Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control

Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical manifestations such as HIV progression to AIDS and autoimmune disease. We sought to identify genetic predictors of lymphocyte levels and reasoned that these may play a role in immune-related diseases. We tested 2.3 million variants for association with five lymphocyte subsets, measured in 2538 individuals from the general population, including CD4+ T cells, CD8+ T cells, CD56+ natural killer (NK) cells, and the derived measure CD4:CD8 ratio. We identified two regions of strong association. The first was located in the major histocompatibility complex (MHC), with multiple SNPs strongly associated with CD4:CD8 ratio (rs2524054, p = 2.1 �� 10���28). The second region was centered within a cluster of genes from the Schlafen family and was associated with NK cell levels (rs1838149, p = 6.1 �� 10���14). The MHC association with CD4:CD8 replicated convincingly (p = 1.4 �� 10���9) in an independent panel of 988 individuals. Conditional analyses indicate that there are two major independent quantitative trait loci (QTL) in the MHC region that regulate CD4:CD8 ratio: one is located in the class I cluster and influences CD8 levels, whereas the second is located in the class II cluster and regulates CD4 levels. Jointly, both QTL explained 8% of the variance in CD4:CD8 ratio. The class I variants are also strongly associated with durable host control of HIV, and class II variants are associated with type-1 diabetes, suggesting that genetic variation at the MHC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.

HIV-1 tropism and CD4 T lymphocyte recovery in a prospective cohort of patients initiating HAART in Ribeirao Preto, Brazil

While human immunodeficiency virus (HIV)-1 chemokine co-receptors 5 tropism and the GWGR motif in the envelope third variable region (V3 loop) have been associated with a slower disease progression, their influence on antiretroviral response remains unclear. The impact of baseline V3 characteristics on treatment response was evaluated in a randomised, double blind, prospective cohort study with patients initiating highly active antiretroviral therapy with lopinavir or efavirenz plus azithothymidine/3TC (1:1) over 48 weeks. Similar virological and immunological responses were observed for both treatment regimens. The 43 individuals had a mean baseline CD4 T cell count of 119 cells/mm(3) [standard deviation (SD) = 99] and a mean viral load of 5.09 log(10) copies/mL (SD = 0.49). The GWGR motif was not associated with a CD4 T cell response, but predicted R5 tropism by the geno2pheno([clinical20%]) algorithm correlated with higher CD4 T cell levels at all monitoring points (p < 0.05). Moreover, higher false-positive rates (FPR) values from this analysis revealed a strong correlation with CD4 T cell recovery (p < 0.0001). Transmitted drug resistance mutations, documented in 3/41 (7.3%) cases, were unrelated to the assigned antiretroviral regimen and had no impact on patient outcomes. In conclusion, naive HIV-1 R5 infected patients exhibited higher CD4 T cell counts at baseline; this difference was sustained throughout therapy. The geno2pheno[clinical] option FPR positively correlated with CD4 T cell gain and may be useful in predicting CD4 T cell recovery.

HIV-1 tropism and CD4 T lymphocyte recovery in a prospective cohort of patients initiating HAART in Ribeir��o Preto, Brazil

While human immunodeficiency virus (HIV)-1 chemokine co-receptors 5 tropism and the GWGR motif in the envelope third variable region (V3 loop) have been associated with a slower disease progression, their influence on antiretroviral response remains unclear. The impact of baseline V3 characteristics on treatment response was evaluated in a randomised, double blind, prospective cohort study with patients initiating highly active antiretroviral therapy with lopinavir or efavirenz plus azithothymidine/3TC (1:1) over 48 weeks. Similar virological and immunological responses were observed for both treatment regimens. The 43 individuals had a mean baseline CD4 T cell count of 119 cells/mm�� [standard deviation (SD) = 99] and a mean viral load of 5.09 log10 copies/mL (SD = 0.49). The GWGR motif was not associated with a CD4 T cell response, but predicted R5 tropism by the geno2pheno[clinical20%] algorithm correlated with higher CD4 T cell levels at all monitoring points (p < 0.05). Moreover, higher false-positive rates (FPR) values from this analysis revealed a strong correlation with CD4 T cell recovery (p < 0.0001). Transmitted drug resistance mutations, documented in 3/41 (7.3%) cases, were unrelated to the assigned antiretroviral regimen and had no impact on patient outcomes. In conclusion, na��ve HIV-1 R5 infected patients exhibited higher CD4 T cell counts at baseline; this difference was sustained throughout therapy. The geno2pheno[clinical] option FPR positively correlated with CD4 T cell gain and may be useful in predicting CD4 T cell recovery.

