Sequential Multiple Assignment Randomized Treatment (SMART) for Bipolar Disorder at Any Phase of Illness and at least Mild Symptom Severity.

Objectives: To sequentially study the effectiveness of lithium and divalproex monotherapy and adjunctive therapy with quetiapine or lamotrigine in the acute and continuation treatment of bipolar I or II disorder at any phase of illness and at least mild symptom severity. Methods: From June 2011 to December 2016, patients with bipolar I or II disorder (using DSM-IV diagnostic criteria) and CGI-S (Clinical Global Impression-Severity) ⩾ 3 were randomized to receive lithium or divalproex monotherapy for 2 weeks. Patients who had CGI-S-depression ⩾ 3 for 2 weeks at any time after 2-week monotherapy were randomly assigned to receive quetiapine or lamotrigine, or remaining on monotherapy for a total of 26 weeks. Results: The rates of early termination due to lack of efficacy and side effects and changes in BISS (Bipolar Inventory of Symptoms Scale) and CGI-S total score were not significantly different between lithium and divalproex. The completion rate was significantly higher with adjunctive therapy than with monotherapy. BISS and CGI-S total scores, and their sub-scores were significantly reduced with adjunctive therapy compared to monotherapy. Adjunctive therapy significantly increased survival times compared to monotherapy (hazard ratio = 6.8), and the monotherapy group had a significantly increased risk for not reaching sustained recovery from depression (hazard ratio = 12.7). Patients who did not need the 2nd randomization and remained on monotherapy had a significantly reduced hazard for discontinuation (hazard ratio = 3.8). Conclusions: The efficacy of lithium and divalproex as monotherapy was modest. Adjunctive lamotrigine and quetiapine to either one was well-tolerated and equally effective in reducing bipolar symptomatology, but adjunctive therapy should be initiated as early as possible when depression symptoms are present.

Immune markers of social cognitive bias in schizophrenia.

Social cognition is impaired in schizophrenia, is relatively independent of purely neurocognitive domains such as attention and executive functioning, and may be the strongest predictor of functional outcome in this disease. Within a motivated reasoning framework, we tested the hypothesis that the anti-inflammatory Th2-associated cytokines, IL-10 and MDC, would be correlated with behavioral measures of social cognitive threat-detection bias (self-referential gaze detection bias and theory of mind (ToM) bias) in delusional versus non-delusional patients. We administered to schizophrenia patients with delusions (n=21), non-delusional patients (n=39) and controls (n=20) a social cognitive task designed to be sensitive to psychosocial stress response (the Waiting Room Task) and collected plasma levels of inflammatory markers using a bead-based flow immunoassay. Results partially supported our hypothesis. The anti-inflammatory cytokine IL-10 was associated with self-referential ToM bias in the delusional cohort as predicted, and not with non-delusional patients or healthy controls. This bias reflects a documented tendency of schizophrenia patients with delusions to excessively attribute hostile intentions to people in their environment. Since this cytokine correlated only with ToM bias and only in delusional patients, elevated levels of this cytokine in the blood may eventually serve as a useful biomarker distinguishing delusional patients from both non-delusional patients and healthy controls.

Investigating symptom domains of bipolar disorder for Spanish-speakers using the Bipolar Inventory of Symptoms Scale.

