Skip to main content
Top

07-03-2016 | Comorbidities | Article

Infection and Lupus: Which Causes Which?

Journal: Current Rheumatology Reports

Authors: Sarah Doaty, Harsh Agrawal, Erin Bauer, Daniel E. Furst

Publisher: Springer US

Abstract

Infection is a leading cause of morbidity and mortality among patients with systemic lupus erythematous (SLE). Dysfunction of the innate and adaptive immune systems increases the risk of infection in patients with SLE. Infectious agents have also been theorized to play a role in the pathogenesis of SLE. This article summarizes our current knowledge of the infectious risk SLE patients face as a result of their underlying disease including abnormal phagocytes and T cells as well as the increased risk of infection associated with immunosuppressive agents used to treat disease. Pathogens thought to play a role in the pathogenesis of disease including EBV, CMV, human endogenous retroviruses (HERVs), and tuberculosis will also be reviewed, as well as the pathologic potential of microbial amyloids and the microbiome.
Literature
1.
Zandman-Goddard G, Shoenfeld Y. Infections and SLE. Autoimmunity. 2005;38:473–85.PubMedCrossRef
2.
Bouza E, Moya JG, Munoz P. Infections in systemic lupus erythematosus and rheumatoid arthritis. Infect Dis Clin North Am. 2001;15:335–61. vii.PubMedCrossRef
3.•
Pasoto SG, Ribeiro AC, Bonfa E. Update on infections and vaccinations in systemic lupus erythematosus and Sjogren’s syndrome. Curr Opin Rheumatol. 2014;26:528–37. Good review of common infections in SLE as well as preventative measures. PubMedCrossRef
4.••
Feldman CH et al. Serious infections among adult Medicaid beneficiaries with systemic lupus erythematosus and lupus nephritis. Arthritis Rheumatol. 2015;67:1577–85. Excellent epidemiologic study of infections in patients with SLE and lupus nephritis. PubMedCrossRef
5.••
Danza A, Ruiz-Irastorza G. Infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies. Lupus. 2013;22:1286–94. Thorough review of contributing factors to infections in SLE as well as prevention and treatment. PubMedCrossRef
6.
Esposito S, Bosis S, Semino M, Rigante D. Infections and systemic lupus erythematosus. Eur J Clin Microbiol Infect Dis. 2014;33:1467–75.PubMedCrossRef
7.
Manzi S et al. Herpes zoster in systemic lupus erythematosus. J Rheumatol. 1995;22:1254–8.PubMed
8.
Alarcon GS. Infections in systemic connective tissue diseases: systemic lupus erythematosus, scleroderma, and polymyositis/dermatomyositis. Infect Dis Clin North Am. 2006;20:849–75.PubMedCrossRef
9.
Nath R et al. High risk of human papillomavirus type 16 infections and of development of cervical squamous intraepithelial lesions in systemic lupus erythematosus patients. Arthritis Rheum. 2007;57:619–25.PubMedCrossRef
10.
Robak E et al. Lymphocyctes Tgammadelta in clinically normal skin and peripheral blood of patients with systemic lupus erythematosus and their correlation with disease activity. Mediators Inflamm. 2001;10:179–89.PubMedPubMedCentralCrossRef
11.
Volc-Platzer B, Anegg B, Milota S, Pickl W, Fischer G. Accumulation of gamma delta T cells in chronic cutaneous lupus erythematosus. J Invest Dermatol. 1993;100:84S–91.PubMedCrossRef
12.
Cuchacovich R, Gedalia A. Pathophysiology and clinical spectrum of infections in systemic lupus erythematosus. Rheum Dis Clin North Am. 2009;35:75–93.PubMedCrossRef
13.
Savill J. Apoptosis in resolution of inflammation. J Leukoc Biol. 1997;61:375–80.PubMed
14.
Surh CD, Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature. 1994;372:100–3.PubMedCrossRef
15.
Gaipl US et al. Disposal of dying cells: a balancing act between infection and autoimmunity. Arthritis Rheum. 2003;48:6–11.PubMedCrossRef
16.
Herrmann M et al. Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 1998;41:1241–50.PubMedCrossRef
17.
Salmon JE, Kimberly RP, Gibofsky A, Fotino M. Defective mononuclear phagocyte function in systemic lupus erythematosus: dissociation of Fc receptor-ligand binding and internalization. J Immunol. 1984;133:2525–31.PubMed
18.
