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					<li><a href="#analysis">Southern Blot Analysis</a></li>
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                    <p class="art-type" id="articleinfo">Research Article</p>
		    <p class="art-title">Unidentified Polymorphism in Ip-10/CXCL10 Gene linked to Type 1 Diabetes</p>
		    <p class="art-author"><?php $authors="Teodora Daneva<sup>*</sup>"; echo (stristr($authors,$coauthor))?str_replace($coauthor,"<a href='".$extpath."authors/".$courl."' target='_blank'>".$coauthor."</a>",$authors):$authors; ?></p>
<p class="art-affl">Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Scineces, Sofia, Bulgaria</p>
		    <p class="art-aff"><b>*Corresponding author: <?php $corresponding_author="Teodora Daneva"; echo ($coauthor!="" && $coauthor==$corresponding_author)?"<a href='".$extpath."authors/".$courl."' target='_blank'>".$coauthor."</a>":$corresponding_author;?></b>,
Institute of Biology and Immunology of Reproduction,
Bulgarian Academy of Scineces,
Sofia,
Bulgaria,
E-mail: <a href="mailto:danevadoki@abv.bg">danevadoki@abv.bg</a></p>
<p class="art-aff"><b>Received:</b>   May 16, 2018
<b>Accepted:</b>     July 5, 2018
<b>Published:</b>  July 10, 2018</p>
<p class="art-aff"><b>Citation:</b> Daneva T. Unidentified Polymorphism in Ip-10/CXCL10 Gene linked to Type 1 Diabetes. <i>Madridge J Diabetes</i>. 2018; 2(1): 51-54. doi: <a href="https://doi.org/10.18689/mjd-1000110">10.18689/mjd-1000110</a></p>
  
<p class="art-aff"><b>Copyright:</b> &copy; 2018 The Author(s). This work is  licensed  under  a  Creative  Commons  Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p>
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<p class="art-subhead" id="abstract">Abstract</p>
<p class="art-para">The  development  of  insulin  dependent  type  1  diabetes  (T1D)  is  considered  to  be  an  autoimmune  proinflammatory  process  mediated  by  T-cell  destruction  of  pancreatic  beta  cells. It is believed to be triggered by some environmental factors and human enteroviruses are  among  the  candidates.  After  infection  the  virus  enters  beta  cells  and  triggers  the  expression of immunological factors as chemokines, interferons, interleukins which attract and activate autoreactive immune cells. The attracted and activated immune cells destroy infected beta cells. The viruses may trigger T1D, but the genes play important role in this process. Improved knowledge of gene polymorphisms of chemokines and their receptors could be useful to predict the onset of diabetes and define its progression.</p>
<p class="art-para">When searching for polymorphisms in the genes encoding chemokines MIG/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 I found a difference in the IP-10 gene between patients with type 1 diabetes and control patients.</p>
<p class="art-para">Identification of this polymorphism would give more light and explanation for the reason and mechanism by which some individuals develop autoimmune diabetes. This knowledge would help us develop a strategy for prediction and prevention of T1D.</p>
<p class="art-para">These investigations will contribute to fighting diabetes on national and international level. The chemokine IP-10 expressed from pancreatic beta cells and its receptor CXCR3, expressed on the surface of immune cells are of interest as a predictive marker for the risk assessment of the autoimmune destruction of beta cells.</p>
<p class="art-para">By  screening  the  people  for  this  polymorphism  we  may  be  able  to  identify  the  predisposed to T1D individuals in early childhood and prevent the development of T1D by trying different experimental preventive therapies and approaches.</p>
<p class="art-para"><b>Keywords:</b> IP-10; Pancreatic beta cells; Type 1 diabetes.</p>

<p class="art-subhead" id="intro">Introduction</p>
<p class="art-para">Type  1  diabetes  (T1D)  is  still  a  mystery  for  doctors  and  scientists.  The  causes  and  mechanisms triggering this disease remain unknown. The development of type 1 diabetes is considered to be an autoimmune proinflammatory process mediated by T-cell destruction of pancreatic beta cells. It is believed to be triggered by some environmental factors and human enteroviruses are among the candidates. After infection, the virus enters beta cells and triggers the expression of immunological factors as chemokines, interferons, interleukins which attract and activate autoreactive immune cells. The attracted and activated immune cells destroy infected beta cells.</p>

