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• HIV and lower risk of multiple sclerosis: protective or subjugating effect?
  Tatiana Koudriavtseva
  Published on: 17 June 2015
• Re:How accurate is the record linkage?
  Julian Gold
  Published on: 6 January 2015
• How accurate is the record linkage?
  Claudio Voci
  Published on: 6 January 2015

• Published on: 17 June 2015

  HIV and lower risk of multiple sclerosis: protective or subjugating effect?

  • Tatiana Koudriavtseva, Head of Multiple Sclerosis Center
  • Other Contributors:
    • Domenico Plantone, Paola Cordiali-Fei

  Dear Sirs, Gold and colleagues recently found a significantly decreased risk of developing multiple sclerosis (MS) after the onset of HIV infection in a large cohort of national linked data set of English Hospital Episode Statistics.(1) The possible causes of this negative association have been hypothesized to be immunodeficiency and antiretroviral treatment (ART) as MS is usually treated with immunosuppressive drugs and...

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  Dear Sirs, Gold and colleagues recently found a significantly decreased risk of developing multiple sclerosis (MS) after the onset of HIV infection in a large cohort of national linked data set of English Hospital Episode Statistics.(1) The possible causes of this negative association have been hypothesized to be immunodeficiency and antiretroviral treatment (ART) as MS is usually treated with immunosuppressive drugs and its pathogenesis has been linked to human endogenous retroviruses. Since the ART might improve HIV-related immunodeficiency being these two variables inversely correlated, and reliable data on the ART could not be deduced with certainty from the database of the study, this supposition leaves some doubts. With this letter we want to discuss the supposed protective mechanism of HIV against MS. HIV is an immunodeficiency syndrome with progressive CD4+ T lymphocyte loss leading to the development of opportunistic infections, cancers and death especially in untreated patients. However, also autoimmune diseases with rheumatological, haematological, endocrinological and neurological manifestations have been already described in the early pre-ART era.(2) Similarly to what was observed for MS,(1) clinical and serological improvement of systemic lupus erythematosus during the onset of HIV has been reported in some cases, therefore, a therapeutic effect of HIV on autoimmune diseases was already hypothesized.(2) In the ART age, while several autoimmune diseases have been shown to occur at a lower rate than before in HIV patients, other ones (e.g. sarcoidosis) have contrariwise a higher incidence.(2) Furthermore, some autoimmune manifestations may occur contemporarily with the immune reconstitution inflammatory syndrome (IRIS) associated with ART, making particularly difficult their diagnosis.(2) Therefore, the hypothetical protective effect of HIV against MS could be explained in part by a possibility of misdiagnosis of the latter, as acknowledged by the authors themselves.(1) In effect, the authors excluded from the analysis of the HIV cohort five people with prior MS and three people with a simultaneous record of HIV and MS, whereas they included 7 new observed cases during the median follow-up period of 2454 days after the diagnosis of HIV. Indeed, HIV infection might manifest with MS-like clinical and radiological features and with presence of oligoclonal bands in cerebrospinal fluid (CSF), as well as severe inflammatory demyelinating lesions have been observed during IRIS after the onset of ART. Since the diagnostic criteria of MS recommend the exclusion of other pathologies, it is logical to assume that after being diagnosed with HIV the new neurological manifestations are more readily attributed to the latter omitting the diagnosis of MS. In our opinion, the effect of HIV on MS is more correct to be defined as subjugating rather than protective. However, we agree with the authors that by studying the relationships between these two diseases we can better understand the pathogenesis of MS due to its immunological similarities with HIV. Even if for a long time the role of CD4+ and CD8+ T lymphocytes has been emphasized in both MS and HIV, more recently a dysregulation of the innate immunity has been extensively demonstrated in HIV, MS and other autoimmune disorders.(3,4) In particular the natural killer (NK) cells have been demonstrated to be implicated in these pathologies influencing the activity of other components of the innate and adaptive immune systems.(5) NK cells foster anti-viral and anti-tumour immunity recognizing and killing virally-infected or neoplastic cells. A small RNA HIV-1 virus has developed specific strategies to evade control of the NK cells.(3) A functional impairment of NK cell response and in particular their decreased cytotoxic activity has been shown since the early phases of HIV infection persisting during disease progression.(3) HIV-infected individuals have shown progressive expansion of functionally anergic NK cell subset, thus it has been hypothesized that these subjects have an incomplete activation of NK cells due to chronic stimulation leading to NK cell exhaustion and anergy.(3) These anergic NK cells, accumulated during progressive HIV-1 infection, have not produced IFNgamma and TNFalpha by a stimulation with MHC-devoid target cells, reducing a consequent activation of antigen-presenting dendritic cells and components of adaptive immunity.(3) Interestingly, NK cells show similar alterations in both HIV infection and autoimmune diseases, even if the latter are not generally considered as infectious disorders.(4) Several studies have reported both a decreased number of peripheral blood NK cells and an impairment of their cytotoxicity in patients with different autoimmune diseases.(4) However, more recent works have demonstrated accumulation of NK cells in target tissues of several autoimmune diseases such as in pancreatic islets in type I diabetes mellitus, hair follicles in alopecia areata, muscles in juvenile dermatomyositis and synovia in rheumatoid arthritis, supporting the possibility that a decrease of circulating NK cells in autoimmune disorders is consequent to their trafficking to the affected tissues.(4) The functional impairment of NK cells was found prevalently in the early phase of autoimmune diseases and, even at the time of their diagnosis it appears more likely that the NK defect is primary and not secondary to the disease progression or to the treatments.(4) Moreover, the NK dysfunction is present in active but not in quiescent phase, suggesting that NK cells may be involved particularly in the initiation of the disease process.(4) Finally, the same killer immunoglobulin-like receptor/HLA associations fostering NK activation protect against the infections and predispose to autoimmune diseases including MS.(4) In MS, the NK cells might lyse directly oligodendrocytes, astrocytes, microglia and activated T cells, thus having a probable immunoregulatory role.(4) Moreover, transitory reductions of NK cytolytic activity, called "valleys", have been demonstrated to precede radiological and clinical relapses whereas the CD56bright NK cells, more efficient cytokine and chemokine producers compared to the potent cytolytic CD56dim effectors, have been shown a substantial enrichment in the CSF.(4) Finally, NK cells show close modifications also during viral infections, being their number and their cytotoxicity reduced in the peripheral blood with a shift from CD56dim to CD56bright cells.(5) Taken together, these features support the hypothesis that MS as well as other autoimmune diseases may be an expression of latent, chronic infections due to an inadequate immune response to pathogens. Such immune reaction weakens further in HIV infection up to be completely subjugated in the most severe HIV stages. References 1. Gold J, Goldacre R, Maruszak H, Giovannoni G, Yeates D, Goldacre M. HIV and lower risk of multiple sclerosis: beginning to unravel a mystery using a record-linked database study. J Neurol Neurosurg Psychiatry. 2015 Jan;86(1):9-12. doi:10.1136/jnnp-2014-307932. 2. Stratton R, Slapak G, Mahungu T, Kinloch-de Loes S. Autoimmunity and HIV. Curr Opin Infect Dis. 2009 Feb;22(1):49-56. doi: 10.1097/QCO.0b013e3283210006. 3. Altfeld M, Fadda L, Frleta D, Bhardwaj N. DCs and NK cells: critical effectors in the immune response to HIV-1. Nat Rev Immunol. 2011 Mar;11(3):176-86. doi: 10.1038/nri2935. 4. Fogel LA, Yokoyama WM, French AR. Natural killer cells in human autoimmune disorders. Arthritis Res Ther. 2013 Jul 11;15(4):216. doi: 10.1186/ar4232. 5. Mandal A, Viswanathan C. Natural killer cells: In health and disease. Hematol Oncol Stem Cell Ther. 2014 Dec 27. pii: S1658-3876(14)00108-3. doi:10.1016/j.hemonc.2014.11.006.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 6 January 2015

