Activation of the interferon‐γ signaling pathway in systemic lupus erythematosus peripheral blood mononuclear cells

Objective

To investigate interferon‐γ (IFNγ) signaling in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) by analyzing IFNγ receptor (IFNγR) expression, STAT‐1 expression and phosphorylation, and the regulation of IFNγ‐inducible genes.

Methods

Fluorocytometry was used to investigate expression of STAT‐1, pSTAT‐1, CD95, HLA–DR, class I major histocompatibility complex (MHC), IFNγ‐inducible 10‐kd protein (IP‐10), monokine induced by IFNγ (Mig), and IFNγR in PBMCs from SLE patients and healthy individuals. STAT‐1 phosphorylation was determined by fluorocytometry and Western blotting after stimulation with IFNα or IFNγ. Quantitative polymerase chain reaction was used to assess messenger RNA (mRNA) expression of the IFNγ‐inducible genes IP‐10 and Mig shortly after preparation or after stimulation with IFNγ in monocytes.

Results

STAT‐1 expression was increased in PBMCs from SLE patients and correlated significantly with disease activity and with the IFN‐inducible expression of CD95 and HLA–DR. STAT‐1 expression also showed a trend toward association with class I MHC expression. In addition, the expression of other IFNγ‐inducible genes, such as IP‐10 or Mig, was increased in SLE monocytes. While STAT‐1 phosphorylation in SLE PBMCs and PBMCs from healthy individuals was similar after IFNα stimulation, incubation with IFNγ induced STAT‐1 phosphorylation only in SLE lymphocytes. Moreover, SLE monocytes showed a considerably higher increase in pSTAT‐1 expression upon IFNγ stimulation than monocytes from healthy individuals. Increased responsiveness of SLE monocytes to IFNγ was also confirmed on the mRNA level, where expression of the IFN‐inducible, STAT‐1–dependent genes IP‐10 and Mig was more efficiently increased in SLE cells. However, IFNγR was similarly expressed on SLE lymphocytes and monocytes and those from healthy individuals.

Conclusion

In addition to supporting the role of IFNs in SLE immunopathogenesis in general, the findings of the present study support a role of IFNγ in this disease.

     

The dynamic changes of circulating invariant natural killer T cells during chronic hepatitis B virus infection

Aim

The protective role of invariant natural killer T cells (iNKTs) against hepatitis B virus (HBV) infection remains controversial. We sought to clarify the role of peripheral iNKT cells during chronic HBV infection.

Methods

Sixty patients with chronic HBV infection were categorized into an immune tolerance phase (HBV-IT) (n = 16), an immune clearance phase (HBV-IC) (n = 19) and an inactive carrier phase (HBV-IA) (n = 25). Twenty healthy individuals were enrolled as healthy controls. Another 21 HBeAg-positive patients were administrated with entecavir (0.5 mg/day) for 6 months. The percentages of circulating iNKT cells and their IFN-γ and IL-4 expression levels were examined by flow cytometry. The relationships between serum HBV DNA, ALT levels, the percentages of iNKT cells, and their IFN-γ and IL-4 levels were analyzed.

Results

Compared to healthy controls, the percentage of iNKT cells decreased in HBV-IT, but increased in HBV-IC and HBV-IA. Circulating IFN-γ-producing iNKT cells gradually increased, whereas IL-4-producing iNKT cells gradually decreased from HBV-IT stage to HBV-IC and HBV-IA stages. The frequency of iNKT cells and their IFN-γ levels were reversely correlated with viral load. The levels of IL-4 expressed by iNKT cells were positively correlated to viral load and the serum ALT levels. After anti-virus therapy, the percentage of IFN-γ-producing iNKT cells increased while the percentage of IL-4-producing iNKT cells decreased.

Conclusions

During chronic HBV infection, the percentages of peripheral iNKT cells and its cytokines expressions of IFN-γ and IL-4 showed dynamic changes. The expression levels of IFN-γ and IL-4 were correlated with the clearance of HBV and liver injury.

     

How do women with lupus manage fatigue? A focus group study

Objective

Half of patients with systemic lupus erythematosus (SLE) consider fatigue to be the most disabling disease symptom. To develop and promote strategies to prevent and control fatigue, this study aimed to describe how women with SLE manage the experience of fatigue.

