Review: Interferons and Autoimmunity

doi:10.1097/00000441-198806000-00007

The American Journal of the Medical Sciences

Volume 295, Issue 6, June 1988, Pages 532-544

https://doi.org/10.1097/00000441-198806000-00007 Get rights and content

ABSTRACT

Autoimmunity can be accelerated in several genetically prone murine models and can even be induced in normal mice by treatment with interferon (IFN) or IFN-inducers. Several cases of IFN-induced autoimmune disease in humans also have been observed; however, more striking is the fact that some of the clinical manifestations in autoimmune diseases and many of the immunological aberrations can be mediated or enhanced by IFN. The finding of high levels of circulating IFN in many patients may be highly significant in that respect, and the characterization of the predominant type of IFN as an unusual acid-labile IFN-α may indicate an infectious etiologic agent in autoimmunity, since this peculiar IFN was mostly associated with viral infections in vivo or in vitro. The induction of MHC class II antigens on previously HLA-DR or la negative cells appears to be caused primarily by IFN-γ and may have a central role in the pathogenesis of autoimmunity in susceptible individuals. Such aberrant HLA-DR expression on nonlymphoid cells can be detected early in the disease in the target organs of many varied autoimmune conditions and may trigger a cascade of self-directed, uncontrolled immune response in conjunction with other factors.

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Cited by (101)

