ABSTRACT
Signal transducer and activator of transcription (STAT)1 heterozygous gain-of-function (GOF) mutations are known to induce immune dysregulation and chronic mucocutaneous candidiasis (CMCC). Previous reports suggest an association between demodicosis and STAT1 GOF. However, immune characterization of these patients is lacking. Here, we present a retrospective analysis of patients with immune dysregulation and STAT1 GOF who presented with facial and ocular demodicosis. In-depth immune phenotyping and functional studies were used to characterize the patients. We identified five patients (three males) from two non-consanguineous Jewish families. The mean age at presentation was 11.11 (range = 0.58-24) years. Clinical presentation included CMCC, chronic demodicosis and immune dysregulation in all patients. Whole-exome and Sanger sequencing revealed a novel heterozygous c.1386C>A; p.S462R STAT1 GOF mutation in four of the five patients. Immunophenotyping demonstrated increased phosphorylated signal transducer and activator of transcription in response to interferon-α stimuli in all patients. The patients also exhibited decreased T cell proliferation capacity and low counts of interleukin-17-producing T cells, as well as low forkhead box protein 3+ regulatory T cells. Specific antibody deficiency was noted in one patient. Treatment for demodicosis included topical ivermectin and metronidazole. Demodicosis may indicate an underlying primary immune deficiency and can be found in patients with STAT1 GOF. Thus, the management of patients with chronic demodicosis should include an immunogenetic evaluation.
Subject(s)
Gain of Function Mutation , Genetic Diseases, Inborn , Immune System Diseases , Mite Infestations , Mites/immunology , STAT1 Transcription Factor , Skin Diseases, Parasitic , Adolescent , Adult , Animals , Child , Chronic Disease , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/immunology , Genetic Diseases, Inborn/parasitology , Humans , Immune System Diseases/genetics , Immune System Diseases/immunology , Immune System Diseases/parasitology , Infant , Male , Middle Aged , Mite Infestations/genetics , Mite Infestations/immunology , Retrospective Studies , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/immunology , Skin Diseases, Parasitic/genetics , Skin Diseases, Parasitic/immunologyABSTRACT
Humans live in a microbial world that includes pathogenic bacteria, viruses, and fungi that cause lethal infections. In addition, a large number of microbial communities inhabit mucosal surfaces where they provide key metabolic activities, facilitating adaptation to changing environments. New genome technologies enable both sequencing of the human genome and sequence-based cataloging of microbial communities inhabiting human mucosal surfaces. These have revealed intricate two-way relationships between the microbiome and the genome, including strong effects of human genotypes on the composition and activity of the microbiome. Likewise, the microbiome plays an important role in training and regulating the immune system, and acts to modify expression of human genetic risk for debilitating chronic inflammatory and immune conditions. These studies are suggesting a new role of the microbiome in human health and disease.
Subject(s)
Genome, Human , Inflammation/parasitology , Microbiota/immunology , Chronic Disease , Genetic Predisposition to Disease , Humans , Immune System Diseases/parasitologyABSTRACT
Many immune-mediated diseases like inflammatory bowel disease, multiple sclerosis, type 1 diabetes, asthma, and food allergy appeared to have increased in frequency in developed countries in the latter part of the twentieth century. Reports from less developed countries suggest that the "epidemic" of immune-mediated diseases now is spreading into these regions as well. The "hygiene hypothesis" was developed to partly explain this phenomenon. It has been proposed that modern-day sanitary living has altered our exposure to organisms that provided protection from these diseases in the past. Alternations in the composition of our intestinal flora and fauna could play a role. Helminths are a group of worm-like parasitic organisms that have adapted to live in various regions of their hosts. Epidemiological and some clinical data suggest that these organisms can protect people from developing immune-mediated diseases. Animal experimentation has shown that helminths stimulate the production of regulatory cytokines, activate regulatory T cells, and induce regulatory dendritic cells and macrophages. This could be the mechanism by which they protect the host from these diseases. Early clinical studies also suggest that helminths may prove useful for treating immunological diseases. More sophisticated clinical studies are underway, testing live helminth agents as therapeutic agents. Also, a strong effort is ongoing to discover the agents produced by helminths that modulate host immune responses with an eye on developing new, highly effective immune modulatory therapeutic agent.