Methods

Four focus groups were conducted with 27 women with SLE, and data were analyzed by means of framework analysis. Two patient representatives with SLE were part of the investigator team.

Results

The analysis revealed three main themes (i.e., learning how to be open about fatigue, learning to listen to the body, and learning to accept fatigue) and six sub-themes (i.e., the search for recognition, legitimization, planning and prioritizing, the body’s limits and self-indulgence, adjusting life to comply with resources, and acceptance of dependence).

Conclusion

Fatigue is the controlling element in everyday life of women with SLE. Patients try to integrate fatigue into their everyday lives by attempting to control it and meet the challenges of structure and planning. This study indicates a need for clinicians to acknowledge patients’ fatigue, including supporting patients’ own resources, offering information, and conversation about fatigue, as well as involving patients’ relatives.

     

Genetic association study of systemic lupus erythematosus and disease subphenotypes in European populations

Epidemiological studies suggest a strong contribution of genetic factors in the pathogenesis of systemic lupus erythematosus (SLE). In the last decades, many risk loci have been identified in several genetic association studies following both candidate gene and genome-wide approaches. The present work was conducted by GAPAID (Genes And Proteins for AutoImmunity Diagnostics) consortium with a dual aim: to replicate the association of several previously reported SLE susceptibility loci in an independent European sample and to explore their relation with some disease subphenotypes. A total of 48 single nucleotide polymorphisms (SNP) from 40 associated loci were typed in a cohort of 208 SLE patients and 152 controls from Rheumatology Units of the University Hospital of Pisa (Italy) and University of Pécs Medical Center (Hungary). Regression analyses were performed to detect disease susceptibility loci and to identify genes affecting specific disease manifestations (renal, neurological, or skin involvement; arthritis; secondary Sjögren syndrome; and secondary antiphospholipid syndrome). Association of previously described risk alleles from HLA locus has been replicated, while IRF5, BLK, ITGAM, and IRF8 loci have been found to be consistent with previous published results. In addition, two new subphenotype-specific associations have been detected: SNP rs5754217 (UBE2L3) with skin involvement and rs3093030 (ICAM1-ICAM4-ICAM5) with hematological disorders. Overall, results from GAPAID project are consistent with previously established associations for HLA, IRF5, BLK, ITGAM, and IRF8 SLE susceptibility loci and report for the first time two subphenotype-specific associations.     

Monogenic Lupus

Purpose of Review

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease known for its clinical heterogeneity. Over time, new insights into the complex genetic origin of SLE have started to explain some of this clinical variability. These findings, reviewed here, have also yielded important understanding in the immune mechanisms behind SLE pathogenesis.

Recent Findings

Several new monogenic disorders with lupus-like phenotype have been described. These can be organized into physiologic pathways that parallel mechanisms of disease in SLE. Examples include genes important for DNA damage repair (e.g., TREX1), nucleic acid sensing and type I interferon overproduction (e.g., STING, TREX1), apoptosis (FASLG), tolerance (PRKCD), and clearance of self-antigen (DNASE1L3).

Summary

Further study of monogenic lupus may lead to better genotype/phenotype correlations in SLE. Eventually, the ability to understand individual patients according to their genetic profile may allow the development of more targeted and personalized approaches to therapy.

     

High frequency of mutant thiopurine S-methyltransferase genotypes in Mexican patients with systemic lupus erythematosus and rheumatoid arthritis

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are treated with immunosuppressive purine analogs, 6-mercaptopurine/6-thioguanine/azathiopurine, which are inactivated by thiopurine S-methyltransferase (TPMT). Non-synonymous polymorphisms in TPMT are associated with increased risk of adverse effects in patients treated with thiopurines. This study aimed to determine the frequency of the most common mutant TPMT alleles in Mexican patients with SLE (a prototype autoimmune disease) and RA (one of the most common autoimmune diseases in Mexico). Five hundred fifty-three consecutive patients from Central Mexico with SLE (178) and RA (375) were included. Subjects were genotyped to identify TPMT*2 (rs1800462), TPMT*3A (rs1800460 and rs1142345), TPMT*3B (rs1800460), and TPMT*3C (rs1142345) mutant alleles. DNA samples were assayed with the 5′ exonuclease technique and TaqMan probes. Mutant alleles were detected in 6.2 and 5.2% of SLE and RA cases, respectively. Of note, 12.4% of SLE cases and 10.1% of RA cases carried mutant genotypes. Among those, the null genotype (TPMT*2/*3A, 0.3%) and the TPMT*3B (0.5%) and TPMT*3C (1.0%) alleles were found in RA, but not SLE cases. Mexican SLE cases displayed the highest frequency of mutant TPMT genotypes worldwide. TPMT genotyping should be performed for Mexican patients with SLE and RA before prescribing purine analogs.     