BACKGROUND: A Spanish language rating scale which assesses the range of bipolar disorder symptoms is needed. There are rating scales commonly used, however they do not address commonly expressed symptoms associated with bipolar disorder and have varied rating systems. There are also few comparisons of symptom severity between Spanish and English speaking patients, due to limitations in available rating scales. METHODS: We conducted psychometric assessment of the Spanish language Bipolar Inventory of Symptoms Scale (BISS) (N=71) for persons with bipolar disorder, which assesses 5 domains: mania, depression, irritability, anxiety and psychosis. The Spanish BISS scores were then compared to the MADRS (Montgomery Asberg Depression Rating Scale) and the YMRS (Young Mania Rating Scale) as well as to BISS scores in an English speaking sample (N=102) with bipolar disorder from the same geographic locations. RESULTS: Chronbach's alphas for the Spanish BISS ranged from 0.6 to 0.93, with the psychosis domain displaying lower reliability. Correlations with the MADRS and YMRS were good and ranged from 0.70 to 0.88. The BISS differentiated well across mood states in English and Spanish versions, with mood state differentiated well using subscales and domains. For the irritability and anxiety domains, Spanish speaking participants had higher scores than English speakers across mood states. Females showed differences in symptom profiles compared to males. LIMITATIONS: The sample sizes in the Spanish speaking manic group were small. The Spanish BISS, tested here primarily in patients of Mexican ancestry, may require revision in other Spanish language populations. CONCLUSIONS: The Spanish BISS, a Spanish language symptom rating scale for bipolar disorder, demonstrates good reliability and validity. Clinical assessment in anxiety and irritability domains is particularly relevant in a Spanish speaking sample. Consistent with prior research, females report higher depression, irritability and anxiety scores irrespective of language spoken.

Metabolomic profiling of schizophrenia patients at risk for metabolic syndrome.

Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia. However, SGAs cause metabolic disturbances that can manifest as metabolic syndrome (MetS) in a subset of patients. The causes for these metabolic disturbances remain unclear. We performed a comprehensive metabolomic profiling of 60 schizophrenia patients undergoing treatment with SGAs that puts them at high (clozapine, olanzapine), medium (quetiapine, risperidone), or low (ziprasidone, aripiprazole) risk for developing MetS, compared to a cohort of 20 healthy controls. Multiplex immunoassays were used to measure 13 metabolic hormones and adipokines in plasma. Mass spectrometry was used to determine levels of lipids and polar metabolites in 29 patients and 10 controls. We found that levels of insulin and tumor necrosis factor alpha (TNF-α) were significantly higher (p < 0.005) in patients at medium and high risk for MetS, compared to controls. These molecules are known to be increased in individuals with high body fat content and obesity. On the other hand, adiponectin, a molecule responsible for control of food intake and body weight, was significantly decreased in patients at medium and high risk for MetS (p < 0.005). Further, levels of dyacylglycerides (DG), tryacylglycerides (TG) and cholestenone were increased, whereas α-Ketoglutarate and malate, important mediators of the tricarboxylic acid (TCA) cycle, were significantly decreased in patients compared to controls. Our studies suggest that high- and medium-risk SGAs are associated with disruption of energy metabolism pathways. These findings may shed light on the molecular underpinnings of antipsychotic-induced MetS and aid in design of novel therapeutic approaches to reduce the side effects associated with these drugs.

Important role of CCR2 in a murine model of coronary vasculitis.

BACKGROUND: Chemokines and their receptors play a role in the innate immune response as well as in the disruption of the balance between pro-inflammatory Th17 cells and regulatory T cells (Treg), underlying the pathogenesis of coronary vasculitis in Kawasaki disease (KD). RESULTS: Here we show that genetic inactivation of chemokine receptor (CCR)-2 is protective against the induction of aortic and coronary vasculitis following injection of Candida albicans water-soluble cell wall extracts (CAWS). Mechanistically, both T and B cells were required for the induction of vasculitis, a role that was directly modulated by CCR2. CAWS administration promoted mobilization of CCR2-dependent inflammatory monocytes (iMo) from the bone marrow (BM) to the periphery as well as production of IL-6. IL-6 was likely to contribute to the depletion of Treg and expansion of Th17 cells in CAWS-injected Ccr2(+/+) mice, processes that were ameliorated following the genetic inactivation of CCR2. CONCLUSION: Collectively, our findings provide novel insights into the role of CCR2 in the pathogenesis of vasculitis as seen in KD and highlight novel therapeutic targets, specifically for individuals resistant to first-line treatments.

CD8α⁺ dendritic cells improve collagen-induced arthritis in CC chemokine receptor (CCR)-2 deficient mice.