Subject(s)
Helminths/immunology , Immune System Diseases/therapy , Macrophages/immunology , T-Lymphocytes, Regulatory/immunology , Therapy with Helminths , Animals , Antigens, Helminth/immunology , Clinical Trials as Topic , Cytokines/metabolism , Humans , Hygiene Hypothesis , Immune System Diseases/immunology , Immune System Diseases/parasitology , Immunomodulation , Macrophages/parasitology , T-Lymphocytes, Regulatory/parasitologyABSTRACT
The use of live helminth infections is currently in clinical trials as a novel approach for the treatment of a range of allergic and autoimmune diseases. This rapid progression from observational studies some 20 years ago to helminth clinical trials can be attributed to huge advances in not just pre-clinical and clinical evidence, pertaining to the efficacy of these parasites in unrelated diseases, but also a greater understanding of the complex immunological mechanisms that underpin these effects. Helminths have exerted significant evolutionary selective pressures on the host immune genome or "immunome". Studies on helminths were pivotal in a paradigm shift in immunology with recent discoveries of a number of novel immune cell populations. Critically, these new discoveries highlight the need to further understand the underlying mechanism behind the desirable therapeutic effects that helminths offer. With these unknown unknowns there is the distinct possibility that a true, fundamental modus operandi for helminth therapy will arrive long after it has been established in the clinic.
Subject(s)
Helminths/immunology , Immune System Diseases/therapy , Therapy with Helminths , Animals , Helminths/physiology , Humans , Immune System Diseases/immunology , Immune System Diseases/parasitology , Translational Research, BiomedicalABSTRACT
Helminth parasites are masters of immune regulation; a likely prerequisite for long-term survival by circumventing their hosts' attempt to eradicate them. From a translational perspective, knowledge of immune events as a response to infection with a helminth parasite could be used to reduce the intensity of unwanted inflammatory reactions. Substantial data have accumulated showing that inflammatory reactions that promote a variety of auto-inflammatory diseases are dampened as a consequence of infection with helminth parasites, via either the mobilization of an anti-worm spectrum of immune events or by the direct effect of secretory/excretory bioactive immunomodulatory molecules released from the parasite. However, many issues are outstanding in the definition of the mechanism(s) by which infection with helminth parasites can affect the outcome, positively or negatively, of concomitant disease. We focus on a subgroup of this complex group of metazoan parasites, the cestodes, summarizing studies from rodent models that illustrate if, and by what mechanisms, infection with tapeworms ameliorate or exaggerate disease in their host. The ability of infection with cestodes, or other classes of helminth, to worsen a disease course or confer susceptibility to intracellular pathogens should be carefully considered in the context of 'helminth therapy'. In addition, poorly characterised cestode extracts can regulate murine and human immunocyte function, yet the impact of these in the context of autoimmune or allergic diseases is poorly understood. Thus, studies with cestodes, as representative helminths, have helped cement the concept that infection with parasitic helminths can inhibit concomitant disease; however, issues relating to long-term effects, potential side-effects, mixed pathogen infections and purification of immunomodulatory molecules from the parasite remain as challenges that need to be addressed in order to achieve the use of helminths as anti-inflammatory agents for human diseases.
Subject(s)
Cestoda/immunology , Cestode Infections/immunology , Host-Parasite Interactions , Immune System Diseases/immunology , Animals , Cestoda/physiology , Cestode Infections/parasitology , Humans , Immune System Diseases/parasitology , MiceABSTRACT
The success of helminth parasites is partly related to their ability to modulate host immune responses towards an anti-inflammatory/regulatory phenotype. This ability resides with the molecules contained in the secretome of various helminths that have been shown to interact with host immune cells and influence their function. Consequently, there exists a unique opportunity to exploit these molecules for the prophylactic and therapeutic treatment of human pro- and auto-inflammatory disorders (for example septic shock, transplant rejection and autoimmune disease). In this review, we describe the mechanisms used by the trematode parasite, Fasciola hepatica, to modulate the immune responses of its host and discuss the potent immune-modulatory effects of three individual molecules within the secretome; namely cathepsin L1, peroxiredoxin and helminth defence molecule. With a focus on the requirements from industry, we discuss the strategies by which these molecules may be clinically developed to control human immune responses in a way that is conducive to the prevention of immune-mediated diseases.