<p class="art-para">Chemokines are a family of small cytokines, or signaling proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive leukocytes. They are chemotactic cytokines. Chemokines are all approximately 8-10 KD in mass and have four cysteine residues in conserved locations that are key to forming their 3-dimensional  shape.  They  are  secondary  pro-inflammatory  mediators  that  are  induced  by  primary  pro-inflammatory  mediators such as interferon gamma (IFN-&gamma;) interleukin-1 (IL-1)  or  tumor  necrosis  factor  (TNF).  There  are  two  major  chemokine  sub-families  based  upon  the  position  of  cysteine  residues, i.e., CXC and CC. All members of the CXC chemokine sub-family  have  an  intervening  amino  acid  between  the  first  two cysteines; members of the CC chemokine sub-family have two adjacent cysteines.
</p>
<p class="art-para">Among CXC chemokines are CXCL9 (MIG), CXCL10 (IP-10), CXCL11 (I-TAC), CXCL12 (SDF1) and others. </p>
<p class="art-para">The gene for CXCL10 is located on human chromosome 4 in a cluster among several other CXC chemokines.</p>

<p class="art-para">CXCL10 is secreted by several cell types in response toIFN-&gamma;.  These  cell  types  include  monocytes,  endothelial  cells  and fibroblasts. CXCL10  has  been  attributed  to  several  roles,  such as chemoattraction for monocytes/macrophages, T cells,NK  cells,  and  dendritic cells,  promotion  of  T  cell  adhesion  toendothelial  cells,  antitumor activity,  and  inhibition  of  bone  marrow colony formation and angiogenesis.</p>

<p class="art-para">This  chemokine  elicits  its  effects  by  binding  to  the  cell  surface chemokine receptor CXCR3 and TLR4.</p>
<p class="art-para">Over  the  last  decade  more  data  has  been  accumulated  about elevated serum levels and increased expression of IP-10/CXCL10 in pancreatic islets before and in the early stages of type 1 diabetes development. Some authors assume that serum  levels  of  IP-10  are  more  reliable  indicator  for  the  development   of   autoimmune   diabetes   than   anti-insulin   autoantibodies and anti-islet autoantibodies <a href="#1" id="ref1">[1</a>,<a href="#2" id="ref2">2]</a>. According to  Xin.  et  al.  Serum  levels  of  IP-10  in  children  with  T1D  are  elevated  compared  to  controls  in  the  onset  of  disease  and  decrease within the time, and it is not linked to the presence of anti islet autoantibodies <a href="#3" id="ref3">[3]</a>.</p>
<p class="art-para">Shingihara  et  al.  also  measured  elevated  IP-10  and  CXCR3  expression levels before diabetes in diabetic mice, and suggest that the serum levels of IP-10 may be an accurate indicator of the development of T1D <a href="#4" id="ref4">[4]</a>. Li et al. establish a very strong expression of IP-10 in the islets of Langerhans of NOD mice compared to control  mice  and  that  IP-10  is  produced  by  beta  cells  and  is  stored  in  the  cytoplasm  of  these  cells  and  plays  an  important  role in the pathogenesis of type 1 diabetes, attracting immune cells that infiltrate the pancreatic islets <a href="#5" id="ref5">[5]</a>.</p>
<p class="art-para">IP-10 and CXCR3 are of interest as a predictive marker for the  risk  assessment  of  the  autoimmune  destruction  of  beta  cells. Uno et al. after the study of 5 patients with diabetes type 1 and 5 control patients for anti-islet antibodies, GAD, IP-10 and  CXCR3  have  concluded  that  mainly  the  interaction  between   IP-10   and   CXCR3   contributes   to   the   selective   destruction  of  beta  cells  <a href="#6" id="ref6">[6]</a>.  Coppieters  et  al.  reported  that  experimental  obstruction  of  the  interaction  between  IP-10  and CXCR3 inhibits invasion of cytotoxic T lymphocytes and protects islet beta cells from death <a href="#7" id="ref7">[7]</a>. There are claims and proves? that type 1 diabetes is the result of pro-inflammatory process mainly via IP-10 and CXCR3, but as a result of local viral infection <a href="#8" id="ref8">[8</a>,<a href="#9" id="ref9">9]</a>. According to the opinion of Shimada et al. and Antonelli et al. CXCL10/CXCR3 system plays a critical role in  the  autoimmune  beta  cell  destruction.  Viral  beta  cell  infections induce cytokines and CXCL10 expression, inducing beta cell failure in T1D. Blocking CXCL10 in new onset diabetes seems a possible approach for T1D treatment <a href="#10" id="ref10">[10</a>,<a href="#11" id="ref11">11]</a>.</p>
<p class="art-para">Some  experimental  data  of  other  authors  show  that  CXCL10  impairs  &beta;  cell  function  and  viability  in  diabetes through TLR4 signaling <a href="#12" id="ref12">[12]</a>.</p>