OBJECTIVE: Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3⁺ regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGFß-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2⁻/⁻) mice had impaired DCs migration and reduced CD8α⁺ DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2⁻/⁻ mice, we tested the hypothesis that CD8α⁺ DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8α⁺ DCs in Ccr2⁻/⁻ and SKG mice. METHODS: To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8α⁺ DCs. RESULTS: Flt3L-mediated expansion of endogenous CD8α⁺ DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8α⁺ DCs ameliorated arthritis in Ccr2⁻/⁻ mice and enhanced TGFß1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype. CONCLUSION: CD8α⁺ DCs were tolerogenic to the development of arthritis. CD8α⁺ DCs deficiency heightened the sensitivity to arthritis in Ccr2⁻/⁻ mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2⁻/⁻ mice was T cell-independent.

In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation.

Neuregulin 1 (NRG1) has been implicated in several disorders including breast cancer, multiple sclerosis, and schizophrenia. Also, recent evidence suggests that NRG1 may play a role in regulation of inflammation and immune system response. We therefore hypothesized that a schizophrenia-associated missense mutation (valine to leucine) we identified within the transmembrane region of NRG1 would also be linked to immune dysregulation. We used plasma samples from families carrying the mutation to measure levels of antibodies to 41 autoimmune markers and six cytokines (IL-1b, IL-6, IL-10, IL-8, IL-12p70, and TNF-α) and used these levels as quantitative traits to evaluate association with the NRG1 mutation, using FBAT. Next, we used Epstein-Barr virus-transformed B cells from heterozygous mutation carriers and wild-type individuals to evaluate protein and mRNA cytokine expression in vitro using quantitative PCR and ELISA assays. In vivo, increased levels of 25 autoimmune markers as well as elevated levels of cytokines were significantly associated with the NRG1 mutation. In vitro, we observed a significant increase in protein secretion levels of IL-6, TNF-α, and IL-8 in mutation carriers compared with controls. At the mRNA level, we observed a significant increase in IL-6 expression, while IL-4 levels appeared to be down-regulated in heterozygous individuals compared with wild-type controls. This is the first report of association of a NRG1 mutation with immune dysregulation. This study could contribute towards understanding the role of NRG1 in the pathogenesis of schizophrenia and other disorders in which inflammation plays an important role.

CCR2 plays a critical role in dendritic cell maturation: possible role of CCL2 and NF-kappa B.

We postulated that CCR2-driven activation of the transcription factor NF-kappaB plays a critical role in dendritic cell (DC) maturation (e.g., migration, costimulation, and IL-12p70 production), necessary for the generation of protective immune responses against the intracellular pathogen Leishmania major. Supporting this notion, we found that CCR2, its ligand CCL2, and NF-kappaB were required for CCL19 production and adequate Langerhans cell (LC) migration both ex vivo and in vivo. Furthermore, a role for CCR2 in upregulating costimulatory molecules was indicated by the reduced expression of CD80, CD86, and CD40 in Ccr2(-/-) bone marrow-derived dendritic cells (BMDCs) compared with wild-type (WT) BMDCs. Four lines of evidence suggested that CCR2 plays a critical role in the induction of protective immunity against L. major by regulating IL-12p70 production and migration of DC populations such as LCs. First, compared with WT, Ccr2(-/-) lymph node cells, splenocytes, BMDCs, and LCs produced lower levels of IL-12p70 following stimulation with LPS/IFN-gamma or L. major. Second, a reduced number of LCs carried L. major from the skin to the draining lymph nodes in Ccr2(-/-) mice compared with WT mice. Third, early treatment with exogenous IL-12 reversed the susceptibility to L. major infection in Ccr2(-/-) mice. Finally, disruption of IL-12p70 in radioresistant cells, such as LCs, but not in BMDCs resulted in the inability to mount a fully protective immune response in bone marrow chimeric mice. Collectively, our data point to an important role for CCR2-driven activation of NF-kappaB in the regulation of DC/LC maturation processes that regulate protective immunity against intracellular pathogens.

Metabolomics tools for identifying biomarkers for neuropsychiatric diseases.