Subject(s)
Fasciola hepatica/immunology , Helminth Proteins/immunology , Immune System Diseases/therapy , Therapy with Helminths , Animals , Fasciola hepatica/physiology , Humans , Immune System Diseases/immunology , Immune System Diseases/parasitology , Protein TransportABSTRACT
Exposure to commensal and pathogenic organisms strongly influences our immune system. Exposure to helminths was frequent before humans constructed their current highly hygienic environment. Today, in highly industrialized countries, contact between humans and helminths is rare. Congruent with the decline in helminth infections is an increase in the prevalence of autoimmune and inflammatory disease. It is possible that exclusion of helminths from the environment has permitted the emergence of immune-mediated disease. We review the protective effects of helminths on expression of inflammatory bowel disease, multiple sclerosis, and animal models of these and other inflammatory diseases. We also review the immune pathways altered by helminths that may afford protection from these illnesses. Helminth exposure tends to inhibit IFN-γ and IL-17 production, promote IL-4, IL-10, and TGF-ß release, induce CD4(+) T cell Foxp3 expression, and generate regulatory macrophages, dendritic cells, and B cells. Helminths enable protective pathways that may vary by specific species and disease model. Helminths or their products likely have therapeutic potential to control or prevent immune-mediated illness.
Subject(s)
Helminths/pathogenicity , Host-Parasite Interactions/immunology , Immune System Diseases/prevention & control , Animals , Helminths/immunology , Humans , Immune System Diseases/immunology , Immune System Diseases/parasitology , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/parasitology , Inflammatory Bowel Diseases/prevention & control , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-7/immunology , Interleukin-7/metabolism , Multiple Sclerosis/immunology , Multiple Sclerosis/parasitology , Multiple Sclerosis/prevention & controlABSTRACT
Immune-mediated diseases (e.g. inflammatory bowel disease, asthma, multiple sclerosis and autoimmune diabetes) are increasing in prevalence and emerge as populations adopt meticulously hygienic lifestyles. This change in lifestyles precludes exposure to helminths (parasitic worms). Loss of natural helminth exposure removes a previously universal Th2 and regulatory immune biasing imparted by these organisms. Helminths protect animals from developing immune-mediated diseases (colitis, reactive airway disease, encephalitis and diabetes). Clinical trials show that exposure to helminths can reduce disease activity in patients with ulcerative colitis or Crohn's disease. This paper summarises work by multiple groups demonstrating that colonization with helminths alters immune reactivity and protects against disease from dysregulated inflammation.
Subject(s)
Helminths/immunology , Immune System Diseases/immunology , Inflammatory Bowel Diseases/immunology , Animals , Asthma/immunology , Asthma/parasitology , Asthma/therapy , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/parasitology , Diabetes Mellitus, Type 1/therapy , Disease Models, Animal , Helminthiasis/immunology , Helminthiasis/parasitology , Humans , Immune System Diseases/parasitology , Immune System Diseases/therapy , Inflammatory Bowel Diseases/parasitology , Inflammatory Bowel Diseases/therapy , Multiple Sclerosis/immunology , Multiple Sclerosis/parasitology , Multiple Sclerosis/therapyABSTRACT
Bacterial and protozoal infections can cause thrombocytopenia and may mimic idiopathic thrombocytopenic purpura (ITP). Brucella species and Toxoplasma are among the infectious agents with protean clinical manifestations which may induce immune thrombocytopenia. In rare cases, thrombocytopenia can be severe and may result bleeding into the skin and from mucosal sites. Prompt recognition of this complication and aggressive therapy are essential, since the mortality associated with bleeding into the central nervous system is high. We report two patients with complaints of severe epistaxis and thrombocytopenia associated with brucellosis and toxoplasmosis. Thrombocytopenic purpura in these cases responded well to the high-dose corticosteroid treatment with platelet recovery within 2-3 days. For cases with infection-induced immune thrombocytopenic purpura, short-term high-dose corticosteroids may be applied as an urgent therapy without worsening of the clinical condition.