Landry M. Phagocyte function and cell-mediated immunity in systemic lupus erythematosus. Arch Dermatol. 1977;113:147–54.PubMedCrossRef
19.
Starkebaum G, Price TH, Lee MY, Arend WP. Autoimmune neutropenia in systemic lupus erythematosus. Arthritis Rheum. 1978;21:504–12.PubMedCrossRef
20.
Yamasaki K, Niho Y, Yanase T. Granulopoiesis in systemic lupus erythematosus. Arthritis Rheum. 1983;26:516–21.PubMedCrossRef
21.
Tsai CY, Wu TH, Yu CL, Tsai YY, Chou CT. Decreased IL-12 production by polymorphonuclear leukocytes in patients with active systemic lupus erythematosus. Immunol Invest. 2002;31:177–89.PubMedCrossRef
22.
Hsieh SC et al. Decreased spontaneous and lipopolysaccharide stimulated production of interleukin 8 by polymorphonuclear neutrophils of patients with active systemic lupus erythematosus. Clin Exp Rheumatol. 1994;12:627–33.PubMed
23.
Molnar L et al. Immune-complex phagocytosis by human polymorphonuclear granulocytes. Acta Physiol Acad Sci Hung. 1978;52:33–9.PubMed
24.
Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol. 2000;76:227–324.PubMedCrossRef
25.
Rupert KL et al. The molecular basis of complete complement C4A and C4B deficiencies in a systemic lupus erythematosus patient with homozygous C4A and C4B mutant genes. J Immunol. 2002;169:1570–8.PubMedCrossRef
26.
Ross SC, Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore). 1984;63:243–73.CrossRef
27.
Marquart HV et al. Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 1995;101:60–5.PubMedPubMedCentralCrossRef
28.
Ho A, Barr SG, Magder LS, Petri M. A decrease in complement is associated with increased renal and hematologic activity in patients with systemic lupus erythematosus. Arthritis Rheum. 2001;44:2350–7.PubMedCrossRef
29.
Mangini AJ, Lafyatis R, Van Seventer JM. Type I interferons inhibition of inflammatory T helper cell responses in systemic lupus erythematosus. Ann N Y Acad Sci. 2007;1108:11–23.PubMedCrossRef
30.
Park YW et al. Impaired differentiation and cytotoxicity of natural killer cells in systemic lupus erythematosus. Arthritis Rheum. 2009;60:1753–63.PubMedCrossRef
31.
Tanaka T et al. Decreased expression of interleukin-2 binding molecules (p70/75) in T cells from patients with systemic lupus erythematosus. Arthritis Rheum. 1989;32:552–9.PubMedCrossRef
32.
Odendahl M et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol. 2000;165:5970–9.PubMedCrossRef
33.
Cronin ME, Balow JE, Tsokos GC. Immunoglobulin deficiency in patients with systemic lupus erythematosus. Clin Exp Rheumatol. 1989;7:359–64.PubMed
34.
Goldstein MF et al. Selective IgM immunodeficiency: retrospective analysis of 36 adult patients with review of the literature. Ann Allergy Asthma Immunol. 2006;97:717–30.PubMedCrossRef
35.
Cassidy JT, Kitson RK, Selby CL. Selective IgA deficiency in children and adults with systemic lupus erythematosus. Lupus. 2007;16:647–50.PubMedCrossRef
36.
Graham RR et al. Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE. Eur J Hum Genet. 2007;15:823–30.PubMedCrossRef
37.
Holmskov U, Malhotra R, Sim RB, Jensenius JC. Collectins: collagenous C-type lectins of the innate immune defense system. Immunol Today. 1994;15:67–74.PubMedCrossRef
38.
Garred P, Voss A, Madsen HO, Junker P. Association of mannose-binding lectin gene variation with disease severity and infections in a population-based cohort of systemic lupus erythematosus patients. Genes Immun. 2001;2:442–50.PubMedCrossRef
39.
Sebastiani GD, Galeazzi M. Infection—genetics relationship in systemic lupus erythematosus. Lupus. 2009;18:1169–75.PubMedCrossRef
40.
Kirou,K. & Boumpas,D. Systemic glucocorticoid therapy on SLE in Lupus Erythematosus and related syndromes (eds. Wallace,D. & Hahn,B.) 2013).
41.
Cutolo M et al. Use of glucocorticoids and risk of infections. Autoimmun Rev. 2008;8:153–5.PubMedCrossRef
42.