Anomalous brain dominance and the immune system: Do left-handers have specific immunological patterns?
2009, Brain and Cognition
Geschwind and Behan (1982) and Geschwind and Galaburda, 1985a, Geschwind and Galaburda, 1985b, Geschwind and Galaburda, 1985c suggested a correlation between brain laterality and immune disorders. To test whether this hypothesis holds true not only for the frequency of immune diseases and circulating autoantibodies, but extends also to cellular immunity, we examined the association between handedness and markers of cellular immunity. Twenty-seven left-handed and 37 right-handed subjects were serologically screened for cellular parameters and 22 left-handed subjects were typed for human leukocyte antigen (HLA). When compared to the right-handers, the left-handed group showed a significant decrease in the inflammatory cell types CD3⁺ T cells (total T cells), CD4⁺ T cells (T-helper cells), and HLA-Dr (MHC-II, antigen-presenting cells) as well as in the CD19⁺ cells (B cells) and CD16/CD57⁺ cells (natural killer cells). We assume a relationship exists between cerebral hemispheric specialisation and the immune system not only for humoral but also for cellular immunity, and we discuss the role of the major histocompatibility complex in neurological and immunological development.
Acquired factor VIII inhibitors in oncohematology: A systematic review
2008, Critical Reviews in Oncology/Hematology
Citation Excerpt :
The mechanisms of autoimmunity induction by IFN-α are only partially known. The pleiotropic effects of IFN on the immune system include increments of autoantibody production, an increase in B and cytotoxic T cells, functional inhibition of suppressor T cells, and induction of class I MHC molecule expression [58,59]. A possible direct toxic effect in target organs triggering autoimmunity has been suggested [60].
Acquired hemophilia A is an uncommon but potentially life-threatening hemorrhagic disorder caused by the onset of autoantibodies against coagulation factor VIII. Acquired hemophilia A is most frequently associated with autoimmune diseases, neoplasia, pregnancy and drug reactions but in approximately 50% of the cases no underlying disorder can be identified. A prompt diagnosis of this acquired bleeding disorder is essential for the appropriate management which is aimed to the control of hemorrhage and the suppression of inhibitor.
Based on electronic and hand searches of the published literature, this systematic review examines the current knowledge on factor VIII autoantibodies associated with oncohematological disorders.
Auto immunity induced by low doses of interferon in melanoma stage I
2006, Annales de Dermatologie et de Venereologie
Le but principal de ce travail était de définir la prévalence d’induction d’anticorps antinucléaires et d’anticorps antinucléosomes lors d’un traitement par interféron alpha à faible dose pendant 18 mois chez des malades ayant un mélanome stade I. Les objectifs secondaires consistaient à rechercher l’existence ou non d’une corrélation avec la rechute clinique, déterminer la prévalence d’apparition de manifestations cliniques de maladies auto-immunes et de dysthyroïdie.
Il s’agissait d’une étude prospective. Les malades inclus dans l’étude étaient atteints d’un mélanome stade I (classification française), opéré depuis 6 semaines maximum, d’indice de Breslow égal ou supérieur à 1,5 mm, sans contre-indication à l’interféron alpha. On utilisait le modèle statistique de régression logistique.
Quatre-vingt-quatre malades ont été inclus (38 femmes et 46 hommes) âgés de 21 à 75 ans. La prévalence d’apparition des anticorps antinucléaires était de 39 p. 100. Aucune des variables suivantes : âge, sexe, phototype, siège du mélanome en zone photoexposée, indice de Breslow, niveau de Clark, n’était significativement associée à la présence d’anticorps antinucléaires. Devant la prévalence trop faible des anticorps antinucléosomes dans l’échantillon (5 p. 100), aucune étude statistique n’a été réalisée. La prévalence de dysthyroïdie clinique et/ou biologique était de 37 p. 100. Soixante pour cent des malades ont eu à un moment donné des anticorps antinucléaires ou une dysthyroïdie. La prévalence de rechutes et de décès n’était pas significativement différente selon la survenue ou non des anticorps antinucléaires et/ou d’une dysthyroïdie.
De nombreuses études ont rapporté l’apparition d’anticorps antinucléaires, le plus souvent sans traduction clinique, lors du traitement par interféron alpha de cancers (tumeurs carcinoïdes, hémopathies) et d’hépatites chroniques virales. Notre étude est, à notre connaissance, la première évaluant l’induction d’une auto-immunité lors du traitement adjuvant par interféron alpha de mélanomes stade I. Pour certains, l’apparition d’auto-anticorps au cours du traitement par interféron alpha pourrait constituer un marqueur d’efficacité du traitement avec amélioration de la survie de ces malades. Dans notre étude, la survenue de phénomènes auto-immuns n’était pas un facteur pronostique de sévérité d’évolution du mélanome et n’était pas prédictive du pronostic ultérieur du mélanome.
The principal aim of this work was to determine the prevalence of antinuclear antibodies and antinucleosomes antibodies during a treatment by interferon alpha with low dose for 18 months among patients with a melanoma stage I. The secondary objective consisted to seek the existence or not of a correlation with the clinical relapse, to determine the prevalence of appearance of clinical signs of autoimmune diseases and dysthyroidie.
It was an exploratory study. The patients included in the study had a melanoma stage I (French classification), whose excision was realized for 6 weeks maximum, with a Breslow index equal or higher than 1,5 mm. The statistical model of logistic regression was used.
Eighty-forth patients were included (38 women and 46 men) old from 21 to 75 years. The prevalence of antinuclear antibodies was 39%. None of the following variables: age, sex, phototype, localisation of melanoma in exposed photo zone, index of Breslow or Clark, were significantly associated with the presence of antinuclear antibodies. As the percentage of patients with anti-nucleosomes was low (5%), no statistical study was carried out. The prevalence of clinical and/or biological dysthyroidie was 37%. 60% of the patients presented at a moment in the evolution antinuclear antibodies or a dysthyroidie. The prevalence of relapses and death different was not correlated significantly with antinuclear antibodies and/or a dysthyroidie.
Many studies report the appearance of antinuclear antibodies, generally without clinical lesions during the treatment by interferon alpha for cancers (tumours carcinoids, hemopathies) and viral chronic hepatitis. Our study is, to our knowledge, the first evaluating the induction of an autoimmunity during the adjuvant treatment by interferon alpha of melanoma stage I. The induction of autoantibody during the treatment by interferon alpha could constitute a marker of effectiveness of the treatment with improvement of the survival of these patients. In our study, however auto immunity markers do not appear as factors of severity of evolution of the melanoma or predictive factors.
