Innate Immune Abnormalities Research Articles

Rare Autoimmune Diseases Role of Genetics - Example of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) presents a complex clinical landscape with diverse manifestations, suggesting a multifactorial etiology. However, the identification of rare monogenic forms of the disease has shed light on specific genetic defects underlying SLE pathogenesis, offering valuable insights into its underlying mechanisms and clinical heterogeneity. By categorizing these monogenic forms based on the implicated signaling pathways, such as apoptotic body clearance, type I interferon signaling, JAK-STAT pathway dysregulation, innate immune receptor dysfunction and lymphocytic abnormalities, a more nuanced understanding of SLE's molecular basis emerges. Particularly in pediatric populations, where monogenic forms are more prevalent, routine genetic testing becomes increasingly important, with a diagnostic yield of approximately 10% depending on the demographic and methodological factors involved. This approach not only enhances diagnostic accuracy but also informs personalized treatment strategies tailored to the specific molecular defects driving the disease phenotype.

Exploration of common genomic signatures of systemic juvenile rheumatoid arthritis and type 1 diabetes

To explore the genetic characteristics of systemic juvenile rheumatoid arthritis (sJRA) and type 1 diabetes mellitus (T1D). The microarray data of sJRA and T1D from Gene Expression Omnibus (GEO) were analyzed. The shared differentially expressed genes (SDEGs) were identified by the Meta-analysis, and genes of extracellular proteins were identified. Then, transcription factors (TFs) and their target genes in SDEGs were obtained by comparing databases from HumanTFDB, and hTFtarget. After that, functional enrichment analyses of the previously identified gene sets were performed by metascape tool. Finally, immune infiltration was analysed by CIBERSORT. We found 175 up-regulated and 245 down-regulated SDEGs, and by constructing a TFs-targeted SDEGs network, 3 key TFs (ARID3A, NEF2, RUNX3) were screened. Functional enrichment analyses and immune infiltration results suggested not only the adaptive immune system but also the innate immune system, and signaling pathways like JAK-STAT are important in the pathogenesis of sJRA and T1D, involving biological processes such as CD4 T cell functions and neutrophil degranulation. This work suggests that innate immune abnormalities also play important roles in sJRA and T1D, CD4 T cell functions, neutrophil degranulation and the JAK-STAT pathway may be involved. The regulatory roles of ARID3A, NEF2, and RUNX3 in this network need to be further investigated.

Periodic Fever in Children: A Report of Three Unusual Cases

Introduction: Periodic fever syndrome (PFS) is a rare monogenic autoinflammatory disease group. The innate immune system abnormalities have a characteristic onset and spontaneous inflammation without any infectious or autoimmune trigger. It differs from autoimmune disorders (e.g., systemic lupus erythematosus (SLE)) occurring due to a defect in the adaptive immune system with auto-antibodies. Case Presentation: The clinical features of three patients presented with a periodic pattern of fever and a different constellation of symptoms were investigated. The final diagnosis of Periodic fever syndrome was reached based on standard diagnostic criteria and genetic testing. All three cases were observed to present with recurrent fever episodes at an interval of 6 - 12 weeks, 3 - 4 weeks, and one month, respectively. The first patient, presenting with a diffuse erythematous plaque-like lesion along the calf with severe calf pain and tenderness with signs of meningeal irritation, was diagnosed with a tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) like phenotype. The genetic panel was negative in this case. The second patient presenting with recurrent pharyngitis, cervical adenitis, and tonsillitis unresponsive to antibiotics was diagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. The last patient presenting with recurrent monoarthritis, hepatosplenomegaly, and a positive Mediterranean fever (MEFV) gene mutation was diagnosed with familial Mediterranean fever (FMF). All three patients had normal growth and development. Conclusions: Although periodic fever syndrome was an uncommon entity, it was recommended that this syndrome should be considered when a patient presented with recurring fever episodes with a characteristic constellation of symptoms.

Innate and adaptive immune abnormalities underlying autoimmune diseases: the genetic connections.