<p class="art-subhead" id="method">Materials and Methods</p>
<p class="art-para">Blood  samples  were  collected  during  routine  clinical  investigations.</p>

<p class="art-subhead" id="isolation">Genomic DNA Isolation</p>
<p class="art-para"><b>Preparation of hypotonic lysis buffer</b><br/>
55g sucrose was dissolved in 400ml H<sub>2</sub>O and 5ml of 1M Tris-HCl  (pH8),  5ml  triton  X-100,  and  2,5ml  1M  MgCl<sub>2</sub>,  were  added to a final volume of 500ml.</p>

<p class="art-para"><b>Preparation of nuclei resuspension buffer</b><br/>
1,5ml of 5M NaCl and 4,8ml of 0,5M EDTA were added to a final volume of 100ml. Preparation of proteinase K solution. 100mg proteinase K was dissolved in 10ml H<sub>2</sub>O.</p>

<p class="art-para">All  DNA  was  isolated  from  white  blood  cells  of  IDDM  and  nondiabetic  donors.  4ml  of  blood  collected  in  tubes  with  anticoagulants were incubated in 30ml hypotonic lysis buffer for 15min on ice in order to lyse red blood cells. After hemolysis the hemolysates were centrifuged 30min at 3500rpm at 4&deg;C in order to  pellet  the  leukocyte  nuclei.  The  pellet  was  resuspended  in  600&mu;l NRB (Nuclei Resuspesion Buffer). 32&mu;l 10% SDS and 30&mu;l proteinase K solution was then added to the resuspended nuclei. After 2-12hr incubation at 55&deg;C in a water bath (till DNA solution is translucent) 700&mu;l Buffer-Saturated Phenol was added and vortexed  to  extract  DNA.  The  mixture  was  centrifuged  5min  at  13000rpm at 4&deg;C. After the centrifugation the upper phase which contains DNA was transferred in new tubes and mixed with fresh 700&mu;l Buffer-Saturated Phenol by vortexing to further purify the DNA. After centrifugation at 13000rpm, 5min at 4&deg;C the upper phase was collected and mixed with 800&mu;l Phenol:Cloroform:Isoamil Alcohol (25:24:1,v/v) by vortexing. After the next centrifugation (5min at 13000rpm at 4&deg;C) the DNA (upper phase) was transferred again  in  new  tubes  and  DNA  was  precipitated  by  adding  1ml  100% ice cold ethanol and mixing. The precipitated DNA was pelleted  by  5min  centrifugation  at  13000rpm  at  4&deg;C.  The  DNA  pellet was washed by 0,5ml 70% ethanol and after drying the pellet was dissolved in 200&mu;l H<sub>2</sub>O. The DNA samples were kept at -80&deg;C in aliquots for further use. </p>




