Skip to main content

Advertisement

SpringerLink
Log in

Impact of Microbes on Autoimmune Diseases

  • Review
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Autoimmune and autoinflammatory diseases arise as a consequence of complex interactions of environmental factors with genetic traits. Although specific allelic variations cluster in predisposed individuals and promote the generation and/or expansion of autoreactive T and B lymphocytes, autoimmunity appears in various disease phenotypes and localizes to diverging tissues. Furthermore, the discovery that allelic variations within genes encoding components of the innate immune system drive self-reactive immune responses as well, led to the distinction of immune responses against host tissues into autoimmune and autoinflammatory diseases. In both categories of disorders, different pathogenic mechanisms and/or subsequent orders of tissue assaults may underlie the target cell specificity of the respective autoimmune attack. Furthermore, the transition from the initial tissue assault to the development of full-blown disease is likely driven by several factors. Thus, the development of specific forms of autoimmunity and autoinflammation reflects a multi-factorial process. The delineation of the specific factors involved in the pathogenic process is hampered by the fact that certain symptoms are assembled under the umbrella of a specific disease, although they might originate from diverging pathogenic pathways. These multi-factorial triggers and pathogenic pathways may also explain the inter-individual divergent courses and outcomes of diseases among humans. Here, we will discuss the impact of different environmental factors in general and microbial pathogens in particular on the regulation/expression of genes encoded within susceptibility alleles, and its consequences on subsequent autoimmune and/or autoinflammatory tissue damage utilizing primarily the chronic cholestatic liver disease primary biliary cirrhosis as model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AMA:

Antimitochondrial antibodies

APC:

Antigen-presenting cell

CTLA-4:

Cytotoxic T lymphocyte antigen 4

DC:

Dendritic cell

GSL:

Glycosphingolipid

IgM:

Immunoglobulin M

IL-10:

Interleukin 10

MS:

Multiple sclerosis

NKT:

Natural killer T cell

PBC:

Primary biliary cirrhosis

PDC-E2:

Pyruvate dehydrogenase complex E2 subunit

RA:

Rheumatoid arthritis

SLE:

Systemic lupus erythematosus

SNP:

Single nucleotide polymorphism

TCR:

T cell receptor

Th cells:

T helper cells

Tyk2:

Tyrosine kinase 2

References

  • Abdulkarim AS, Petrovic LM, Kim WR et al (2004) Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae? J Hepatol 40:380–384

    Article  PubMed  Google Scholar 

  • Agarwal K, Jones DE, Daly AK et al (2000) CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol 32:538–541

    Article  PubMed  CAS  Google Scholar 

  • Aizu K, Li W, Yajima T et al (2006) An important role of Tyk2 in APC function of dendritic cells for priming CD8+ T cells producing IFN-gamma. Eur J Immunol 36:3060–3070

    Article  PubMed  CAS  Google Scholar 

  • Ala A, Stanca CM, Bu-Ghanim M et al (2006) Increased prevalence of primary biliary cirrhosis near Superfund toxic waste sites. Hepatology 43:525–531

    Article  PubMed  Google Scholar 

  • Alvaro D, Invernizzi P, Onori P et al (2004) Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol 41:905–912

    Article  PubMed  CAS  Google Scholar 

  • Amadori A, Zamarchi R, De Silvestro G et al (1995) Genetic control of the CD4/CD8 T-cell ratio in humans. Nat Med 1:1279–1283

    Article  PubMed  CAS  Google Scholar 

  • Amedei A, Bergman MP, Appelmelk BJ et al (2003) Molecular mimicry between Helicobacter pylori antigens and H+, K+—adenosine triphosphatase in human gastric autoimmunity. J Exp Med 198:1147–1156

    Article  PubMed  CAS  Google Scholar 

  • Baba N, Kobashi H, Yamamoto K et al (2006) Gene expression profiling in biliary epithelial cells of primary biliary cirrhosis using laser capture microdissection and cDNA microarray. Transl Res 148:103–113

    Article  PubMed  CAS  Google Scholar 

  • Bacon CM, McVicar DW, Ortaldo JR et al (1995a) Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med 181:399–404

    Article  PubMed  CAS  Google Scholar 

  • Bacon CM, Petricoin EF 3rd, Ortaldo JR et al (1995b) Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci USA 92:7307–7311

    Article  PubMed  CAS  Google Scholar 

  • Ban M, Goris A, Lorentzen AR et al (2009) Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor. Eur J Hum Genet 17:1309–1313

    Article  PubMed  CAS  Google Scholar 

  • Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  PubMed  CAS  Google Scholar 

  • Basta T, Keck A, Klein J et al (2004) Detection and characterization of conjugative degradative plasmids in xenobiotic-degrading Sphingomonas strains. J Bacteriol 186:3862–3872

    Article  PubMed  CAS  Google Scholar 

  • Beeson PB (1994) Age and sex associations of 40 autoimmune diseases. Am J Med 96:457–462