The repertoire of biochemicals (or small molecules) present in cells, tissue, and body fluids is known as the metabolome. Today, clinicians utilize only a very small part of the information contained in the metabolome, as revealed by the quantification of a limited set of analytes to gain information on human health. Examples include measuring glucose or cholesterol to monitor diabetes and cardiovascular health, respectively. With a focus on comprehensively studying the metabolome, the rapidly growing field of metabolomics captures the metabolic state of organisms at the global or "-omics" level. Given that the overall health status of an individual is captured by his or her metabolic state, which is a reflection of what has been encoded by the genome and modified by environmental factors, metabolomics has the potential to have a great impact upon medical practice by providing a wealth of relevant biochemical data. Metabolomics promises to improve current, single metabolites-based clinical assessments by identifying metabolic signatures (biomarkers) that embody global biochemical changes in disease, predict responses to treatment or medication side effects (pharmachometabolomics). State of the art metabolomic analytical platforms and informatics tools are being used to map potential biomarkers for a multitude of disorders including those of the central nervous system (CNS). Indeed, CNS disorders are linked to disturbances in metabolic pathways related to neurotransmitter systems (dopamine, serotonin, GABA and glutamate); fatty acids such as arachidonic acid-cascade; oxidative stress and mitochondrial function. Metabolomics tools are enabling us to map in greater detail perturbations in many biochemical pathways and links among these pathways this information is key for development of biomarkers that are disease-specific. In this review, we elaborate on some of the concepts and technologies used in metabolomics and its promise for biomarker discovery. We also highlight early findings from metabolomic studies in CNS disorders such as schizophrenia, Major Depressive Disorder (MDD), Bipolar Disorder (BD), Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD).

CCR5 expression levels influence NFAT translocation, IL-2 production, and subsequent signaling events during T lymphocyte activation.

Ligands of CCR5, the major coreceptor of HIV-1, costimulate T lymphocyte activation. However, the full impact of CCR5 expression on T cell responses remains unknown. Here, we show that compared with CCR5(+/+), T cells from CCR5(-/-) mice secrete lower amounts of IL-2, and a similar phenotype is observed in humans who lack CCR5 expression (CCR5-Delta32/Delta32 homozygotes) as well as after Ab-mediated blockade of CCR5 in human T cells genetically intact for CCR5 expression. Conversely, overexpression of CCR5 in human T cells results in enhanced IL-2 production. CCR5 surface levels correlate positively with IL-2 protein and mRNA abundance, suggesting that CCR5 affects IL-2 gene regulation. Signaling via CCR5 resulted in NFAT transactivation in T cells that was blocked by Abs against CCR5 agonists, suggesting a link between CCR5 and downstream pathways that influence IL-2 expression. Furthermore, murine T cells lacking CCR5 had reduced levels of intranuclear NFAT following activation. Accordingly, CCR5 expression also promoted IL-2-dependent events, including CD25 expression, STAT5 phosphorylation, and T cell proliferation. We therefore suggest that by influencing a NFAT-mediated pathway that regulates IL-2 production and IL-2-dependent events, CCR5 may play a critical role in T cell responses. In accord with our prior inferences from genetic-epidemiologic studies, such CCR5-dependent responses might constitute a viral entry-independent mechanism by which CCR5 may influence HIV-AIDS pathogenesis.

The XVth World Congress of Psychiatric Genetics, October 7-11, 2007: Rapporteur summaries of oral presentations.

The World Congress of Psychiatric Genetics (WCPG) has become an annual event since the early 1990's sponsored by the International Society of Psychiatric Genetics (ISPG). Each year the latest published and unpublished findings are aired for discussion by representatives of the majority of research programs on this topic world-wide. The 2007 congress was held in New York City and attracted over 1000 researchers. The topics emphasized included results from whole genome association studies, the significance of copy number variation and the important contributions of epigenetic events to psychiatric disorders. There were over 20 oral sessions devoted to these and other topics of interest. Young investigator recipients of travel awards served as rapporteurs to summarize sessions and these summaries follow.

Role of astrocytes and chemokine systems in acute TNFalpha induced demyelinating syndrome: CCR2-dependent signals promote astrocyte activation and survival via NF-kappaB and Akt.