The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome

There is growing interest in the use of the ketogenic diet (KD) to treat inherited metabolic diseases including mitochondrial disorders. However, neither the mechanism whereby the diet may be working, nor if it could benefit all patients with mitochondrial disease, is known. This study focusses on decanoic acid (C10), a component of the medium chain triglyceride KD, and a ligand for the nuclear receptor PPAR-γ known to be involved in mitochondrial biogenesis. The effects of C10 were investigated in primary fibroblasts from a cohort of patients with Leigh syndrome (LS) caused by nuclear-encoded defects of respiratory chain complex I, using mitochondrial respiratory chain enzyme assays, gene expression microarray, qPCR and flow cytometry. Treatment with C10 increased citrate synthase activity, a marker of cellular mitochondrial content, in 50 % of fibroblasts obtained from individuals diagnosed with LS in a PPAR-γ-mediated manner. Gene expression analysis and qPCR studies suggested that treating cells with C10 supports fatty acid metabolism, through increasing ACADVL and CPT1 expression, whilst downregulating genes involved in glucose metabolism (PDK3, PDK4). PCK2, involved in blocking glucose metabolism, was upregulated, as was CAT, encoding catalase. Moreover, treatment with C10 also decreased oxidative stress in complex I deficient (rotenone treated) cells. However, since not all cells from subjects with LS appeared to respond to C10, prior cellular testing in vitro could be employed as a means for selecting individuals for subsequent clinical studies involving C10 preparations.     

<Emphasis Type="Italic">C-reactive protein</Emphasis> +1444CT (rs1130864) genetic polymorphism is associated with the susceptibility to systemic lupus erythematosus and C-reactive protein levels

The T rare allele of +1444CT (rs1130864) polymorphism of C-reactive protein (CRP) has been associated with increased CRP levels in some inflammatory conditions, but its role on systemic lupus erythematosus (SLE) susceptibility and on CRP levels in SLE patients remains uncertain. The objective of the study was to evaluate the association between the rs1130864 CRP polymorphism with SLE susceptibility, disease activity, and CRP levels in SLE Brazilian patients. The study enrolled 176 SLE patients and 137 controls. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). The rs1130864 CRP polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. SLE patients presented higher body mass index (p = 0.046) and CRP levels (p = 0.017) than controls. The genotype and allele frequencies of patients differed from controls [CC vs. CT = odds ratio (OR) 1.730, 95% confidence interval (CI) 1.068–2.803, p = 0.035; CC vs. TT = OR 3.667, 95% CI 1.410–9.533, p = 0.009; C vs. T = OR 1.883, 95% CI 1.299–2.728, p = 0.001)]. Patients carrying the T allele presented higher CRP levels (p = 0.009), were more frequent Caucasians (p = 0.018), and with no use of immunosuppressive treatment (p = 0.004) than those carrying the C allele. However, the SLEDAI and anti-double-stranded DNA positivity did not differ from those carrying T vs. C allele (p = 0.595 and p = 0.243, respectively). The rs1130864 CRP polymorphism was associated with SLE susceptibility and CRP levels, but not with disease activity, suggesting that this polymorphism may play a role in the pathophysiology of SLE through increasing the CRP that, probably, plays an inflammatory role in SLE pathophysiology.     

Complete genome sequence of the <Emphasis Type="Italic">Vibrio vulnificus</Emphasis> strain VV2014DJH,a human-pathogenic bacterium isolated from a death case in China

Background

Vibrio vulnificus, an opportunistic pathogen, is the causative agent of life-threatening septicemia and severe wound infections. However, the pathogenicity and virulence factors of V. vulnificus are not fully understood. Here we report the complete genome sequence of V. vulnificus VV2014DJH, which was isolated from a death case.

