulation may have earlier and stronger effects than top‐down immune mechanisms on within‐host community dynamics. Our findings demonstrate the potential power of experimental ecology to disentangle mechanisms of population regulation in complex communities.

Antigen specificity of adaptive immune responses is often in the host's best interests, but with important and as yet unpredictable exceptions. For example, antibodies that bind to multiple flaviviral or malarial species can provide hosts with simultaneous protection against many parasite genotypes. Vaccinology often aims to harness such imprecision, because cross-reactive antibodies might provide broad-spectrum protection in the face of antigenic variation by parasites. However, the causes of cross-reactivity among immune responses are not always known, and here, we explore potential proximate and evolutionary explanations for cross-reactivity. We particularly consider whether cross-reactivity is the result of constraints on the ability of the immune system to process information about the world of antigens, or whether an intermediate level of cross-reactivity may instead represent an evolutionary optimum. We conclude with a series of open questions for future interdisciplinary research, including the suggestion that the evolutionary ecology of information processing might benefit from close examination of immunological data.

Background Growing evidence points towards a role of gastrointestinal (GI) helminth parasites of ruminants in modifying the composition of the host gut flora, with likely repercussions on the pathophysiology of worm infection and disease, and on animal growth and productivity. However, a thorough understanding of the mechanisms governing helminth-microbiota interactions and of their impact on host health and welfare relies on reproducibility and replicability of findings. To this aim, in this study, we analysed quantitative and qualitative fluctuations in the faecal microbiota composition of lambs vaccinated against, and experimentally infected with, the parasitic GI nematode Teladorsagia circumcincta over the course of two separate trials performed over two consecutive years. Methods Two trials were conducted under similar experimental conditions in 2017 and 2018, respectively. In each trial, lambs were randomly assigned to one of the following experimental groups: (i) vaccinated/infected, (ii) unvaccinated/infected and (iii) unvaccinated/uninfected. Faecal samples collected from individual animals were subjected to DNA extraction followed by high-throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene and bioinformatics and biostatistical analyses of sequence data. Results Substantial differences in the populations of bacteria affected by immunisation against and infection by T. circumcincta were detected when comparing data from the two trials. Nevertheless, the abundance of Prevotella spp. was significantly linked to helminth infection in both trials. Conclusions Despite the largely conflicting findings between the two trials, our data revealed that selected gut microbial populations are consistently affected by T. circumcincta infection and/or vaccination. Nevertheless, our study calls for caution when interpreting data generated from in vivo helminth-microbiome interaction studies that may be influenced by several intrinsic and extrinsic host-, parasite- and environment-related factors.