Interaction between human interleukin-16 and CD4 receptor of HIV-1

AIM: To study the interaction between human interleukin-16 (IL-16) and the receptor CD4 (T-lymphocyte differentiation antigen) of human immunodeficiency virus type 1 (HIV-1). METHODS: Two structurally con served regions (SCRs) of human IL-16 were built by the SYBYL/Biopolymer module using the corresponding transmembrane (TM) domain of human interleukin-1 (HIL-4) and HIL-2 as the templates. The coordinates for amino-terminal residue sequence, carboxyl-terminal residue sequences, and cytoplasm loops were generated using Biopolymer's LOOP SEARCH algorithm. RESULTS: HIL-16 first formed a homodimer, then contacted with CD4 dimer further forming a dimeric complex. Subsequently, the dimeric complex constructed the tetrameric complex by two disulfide bridges between the cysteines of HIL-16 (Cys31-Cys31). CONCLUSION: The interaction model is useful to propose the action mechanism of HIL-16 and is beneficial for rational designing of novel anti-HIV drugs.

Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS

In persons with HIV/AIDS (PWHAs), Hodgkin lymphoma (HL) risk is increased. However, HL incidence in PWHAs has unexpectedly increased since highly active antiretroviral therapy (HAART) was introduced. We linked nationwide HIV/AIDS and cancer registry data from 1980 through 2002. Immunity was assessed by CD4 T-lymphocyte counts at AIDS onset. Annual HL incidence rates were calculated for 4 through 27 months after AIDS onset. During 477 368 person years (py's) of follow-up in 317 428 persons with AIDS (PWAs), 173 HL cases occurred (36.2 per 105 py's). Incidence was significantly higher in 1996 to 2002 than earlier. Incidence in PWAs with 150 to 199 CD4 cells/��L was 53.7 per 105 py's, whereas in PWAs with fewer than 50 CD4 cells/��L, it was 20.7 per 105 py's (Ptrend = .002). For each HL subtype, incidence decreased with declining CD4 counts, but nodular sclerosing decreased more precipitously than mixed cellularity, thereby increasing the proportion of mixed cellularity HL seen in PWAs. We conclude that HL incidence is lower with severe immunosuppression than with moderate immunosuppression, and HAART-related improvements in CD4 counts likely explain the increasing HL incidence in PWHAS observed since 1996. With more severe immunosuppression, nodular sclerosing HL becomes infrequent, explaining the higher proportion of mixed cellularity HL found in PWAs. Pathogenesis implications are discussed.

The role of inflammation in the pathogenesis of non-small cell lung cancer

The link between chronic immune activation and tumorigenesis is well established. Compelling evidence has accumulated that histologic assessment of infiltration patterns of different host immune response components in non-small cell lung cancer specimens helps identify different prognostic patient subgroups. This review provides an overview of recent insights gained in the understanding of the role played by chronic inflammation in lung carcinogenesis. The usefulness of quantification of different populations of lymphocytes, natural killer cells, macrophages, and mast cells within the tumor microenvironment in non-small cell lung cancer is also discussed. In particular, the importance of assessment of inflammatory cell microlocalization within both the tumor islet and surrounding stromal components is emphasized. Copyright �� 2010 by the International Association for the Study of Lung Cancer.

Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive ��/�� T cells in patients with active ankylosing spondylitis

Objective Ankylosing spondylitis (AS) is a common inflammatory arthritis affecting primarily the axial skeleton. IL23R is genetically associated with AS. This study was undertaken to investigate and characterize the role of interleukin-23 (IL-23) signaling in AS pathogenesis. Methods The study population consisted of patients with active AS (n = 17), patients with psoriatic arthritis (n = 8), patients with rheumatoid arthritis, (n = 9), and healthy subjects (n = 20). IL-23 receptor (IL-23R) expression in T cells was determined in each subject group, and expression levels were compared. Results The proportion of IL-23R-expressing T cells in the periphery was 2-fold higher in AS patients than in healthy controls, specifically driven by a 3-fold increase in IL-23R-positive ��/�� T cells in AS patients. The proportions of CD4+ and CD8+ cells that were positive for IL-17 were unchanged. This increased IL-23R expression on ��/�� T cells was also associated with enhanced IL-17 secretion, with no observable IL-17 production from IL-23R-negative ��/�� T cells in AS patients. Furthermore, ��/�� T cells from AS patients were heavily skewed toward IL-17 production in response to stimulation with IL-23 and/or anti-CD3/CD28. Conclusion Recently, mouse models have shown IL-17-secreting ��/�� T cells to be pathogenic in infection and autoimmunity. Our data provide the first description of a potentially pathogenic role of these cells in a human autoimmune disease. Since IL-23 is a maturation and growth factor for IL-17-producing cells, increased IL-23R expression may regulate the function of this putative pathogenic ��/�� T cell population.