Results

The genome of the V. vulnificus VV2014DJH contains two circular chromosomes with a mean G+C content of 46.8%, but does not consists of any plasmids. The chromosome I and chromosome II consist of 3,303,590 and 1,770,972 bp, respectively. In addition, the genome consists of 4617 protein coding genes, 172 RNA genes and type I, II and III secretion systems were predicted.

Conclusions

In this study, the genomic information of the V. vulnificus VV2014DJH has been described. The information would contribute to the increasing scope and depth of Vibrio genome database, and provide insights into the pathogenicity and virulence factors of V. vulnificus.

     

Coordinate overexpression of interferon‐α–induced genes in systemic lupus erythematosus

Objective

To study the contribution of interferon‐α (IFNα) and IFNγ to the IFN gene expression signature that has been observed in microarray screens of peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE).

Methods

Quantitative real‐time polymerase chain reaction analysis of healthy control PBMCs was used to determine the relative induction of a panel of IFN‐inducible genes (IFIGs) by IFNα and IFNγ. PBMCs from 77 SLE patients were compared with those from 22 disease controls and 28 healthy donors for expression of IFIGs.

Results

Expression of IFNα‐inducible genes was significantly higher in SLE PBMCs than in those from disease controls or healthy donors. The level of expression of all IFIGs in PBMCs from SLE patients with IFNα pathway activation correlated highly with the inherent responsiveness of those genes to IFNα, suggesting coordinate activation of that cytokine pathway. Expression of genes preferentially induced by IFNγ was not significantly increased in SLE PBMCs compared with control PBMCs. IFNα‐regulated gene‐inducing activity was detected in some SLE plasma samples.

Conclusion

The coordinate activation of IFNα‐induced genes is a characteristic of PBMCs from many SLE patients, supporting the hypothesis that IFNα is the predominant stimulus for IFIG expression in lupus.

     

Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti–RNA binding protein autoantibodies

Objective

Peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) have increased expression of genes typically induced by type I interferon (IFN). However, it has been difficult to identify and quantify the factors responsible for activation of the IFN pathway in SLE. To characterize these mediators, we developed an assay that measures the functional effects of plasma or serum components on the gene expression of cultured target cells.

Methods

WISH epithelial cell line cells were cultured with medium, with recombinant IFNα, IFNβ, or IFNγ, or with 50% plasma from SLE patients (n = 73), rheumatoid arthritis (RA) patients (n = 19), or healthy donors (n = 30). Real‐time quantitative polymerase chain reaction was used to determine WISH cell expression of IFN target genes, including PRKR, IFIT1, IFI44, MX1, and C1orf29 (preferentially induced by IFNα) and CXCL9 (Mig) (preferentially induced by IFNγ).

Results

IFNα‐regulated genes were induced by SLE plasma samples, but not by most of the RA or healthy control plasma samples. The activity in SLE plasma was inhibited >90% by anti‐IFNα antibody, but not by anti‐IFNβ or anti‐IFNγ antibodies. The expression of each IFNα target gene induced by SLE plasma correlated with the expression of that gene studied ex vivo in PBMCs from the same patients and with the titer of anti–RNA binding protein (anti‐RBP)–specific autoantibodies. Plasma activity paralleled PBMC expression of IFNα‐inducible genes over time.

Conclusion

IFNα in SLE plasma is a major stimulus of IFN target gene expression and is related to expression of those genes in PBMCs from SLE patients and to the titer of anti‐RBP autoantibodies. These data provide additional support for the view that IFNα mediates immune system activation and dysregulation in SLE.