Behavioral effects of infection with interferon-gamma adenovector
2004, Behavioural Brain Research
Anxiety and depression of unknown etiology are frequent complications of the systemic autoimmune disease lupus erythematosus (SLE). To elucidate key pathogenic factors we study the “autoimmunity-associated behavioral syndrome” (AABS) in lupus-prone MRL-lpr mice. Based on the evidence that serum levels of the neuroactive cytokine interferon-gamma (IFN-gamma) are increased both in human and murine forms of SLE, the present study examines whether sustained IFN-gamma production in non-autoimmune mice induces deficits comparable to AABS, particularly in tasks reflective of emotional reactivity and motivated behavior. For this purpose, wild-type and IFN-gamma knockout C57BL/6J mice were infected with adenovirus carrying the cDNA for murine IFN-gamma (i.p. 2×10⁸ pfu of virus per mouse) and shortly thereafter tested in the behavioral battery used in the detection of AABS. Serum levels of IFN-gamma were found to peak 24 h after the infection, normalized within 5 days. Although all infected animals showed reduced food/water intake and body weight, the recovery rate was slower in groups injected with IFN-gamma virus. No deficits were observed in the models of anxiety, but blunted responsiveness in the sucrose preference test (a putative model of anhedonia) lasted well beyond the IFN-gamma clearance period. These results suggest that a relatively brief elevation in systemic IFN-gamma levels impairs ingestive behavior and leads to prolonged changes in motivated behavior. As such, they are consistent with the hypothesis that upregulation in synthesis of pro-inflammatory cytokines contributes to induction of AABS and more specifically, to limbic system dysfunction during lupus-like disease.
Sarcoidosis and interferon therapy: Report of five cases and review of the literature
2003, European Journal of Internal Medicine
Background: Sarcoidosis is a multi-system disease of unknown etiology. Interferons (IFN) have been implicated in its pathogenesis. The objective of this study was to examine the causal relationship between sarcoidosis and IFN therapy. Methods: Patients admitted for sarcoidosis (n=60) were reviewed for a history of IFN therapy. In addition, all cases of sarcoidosis in a cohort of hepatitis C-infected patients treated with IFN-α (n=1159) were analyzed. Results: Five patients with prior IFN-α therapy and sarcoidosis were identified; an additional 23 have been reported in the literature. The median age of the 28 reported patients was 50 years, 16 (57%) were female, and 16 (57%) had isolated cutaneous disease. The median time to diagnosis was 4 months (range 1–16 months) following the introduction of IFN. A remission was observed in all patients with adequate follow-up (n=27): 15 (53%) upon dosage reduction or IFN discontinuation, seven (25%) with systemic corticosteroids, three (11%) with topical treatment, and three (11%) despite ongoing IFN therapy. Relapse was observed in both of the patients rechallenged with IFN. Conclusions: There is a potential causal relationship between IFN therapy and sarcoidosis. In patients with sarcoidosis in the setting of IFN therapy, the majority respond to IFN withdrawal or dosage reduction; however, some require corticosteroid therapy.
Interferon alpha and auto-immunity
2002, Revue de Medecine Interne
-L'objectif de ce travail est l'analyse du potentiel iatrogène de l'interféron (IFN) alpha exogene, et, en amont, du rôle de l'IFN alpha endogene en pathologie auto-immune dans les modèles expérimentaux et dans les maladies humaines spontanées.
-L'IFN alpha apparaît surtout comme un promoteur de l'immunité cellulaire, en favorisant la filierelymphocytaire T de type auxiliaire TH1 ou la differentiation des cellules dendritiques. L'utilisation thérapeutique de l'IFN alpha recombinant s'accompagne d'effets latéraux auto-immuns, hautement dependants de la dose administrée et du contexte pathologique. Le spectre des manifestations auto-immunes observées sous IFN s'dtend de l'apparition isolée d'auto-anticorps chez un patient asymptomatique à la survenue d'une maladie auto-immune parfois severe, comme par exemple un lupus systdmique. La cible antigénique des auto-anticorps est varide : cellules sanguines (leucocytes, hématies, plaquettes), facteurs de la coagulation (facteur VIII, antiprothrombinase), immunoglobulines (activité rhumatoide avec ou sans cryoglobulinémie), composants intra-cellulaires (noyau, enzymes), hormones (insuline, thyroidiennes), facteur intrinséque, épiderme La pathologie la plus fréquemment induite ou favorisée par l'IFN est une thyroïdite, sous trois formes : hypothyroïdie, hyperthyroïdie ou dysthyroïdie biphasique. En fait, l'incidence reelle en est discutée ; elle apparaît faible lors de l'utilisation de l'IFN à faible dose en situation hépatologique, inférieure à 1 % dans une étude récente. La possibilité d'auto-immunité liée à la pathologie traitée avant tout traitement par IFN rend l'interprétation des phénomènes plus complexe : la forte prévalence des FAN ou des anti-DNA dans la leucémie myéloïde chronique ou les auto-anticorps anti-muscle lisse ou anti-LKM daps l'hépatite C en sont des exemples.
-L'IFN alpha est plus probablement un agent favorisant qu'un inducteur de novo de pathologie auto-immune. Son utilisation thérapeutique future comme immunomodulateur doit donc faire l'objet de protocoles ≪prudents≫
-To assess the role of endogenous interferon alpha (IFN) in auto-immune experimental models and human diseases, and toevaluate its iatrogenic potential as a therapeutic agent.
-IFN is a cytokine involved in cellular immunity, that promotes both differentiation of dendritic cells and the TH1 pathway.Auto-immune side-effects of recombinant IFN depend on IFN dosage and the pathology concerned. The spectrum extends from occurrence of auto-antibodies in an asymptomatic patient to overt disease such as systemic lupus. Antigenic targets of auto-antibodies are diverse: blood cells, coagulation factors, immunoglobulin, hormones, intrinsic factor, intracellular components. Thyroiditis is the most frequently reported auto-immune disease occurring during IFN treatment, including hypothyroidism, hyperthyroidism or a bi-phasic pattern. Currently, true incidence of thyroiditis remains debated. It appears very low (under l%) in hepatologic series using low-dose IFN. The fact that auto-immunity may be related to the treated disease-before use of IFN-must also be addressed: e.g. antinuclear factors and anti-DNA antibodies in chronic myeloid leukemia or anti-actin and anti-LKM antibodies in chronic C hepatitis.
-Recombinant alpha interferon appears more as a trigger than a de novo inducer of auto-immune disorders. Its use as an immunomodulator agent should be treated with caution.