Chemotactic factors known as chemokines play an important role in the pathogenesis of multiple sclerosis (MS). Transgenic expression of TNFalpha in the central nervous system (CNS) leads to the development of a demyelinating phenotype (TNFalpha-induced demyelination; TID) that is highly reminiscent of MS. Little is known about the role of chemokines in TID but insights derived from studying this model might extend our current understanding of MS pathogenesis and complement data derived from the classic autoimmune encephalomyelitis (EAE) model system. Here we show that in TID, chemokines and their receptors were significantly increased during the acute phases of disease. Notably, the CCL2 (MCP-1)-CCR2 axis and the closely related ligand-receptor pair CCR1-CCL3 (MIP-1alpha) were among the most up-regulated during disease. On the other hand, receptors like CCR3 and CCR4 were not elevated. This significant increase in the levels of chemokines/receptors correlated with robust immune infiltration of the CNS by inflammatory cells, i.e., macrophages, and immune cells particularly T and B cells. Immunostaining and confocal microscopy, along with in vitro studies revealed that astrocytes were a major source of locally produced chemokines and expressed functional chemokine receptors such as CCR2. Using an in vitro system we demonstrate that expression of CCR2 was functional in astrocytes and that signaling via this receptor lead to activation of NF-kB and Akt and was associated with increased astrocyte survival. Collectively, our data suggests that transgenic murine models of MS are useful to dissect mechanisms of disease and that in these models, up-regulation of chemokines and their receptors may be key determinants in TID.

CC chemokine receptor 5 influences late-stage atherosclerosis.

Members of the chemokine system, play a central role in inflammatory processes that underlie the pathogenesis of atherosclerosis and possibly, aortic valve sclerosis. Here we show that genetic inactivation of CC chemokine receptor 5 (CCR5) in the atherosclerosis-prone Apoe-/- mice (Apoe-/- Ccr5-/-) fed a normal chow or a high-fat diet (HFD) are protected against advanced atherosclerosis as well as age-associated aortic valve thickening (AAAVT)--a murine correlate of aortic valve sclerosis. Notably, human sclerotic valves contained CCR5+ cells. We confirm that Apoe-/- Ccr5-/- mice does not influence early-atherosclerotic stage. Adoptive transfer studies showed that the atheroprotective effect of CCR5 inactivation resided in the bone marrow compartment, but was not dependent on T-cells. The CCR5-null state was associated with phenotypes postulated to be atheroprotective such as reduced macrophage accumulation in the plaque, and lower circulating levels of IL-6 and MCP-5. The lack of CCR5 expression in Apoe-/- mice was also associated with higher numbers of endothelial progenitor cells (EPCs)--another postulated athero-protective factor. Compared with controls, carriers of a polymorphism in the Ccr5 gene that leads to the lack of CCR5 in the cell surface had an increased mean percentage of EPCs, but this difference did not reach statistical significance. Collectively, these findings underscore a critical role of CCR5 in age-associated cardiovascular diseases, and highlight that the effects of the chemokine system can be temporally constrained to distinct stages of these disease processes.

Development of a synthetic promoter for macrophage gene therapy.

Macrophages have the potential to deliver therapeutic genes to many target tissues. Macrophage-specific synthetic promoters (SPs) generated by random ligation of myeloid/macrophage cis elements had activity up to 100-fold that of a native macrophage promoter in macrophage cell lines, but were minimally active in nonmyeloid cells. Mouse bone marrow cells (BMCs) transduced ex vivo with lentivectors expressing green fluorescent protein (GFP) driven either by an SP (SP-GFP) or a cytomegalovirus (CMV) promoter (CMV-GFP) were used for syngeneic transplantation of lethally irradiated mice. Blood leukocytes showed stable GFP expression for up to 15 months after transplantation. SP-GFP expression was selective for CD11b+ macrophages, whereas CMV-GFP expression was observed in erythrocytes, as well as in both CD11b+ and CD11b- leukocytes. Furthermore, SP-GFP expression was much stronger than CMV-GFP expression in CD11b+ macrophages. apoE-/- BMCs transduced with the lentiviral vector encoding human apoE were used to transplant apoE-/- mice. Macrophage expression of apoE from 10 to 26 weeks of age significantly reduced atherosclerotic lesions in recipient apoE-/- mice. Thus, the novel SPs, especially when combined with lentivectors, are useful for macrophage-specific delivery of therapeutic genes.