     

Analysis of PD-1 and Tim-3 expression on CD4<Superscript>+</Superscript> T cells of patients with rheumatoid arthritis; negative association with DAS28

Expression of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed cell death-1 (PD-1) was studied on CD4⁺ T cells of patients with rheumatoid arthritis (RA). Association of Tim-3 and PD-1 expression with disease activity of RA patients was also addressed. A total of 37 RA patients and 31 sex- and age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joints scoring system (DAS28). A three-color flow cytometry method was applied to determine the frequency of Tim-3⁺/PD-1⁺/CD4⁺ T cells. To measure the cytokine production, peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycin. Concentrations of IL-17, IL-10, IFN-γ, and TNF-α were measured in culture supernatants by ELISA. The frequency of PD-1⁺/CD4⁺ and Tim-3⁺/PD-1⁺/CD4⁺ T cells was significantly higher in patients with RA compared to that in controls (p?=?0.0013 and p?=?0.050, respectively). The percentage of Tim-3⁺/CD4⁺ T cells was similar in patients and controls (p?=?0.4498). The RA patients have produced significant higher levels of TNF-α, IL-17, and IFN-γ than those of healthy controls (p?=?0.0121, p?=?0.0417, and p?=?0.0478, respectively). Interestingly, an inverse correlation was found between the frequency of Tim-3⁺/CD4⁺ cells and DAS28 of RA patients (r?=???0.4696, p?=?0.0493). Similarly, the percentage of Tim-3⁺/PD-1⁺/CD4⁺ T cells was also revealed an inverse correlation with DAS28 (r?=???0.5268, p?=?0.0493). Moreover, significant positive correlations were detected between the concentrations of TNF-α (r?=?0.6418, p?=?0.0023) and IL-17 (r?=?0.4683, p?=?0.0373) with disease activity of RA patients. Our results indicate that Tim-3 and PD-1 are involved in immune dysregulation mechanisms of rheumatoid arthritis and could be considered as useful biomarkers for determination of disease activity and progression.     

Interferon-gamma release assay performance in northeastern Brazil: influence of the IFNG + 874 A>T polymorphism

Introduction

Latent tuberculosis infection diagnosis based on the release of interferon-gamma in cultures of peripheral blood cells stimulated with Mycobacterium tuberculosis antigens has replaced the tuberculin skin test in many countries with low tuberculosis prevalence. The IFN-γ production can be influenced by genetic polymorphisms, of which the IFNG + 874 (rs62559044) locus is the most studied. We investigated the possible influence of the IFNG + 874 A/T polymorphism on interferon-gamma test performance.

Mannose-binding lectin (MBL) codon 54 (rs1800450) polymorphism predisposes towards medium vessel vasculitis in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple etiological factors. Mannose-binding lectin (MBL) plays a key role in innate immunity by activating antibody-independent lectin complement pathway, opsonisation, phagocytosis, and immune complex (IC) clearance. Genetic polymorphisms in the promoter and coding regions of MBL gene affect the circulatory levels and biological activity of MBL. Defects in MBL can lead to defective opsonisation and, hence, hamper clearance of apoptotic debris, the persistence of which can drive autoantibody formation in lupus. The exon1 variants at codon 52, 54, and 57 have been reported to augment the risk of SLE in different ethnic populations. Three hundred South Indian Tamil patients with SLE and 460 age-, sex-, and ethnicity-matched controls were genotyped for three polymorphisms at codon 52, 54, and 57 in exon1 of MBL gene by Taqman real-time PCR. The three polymorphisms in exon1 of MBL were observed not to confer risk of developing SLE. However, MBL codon 54 rs1800450 polymorphism was associated with the development of medium vessel vasculitis and gangrene (OR-2.29, CI 95% 1.08–4.83, p = 0.02), whereas, the ancestral allele G conferred protection (OR-0.44, CI 95% 0.21–0.93, p = 0.02). Genetic variants in the exon1 of MBL gene per se are not risk factors for SLE in South Indian Tamils. However, the association of codon 54 (rs1800450) with medium vessel vasculitis suggests that it may be a genetic modifier of clinical phenotype in SLE.     

Angiotensin II type 1 receptor gene polymorphism and serum angiotensin-converting enzyme level in Egyptian children with systemic lupus erythematosus