With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between environmental and genetic factors. In a nutshell, etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage. In recent years, population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity, providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways. In this review, we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics. An overview of the genetic basis of autoimmunity is followed by 3 chapters detailing susceptibility genes involved in innate immunity, adaptive immunity and inflammatory cell death processes respectively. With such attempts, we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the 'usual suspects' of a limited subset of validated therapeutic targets.

Serum microRNAs in ASD: Association With Monocyte Cytokine Profiles and Mitochondrial Respiration.

Our previous research has shown that purified peripheral blood monocytes (PRMo) from individuals who are diagnosed with autism spectrum disorders (ASDs) and have innate immune abnormalities reveal altered interleukin-1ß (IL-1ß)/IL-10 ratios. We also found, in separate studies, that microRNA (miRNA) expression in PBMo and mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) differed in the IL-1ß/IL-10-based ASD subgroups. This study explored whether serum miRNAs are associated with both altered innate immune responses and changes in mitochondrial respiration as a link of regulatory mechanisms for these two common abnormalities in ASD subjects. Serum miRNA levels were examined by high-throughput deep sequencing in ASD and non-ASD control sera with concurrent measurement of PBMo cytokine production and mitochondrial respiration by PBMCs. ASD samples were examined as a whole group and with respect to the previously defined IL-1ß/IL-10-based ASD subgroups (high, normal, and low groups). Serum miRNA levels differed between the overall ASD sera (N = 116) and non-ASD control sera (N = 35) and also differed across the IL-1ß/IL-10-based ASD subgroups. Specifically, miRNA levels were increased and decreased in eight and nine miRNAs, respectively, in the high-ratio ASD subgroup (N = 48). In contrast, the low- (N = 25) and normal- (N = 43) ratio ASD subgroups only showed decreased miRNAs levels (18 and 10 miRNAs, respectively). Gene targets of the altered miRNAs in the high and/or low IL-1β/IL-10 ratio ASD subgroups were enriched in pathways critical for monocyte functions and metabolic regulation. Gene targets of the altered miRNAs in all the ASD subgroups were enriched in pathways of neuronal development and synaptic plasticity, along with cell proliferation/differentiation. ASD subgroup-specific associations were observed between serum miRNA expression and IL-1ß/IL-10 ratios, mitochondrial respiration, and monocyte cytokine profiles (IL-10, CCL2, and TNF-α). In summary, our results indicate that serum levels of select miRNAs may serve as promising biomarkers for screening and monitoring changes in innate immunity and mitochondrial respiration in ASD.

Interleukin-1β/Interleukin10 Ratio Produced by Monocytes as a Biomarker of Neuroinflammation in Autism

Objective: Innate immune abnormalities have been frequently reported in children with autism spectrum disorders (ASD), but a role of innate immunity in ASD is not well understood. This study explored a possible role of innate immunity in ASD clinical features and co-morbidities.Methods: Purified peripheral blood monocytes (PBMo) from ASD (N=125) and non-ASD (N=36) subjects were cultured overnight with or without stimulants of innate immunity, and production of pro-inflammatory and counter-regulator cytokines were assessed. Behavioral symptoms were assessed by aberrant behavioral checklist (ABC) at the time of PBMo sampling.Results: ASD PBMo revealed highly variable IL-1β/IL-10 ratios, in contrast to a tight range of IL-1β/IL-10 ratios in non-ASD control cells. There was no association between cytokine levels or IL-1β/IL-10 ratios and ABC subscale scores when ASD data was analyzed, as a whole. However, when ASD data was separated into high, low, or normal (equivalent to controls) IL-1β/IL-1 ratio groups, IL-1β levels were positively associated with stereotypy in the high ratio group. In contrast, IL-1β and IL-10 levels were negatively associated with irritability, lethargy, and hyperactivity in the normal ratio group. The low ratio group revealed a negative association between IL-1β levels and lethargy. When longitudinal changes in cytokine production from PBMo were studied in selected ASD subjects, fluctuating ratios were found in ASD subjects with deviated (high or low) IL-1β/IL-10 ratios, but ratios remained stable in ASD subjects with normal ratios. ASD subjects with deviated ratios were found to have higher frequencies of non-IgE mediated food allergy (NFA) (p<0.05) and seizure disorder (p<0.01) than those with normal ratios.Conclusion: IL-1β and IL-10 produced by innate immune responses play crucial roles in the neuroimmune network. Thus the deviated (high or low) IL-1β/IL-10 ratio from ASD monocytes may be a promising candidate biomarker for assessing changes of neuroimmune regulations and risk of comorbidities (NFA and seizure disorders) in ASD.