Dixon WG, Kezouh A, Bernatsky S, Suissa S. The influence of systemic glucocorticoid therapy upon the risk of non-serious infection in older patients with rheumatoid arthritis: a nested case–control study. Ann Rheum Dis. 2011;70:956–60.PubMedPubMedCentralCrossRef
43.
Ruiz-Irastorza G et al. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther. 2009;11:R109.PubMedPubMedCentralCrossRef
44.
Badsha H et al. Low-dose pulse methylprednisolone for systemic lupus erythematosus flares is efficacious and has a decreased risk of infectious complications. Lupus. 2002;11:508–13.PubMedCrossRef
45.
Klein NC, Go CH, Cunha BA. Infections associated with steroid use. Infect Dis Clin North Am. 2001;15:423–32. viii.PubMedCrossRef
46.•
van der Goes MC, Jacobs JW, Bijlsma JW. The value of glucocorticoid co-therapy in different rheumatic diseases—positive and adverse effects. Arthritis Res Ther. 2014;16 Suppl 2:S2. Highlights the role of glucocorticoids in the development of infection in patients with SLE.PubMedPubMedCentralCrossRef
47.
Belard E et al. Prednisolone treatment affects the performance of the QuantiFERON gold in-tube test and the tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection. Inflamm Bowel Dis. 2011;17:2340–9.PubMedCrossRef
48.
Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus. 2005;14 Suppl 1:s2–8.PubMedCrossRef
49.
Subedi A, Magder LS, Petri M. Effect of mycophenolate mofetil on the white blood cell count and the frequency of infection in systemic lupus erythematosus. Rheumatol Int. 2015;35:1687–92.PubMedCrossRef
50.
Houssiau FA et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis. 2010;69:2083–9.PubMedPubMedCentralCrossRef
51.
Dooley MA et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011;365:1886–95.PubMedCrossRef
52.
Martinez-Martinez MU et al. Invasive fungal infections in patients with systemic lupus erythematosus. J Rheumatol. 2012;39:1814–8.PubMedCrossRef
53.
Ritter ML, Pirofski L. Mycophenolate mofetil: effects on cellular immune subsets, infectious complications, and antimicrobial activity. Transpl Infect Dis. 2009;11:290–7.PubMedPubMedCentralCrossRef
54.
Pryor BD, Bologna SG, Kahl LE. Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus. Arthritis Rheum. 1996;39:1475–82.PubMedCrossRef
55.
Haga HJ, D’Cruz D, Asherson R, Hughes GR. Short term effects of intravenous pulses of cyclophosphamide in the treatment of connective tissue disease crisis. Ann Rheum Dis. 1992;51:885–8.PubMedPubMedCentralCrossRef
56.
Gurwitz JH et al. Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med. 1994;154:97–101.PubMedCrossRef
57.
Migita K et al. Rates of serious intracellular infections in autoimmune disease patients receiving initial glucocorticoid therapy. PLoS One. 2013;8:e78699.PubMedPubMedCentralCrossRef
58.
Md Yusof MY, Vital EM, Buch MH. B cell therapies, approved and emerging: a review of infectious risk and prevention during use. Curr Rheumatol Rep. 2015;17:65.PubMedCrossRef
59.
Diaz-Lagares C et al. Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label. Arthritis Res Ther. 2011;13:R112.PubMedPubMedCentralCrossRef
60.
Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy: a national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum. 2009;60:3761–5.PubMedCrossRef
61.••
Calabrese LH, Molloy E, Berger J. Sorting out the risks in progressive multifocal leukoencephalopathy. Nat Rev Rheumatol. 2015;11:119–23. Excellent review of the risk of PML associated with various immunosuppressive agents. PubMedCrossRef
62.
Navarra SV et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:721–31.PubMedCrossRef
63.
Fredericks CA, Kvam KA, Bear J, Crabtree GS, Josephson SA. A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab. Lupus. 2014;23:711–3.PubMedCrossRef
64.
Leblanc-Trudeau C, Masetto A, Bocti C. Progressive multifocal leukoencephalopathy associated with belimumab in a patient with systemic lupus erythematosus. J Rheumatol. 2015;42:551–2.PubMedCrossRef
65.
Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology. 2015;23:231–69.PubMedCrossRef
66.•
Nelson P, Rylance P, Roden D, Trela M, Tugnet N. Viruses as potential pathogenic agents in systemic lupus erythematosus. Lupus. 2014;23:596–605. Good review of the potential role of HERVs in the pathogenesis of SLE. PubMedCrossRef
67.