Angiotensin II, the major effective molecule of the renin-angiotensin system, plays a vital role in the development of systemic lupus erythematosus (SLE). To study angiotensin II type 1 receptor (AT1R) gene polymorphism at (A1166C) in Egyptian children with SLE and its correlation with serum ACE level and SLE manifestations. AT1R gene polymorphism (A1166C) was done in 123 children with SLE in comparison to 100 healthy controls using polymerase chain reaction-based restriction fragment length polymorphism method (PCR-RFLP) and the tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) to confirm the results of the genotyping. Serum ACE level measurement was done using ELISA technique. The frequencies of C-containing genotypes (AC?+?CC) and C-allele of AT1R (A1166C) were significantly higher in SLE patients compared to controls (p?<?0.0001, OR?=?4.9, 95% CI?=?2.7–8.8; p ? 0.0001, OR?=?3.6, 95% CI?=?2.2–5.9, respectively). Lupus nephritis (LN) patients had significantly higher frequency of (AC?+?CC) genotypes and C-allele compared with controls (p ? 0.0001, OR?=?5.1, 95% CI?=?2.7–9.7; p ? 0.0001, OR?=?3.5, 95% CI?=?2.1–6.02, respectively). Mean serum ACE levels were significantly higher in SLE patients compared to controls (p ? 0.0001). There were no associations between AT1R gene polymorphism and serum ACE level and the clinical manifestations of SLE. The AT1R gene polymorphism can be considered a risk factor for the development of SLE in Egyptian children.     

Gene-based aggregate SNP associations between candidate AD genes and cognitive decline

Single nucleotide polymorphisms (SNPs) in and near ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, complement receptor 1 (CR1), EPHA1, EXOC3L2, FERMT2, HLA cluster (DRB5-DQA), INPP5D, MEF2C, MS4A cluster (MS4A3-MS4A6E), NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1 have been associated with Alzheimer’s disease (AD) in large meta-analyses. We aimed to determine whether established AD-associated genes are associated with longitudinal cognitive decline by examining aggregate variation across these gene regions. In two single-sex cohorts of older, community-dwelling adults, we examined the association between SNPs in previously implicated gene regions and cognitive decline (age-adjusted person-specific cognitive slopes) using a Sequence Kernel Association Test (SKAT). In regions which showed aggregate significance, we examined the univariate association between individual SNPs in the region and cognitive decline. Only two of the original AD-associated SNPs were significantly associated with cognitive decline in our cohorts. We identified significant aggregate-level associations between cognitive decline and the gene regions BIN1, CD33, CELF1, CR1, HLA cluster, and MEF2C in the all-female cohort and significant associations with ABCA7, HLA cluster, MS4A6E, PICALM, PTK2B, SLC24A4, and SORL1 in the all-male cohort. We also identified a block of eight correlated SNPs in CD33 and several blocks of correlated SNPs in CELF1 that were significantly associated with cognitive decline in univariate analysis in the all-female cohort.     

A broad upregulation of cerebral chemokine genes by peripherally-generated inflammatory mediators

Previously, we have shown that peripheral challenge of mice with double stranded RNA (dsRNA), a viral mimic, evokes global upregulation of cerebral inflammatory genes and, particularly, genes encoding chemokines. Because chemokine networks are potent modulators of brain function, the present study was undertaken to comprehensively characterize the cerebral response of chemokine ligand and receptor genes to peripheral immune system stimulation. Briefly, C57BL/6 mice were intraperitoneally injected with 12 mg/kg of polyinosinic-polycytidylic acid (PIC) and the expression of 39 mouse chemokine ligand and 20 receptor genes was monitored in the cerebellum by real time quantitative RT-PCR within 24 h. Almost half of the ligand genes featured either transient or sustained upregulation from several- to several thousand-fold. Five CXC type genes, i.e., Cxcl9, Cxcl11, Cxcl10, Cxcl2 and Cxcl1, were the most robustly upregulated, and were followed by six CC type genes, i.e., Ccl2, Ccl7, Ccl5, Ccl12, Ccl4 and Ccl11. Seven genes showed moderate upregulation, whereas the remaining genes were unresponsive. Six receptor genes, i.e., Cxcr2, Ccr7, Cxcr5, Ccr6, Ccr1 and Ccr5, featured a several-fold upregulation. Similar chemokine gene response was observed in the forebrain and brainstem. This upregulation of chemokine genes could be induced in naïve mice by transfer of blood plasma from PIC-challenged mice. Employing oligodeoxynucleotide-labeled PIC we further showed that intraperitoneally injected PIC was not transferred to the blood. In conclusion, peripheral PIC challenge elicits a broad upregulation of cerebral chemokine genes, and this upregulation is mediated by blood-borne agents.