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B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH[MOG] mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG[35-55], IgH[MOG] mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH[MOG] meninges and by CD4+ T helper 17 (Th17) cells in the CNS. Production of the Th17 maintenance factor IL-23 is observed from IgH[MOG] CNS-infiltrating and meningeal B cells, and in vivo blockade of IL-23p19 attenuates disease severity in IgH[MOG] mice. In the CNS parenchyma and dura mater of IgH[MOG] mice, we observe an increased frequency of CD4+PD-1+CXCR5- T cells that share numerous characteristics with the recently described T peripheral helper (Tph) cell subset. Further, CNS-infiltrating B and Tph cells from IgH[MOG] mice show increased reactive oxygen species (ROS) production. Meningeal inflammation, Tph-like cell accumulation in the CNS and B/Tph cell production of ROS were all reduced upon p19 blockade. Altogether, MOG-specific B cells promote autoimmune inflammation of the CNS parenchyma and meninges in an IL-23-dependent manner. B cells are crucial in multiple sclerosis (MS) pathology but the mechanisms are incompletely understood. In a mouse model of MS, the authors show that B cells make IL-23, and that IL-23 invokes meningeal inflammation and CNS presence of T peripheral helper cells. [ABSTRACT FROM AUTHOR]

We utilized a vitamin D receptor (VDR) gene knockout model to study the effects of maternal and fetal absence of VDR on maternal fertility, fetal-placental calcium transfer, and fetal mineral homoeostasis. Vdr null mice were profoundly hypocalcemic, conceived infrequently, and had significantly fewer viable fetuses in utero that were also of lower body weight. Supplementation of a calcium-enriched diet increased the rate of conception in Vdr nulls but did not normalize the number or weight of viable fetuses. Among offspring of heterozygous (Vdr.sup.+/-] ) mothers (wild type, [Vdr.sup.+/-] , and Vdr null fetuses), there was no alteration in serum Ca, P, or Mg, parathyroid hormone, placental [sup.45]Ca transfer, Ca and Mg content of the fetal skeleton, and morphology and gene expression in the fetal growth plates. Vdr null fetuses did have threefold increased 1,25-dihydroxyvitamin D levels accompanied by increased 1[alpha]-hydroxylase mRNA in kidney hut not placenta; a small increase was also noted in placental expression of parathyroid hormone-related protein (PTHrP). Among offspring of Vdr null mothers, [Vdr.sup.+/-] and Vdr null fetuses had normal ionized calcium levels and a skeletal ash weight that was appropriate to the lower body weight. Thus our findings indicate that VDR is not required by fetal mice to regulate placental calcium transfer, circulating mineral levels, and skeletal mineralization. Absence of maternal VDR has global effects on fetal growth that were partly dependent on maternal calcium intake, but absence of maternal VDR did not specifically affect fetal mineral homeostasis. fetus; calcitriol; skeletal mineralization; parathyroid hormone-related protein; parathyroid hormone; calbindin-[D.sub.9k]; calcium-adenosinetriphosphatase; calcium transporter 1 and 2; 1[alpha]-hydroxylase; placenta

We used the calcitonin/calcitonin gene-related peptide (CGRP)-[alpha] gene knockout model (Ct/Cgrp null) to determine whether calcitonin and CGRP[alpha] are required for normal fetal mineral homeostasis and placental calcium transfer. Heterozygous (Ct/[Cgrp.sup.+/-]) and Ct/Cgrp null females were mated to Ct/[Cgrp.sup.+/-] males. One or two days before term, blood was collected from mothers and fetuses and analyzed for ionized Ca, Mg, P, parathyroid hormone (PTH), and calcitonin. Amniotic fluid was collected for Ca, Mg, and P. To quantity skeletal mineral content, fetuses were reduced to ash, dissolved in nitric acid, and analyzed by atomic absorption spectroscopy for total Ca and Mg. Placental transfer of [sup.45]Ca at 5 min was assessed. Ct/Cgrp null mothers had significantly fewer viable fetuses in utero compared with Ct/[Cgrp.sup.+/-] and wild-type mothers. Fetal serum Ca, P, and PTH did not differ by genotype, but serum Mg was significantly reduced in null fetuses. Placental transfer of [sup.45]Ca at 5 min was normal. The calcium content of the fetal skeleton was normal; however, total Mg content was reduced in Ct/Cgrp null skeletons obtained from Ct/Cgrp null mothers. In summary, maternal absence of calcitonin and CGRP[alpha] reduced the number of viable fetuses. Fetal absence of calcitonin and CGRP[alpha] selectively reduced serum and skeletal magnesium content but did not alter ionized calcium, placental calcium transfer, and skeletal calcium content. These findings indicate that calcitonin and CGRP[alpha] are not needed for normal fetal calcium metabolism but may regulate aspects of fetal Mg metabolism. fetus; placental calcium transfer; skeletal mineralization: mineral homeostasis