  Re:How accurate is the record linkage?

  • Julian Gold

  We thank Dr. Voci for his comments[1] on our article.[2] As described in the paper, our data comprise Hospital Episode Statistics (HES) obtained from the English national Health and Social Care Information Centre (HSCIC) and mortality record abstracts obtained from the Office for National Statistics. All data from both sources were anonymised to the same standard by encryption of personal identifiers before being supplied...

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  We thank Dr. Voci for his comments[1] on our article.[2] As described in the paper, our data comprise Hospital Episode Statistics (HES) obtained from the English national Health and Social Care Information Centre (HSCIC) and mortality record abstracts obtained from the Office for National Statistics. All data from both sources were anonymised to the same standard by encryption of personal identifiers before being supplied to the Oxford study team for record linkage studies.

  The main data item used in the algorithm for linkage between successive HES records for the same person was "HES ID", an encrypted unique personal identifier generated by HSCIC. HES ID was present for 100% of the HIV HES records, 100% of the reference cohort, and 100% of the multiple sclerosis HES records. For the linkage of HES records to death records, probabilistic matching was used, based on encrypted NHS number, encrypted postcode, encrypted date of birth, and sex.

  To illustrate the quality of the matching, and further to Dr. Voci's suggestion, we have followed up the HIV cohort for tuberculosis, a disease known to be associated with HIV. The rates in the HIV cohort were very substantially elevated compared with those in the reference cohort comprising people without HIV: there were 539 observed and 33.8 expected cases of tuberculosis in the HIV cohort; and 4763 observed and 5268.2 expected cases of tuberculosis in the reference cohort. The rate ratio, standardised for age and other factors as described in our original article,2 was 17.6 (95% CI 16.1 to 19.3). Restricting the outcomes to death records only, the standardised rate ratio was also very high: there were 34 observed and 1.4 expected cases of tuberculosis in the HIV cohort, and 496 observed and 528.6 expected cases of tuberculosis in the reference cohort. The standardised rate ratio was 25.5 (95% CI 17.5 to 36.17), i.e. there was a 25-fold increased death rate from tuberculosis in the HIV cohort. We have confidence in the dataset and the methods used to match and link records in it.

  References

  1. Voci C. How accurate is the record linkage? J Neurol Neurosurg Psychiatry

  2. Gold J, Goldacre R, Maruszak H, et al. HIV and lower risk of multiple sclerosis: beginning to unravel a mystery using a record-linked database study. J Neurol Neurosurg Psychiatry 2014 Aug 4 [Epub ahead of print] doi: 10.1136/jnnp-2014-307932

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 6 January 2015

  How accurate is the record linkage?

  • Claudio Voci, Scientist

  This is an interesting study. However, I am somewhat concerned whether the record linkage could be appropriately performed. In most healthcare information systems, HIV patients characteristics are protected. Did the authors have enough information on the patients to perform probabilistic matching? It would be of interest if the authors could show that the matching is adequate by showing that there is not a general reduce...

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  This is an interesting study. However, I am somewhat concerned whether the record linkage could be appropriately performed. In most healthcare information systems, HIV patients characteristics are protected. Did the authors have enough information on the patients to perform probabilistic matching? It would be of interest if the authors could show that the matching is adequate by showing that there is not a general reduced risk of developing other autoimmune diseases and confirming known HIV associations, for example with TB.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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