CC chemokine receptor (CCR)-2 prevents arthritis development following infection by Mycobacterium avium.

The host factors that influence autoimmune arthritides such as rheumatoid arthritis have not been fully elucidated. We previously found that genetic inactivation of CC chemokine receptor 2 (CCR2) in the arthritis-prone DBA/1j mouse strain significantly increases the susceptibility of this strain to autoimmune arthritis induced by immunization with collagen type II (CII) and complete Freund's adjuvant (CFA). Here, we show that following intradermal infection with Mycobacterium avium, a similar arthritis phenotype was detected in Ccr2-null mice in the DBA/1j, but not in the BALB/c background. The failure to develop arthritis in Ccr2-null BALB/c mice occurred in the face of high bacterial burdens and low interferon gamma (IFNgamma) production. By contrast, Ccr2-null DBA/1j mice had low bacterial burdens, produced normal amounts of IFNgamma, and had high titers of autoantibodies against CII. Thus, the Ccr2-null state in an arthritic-prone genetic background leads to increased arthritis susceptibility following infectious (M. avium) and noninfectious (CII/CFA) challenges. Because CCR2 serves as a negative regulator of murine arthritis, caution might need to be exercised while testing CCR2 blockers in human arthritis or other diseases. These findings also indicate that Ccr2-null DBA/1j mice might serve as a valuable model system to uncover the immunological determinants of arthritis and to test novel antiarthritic agents.

Differential necrosis despite similar perfusion in mouse strains after ischemia.

BACKGROUND: Numerous mouse models have been used to study the tissue response to ischemia, but multiple technical differences make comparisons difficult. We have comprehensively characterized the mouse hind limb ischemia model and determined how different genetic backgrounds of mice affect recovery. MATERIALS AND METHODS: Severity of tissue necrosis and restoration of perfusion after femoral artery excision or femoral artery transection, using five different surgical procedures, were evaluated using laser Doppler imaging in a mouse model of hind limb ischemia. Severity of necrosis was concurrently measured using a five-point scale. RESULTS: Significant differences were observed depending upon the surgical procedure used to initiate ischemia as well as the strain of mouse used. First, a progressively delayed and incomplete recovery of vascular perfusion occurred in relation to the anatomical position and extent of the arterial defect. Second, among mouse strains, the severity of tissue necrosis varied despite similar restoration of perfusion. Thus, DBA/1J mice had significantly increased severity and incidence of tissue loss as compared with either C57Bl/6J (P = 0.01) or BALB/c (P = 0.01) mice. Finally, contrary to previous reports, T-cell-mediated immune events did not modify ischemia-induced hind limb perfusion and necrosis as responses in nude mice were not different than controls on either BALB/c or C57Bl/6J backgrounds. CONCLUSIONS: Surgical approach, mouse strain, and measures of hind limb perfusion and tissue injury are crucial considerations in the study of ischemia. Understanding how different genetic backgrounds in mice can affect necrosis may provide insights into the diverse healing responses observed in humans.

The complex role of the chemokine receptor CCR2 in collagen-induced arthritis: implications for therapeutic targeting of CCR2 in rheumatoid arthritis.

CCR2 has been widely considered as a potential therapeutic target for autoimmune disease, particularly rheumatoid arthritis, and various CCR2 blocking agents have been developed, some of which have entered clinical trials. In this review, we examine the relevant information regarding the role of CCR2, and to a lesser extent of the closely related chemokine receptor CCR5, in the immunopathogenesis of collagen-induced arthritis, an animal model of rheumatoid arthritis. Experimental evidence showing that CIA is accelerated and exacerbated when CCR2 is genetically inactivated (knockout mice) or blocked with specific antibodies warrant additional investigations before the relevance of the findings in rodent models can be applied to human patients with RA.

The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility.

Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1alphaP), a potent human immunodeficiency virus-1 (HIV-1)-suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.