The expression of calcitropic genes and proteins was localized within murine placenta during late gestation (the time frame of active calcium transfer) with an analysis of several gene-deletion mouse models by immuno-histochemistry and in situ hybridization. Parathyroid hormone-related protein (PTHrP), the PTH/PTHrP receptor, calcium receptor, calbindin-[D.sub.9k], [Ca.sup.2+]-ATPase, and vitamin D receptor were all highly expressed in a localized structure of the murine placenta, the intraplacental yolk sac, compared with trophoblasts. In the PTHrP gene-deleted or Pthrp-null placenta in which placental calcium transfer is decreased, calbindin-[D.sub.9k] expression was downregulated in the intraplacental yolk sac but hot in the trophoblasts. These observations indicated that the intraplacental yolk sac contains calcium transfer and calcium-sensing capability and that it is a probable route of maternal-fetal calcium exchange in the mouse. parathyroid hormone receptors; fetus; fetal development; placental calcium transfer; calcium receptor; calcitonin; calcitriol; vitamin D receptor; calbindin; vitamin D-dependent calcium-binding protein; calcium-ATPase; trophoblasts; in situ hybridization; immunohistochemistry; gene knockout mice

Antiretroviral therapy (ART) effectively extends the life expectancy of human immunodeficiency virus (HIV)-infected individuals; however, agerelated morbidities have emerged as major clinical concerns. In this context, coinfection with cytomegalovirus (CMV) accelerates immune senescence and elevates risk for other agerelated morbidities, possibly through increased inflammation. We investigated potential relationships between CMV memory inflation, immune senescence, and inflammation by measuring markers of inflammation and telomere lengths of different lymphocyte subsets in HIVinfected individuals seropositive for antiCMV antibodies. Our study cohort consists mainly of middle aged men who have sex with men (MSM) and heterosexuals who are stable under longterm ART. Median levels of IL6, TNFα, and CRP were significantly higher in those coinfected with CMV. Lymphocyte telomere length in general correlated with age, but for 32/32 subjects tested, there was a consistent hierarchy of telomere lengths with CD8+ T cells' shorter than the general lymphocyte population, CD57+CD8+ T cells' shorter than CD8+ T cells' and CMVspecific CD57+CD8+ T cells' the shortest of all. Telomeres of HIVspecific CD8+ T cells were longer than those of CMVspecific CD8+ T cells in all cases tested and over 10 years, CMV-specific CD8+ T cell telomeres of two HIVinfected individuals eroded faster than those of HIVspecific CD8+ T cells. These data indicate that CMVspecific CD8+ T cells of HIVinfected individuals are the lymphocytes closest to telomereimposed replicative senescence. Exhaustive proliferation of CMVspecific CD8+ T cells in HIVinfected individuals is a potential source of senescent lymphocytes affecting systemic immune function and inflammation. [ABSTRACT FROM AUTHOR]