Lin YC et al. Tuberculosis as a risk factor for systemic lupus erythematosus: results of a nationwide study in Taiwan. Rheumatol Int. 2012;32:1669–73.PubMedCrossRef
68.
Radic M. Role of Helicobacter pylori infection in autoimmune systemic rheumatic diseases. World J Gastroenterol. 2014;20:12839–46.PubMedPubMedCentralCrossRef
69.
Petri M. Infection in systemic lupus erythematosus. Rheum Dis Clin North Am. 1998;24:423–56.PubMedCrossRef
70.••
Spaulding CN, Dodson KW, Chapman MR, Hultgren SJ. Fueling the fire with fibers: bacterial amyloids promote inflammatory disorders. Cell Host Microbe. 2015;18:1–2. Excellent review of emerging data that implicates bacterial amyloids in the pathogenesis of SLE. PubMedCrossRef
71.•
Hanlon P, Avenell A, Aucott L, Vickers MA. Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and systemic lupus erythematosus. Arthritis Res Ther. 2014;16:R3. Thorough review of the current literature on the relationship between EBV and SLE. PubMedPubMedCentralCrossRef
72.
Draborg AH et al. Reduced response to Epstein-Barr virus antigens by T-cells in systemic lupus erythematosus patients. Lupus Sci Med. 2014;1:e000015.PubMedPubMedCentralCrossRef
73.
Iwakiri D et al. Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3. J Exp Med. 2009;206:2091–9.PubMedPubMedCentralCrossRef
74.
Draborg AH, Duus K, Houen G. Epstein-Barr virus and systemic lupus erythematosus. Clin Dev Immunol. 2012;2012:370516.PubMedPubMedCentralCrossRef
75.
Sciascia S, Cuadrado MJ, Karim MY. Management of infection in systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2013;27:377–89.PubMedCrossRef
76.
Mohamed AE, Hasen AM, Mohammed GF, Elmaraghy NN. Real-Time PCR of cytomegalovirus and Epstein-Barr virus in adult Egyptian patients with systemic lupus erythematosus. Int J Rheum Dis. 2015;18:452–8.PubMedCrossRef
77.
Casali P. Polyclonal B cell activation and antigen-driven antibody response as mechanisms of autoantibody production in SLE. Autoimmunity. 1990;5:147–50.PubMedCrossRef
78.
Rasmussen NS, Draborg AH, Nielsen CT, Jacobsen S, Houen G. Antibodies to early EBV, CMV, and HHV6 antigens in systemic lupus erythematosus patients. Scand J Rheumatol. 2015;44:143–9.PubMedPubMedCentralCrossRef
79.
Rigante D, Esposito S. Infections and systemic lupus erythematosus: binding or sparring partners? Int J Mol Sci. 2015;16:17331–43.PubMedPubMedCentralCrossRef
80.
Tugnet N, Rylance P, Roden D, Trela M, Nelson P. Human endogenous retroviruses (HERVs) and autoimmune rheumatic disease: is there a link? Open Rheumatol J. 2013;7:13–21.PubMedPubMedCentral
81.
Meyer O. Parvovirus B19 and autoimmune diseases. Joint Bone Spine. 2003;70:6–11.PubMedCrossRef
82.
Kerr JR, Boyd N. Autoantibodies following parvovirus B19 infection. J Infect. 1996;32:41–7.PubMedCrossRef
83.
Loizou S, Cazabon JK, Walport MJ, Tait D, So AK. Similarities of specificity and cofactor dependence in serum antiphospholipid antibodies from patients with human parvovirus B19 infection and from those with systemic lupus erythematosus. Arthritis Rheum. 1997;40:103–8.PubMedCrossRef
84.
Aslanidis S, Pyrpasopoulou A, Kontotasios K, Doumas S, Zamboulis C. Parvovirus B19 infection and systemic lupus erythematosus: activation of an aberrant pathway? Eur J Intern Med. 2008;19:314–8.PubMedCrossRef
85.
Tzang BS et al. The association of VP1 unique region protein in acute parvovirus B19 infection and anti-phospholipid antibody production. Clin Chim Acta. 2007;378:59–65.PubMedCrossRef
86.
Tzang BS et al. Induction of antiphospholipid antibodies and antiphospholipid syndrome-like autoimmunity in naive mice with antibody against human parvovirus B19 VP1 unique region protein. Clin Chim Acta. 2007;382:31–6.PubMedCrossRef
87.