Immune Regulation of sickle Cell Alloimmunization.

Red blood cell (RBC) transfusion remains an important treatment for patients with sickle cell disease (SCD) and the majority of patients receive transfusions by adulthood. However, SCD patients are at a high risk of alloimmunization, which can cause life-threatening complications. The high rate of alloimmunization can in part be explained by chronic inflammatory condition in SCD characterized by significant immune and inflammatory activation. Heightened immune effector cell responses and/or impaired regulatory networks are likely to drive alloantibody production in alloimmunized SCD patients. In support of this, altered T cell immunoregulation, known to control antibody responses, have been reported in alloimmunized SCD patients. In addition, stronger follicular help T cell responses that help antibody production by B cells were described in alloimmunized as compared to non-alloimmunized SCD patients. Furthermore, several innate immune abnormalities have been identified in alloimmunized SCD patients, including a compromised anti-inflammatory response against extracellular cell free heme. The data support a model in which alloimmunized SCD patients are unable to switch off their proinflammatory state in response to the ongoing hemolytic state characteristic of SCD, placing this patient subset at a higher risk to develop a strong immune response against allogeneic determinants on transfused RBCs, thus increasing the risk of further alloimmunization. A detailed mechanistic understanding of innate immune abnormalities that can contribute to pathogenic T cell responses in alloimmunized SCD patients will lay the foundation for identification of biomarkers of alloimmunization with the goal that this information will ultimately help guide therapy in these patients.

Streptozotocin induced oxidative stress, innate immune system responses and behavioral abnormalities in male mice

Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction in the etiology of psychiatric disorders such as anxiety and depression. To investigate the possible role of mitochondrial-induced sterile inflammation in the co-occurrence of anxiety and depression, in this study, we treated adult male mice with the intracerebroventricular (i.c.v.) infusion of a single low dose of streptozotocin (STZ, 0.2mg/mouse). Using valid and qualified behavioral tests for the assessment of depressive and anxiety-like behaviors, we showed that STZ-treated mice exhibited behaviors relevant to anxiety and depression 24h following STZ treatment. We observed that the co-occurrence of anxiety and depressive-like behaviors in animals were associated with abnormal mitochondrial function, nitric oxide overproduction and, the increased activity of cytosolic phospholipase A2 (cPLA2) in the hippocampus. Further, STZ-treated mice had a significant upregulation of genes associated with the innate immune system such as toll-like receptors 2 and 4. Pathological evaluations showed no sign of neurodegeneration in the hippocampus of STZ-treated mice. Results of this study revealed that behavioral abnormalities provoked by STZ, as a cytotoxic agent that targets mitochondria and energy metabolism, are associated with abnormal mitochondrial activity and, consequently the initiation of innate-inflammatory responses in the hippocampus. Our findings highlight the role of mitochondria and innate immunity in the formation of sterile inflammation and behaviors relevant to anxiety and depression. Also, we have shown that STZ injection (i.c.v.) might be an animal model for depression and anxiety disorders based on sterile inflammation.

Autoimmunity and infection in common variable immunodeficiency (CVID).

