Response to 'Fragment of tegument protein pp65 of human cytomegalovirus induces autoantibodies in BALB/c mice'

  • Gn Kim1 and

    Affiliated with

    • Think-You Kim1Email author

      Affiliated with

      Arthritis Research & Therapy201214:404

      DOI: 10.1186/ar4023

      Published: 10 September 2012

      We read with interest the recent paper by Hsieh and colleagues [1] asserting that cytomegalovirus (CMV) induces systemic lupus erythematosus (SLE) in genetically susceptible individuals. This assertion is based on the idea that SLE-associated autoantibodies that had been induced by a certain fragment of CMV were found in rodents. However, our previous studies have reported that autoantibodies detected in SLE and viral infection are different, especially with regard to the anti-microtubule organizing center with microtubule (anti-MTOC-MT) [24]. We conducted a retrospective study comparing autoantibodies in three groups: anti-CMV IgM-positive SLE patients (SLE-CMV group); anti-CMV IgM-positive patients without SLE (CMV group); and anti-CMV IgM-negative SLE patients (SLE group). This study was approved by the institutional review board of Hanyang University Medical Center.

      Autoantibodies from 245 patients were analyzed from January 2005 to March 2012 by the autoimmune target (AIT) test, which was developed to overcome the limitations of the antinuclear antibody test using the human macrophage cell line (IT-1) as a substrate [2].

      What is noteworthy is that anti-MOTC-MT was highly detected in the CMV group, while it was not detected in all SLE patients regardless of CMV infection. Moreover, if CMV is a cause of SLE, detected autoantibodies between the SLE-CMV and CMV groups should overlap, but they show a clear distinction (Table 1).
      Table 1

      Immunofluorescence patterns and titers of AIT test in SLE-CMV, SLE and CMV groups

       

      Titer

       

      Patterns from AIT test

      ≤1:20

      1:40

      1:80

      1:160

      1:320

      1:640

      1:1280

      ≥1:2560

      Total

      SLE-CMV groupa

               

         Homogeneous

           

      2

       

      9

      11

         Homogeneous + speckled

           

      4

       

      13

      17

         Homogeneous + cytoplasmic

             

      1

      1

         Homogeneous + diffuse granular

             

      4

      4

         Homogeneous + speckled + cytoplasmic

             

      3

      3

         Speckled

            

      1

      8

      9

         Speckled + cytoplasmic

         

      1

         

      1

      2

         Diffuse granular + cytoplasmic

             

      1

      1

         Diffuse cytoplasmic + speckled

             

      3

      3

         Diffuse cytoplasmic + diffuse granular

             

      2

      2

         Total

      0

      0

      0

      1

      0

      6

      1

      45

      53

      SLE groupb

               

         Homogeneous

           

      1

      2

      15

      18

         Homogeneous + speckled

          

      2

       

      3

      33

      38

         Homogeneous + cytoplasmic

             

      2

      2

         Homogeneous + diffuse granular

            

      1

      12

      13

         Homogeneous + speckled + cytoplasmic

          

      2

       

      1

      4

      7

         Speckled

          

      5

      3

      5

      34

      47

         Speckled + cytoplasmic

          

      1

      3

      3

      3

      10

         Diffuse granular + cytoplasmic

          

      2

       

      1

      5

      8

         Diffuse granular

           

      1

      5

      7

      13

         Diffuse cytoplasmic + speckled

             

      9

      9

         Diffuse cytoplasmic + diffuse granular

           

      1

      1

       

      2

         Diffuse cytoplasmic + nucleolar

           

      1

       

      2

      3

         Total

      0

      0

      0

      0

      12

      10

      22

      126

      170

      CMV groupc

               

         MTOC-MT

        

      4

      4

      1

      1

      1

       

      11

         MTOC-MT + IF + speckled

       

      1

      1

      2

        

      1

       

      5

         Speckled

        

      2

           

      2

         Negative

      4

             

      4

         Total

      4

      1

      7

      6

      1

      1

      2

      0

      22

      aSLE-CMV group, anti-CMV IgM-positive SLE patients; bSLE group, anti-CMV IgM-negative SLE patients; cCMV group, anti-CMV IgM-positive patients without SLE. The AIT test was performed using an indirect immunofluorescent test kit (IT-AIT™; ImmunoThink Co., Seoul, Republic of Korea). In the CMV group, anti-MTOC-MT-positive patients accounted for 72.7% of the total patients in the CMV group and 88.9% of autoantibody-positive patients, but in the SLE-CMV group, anti-MTOC-MT was not detected at all (P < 0.001). Patients in the SLE-CMV group showed high titers of over 1:640 except for one who received steroid pulse therapy just before the test, but the proportion of patients in the CMV group with a titer over 1:640 was not more than 13.6% (P < 0.001). In addition, most of the autoantibody frequently found in the SLE-CMV group was not found in the CMV group. AIT, autoimmune target; CMV, cytomegalovirus; IF, intermediate filament; MTOC-MT, microtubule organizing center with microtubule; SLE, systemic lupus erythematosus.

      CMV becomes latent in multiple organs and can later be reactivated during severe dysregulation of the immune system. In our study, over 90% of patients in the three groups were anti-CMV IgG-positive. Detection of anti-CMV IgG implies the presence of latent virus, but anti-CMV IgG does not protect the individual from reactivation of the latent virus. In contrast, anti-CMV IgM responses are often seen during reactivation of CMV, so it seems that CMV infection in the SLE-CMV group was not caused by primary infection but by reactivation of CMV. MTOC, cytokines and T cells are closely coordinated to maintain the immune system [5] and anti-MTOC-MT is not found in SLE patients owing to impairment of the immune system. In conclusion, we postulate that CMV is not sufficiently intense to cause SLE, but is reactivated in some SLE patients as an innocent bystander.

      Abbreviations

      AIT: 

      autoimmune target

      CMV: 

      cytomegalovirus

      MTOC-MT: 

      microtubule organizing center with microtubule

      SLE: 

      systemic lupus erythematosus.

      Declarations

      Authors’ Affiliations

      (1)
      Department of Early Arthritis/Laboratory of Medicine, The Hospital for Rheumatic Diseases, Hanyang University Medical Center

      References

      1. Hsieh AH, Jhou YJ, Liang CT, Chang M, Wang SL: Fragment of tegument protein pp65 of human cytomegalovirus induces autoantibodies in BALB/c mice. Arthritis Res Ther 2011, 13:R162.PubMedView Article
      2. Jearn LH, Kim DA, Kim TY: Limitations of antinuclear antibody tests (HEp-2) are overcome with the autoimmune target test (IT-1) in systemic lupus erythematosus. J Rheumatol 2009, 36:1833–1834.PubMedView Article
      3. Sir JU, Kim TY: MTOC-MT is a major target antigen of autoantibody detected by autoimmune target tests in patients with hepatitis A virus infection. J Clin Pathol 2010, 63:1129.PubMedView Article
      4. Sir JU, Kim TY: Autoantibodies are commonly detected by the AIT test in patients with chronic hepatitis C virus infection. J Viral Hepat 2010, 17:379.PubMedView Article
      5. Martín-Cófreces NB, Robles-Valero J, Cabrero JR, Mittelbrunn M, Gordón-Alonso M, Sung CH, Alarcón B, Vázquez J, Sánchez-Madrid F: MTOC translocation modulates IS formation and controls sustained T cell signaling. J Cell Biol 2008, 182:951–62.PubMedView Article

      Copyright

      © BioMed Central Ltd 2012

      Advertisement