Tzang BS et al. Increased cardiac injury in NZB/W F1 mice received antibody against human parvovirus B19 VP1 unique region protein. Mol Immunol. 2011;48:1518–24.PubMedCrossRef
88.
Pavlovic M, Kats A, Cavallo M, Shoenfeld Y. Clinical and molecular evidence for association of SLE with parvovirus B19. Lupus. 2010;19:783–92.PubMedCrossRef
89.
Lindqvist KJ, Coleman RE, Osterland CK. Autoantibodies in chronic pulmonary tuberculosis. J Chronic Dis. 1970;22:717–25.PubMedCrossRef
90.
SINGER JM, PLOTZ CM, PERLATA FM, LYONS HC. The presence of anti-gamma globulin factors in sera of patients with active pulmonary tuberculosis. Ann Intern Med. 1962;56:545–52.PubMedCrossRef
91.
Evans ML, Chapman MR. Curli biogenesis: order out of disorder. Biochim Biophys Acta. 2014;1843:1551–8.PubMedPubMedCentralCrossRef
92.
Kai-Larsen Y et al. Uropathogenic Escherichia coli modulates immune responses and its curli fimbriae interact with the antimicrobial peptide LL-37. PLoS Pathog. 2010;6:e1001010.PubMedPubMedCentralCrossRef
93.••
Gallo PM et al. Amyloid-DNA composites of bacterial biofilms stimulate autoimmunity. Immunity. 2015;42:1171–84. Implicates biofilm forming bacteria as potential pathogenic factors in SLE. PubMedCrossRef
94.
Tukel C et al. Toll-like receptors 1 and 2 cooperatively mediate immune responses to curli, a common amyloid from enterobacterial biofilms. Cell Microbiol. 2010;12:1495–505.PubMedCrossRef
95.
Theander E, Nilsson I, Manthorpe R, Jacobsson LT, Wadstrom T. Seroprevalence of Helicobacter pylori in primary Sjogren’s syndrome. Clin Exp Rheumatol. 2001;19:633–8.PubMed
96.
Sorrentino D et al. Helicobacter pylori associated antigastric autoantibodies: role in Sjogren’s syndrome gastritis. Helicobacter. 2004;9:46–53.PubMedCrossRef
97.
Sawalha AH, Schmid WR, Binder SR, Bacino DK, Harley JB. Association between systemic lupus erythematosus and Helicobacter pylori seronegativity. J Rheumatol. 2004;31:1546–50.PubMed
98.
Chen M et al. Toxoplasma gondii infection inhibits the development of lupus-like syndrome in autoimmune (New Zealand Black x New Zealand White) F1 mice. Int Immunol. 2004;16:937–46.PubMedCrossRef
99.••
Hevia A et al. Intestinal dysbiosis associated with systemic lupus erythematosus. MBio. 2014;5:e01548–14. Original data to support relationship between gut microbiome and the pathogenesis of SLE. PubMedPubMedCentralCrossRef
100.•
Johnson BM, Gaudreau MC, Al-Gadban MM, Gudi R, Vasu C. Impact of dietary deviation on disease progression and gut microbiome composition in lupus-prone SNF1 mice. Clin Exp Immunol. 2015;181:323–37. Original research highlighting the effect of dietary changes, their impact on the microbiome and the progression of SLE. PubMedCrossRef
101.•
Calixto OJ, Franco JS, Anaya JM. Lupus mimickers. Autoimmun Rev. 2014;13:865–72. Highlights the similarities and differences between clinical features of SLE and infections that mimic SLE. PubMedCrossRef
102.
Firooz N et al. High-sensitivity C-reactive protein and erythrocyte sedimentation rate in systemic lupus erythematosus. Lupus. 2011;20:588–97.PubMedCrossRef
103.••
Song GG, Bae SC, Lee YH. Diagnostic accuracies of procalcitonin and C-reactive protein for bacterial infection in patients with systemic rheumatic diseases: a meta-analysis. Clin Exp Rheumatol. 2015;33:166–73. Highlights recent data on biomarkers used to differentiate between infection and disease flare. PubMed
104.•
Beca S, Rodriguez-Pinto I, Alba MA, Cervera R, Espinosa G. Development and validation of a risk calculator to differentiate flares from infections in systemic lupus erythematosus patients with fever. Autoimmun Rev. 2015;14:586–93. Novel risk calculator to differentiate between infection and disease flare. PubMedCrossRef