Common variable immunodeficiency (CVID) is a heterogeneous group of diseases, characterized by primary hypogammaglobulinemia. B and T cell abnormalities have been described in CVID. Typical clinical features of CVID are recurrent airway infections; lymphoproliferative, autoinflammatory, or neoplastic disorders; and autoimmune diseases among which autoimmune thrombocytopenia (ITP) is the most common. The coexistence of immunodeficiency and autoimmunity appears paradoxical, since one represents a hypoimmune state and the other a hyperimmune state. Considering both innate and adaptive immune response abnormalities in CVID, it is easier to understand the mechanisms that lead to a breakdown of self-tolerance. CD21(low) B cells derive from mature B cells that have undergone chronic immune stimulation; they are increased in CVID patients. The expansion of CD21(low) B cells is also observed in certain autoimmune diseases. We have studied CD21(low) B cells in patients with CVID, CVID, and ITP and with ITP only. We observed a statistically significant increase in the CD21(low) population in the three pathological groups. Moreover, we found statistical differences between the two groups of CVID patients: patients with ITP had a higher percentage of CD21(low) cells. Our data suggest that CD21(low) cells are related to autoimmunity and may represent a link between infection and autoimmunity.

Alveolar-like Stem Cell-derived Myb(-) Macrophages Promote Recovery and Survival in Airway Disease.

Abnormal alveolar macrophages (AM) are found in chronic obstructive pulmonary disease, asthma, cystic fibrosis, and adenosine deaminase deficiency (ADA(-/-)). There is no specific treatment strategy to compensate for these innate immune abnormalities. Recent findings suggest AMs are of early embryonic or fetal origin. Pluripotent stem cells (PSCs) as a source of embryonic-derived AMs for therapeutic use in acute and chronic airway diseases has yet to be investigated. To determine if embryonic Myb(-/-) alveolar-like macrophages have therapeutic value on pulmonary transplantation in acute and chronic airway diseases. Directed differentiation of murine PSCs was used in factor-defined media to produce expandable embryonic macrophages conditioned to an alveolar-like phenotype with granulocyte-macrophage colony-stimulating factor. AMs were partially depleted in mice to create an acute lung injury. To model a chronic lung disease, ADA(-/-) mice were used. Alveolar-like macrophages were intratracheally transplanted to the injured animals and therapeutic potential was determined. The differentiation protocol is highly efficient and adaptable to human PSCs. The PSC macrophages are phenotypically like AMs both functionally and by ligand marker characterization. They engulf bacteria and apoptotic cells and are better phagocytes than bone marrow-derived macrophages. In vivo, these macrophages remain in healthy airways for at least 4 weeks, can engulf neutrophils during acute lung injury, enhance pulmonary tissue repair, and promote survival in ADA(-/-) mice. Animals receiving the macrophages do not develop abnormal pathology or teratomas. PSCs are a reliable source to produce therapeutically active alveolar-like macrophages to treat airway disease.

Feeding practices and nutritional status of HIV-exposed and HIV-unexposed infants in the Western Cape.

BackgroundOptimal infant- and young child–feeding practices are crucial for nutritional status, growth, development, health and, ultimately, survival. Human breast milk is optimal nutrition for all infants. Complementary food introduced at the correct age is part of optimal feeding practices. In South Africa, widespread access to antiretrovirals and a programme to prevent mother-to-child transmission of HIV have reduced HIV infection in infants and increased the number of HIV-exposed uninfected (HEU) infants. However, little is known about the feeding practices and nutritional status of HEU and HIV-unexposed (HU) infants.ObjectiveTo assess the feeding practices and nutritional status of HIV-exposed and HIV-unexposed (HU) infants in the Western Cape.DesignProspective substudy on feeding practices nested in a pilot study investigating the innate immune abnormalities in HEU infants compared to HU infants. The main study commenced at week 2 of life with the nutrition component added from 6 months. Information on children’s dietary intake was obtained at each visit from the caregiver, mainly the mother. Head circumference, weight and length were recorded at each visit. Data were obtained from 6-, 12- and 18-month visits. World Health Organization feeding practice indicators and nutrition indicators were utilised.SettingTygerberg Academic Hospital, Western Cape. Mothers were recruited from the postnatal wards.SubjectsForty-seven mother–infant pairs, 25 HEU and 22 HU infants, participated in this nutritional substudy. Eight (17%) infants, one HU and seven HEU, were lost to follow-up over the next 12 months. The HEU children were mainly Xhosa (76%) and HU were mainly mixed race (77%).ResultsThe participants were from poor socio-economic backgrounds. In both groups, adherence to breastfeeding recommendations was low with suboptimal dietary diversity. We noted a high rate of sugar- and salt-containing snacks given from a young age. The HU group had poorer anthropometric and nutritional indicators not explained by nutritional factors alone. However, alcohol and tobacco use was much higher amongst the HU mothers.ConclusionAdherence to breastfeeding recommendations was low. Ethnicity and cultural milieu may have influenced feeding choices and growth. Further research is needed to understand possible reasons for the poorer nutritional and anthropometric indicators in the HU group.