Unique and cross-reactive T cell epitope peptides of the major bahia grass pollen allergen, pas n 1

Background Bahia grass pollen (BaGP) is a major cause of allergic rhinitis. Subcutaneous allergen-specific immunotherapy is effective for grass pollen allergy, but is unsuitable for patients with moderate to severe asthma due to the risk of anaphylaxis. T cell-reactive but IgE nonreactive peptides provide a safer treatment option. This study aimed to identify and characterize dominant CD4+ T cell epitope peptides of the major BaGP allergen, Pas n 1. Methods Pas n 1-specific T cell lines generated from the peripheral blood of BaGP-allergic subjects were tested for proliferative and cytokine response to overlapping 20-mer Pas n 1 peptides. Cross-reactivity to homologous peptides from Lol p 1 and Cyn d 1 of Ryegrass and Bermuda grass pollen, respectively, was assessed using Pas n 1 peptide-specific T cell clones. MHC class II restriction of Pas n 1 peptide T cell recognition was determined by HLA blocking assays and peptide IgE reactivity tested by dot blotting. Results Three Pas n 1 peptides showed dominant T cell reactivity; 15 of 18 (83%) patients responded to one or more of these peptides. T cell clones specific for dominant Pas n 1 peptides showed evidence of species-specific T cell reactivity as well as cross-reactivity with other group 1 grass pollen allergens. The dominant Pas n 1 T cell epitope peptides showed HLA binding diversity and were non-IgE reactive. Conclusions The immunodominant T cell-reactive Pas n 1 peptides are candidates for safe immunotherapy for individuals, including those with asthma, who are allergic to Bahia and possibly other grass pollens.

Immunopathogenesis of ankylosing spondylitis

Ankylosing spondylitis is a model immunogenetic disease with major common and rare genetic risk factors, likely environmental contributors to its pathogenesis and, to date, no treatment that has been shown to induce disease remission in long-term studies. The discovery of the association of HLA-B27 with the disease in the early 1970s triggered extensive efforts to elucidate the mechanism of this association. However, the precise role of HLA-B27 in ankylosing spondylitis pathogenesis remains unclear. In recent years, rapid progress made in the discovery of non-MHC genes involved in susceptibility to ankylosing spondylitis has combined with increasing ability to investigate the immune system to make rapid progress in unraveling the etiopathogenesis of the condition. �� 2013 Future Medicine Ltd.

The role of IL-17-secreting mast cells in inflammatory joint disease

The proinflammatory cytokine IL-17 has an important role in pathogenesis of several inflammatory diseases. In immune-mediated joint diseases, IL-17 can induce secretion of other proinflammatory cytokines such as IL-1, IL-6 and TNF, as well as matrix metalloproteinase enzymes, leading to inflammation, cartilage breakdown, osteoclastogenesis and bone erosion. In animal models of inflammatory arthritis, mice deficient in IL-17 are less susceptible to development of disease. The list of IL-17-secreting cells is rapidly growing, and mast cells have been suggested to be a dominant source of IL-17 in inflammatory joint disease. However, many other innate sources of IL-17 have been described in both inflammatory and autoinflammatory conditions, raising questions as to the role of mast cells in orchestrating joint inflammation. This article will critically assess the contribution of mast cells and other cell types to IL-17 production in the inflammatory milieu associated with inflammatory arthritis, understanding of which could facilitate targeted therapeutic approaches. �� 2013 Macmillan Publishers Limited. All rights reserved.