<p class="art-subhead" id="analysis">Southern Blot Analysis</p>
<p class="art-para"><b>Preparation of TE buffer (10X)</b><br/>50ml  Tris-HCl  1M  pH8,  10ml  EDTA  0,5M  and  H<sub>2</sub>O  were  added to a final volume of 500ml. </p>
<p class="art-para">After   isolation   of   DNA   from   leucocytes   by   phenol-chlorophorm-isoamylalcohol method, 20&mu;g of the DNA were incubated with restriction enzymes (20U), at 65&deg;C overnight in a water  bath  under  constant  shacking.  The  digested  DNA  was  then  loaded  onto  a  1,2%  agarose  gel  for  electrophoretic separation. After electrophoresis the gel was acidified 30min in 0,25N HCl, then twice 20min in denaturation solution containing 9%NaCl and 2%NaOH (g/v). After denaturation the gel was neutralized  by  washing  twice  20min  in  neutralization  solution  containing 9%NaCl, 6%Tris and 0,018% EDTA (pH7,2). DNA was then transferred from the gel onto a nylon membrane by filter paper  wick  method  overnight,  and  the  next  morning  fixed  for  5min by UV-cross linking (1200&mu;J; 254nm). After prehybridization of   the   membrane   using   10ml   prehybridization   solution   (containing   25ml   Formamid;   10,4ml   20x   SSC;   4,2ml   50x   Denarth's;  2,1ml  1M  NaH2PO4 pH6,5; 4,2ml 10% Glycine and 0,8ml (10 mg/ml) salmon sperm DNA in 50ml end volume with H<sub>2</sub>O)  for  5  hours  at  42&deg;C  in  the  cylinder,  the  membrane  was  hybridized by incubation with the 32P-radiolabeled DNA-probe using Ultrahyb hybridization solution (10ml) at 42&deg;C overnight.</p>
<p class="art-para">Probe labeling: for random primed labeling 11,5&mu;l probe, (or 5-8&mu;l probe + 6,5-3,5&mu;l H<sub>2</sub>O up to 11,5&mu;l end volume), and 2,5&mu;l primer solution were boiled for 3min. The reaction was then  cooled  on  ice,  and  5&mu;l  labeling  buffer  (-dCTP),  5&mu;l 32PdCTP and 1&mu;l Klenov were added before incubating the contents  for  10min  at  37&deg;C  in  a  water  bath.  After  10min  synthesis in a water bath 5&mu;l salmon sperm DNA and 50&mu;l TE buffer  were  added  to  the  reaction  mixture,  which  was  then  denatured  in  a  boiling  water  bath  for  3min,  centrifuged  to  collect  the  condensate  and  placed  on  ice.  The  radio  labeled  probe  was  added  to  10ml  of  fresh  ULTRAhyb  hybridization  buffer, mixed thoroughly in the cylinder and then hybridized with the membrane.</p>
<p class="art-para">After  overnight  hybridization  blots  were  washed  using  NorthernMax High Stringency Wash solution #1 (2x SSC, 0,1% SDS; twice for 10min at 45&deg;C), followed by NorthernMax Low Stringency Wash solution #2 (0,1x SSC, 0,1% SDS; twice for 10min  at  50&deg;C),  and  exposed  for  autoradiography  to  Kodak  XAR5-Omat films at -80&deg;C.</p>
<p class="art-subhead" id="result">Results and Discussion</p>
<p class="art-para">When searching for polymorphisms in the genes encoding CXCL9, CXCL10 and CXCL11 I found a difference in the IP-10 gene  between  patients  with  type  1  diabetes  and  control  patients. What particularly attracted my attention is that over the  small  number  of  patients  studied  (10)  in  9  there  was  a  difference compared to the 9 controls (Fig.1). </p>

<div class="art-img">
<img src="<?php echo $imgpath;?>images/mjd-110-f001.gif" class="img-responsive center-block"/></div>

<p class="art-para">The main hypothesis is that type 1 diabetes is the result of pro-inflammatory  process  of  the  pancreatic  islets  mainly  via  IP-10  and  CXCR3  as  a  result  of  local  viral  infection.  To  the  opinion  of  many  authors  CXCL10/CXCR3  system  plays  a  critical  role  in  the  autoimmune  beta  cell  destruction.  Viral  beta cell infections induce cytokines and CXCL10 expression, attracting CXCR3 and TLR4 expressing autoreactive immune cells inducing beta cell destruction and T1D.</p>

<p class="art-para">The   upregulation   of   CXCL10 and   CXCR3   has   been   documented  in  many  autoimmune  disorders.  Many  studies  have  suggested  that  the  CXCL10/CXCR3  axis  plays  a  critical  role in the autoimmune process and in &beta;-cell destruction in Type 1 Diabetes. Serum CXCL10 level &bdquo;Th1 chemokine" is high in  T1D  patients,  and  this  suggests  that  CXCL10  may  be  a  candidate  for  a  predictive  marker  of  T1D.  Blocking  of  the  CXCL10  chemokine  expression  in  newly  onset  of  diabetes  seems to be a possible approach for the therapy of T1D <a href="#13" id="ref13">[13]</a>.</p>

<p class="art-para">Milicic et all. 2014 analyzed the level of, CXCR3(+) (Th1), CCR4(+) (Th2) T memory cells, IP-10(Th1) and TARC (thymus and activation-regulated chemokine)(Th2), in 51 first degree relatives  (FDRs)  of  type  1  diabetics  (T1D)  (17  high  risk  FDRs  (GADA(+), IA-2(+) and 34 low risk FDRs (GADA(-), IA-2(-), 24 recent-onset T1D (R-T1D), and 18 healthy subjects. High risk FDRs showed higher levels of CXCR3(+) and lower level of CCR4(+) T memory cells compared to low risk. Simultaneously, both IP-10 and TARC levels were increased in high risk versus low risk FDRs. The level of CXCR3(+) T memory cells together with  high  levels  of  IP-10  might  influence  the  risk  for  T1D <a href="#14" id="ref14">[14]</a>.</p>