Advances in the genetically complex autoinflammatory diseases.

Monogenic diseases usually demonstrate Mendelian inheritance and are caused by highly penetrant genetic variants of a single gene. In contrast, genetically complex diseases arise from a combination of multiple genetic and environmental factors. The concept of autoinflammation originally emerged from the identification of individual, activating lesions of the innate immune system as the molecular basis of the hereditary periodic fever syndromes. In addition to these rare, monogenic forms of autoinflammation, genetically complex autoinflammatory diseases like the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, chronic recurrent multifocal osteomyelitis (CRMO), Behçet's disease, and systemic arthritis also fulfill the definition of autoinflammatory diseases-namely, the development of apparently unprovoked episodes of inflammation without identifiable exogenous triggers and in the absence of autoimmunity. Interestingly, investigations of these genetically complex autoinflammatory diseases have implicated both innate and adaptive immune abnormalities, blurring the line between autoinflammation and autoimmunity. This reinforces the paradigm of concerted innate and adaptive immune dysfunction leading to genetically complex autoinflammatory phenotypes.

Mechanisms of sickle cell alloimmunization

Red blood cell (RBC) alloimmunization can be a life-threatening complication for patients with sickle cell disease (SCD) receiving therapeutic transfusions. Despite provision of extended antigen-matched donor RBCs, patients continue to develop antibodies due to high degree of polymorphisms in the immunogenic antigens in individuals of African ancestry. Identification of biomarkers of alloimmunization in this patient population is therefore of great interest and will help to identify in advance patients most likely to make antibodies in response to transfusion. We have recently identified altered T cell responses and innate immune abnormalities in alloimmunized SCD patients. In this paper, we summarize this work and propose our working model of how innate immune abnormalities can contribute to pathogenic T cell responses in alloimmunized SCD patients. We believe that unravelling the basis of such altered interactions at the cellular and molecular level will help future identification of biomarkers of alloimmunization with the goal that this information will ultimately help guide therapy in these patients.

Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes.

Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematologic malignancies that are characterized by defective bone marrow (BM) hematopoiesis and by the occurrence of intramedullary apoptosis. During the past decade, the identification of key genetic and epigenetic alterations in patients has improved our understanding of the pathophysiology of this disease. However, the specific molecular mechanisms leading to the pathogenesis of MDS have largely remained obscure. Recently, essential evidence supporting the direct role of innate immune abnormalities in MDS has been obtained, including the identification of multiple key regulators that are overexpressed or constitutively activated in BM hematopoietic stem and progenitor cells. Mounting experimental results indicate that the dysregulation of these molecules leads to abnormal hematopoiesis, unbalanced cell death and proliferation in patients' BM, and has an important role in the pathogenesis of MDS. Furthermore, there is compelling evidence that the deregulation of innate immune and inflammatory signaling also affects other cells from the immune system and the BM microenvironment, which establish aberrant associations with hematopoietic precursors and contribute to the MDS phenotype. Therefore, the deregulation of innate immune and inflammatory signaling should be considered as one of the driving forces in the pathogenesis of MDS. In this article, we review and update the advances in this field, summarizing the results from the most recent studies and discussing their clinical implications.

Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype?

BackgroundSome children with autism spectrum disorders (ASD) are characterized by fluctuating behavioral symptoms following immune insults, persistent gastrointestinal (GI) symptoms, and a lack of response to the first-line intervention measures. These children have been categorized as the ASD-inflammatory subtype (ASD-IS) for this study. We reported a high prevalence of non-IgE mediated food allergy (NFA) in young ASD children before, but not all ASD/NFA children reveal such clinical features of ASD-IS. This study addressed whether behavioral changes of ASD-IS are associated with innate immune abnormalities manifested in isolated peripheral blood (PB) monocytes (Mo), major innate immune cells in the PB.MethodsThis study includes three groups of ASD subjects (ASD-IS subjects (N = 24), ASD controls with a history of NFA (ASD/NFA (N = 20), and ASD/non-NFA controls (N = 20)) and three groups of non-ASD controls (non-ASD/NFA subjects (N = 16), those diagnosed with pediatric acute onset-neuropsychiatric syndrome (PANS, N = 18), and normal controls without NFA or PANS (N = 16)). Functions of purified PB Mo were assessed by measuring the production of inflammatory and counter-regulatory cytokines with or without stimuli of innate immunity (lipopolysaccharide (LPS), zymosan, CL097, and candida heat extracts as a source of β-lactam). In ASD-IS and PANS subjects, these assays were done in the state of behavioral exacerbation (‘flare’) and in the stable (‘non-flare’) condition. ASD-IS children in the ‘flare’ state revealed worsening irritability, lethargy and hyperactivity.Results‘Flare’ ASD-IS PB Mo produced higher amounts of inflammatory cytokines (IL-1β and IL-6) without stimuli than ‘non-flare’ ASD-IS cells. With zymosan, ‘flare’ ASD-IS cells produced more IL-1β than most control cells, despite spontaneous production of large amounts of IL-1ß. Moreover, ‘flare’ ASD-IS Mo produced less IL-10, a counterregulatory cytokine, in response to stimuli than ‘non-flare’ cells or other control cells. These changes were not observed in PANS cells.ConclusionsWe observed an imbalance in the production of inflammatory (IL-1ß and IL-6) and counterregulatory (IL-10) cytokines by ‘flare’ ASD-IS monocytes, which may indicate an association between intrinsic abnormalities of PB Mo and changes in behavioral symptoms in the ASD-IS subjects.

Innate Immune Responses Differ In Patients With Food Protein Induced Enterocolitis Syndrome (fpies) Who Respond Well To The Restrictive Diet And Those Who Do Not

FPIES is a benign condition with an excellent response to the avoidance of the offending food, i.e., restrictive diet (RD). This study hypothesized that FPIES patients with poor responses to the RD (FPIES-PR) have innate immune abnormalities compared to those with good responses to the RD (FPIES-GR). This study include FPIES-PR (N=18, 1.1 -5.1 yr), FPIES-GR (N=18, 0.6-4.8 yr), and normal control (N=16, 1.0-5.5 yr) children. In addition to detailed clinical features and routine food allergy (FA) workup, we examined responses to agonists of toll like receptors (TLRs) and representative luminal antigens (Ags) (soy, cow's milk, and wheat proteins, and candida Ag) by measuring production of proinflammatory and counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) when their GI symptoms were under control following implementation of the RD. FPIES-PR children revealed more severe clinical features as evidenced by higher frequency of failure to thrive (FTT), requirement for the use of free amino acid (FAA) formulas, intolerance to probiotics, and severe anaphylaxis like reaction to rice than FPIES-GR children (all p<0.005). FPIES-PR PBMCs revealed lower production of counter-regulatory cytokine (sTNFRII and IL-10) in the absence of stimulus and with TLR 5, 7/8, and 9 agonists (sTNFRII) and with TLR2/6, 5, and 9 agonists (IL-10) as compared to normal controls. FPIES-GR PBMCs only revealed lower IL-10 production with TLR2/6 agonist than controls. These findings indicate that decreased production of counter-regulatory cytokines in response to stimuli of innate immunity may be associated with apparent failure of developing oral tolerance in FPIES-PR children.

Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes

Innate/adaptive immune responses and transcript profiles of peripheral blood monocytes were studied in ASD children who exhibit fluctuating behavioral symptoms following infection and other immune insults (ASD/Inf, N=30). The ASD/Inf children with persistent gastrointestinal symptoms (ASD/Inf+GI, N=19), revealed less production of proinflammatory and counter-regulatory cytokines with stimuli of innate immunity and marked changes in transcript profiles of monocytes as compared to ASD/no-Inf (N=28) and normal (N=26) controls. This included a 4–5 fold up-regulation of chemokines (CCL2 and CCL7), consistent with the production of more CCL2 by ASD/Inf+GI cells. These results indicate dysregulated innate immune defense in the ASD/Inf+GI children, rendering them more vulnerable to common microbial infection/dysbiosis and possibly subsequent behavioral changes.

Children with autism spectrum disorders experiencing neuropsychiatric symptoms, cognitive skills, and gastrointestinal symptoms exhibit distinct innate immune abnormalities and transcriptional profiles in peripheral blood monocytes (47.7)

Abstract ASD is considered a behavioral syndrome associated with multiple genetic and environmental factors. This study focuses on a subset of ASD children characterized by fluctuating behavioral symptoms and cognitive skills, triggered by immune insults, in addition to chronic GI symptoms (ASD-immune subtype; ASD-IS). The study included ASD-IS (N=19), control ASD (N=29), and normal control (N=26) children. We evaluated production of pro-inflammatory and counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in response to agonists of toll like receptors (TLRs), polyclonal T cell stimulants, and recall antigens (Ags), and transcriptional profiles of PB monocytes. ASD-IS PBMCs produced less pro-inflammatory (IL-1β, IL-6, IL-12, and IL-23) and counter-regulatory (IL-10 and sTNFRII) cytokines with TLR agonists and less Th1 cytokines (IFN-γ and TNF-α) with recall Ags than control cells. ASD-IS PBMC also produced higher amounts of CCL2 than controls. Transcript profiles of ASD-IS monocytes were distinguished by altered mRNA expression (&amp;gt;2x) in &amp;gt;900 genes compared with either ASD or normal controls. Among these, 392 genes overlapped in the two control groups, including genes regulating TLR signaling, inflammatory responses, cell migration/adhesion, chemokines (CCL2 and CCL7), and genes associated with risks for autism, sychizophrenia, and depression. Our findings indicate a role of innate immunity in the puzzling clinical features observed in ASD-IS children.

In This Issue

![Figure][1]</img> Disruptions in T and B cell immunity have long been known to be vital to the development of systemic lupus erythematosus (SLE). However, the roles of innate immune abnormalities in SLE pathogenesis are less thoroughly understood. Denny et al. (p. [3284][2]) sought to define the

A recent perspective on alcohol, immunity, and host defense.

Multiple line of clinical and experimental evidence demonstrates that both acute, moderate, and chronic, excessive alcohol use result in various abnormalities in the functions of the immune system. Medline and PubMed databases were used to identify published reports with particular interest in the period of 2000-2008 in the subject of alcohol use, infection, inflammation, innate, and adaptive immunity. This review article summarizes recent findings relevant to acute or chronic alcohol use-induced immunomodulation and its consequences on host defense against microbial pathogens and tissue injury. Studies with in vivo and in vitro alcohol administration are both discussed. The effects of alcohol on lung infections, trauma and burn injury, liver, pancreas, and cardiovascular diseases are evaluated with respect to the role of immune cells. Specific changes in innate immune response and abnormalities in adaptive immunity caused by alcohol intake are detailed. Altered inflammatory cell and adaptive immune responses after alcohol consumption result in increased incidence and poor outcome of infections and other organ-specific immune-mediated effects.