Subject(s)
Brucellosis/complications , Immune System Diseases/microbiology , Immune System Diseases/parasitology , Purpura, Thrombocytopenic/microbiology , Purpura, Thrombocytopenic/parasitology , Toxoplasmosis/complications , Adrenal Cortex Hormones/administration & dosage , Adult , Dose-Response Relationship, Drug , Epistaxis/microbiology , Epistaxis/parasitology , Female , Humans , Immune System Diseases/drug therapy , Middle Aged , Purpura, Thrombocytopenic/drug therapyABSTRACT
It has been proposed that CD30, a member of the tumour necrosis factor (TNF) receptor superfamily, is preferentially up-regulated on Th2-type human T cells. In order to investigate a correlation between infection with Echinococcus multilocularis and CD30 expression, we analysed regulation of CD30 mRNA, a variant form of CD30 mRNA (CD30v) and CD30 ligand (CD30L) mRNA expression on PBMC from patients with alveolar echinococcosis (AE) using reverse transcriptase-polymerase chain reaction (RT-PCR). In PBMC of patients with AE as well as healthy donors, spontaneous expression of CD30L mRNA and the CD30v mRNA could be detected. However, the intact form of CD30 mRNA could be detected neither in freshly isolated PBMC of patients nor in PBMC of healthy individuals. Expression of CD30L mRNA and the variant form of CD30 mRNA was frequently detected at individual time points during 72 h of culture of PBMC stimulated with crude Echinococcus antigen. In contrast to CD30v or CD30L mRNA expression, induction of CD30 mRNA expression was detected only in three out of six (50%) healthy donors and in 10 out of 21 (48%) patients with alveolar echinococcosis after 72 h of incubation. As a control, mitogenic stimulation of PBMC of both healthy individuals and infected patients led to expression of intact CD30 mRNA within 24 h of culture. These data demonstrate the different expression of two different forms of CD30 mRNA in PBMC of human individuals. The specific induction of CD30 expression is correlated only in rare cases with the clinical status of patients with AE, indicating the lack of a general induction of CD30 mRNA in this Th2-type-dominated helminthic disease. The data provide further evidence that the CD30 receptor is not an exclusive marker for a Th2-type response.
Subject(s)
Echinococcosis, Pulmonary/genetics , Immune System Diseases/parasitology , Ki-1 Antigen/genetics , Leukocytes, Mononuclear/immunology , Membrane Glycoproteins/genetics , RNA, Messenger/genetics , Th2 Cells/immunology , Adult , Aged , CD3 Complex/analysis , CD30 Ligand , Cell Line , Female , Genetic Variation , Humans , Ki-1 Antigen/blood , Male , Membrane Glycoproteins/blood , Middle Aged , Pulmonary Alveoli/parasitology , RNA, Messenger/bloodABSTRACT
The infectious disease background and particularly the helminth infections that are endemic in Africa could have profound effects on the host immune system. Studies that we have performed on an Ethiopian HIV- immigrant population that has recently reached Israel, lend support to this notion. They have indeed revealed a very high prevalence of helminth and several other infections with an extreme immune dysregulation, consisting of: (i) highly elevated plasma IgE, IgG, placental isoferritin, p75 soluble TNF receptor (sTNFR) levels and very high blood eosinophilia; (ii) increased secretion from phytohaemagglutinin (PHA)-simulated peripheral blood mononuclear cells (PBMC) of the cytokines IL-2, IL-4, IL-10 and p75 sTNFR, and decreased secretion of interferon-gamma (IFN-gamma) and IL-6; (iii) increased and decreased surface expression of p75 TNFR and IL-6 receptor on lymphocytes, respectively. The causal relationship between this immune dysregulation and the infectious background is highly suggestive, and could have far-reaching implications in the resistance to other infections.
Subject(s)
Cytokines/biosynthesis , Helminthiasis/immunology , Immune System Diseases/parasitology , Leukocytes, Mononuclear/immunology , Black or African American , Black People , Cells, Cultured , Ethiopia/ethnology , Helminthiasis/ethnology , Humans , Immune System Diseases/epidemiology , Immune System Diseases/ethnology , Immunoglobulins/blood , Israel/epidemiology , Leukocytes, Mononuclear/pathologyABSTRACT
Although the definitive diagnosis of diseases caused by worms and protozoa depends upon the demonstration of adult parasite or its ovum in excreta, blood and tissue biopsies of the patient, immunological methods can be of help in the identification of associated immunological syndromes, pathogeneses of these infections in man and as a guide to therapy. However, the non-availability of pure antigens is a limiting factor in effective application of these tests. The present paper describes the immunological syndromes associated with these diseases as well as some of the in-use immunodiagnostic tests.