<p class="art-para">My   hypothesis   is   that   to   happen   the   autoimmune   destruction,  there  must  be  some  genetic  differences  in  the  gene coding at least one of both - receptor or ligand, which leads  to  a  different  way  of  interaction  and  stimulation.  All  individuals   throughout   their   life   are   subjected   to   viral   infections,  but  only  a  small  percentage  of  the  population  react  with  such  hypersensitivity  and  develop  autoimmune  diabetes.  Genetic  polymorphisms  in  the  genes  encoding  IP-10 and it receptor CXCR3 on the surface of immune cells may be the reason for that.</p>

<p class="art-para">I found a genetic polymorphism in the gene encoding the chemokine  IP-10.  This  polymorphism  was  found  only  in  patients with Type 1 diabetes, but not in nondiabetic patients. Investigating larger groups of people for the presence of this polymorphism  to  check  for  any  link  to  type  1  diabetes  is  necessary.  Identification  of  this  polymorphism  would  give  further explanation for its role in pro-inflammatory destruction of beta cells.</p>

<p class="art-para">These  investigations  would  contribute  fighting  diabetes  on  national  and  international  level.  By  screening  people  for  this  polymorphism  it  would  be  possible  to  identify  the  predisposed  to  T1D  individuals  in  early  childhood  and  to  prevent   the   development   of   T1D   by   trying   different   experimental preventive therapies.</p>

<p class="art-para">Identification of this polymorphism would give more light and  explanation  for  the  reason  and  mechanism  by  which  some    individuals    develop    autoimmune    diabetes. This knowledge  would  help  to  develop  a  strategy  for  prediction  and  prevention  of  T1D  and  to  dissolve  an  important  health  problem.</p>

<p class="art-para">Type  1  diabetes  is  a  growing  social  problem.  Until  now  there  are  many  hypotheses,  but  none  of  them  answers  the  questions  why,  when  and  how  some  individuals  develop  diabetes. Researchers are working on preventing the disease or  preventing  further  destruction  of  the  islet  cells  in  people  who  are  newly  diagnosed  but  there's  no  known  way  to  prevent type 1 diabetes.</p>
<p class="art-para">The attempts to stop the process of autoimmune destruction of pancreatic beta cells by blocking T cell receptors or antiviral vaccines delays but do not stop the disease. Since there is no know  way  to  prevent  T1D  so  far,  the  disease  is  not  only  incurable, but unpreventable and unpredictable. Researchers are still working towards fully understanding what causes or triggers T1D. Without fully understanding what triggers T1D remains difficult to prevent.</p>
<p class="art-para">Researchers    have    made    significant    progress    in    understanding the cause of type 1 diabetes, and they're still working hard to figure out why certain viruses trigger it and why  T  cells  turn  against  beta  cells.  T1D  is  considered  an  inflammatory  disease  characterized  by  leukocyte  infiltration  at   the   islets   of   Langerhans.   Chemokines   are   important   participators in the recruitment of specific subpopulations of inflammatory  cells  into  pancreas.  The  medical  community  wants to better understand the cases of diabetes in order to prevent   it.   Identification   of   this   polymorphism   would   contribute  for  further  scientific  advance  in  disclosing  the  mechanism triggering T1D.</p>
<p class="art-para">The viruses may trigger T1D, but the genes play important role    in    this    process.    Improved    knowledge    of    gene    polymorphisms  of  chemokines  and  their  receptors  could  be  useful   to   predict   the   onset   of   diabetes   and   define   its   progression.   After   the   successful   identification   of   this   polymorphism    there    is    a    potential    to    continue    the    investigations  further  by  developing  tests  for  screening  and  identification  of  predisposed  to  T1D  individuals  and  for  research   approaches   focused   on   the   development   of   preventive methods and approaches against T1D.</p>
<p class="art-para">On the basis of the results would be developed predictive test  for  T1D  predisposition,  and  working  further  we  could  search explanation how and when some individuals develop T1D.</p>
<p class="art-para">Identification  of  this  polymorphism  will  disclose  the  possible  mechanism  and  reason  for  development  of  Type  1  diabetes.    Revealing    the    possible    mechanism    of    T1D    development, will allow the scientists and medical specialists to predict who is predisposed to develop T1D and to work on developing strategies and approaches for its prevention and treatment.</p>


<p class="art-subhead" id="conflict">Conflict of interest</p>
<p class="art-para">The authors declare that they have no competing interests.</p>

<p class="art-subhead" id="references">References</p>
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