Objective. Measuring NKG2C(+)CD57(+) natural killer (NK) cell expansion to investigate NK responses against human cytomegalovirus (HCMV) and assessing relationships with adaptive immunity against HCMV. Methods. Expansion of NKG2C(+)CD57(+) NK was measured in peripheral blood mononuclear cells (PBMC) from groups distinguished by HCMV and human immunodeficiency virus (HIV) infection status. Anti-HCMV antibody levels against HCMV-infected MRC-5 cell lysate were assessed by ELISA and HCMV-specific CD8(+) T cell responses characterized by intracellular flow cytometry following PBMC stimulation with immunodominant HCMV peptides. Results. Median NK, antibody, and CD8(+) T cell responses against HCMV were significantly greater in the HCMV/HIV coinfected group than the group infected with CMV alone. The fraction of CMV-specific CD8(+) T cells expressing CD28 correlated inversely with NKG2C(+)CD57(+) NK expansion in HIV infection. Conclusion. Our data reveal no significant direct relationships between NK and adaptive immunity against HCMV. However, stronger NK and adaptive immune responses against HCMV and an inverse correlation between NKG2C(+)CD57(+) NK expansion and proliferative reserve of HCMV-specific CD8(+) T cells, as signified by CD28 expression, indicate parallel evolution of NK and T cell responses against HCMV in HIV infection. Similar aspects of chronic HCMV infection may drive both NK and CD8(+) T cell memory inflation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "CD8 T-cell expansion and inflammation linked to CMV coinfection in ART-treated HIV infection" in the 2016 issue.

Expansion of natural killer (NK) cells expressing NKG2C occurs following human cytomegalovirus (HCMV) infection and is amplified by human immunodeficiency virus (HIV) co-infection. These NKG2C-expressing NK cells demonstrate enhanced CD16-dependent cytokine production and downregulate FcεRIγ and promyelocytic leukemia zinc finger protein (PLZF). Lacking NKG2C diminishes resistance to HIV infection, but whether this affects NK cell acquisition of superior antibody-dependent function is unclear. Therefore, our objective was to investigate whether HCMV-driven NK cell differentiation is impaired in NKG2C null HIV-infected individuals. Phenotypic (CD2, CD16, CD57, NKG2A, FcεRIγ, and PLZF expression) and functional (cytokine induction and cytotoxicity) properties were compared between HIV⁻infected NKG2C null and NKG2C-expressing groups. Cytokine production was compared following stimulation through natural cytotoxicity receptors or through CD16. Cytotoxicity was measured by anti-CD16-redirected lysis and by classical antibody-dependent cell-mediated cytotoxicity (ADCC) against anti-class I human leukocyte antigen (HLA) antibody-coated cells. Our data indicate highly similar HCMV-driven NK cell differentiation in HIV infection with or without NKG2C. While the fraction of mature (CD57 pos ) NK cells expressing CD2 ( p = 0.009) or co-expressing CD2 and CD16 (p = 0.03) was significantly higher in NKG2C null HIV-infected individuals, there were no significant differences in NKG2A, FcεRIγ, or PLZF expression. The general phenotypic and functional equivalency observed suggests NKG2C-independent routes of HCMV-driven NK cell differentiation, which may involve increased CD2 expression .

Antiretroviral therapy (ART) effectively extends the life expectancy of human immunodeficiency virus (HIV)-infected individuals; however, age-related morbidities have emerged as major clinical concerns. In this context, coinfection with cytomegalovirus (CMV) accelerates immune senescence and elevates risk for other age-related morbidities, possibly through increased inflammation. We investigated potential relationships between CMV memory inflation, immune senescence, and inflammation by measuring markers of inflammation and telomere lengths of different lymphocyte subsets in HIV-infected individuals seropositive for anti-CMV antibodies. Our study cohort consists mainly of middle aged men who have sex with men (MSM) and heterosexuals who are stable under long-term ART. Median levels of IL-6, TNF-α, and CRP were significantly higher in those coinfected with CMV. Lymphocyte telomere length in general correlated with age, but for 32/32 subjects tested, there was a consistent hierarchy of telomere lengths with CD8 + T cells' shorter than the general lymphocyte population, CD57 + CD8 + T cells' shorter than CD8 + T cells' and CMV-specific CD57 + CD8 + T cells' the shortest of all. Telomeres of HIV-specific CD8 + T cells were longer than those of CMV-specific CD8 + T cells in all cases tested and over 10 years, CMV-specific CD8 + T cell telomeres of two HIV-infected individuals eroded faster than those of HIV-specific CD8 + T cells. These data indicate that CMV-specific CD8 + T cells of HIV-infected individuals are the lymphocytes closest to telomere-imposed replicative senescence. Exhaustive proliferation of CMV-specific CD8 + T cells in HIV-infected individuals is a potential source of senescent lymphocytes affecting systemic immune function and inflammation.