Avalia����o da resposta imunol��gica ap��s vacina����o ou infec����o por Neisseria meningitidis

A doen��a meningoc��cica (DM) ��, ainda hoje, um s��rio problema de sa��de p��blica, estando associada a elevadas taxas de morbidade e letalidade no mundo. A DM evoca prote����o imunol��gica persistente contra a doen��a em pessoas com sistema imunol��gico normal. Em contraste, a prote����o induzida por vacinas meningoc��cicas sempre requer a administra����o de doses refor��o (booster) da vacina. No Brasil, Neisseria meningitidis dos sorogrupos C (MenC) e B (MenB) s��o as principais causas de DM durante os ��ltimos anos. Atualmente, n��o existe uma vacina universal contra o meningococo B (MenB). A infec����o pelo v��rus da imunodefici��ncia humana (HIV) tem sido apontada como um fator de risco para a mortalidade da DM. Um dos pilares do tratamento do HIV �� a utiliza����o de vacinas para doen��as imuno-preven��veis. A vacina conjugada anti-MenC �� frequentemente recomendada para crian��as e adolescentes infectados pelo HIV no Brasil e em muitos outros pa��ses. Poucos estudos t��m abordado os mecanismos pelos quais as vacinas meningoc��cicas geram e sustentam a mem��ria imunol��gica. Os objetivos deste estudo foram: 1) avaliar a resposta de anticorpos bactericidas e de linf��cito T (LT) CD4 de mem��ria contra o meningococo ap��s a infec����o; 2) avaliar a resposta de anticorpos bactericidas e de LT CD4 de mem��ria e linf��cito B de mem��ria (LBm) contra o meningococo ap��s o booster da vacina cubana VA-MENGOC-BC em volunt��rios imunizados h�� aproximadamente 17 anos; 3) investigar a resposta de anticorpos funcionais (bactericidas e opsonizantes) ap��s imuniza����o com a vacina conjugada anti-MenC (CRM197) em indiv��duos infectados pelo v��rus HIV. Ap��s a infec����o, 83% dos pacientes diagnosticados como tendo DM pelo teste de l��tex e/ou cultura tiveram t��tulos de anticorpos bactericidas protetores, mas n��o houve uma associa����o entre os t��tulos de anticorpos bactericidas e a concentra����o de imunoglobulina total espec��fica. Houve aumento na frequ��ncia de linf��citos T de mem��ria central (TCM) (mediana de 15%) ativados, principalmente ap��s est��mulo com a cepa MenC. Nos volunt��rios pr��-vacinados, 3 de 5 indiv��duos soroconverteram 7 ou 14 dias ap��s a administra����o da dose booster. Houve um aumento importante da popula����o TCM 14 dias ap��s o booster, mas sem ativa����o celular diferenciada dos grupos controles. Observamos resposta positiva de LBm na maioria dos volunt��rios, mas sem correla����o com os anticorpos bactericidas. Em rela����o aos pacientes HIV positivos, os resultados mostraram a necessidade de uma segunda dose da vacina, j�� que apenas 15% soroconverteram a uma ��nica dose e a segunda dose resultou em soroconvers��o de cerca de 55% dos indiv��duos. Observamos correla����o positiva (r= 0,43) e significativa (P= 0,0007) entre os anticorpos opsonizantes e bactericidas ap��s a vacina����o. N��o observamos diferen��as significativas quando relacionamos os t��tulos de anticorpos bactericidas com o n��mero absoluto de LT CD4 P= 0,051) e LT CD4 nadir (P= 0,09) entre os pacientes que soroconverteram (n= 43) ou n��o soroconverteram (n= 106) ap��s a primeira dose. Desta forma, os resultados desta tese indicaram que: 1) os pacientes convalescentes da DM adquirem anticorpos bactericidas ap��s infec����o por N. meningitidis; 2) nos volunt��rios vacinados, a dose booster da vacina anti-MenB n��o foi plenamente eficaz em ativar a mem��ria imunol��gica atrav��s da produ����o de anticorpos bactericidas ou ativa����o de LTm; 3) os pacientes HIV positivos necessitam de uma dose booster da vacina conjugada anti-MenC.

Establishment of AIDS Animal Model with SIVmac239 Infected Chinese Rhesus Monkey

In the present research, two Chinese rhesus monkeys were inoculated intravenously with 5000 TCID50 of SIVmac239. The changes in the numbers of CD4+ T lymphocyte in peripheral blood, plasma viral loads, proviral DNA and humoral antibodies against virus were periodically monitored during 121 days. At the early stage of infection, proviral DNA had been detected in PBMCs, and infectious SIVmac239 virus had been isolated from PBMCs. At the same period, the numbers of CD4+ T lymphocytes were significantly decreased, and maintained at low level during the 121-day period of infection. Plasma viral loads reached the peak at week 2 post-inoculation and kept at a steady state subsequently. Moreover, antibodies against viral proteins were detected from plasma. All the results showed that the two Chinese rhesus monkeys had been infected with SIVmac239 successfully. This animal model can be applied for further AIDS researches.

HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing

HIV upregulates cell-surface expression of specific ligands for the activating NKG2D receptor, including ULBP-1, -2, -3, but not MICA or MICB, in infected cells both in vitro and in vivo. However, the viral factor(s) involved in NKG2D ligand expression still remains undefined. HIV-1 Vpr activates the DNA damage/stress-sensing ATR kinase and promotes G2 cell-cycle arrest, conditions known to upregulate NKG2D ligands. We report here that HIV-1 selectively induces cell-surface expression of ULBP-2 in primary CD4+ T-lymphocytes by a process that is Vpr-dependent. Importantly, Vpr enhanced the susceptibility of HIV-1-infected cells to NK cell-mediated killing. Strikingly, Vpr alone was sufficient to upregulate expression of all NKG2D ligands and thus promoted efficient NKG2D-dependent NK cell-mediated killing. Delivery of virion-associated Vpr via defective HIV-1 particles induced analogous biological effects in non-infected target cells, suggesting that Vpr may act similarly beyond infected cells. All these activities relied on Vpr ability to activate the ATR-mediated DNA damage/stress checkpoint. Overall, these results indicate that Vpr is a key determinant responsible for HIV-1-induced upregulation of NKG2D ligands and further suggest an immunomodulatory role for Vpr that may not only contribute to HIV-1-induced CD4+ T-lymphocyte depletion but may also take part in HIV-1-induced NK cell dysfunction.

Impact de la maladie du greffon contre l���h��te sur la reconstitution immunitaire suite �� une transplantation allog��nique de cellules souches h��matopo����tiques

La transplantation allog��nique de cellules souches h��matopo����tiques (ASCT) est couramment utilis��e pour traiter diff��rents cancers h��matologiques. Malheureusement, l���effet b��n��fique de cette technique est limit�� par la r��action du greffon contre l���h��te (GVHD) qui demeure la cause principale de mortalit�� post-greffe. La GVHD endommage diff��rents organes et retarde la reconstitution immunitaire des lymphocytes T (LT) ce qui augmente les risques d���infection et de rechute. Le d��veloppement de nouveaux traitements permettant d���acc��l��rer la reconstitution immunitaire augmenterait donc les chances de survie des patients greff��s. Il existe deux fa��ons de r��g��n��rer des LT: via la thymopo����se qui consiste �� produire de nouveaux LT, ou par la prolif��ration hom��ostatique (PH) qui implique l���expansion rapide des LT matures retrouv��s dans le greffon. La PH requiert deux signaux essentiels: l���interleukine-7 (IL-7) et la pr��sentation d���antig��nes du soi par les cellules dendritiques (DC) via le complexe majeur d���histocompatibilit�� (CMH) I pour les LT CD8+ et le CMH II pour les LT CD4+. Dans un contexte d���ASCT, la chimioth��rapie et la GVHD endommagent le thymus rendant la thymopo����se inefficace. Par cons��quent, la reconstitution immunitaire repose presque enti��rement sur la PH des LT. L���objectif de cette th��se ��tait de comprendre comment la GVHD affecte la reconstitution des LT. Gr��ce �� un mod��le murin, nous avons d��montr�� que la PH des LT CD4+ est absente durant la GVHD et ce, d�� �� de faibles niveaux d���IL-7 et une diminution du nombre de DC. La perte des DC est en grande partie caus��e par des niveaux r��duits de stromal derived factor-1�� (SDF-1��) et par l���absence de prog��niteurs de DC dans la moelle osseuse des souris en GVHD. Le traitement des souris en GVHD avec du SDF-1�� permet d���augmenter le nombre de DC, et lorsqu���administr�� avec l���IL-7, am��liore significativement la PH des LT CD4+. Contrairement aux LT CD4+, l���administration d���IL-7 seule est suffisante pour restaurer la PH des LT CD8+ durant la GVHD et ce, m��me en absence des DC. Ces diff��rences s���expliquent pour deux raisons : 1) l���expression du CMH I, contrairement au CMH II, n���est pas limit��e aux DC mais est ��galement exprim��e par les cellules stromales du receveur ce qui est suffisant pour induire la PH des LT CD8+ et 2) les LT CD8+ r��pondent �� des concentrations plus faibles d���IL-7 syst��mique comparativement aux LT CD4+. En conclusion, l���ensemble de ces r��sultats permettra de mettre en place des ��tudes translationnelles sur le potentiel th��rapeutique du SDF-1�� et de l���IL-7 dans la reconstitution immunitaire des patients greff��s.