View all citing articles on Scopus

: The author thanks Professor Michel Revel for many helpful discussions and suggestions.

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ReviewReview: Interferons and Autoimmunity

ABSTRACT

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Lancet

Interferon-activated genes

Trends in Biochemical Sciences

The pathogenesis of autoimmunity in New Zealand mice. II. Acceleration of glomerulonephritis by polyinosinic polycytidylie acid

Lab Invest

Treatment of NZB/NZW F1 hybrid mice with mycobacterium bovis strain BCG or type II interferon preparations accelerates autoimmune disease

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J Exp Med

Interferon treatment of NZB mice: accelerated progression of autoimmune disease

Infect Immun

Adverse effects of interferon treatment on the life span of NZB mice

Biomedicine [Express]

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Systemic lupus erythematosus: insights from animal models

Ann Intern Med

Progressive glomerulonephritis in mice treated with interferon preparations at birth

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Can interferon induce disease?

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Release of DNA in circulating blood and induction of anti-DNA antibodies after injection of bacterial lipopolysaccharides

J Exp Med

The induction of autoimmunity in normal mice (abstract)

Clin Res

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Virus and interferon effects on cellular prostaglandin biosynthesis

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Interferon triggers experimental synovitis and may potentiate auto-immune disease in humans

Clin Rheumatol

Lupus serum and normal human serum contain anti-DNA antibodies with the same idiotypic marker

J Immunol

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Human lupus inclusions and interferon

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Blood lymphocyte inclusions associated with α-interferon (abstract)

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Modulation of immunity by interferon

Autoimmunity: a perspective

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Peripheral blood Ia-positive T cells. Increases in certain diseases and after immunization

J Exp Med

Betaj-microglobulin levels, autoimmune diseases and interferon

Arthritis Rheum

T lymphocyte subsets in systemic lupus erythematosus. Correlations with corticosteroid therapy and disease activity

Arthritis Rheum

Analysis of T cell subsets in cancer patients treated with interferon

Am J Med

Immunomodulation by interferons: recent developments

Relationship between circulating interferon and anti-interferon antibodies and impaired natural killer cell activity in systemic lupus erythematosus

Review
Review: Interferons and Autoimmunity