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Natural Autoantibodies in Healthy Neonatals Recognizing a Peptide

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Natural Autoantibodies in Healthy Neonatals Recognizing a Peptide Strana 352 VOJNOSANITETSKI PREGLED Vojnosanit Pregl 2014; 71(4): 352–361. UDC: 616.017 ORIGINAL ARTICLE DOI: 10.2298/VSP1404352D Natural autoantibodies in healthy neonatals recognizing a peptide derived from the second conserved region of HIV-1 gp120 Prirodna antitela prisutna kod zdrave novoroÿenþadi koja prepoznaju peptid poreklom iz drugog konzerviranog regiona HIV-1 gp120 Ana Djordjeviü Vujiþiü*, Branislava Gemoviü†, Veljko Veljkoviü†, Sanja Glišiü†, Nevena Veljkoviü† *Institute of Neonatology, University of Belgrade, Belgrade, Serbia; †Centre for Multidisciplinary Research and Engineering, Vinca Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia Abstract tibodies in sera of HIV negative newborn babies. Further, in order to identify which of already known innate antigens are Background/Aim. High sera reactivity with a peptide derived the most similar to NTM1 peptide we screened innate immune from human immunodeficiency virus HIV-1 envelope protein antigen sequence database collected from the literature. This gp120, NTM1, correlate with non-progressive HIV-1 infection screening revealed that the most similar sequence are ribonu- and also may have protective role in breast and prostate cancer. cleoproteins RO60, in addition to previously identified N- We also detected a low NTM1 reactive antibodies titer in terminus of vasoactive intestinal peptide. Conclusion. The re- healthy HIV negative sera and showed that antibody levels can sults of this study confirm the hypothesis that NTM1 recog- be significantly increased with vigorous physical activity. How- nizing antibodies are a part of humoral innate immune re- ever, the immune system seems to be unresponsive or tolerant sponse. Further, computational similarity screening revealed a to this peptide, implicating that the NTM1 sequence encom- vasoactive intestinal peptide and RO60 as the most similar se- passes or overlaps a certain innate immune epitope. The aim of quences and the strongest candidate antigens. In the light of the this study was to present evidences that NTM1 – binding anti- presented results, it is appealing that testing blood reactivity at bodies – are components of innate immune humoral response, birth, with specific innate antigens, particularly a vasoactive in- by confirming their presence in sera of newborn babies. For testinal peptide, can reveal the potential to develop or boost this purpose we collected a set of 225 innate antigen sequences protective immune response in breast and prostate cancer and reported in the literature and screened it for candidate antigens HIV infection later in life. with the highest sequence and spectral similarity to NTM1 de- rived from HIV-1 gp120. Methods. Sera from 18 newborns Key words: were tested using ELISA, with peptide NTM1. Sequences from immunity, innate; infant, newborn; infant, premature; innate antigen database were aligned by an EMBOSS Water antibodies; vasoactive intestinal peptide; hiv envelope bioinformatics tool. Results. We identified NTM1 reactive an- protein gp120. Apstrakt su vezivna antitela, NTMI, sastavni delovi uroĀenog humo- ralnog imunog odgovora potvĀivanjem njihovog prisustva u Uvod/Cilj. Visoka reaktivnost seruma na peptid NTM1, serumu novoroĀenÿadi. U tu svrhu, sakupili smo ukupno poreklom iz proteina omotaÿa gp120 virusa humane imu- 225 uroĀenih sekvenci antigena prikazanih u literaturi i testi- nodeficijencije, HIV-1, koreliše sa neprogresivnom HIV-1 rali ih za kandidate antigena sa najveýom sliÿnošýu sekvence infekcijom, a, takoĀe, može imati zaštitnu ulogu u kanceru i spektra NTM1 nastalih iz HIV-1 gp120. Metode. Serumi dojke i prostate. Nedavno smo detektovali nizak titar anti- 18 novoroĀenÿadi testirani su ELISA probama sa NTM1 tela reaktivnih na NTM1 i u zdravim HIV-negativnim se- peptidom vezanim za ploÿu. Poravnavanje sekvenci uroĀe- rumima i pokazali smo da se nivo ovih antitela može zna- nih antigena vršeno je bioinformatiÿkim alatom EMBOSS ÿajno poveýati energiÿnom fiziÿkom aktivnošýu. MeĀutim, Water. Rezultati. U serumima HIV negativnih novoroĀen- postoje dokazi da je ovaj peptid neimunogen ili da je nevid- ÿadi identifikovali smo antitela reaktivna na NTM1. Dalje, ljiv za imuni sistem ÿoveka, ÿime se sugeriše da NTM1 sek- da bi utvrdili koji od veý poznatih antigena uroĀene imuno- venca obuhvata ili se preklapa sa odreĀenim epitopom uro- sti je najsliÿniji peptidu NTM1, pretražili smo bazu sekvenci Āene imunosti. Cilj ove studije bio je da se dokumentuje da antigena uroĀene imunosti formirane na osnovu literaturih Correspondence to: Ana Djordjeviý Vujiÿiý, Institute of Neonatology, University of Belgrade, Kralja Milutina 50, Beograd, Republika Srbija. Phone.: +381 11 363 01 26, Fax.: +381 11 361 90 45. E-mail: [email protected] Volumen 71, Broj 4 VOJNOSANITETSKI PREGLED Strana 353 podataka. Ovo pretraživanje pokazalo je da, pored predho- specifiÿnim uroĀenim antigenima, pre svega vazoaktivnim dno identifikovanog N-terminusa vazoaktivnog intestinal- intestinalnim peptidom na roĀenju, može otkriti potencijal nog peptida, najsliÿnija je NTM1 peptidu sekvenca ribonu- za razvoj protektivnog imunog odgovora kasnije u životu i kleoproteina RO60. Zakljuÿak. Ovom studijom potvrdili to ne samo za odreĀene autoimune bolesti, veý i za kancer smo hipotezu da su antitela koja prepoznaju NTM1 deo dojke i prostate, kao i HIV infekcije. uroĀenog humoralnog imunog odgovora. Dalje, kompjuter- skim pretraživanjem sliÿnosti utvrdili smo da su vazoaktivni Kljuÿne reÿi: intestinalni peptid i RO60 sekvence najsliÿnije NTM1 i, ta- imunitet, prirodni; novoroĀenÿe; novoroĀenÿe, ko, najjaÿi kandidati za antigene. U svetlu predstavljenih re- prevremeno; antitela; vazoaktivni intestinalni peptid; zultata, privlaÿna je ideja da testiranje reaktivnosti krvi sa protein omotaÿa gp120 virusa hiv. Introduction gens, as well as the removal of possible autoantigens through scavenging dead or apoptotic cellular debris through the lifetime In spite tremendous progress that has been made by in- (for review see Lutz et al. 20). In general, mediators of innate troducing highly active antiretroviral therapy (HAART) in in- humoral immunity are low-affinity polyreactive antibodies with hibiting HIV-1 virus through disrupting reverse transcription, an ability to bind to diverse, similar epitopes. integration or proteolytic processing of viral proteins, some The aim of this study was to present evidences that important problems as persistent viral reservoirs, drug resis- NTM1-binding antibodies are components of innate immune tance and toxicities still remain. HAART can effectively keep humoral response, by confirming their presence in sera of the viral replication at an undetectable level, prolonging the newborn babies. For this purpose we collected a set of 225 life expectancy of the infected and reducing the viral transmis- innate antigen sequences reported in the literature and sion. However, several host and virus factors can slow down screened it for candidate antigens with the highest sequence and block the disease progression 1–4 and also, various immu- and spectral similarity to NTM1 derived from HIV-1 gp120. nological factors 5, 6 might play an important role. NTM1 pep- Computational similarity screening revealed VIP and a ribo- tide, derived from the C-terminus of the second conserved re- nucleoprotein, RO60, as the most similar sequences and the gion of HIV-1 envelope protein gp120, and anti-NTM1 anti- strongest candidate antigens, although other highly similar bodies have been suggested to be important in controlling HIV sequences were also identified. These results imply that disease. These antibodies have been significantly prevalent in testing blood reactivity with specific innate antigens at birth sera of long-term nonprogressors (LTNP), the HIV positives can reveal potential to develop or boost protective immune that are capable of keeping viral load bellow 10 000 copies/mL response in breast and prostate cancer and HIV infection. without any retroviral therapy for more than 10 years. The same is observed in patients in asymptomatic phase of the Methods HIV-1 disease 7. NTM1 binding antibodies are reported in a Sequences small number of healthy individuals and extremely high titer values are detected in elite athletes 8. Although the immune The HIV1 gp120 NTM1 sequence was as in paper of system seems to be unresponsive or tolerant to this peptide 9–11, Djordjevic et al. 21 Innate immune antigen sequences are the titer NTM1 recognizing antibodies can be increased by listed in Addendum 1. continuous and vigorous exercising 12. Taken together these Sequence alignments data implicate that NTM1 peptide encompasses or overlaps the innate immune epitope sequence involved in cellular pathway Sequence alignments are calculated by an EMBOSS activated by physical activity. Based on the sequence similar- Water, a tool that uses the Smith-Waterman algorithm to cal- ity and in vitro cross-reactivity we previously hypothesized culate the local alignment of two sequences 22. Sequences that the candidate binding antigen for these was vasoactive with scores higher than 20 (scores were from 7 to 23) are intestinal peptide (VIP), the pleiotropic extracellular molecule selected as candidate antigens. important in many physiologic functions, including glucose Human subjects homeostasis, neuroprotection, memory, gut function, modula- tion of the immune system and circadian function. Due to its Sera were collected from 9 preterm and 9 term new- important immunomodulatory and neuromodulatory activities,
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