    Article  PubMed  CAS  Google Scholar 

  • Bellone M, Iezzi G, Rovere P et al (1997) Processing of engulfed apoptotic bodies yields T cell epitopes. J Immunol 159:5391–5399

    PubMed  CAS  Google Scholar 

  • Benson GD, Kikuchi K, Miyakawa H et al (2004) Serial analysis of antimitochondrial antibody in patients with primary biliary cirrhosis. Clin Dev Immunol 11:129–133

    Article  PubMed  CAS  Google Scholar 

  • Bittencourt PL, Palacios SA, Farias AQ et al (2003) Analysis of major histocompatibility complex and CTLA-4 alleles in Brazilian patients with primary biliary cirrhosis. J Gastroenterol Hepatol 18:1061–1066

    Article  PubMed  CAS  Google Scholar 

  • Bjorses P, Aaltonen J, Horelli-Kuitunen N et al (1998) Gene defect behind APECED: a new clue to autoimmunity. Hum Mol Genet 7:1547–1553

    Article  PubMed  CAS  Google Scholar 

  • Bluestone JA (1995) New perspectives of CD28-B7-mediated T cell costimulation. Immunity 2:555–559

    Article  PubMed  CAS  Google Scholar 

  • Bogdanos DP, Baum H, Butler P et al (2003) Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection. Dig Liver Dis 35:801–805

    Article  PubMed  CAS  Google Scholar 

  • Bogdanos DP, Baum H, Grasso A et al (2004a) Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol 40:31–39

    Article  PubMed  CAS  Google Scholar 

  • Bogdanos DP, Pares A, Baum H et al (2004b) Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis. J Autoimmun 22:353–362

    Article  PubMed  CAS  Google Scholar 

  • Bogdanos DP, Baum H, Okamoto M et al (2005) Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic. Hepatology 42:458–465

    Article  PubMed  CAS  Google Scholar 

  • Bouman A, Heineman MJ, Faas MM (2005) Sex hormones and the immune response in humans. Hum Reprod Update 11:411–423

    Article  PubMed  CAS  Google Scholar 

  • Burroughs AK, Rosenstein IJ, Epstein O et al (1984) Bacteriuria and primary biliary cirrhosis. Gut 25:133–137

    Article  PubMed  CAS  Google Scholar 

  • Butler P, Valle F, Hamilton-Miller JM et al (1993) M2 mitochondrial antibodies and urinary rough mutant bacteria in patients with primary biliary cirrhosis and in patients with recurrent bacteriuria. J Hepatol 17:408–414

    Article  PubMed  CAS  Google Scholar 

  • Butterworth M, McClellan B, Allansmith M (1967) Influence of sex in immunoglobulin levels. Nature 214:1224–1225

    Article  PubMed  CAS  Google Scholar 

  • Chan SH, Perussia B, Gupta JW et al (1991) Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med 173:869–879

    Article  PubMed  CAS  Google Scholar 

  • Chuang YH, Lian ZX, Yang GX et al (2008) Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology 47:571–580

    Article  PubMed  CAS  Google Scholar 

  • Cohen JH, Danel L, Cordier G et al (1983) Sex steroid receptors in peripheral T cells: absence of androgen receptors and restriction of estrogen receptors to OKT8-positive cells. J Immunol 131:2767–2771

    PubMed  CAS  Google Scholar 

  • Confavreux C, Hutchinson M, Hours MM et al (1998) Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group. N Engl J Med 339:285–291

    Article  PubMed  CAS  Google Scholar 

  • Coppel RL, McNeilage LJ, Surh CD et al (1988) Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: dihydrolipoamide acetyltransferase. Proc Natl Acad Sci USA 85:7317–7321

    Article  PubMed  CAS  Google Scholar 

  • Corvini PF, Hollender J, Ji R et al (2006) The degradation of alpha-quaternary nonylphenol isomers by Sphingomonas sp. strain TTNP3 involves a type II ipso-substitution mechanism. Appl Microbiol Biotechnol 70:114–122

    Article  PubMed  CAS  Google Scholar 

  • Couturier N, Bucciarelli F, Nurtdinov RN et al (2011) Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility. Brain 134(Pt 3):693–703

    Article  PubMed  Google Scholar 

  • Cunningham MW (2000) Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 13:470–511

    Article  PubMed  CAS  Google Scholar 

  • Cunningham M, Gilkeson G (2011) Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol 40:66–73

    Article  PubMed  CAS  Google Scholar 

  • Curtsinger JM, Schmidt CS et al (1999) Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. J Immunol 162:3256–3262

    PubMed  CAS  Google Scholar 

  • Daniels JA, Torbenson M, Anders RA et al (2009) Immunostaining of plasma cells in primary biliary cirrhosis. Am J Clin Pathol 131:243–249

    Article  PubMed  Google Scholar 

  • Davidson A, Diamond B (2001) Autoimmune diseases. N Engl J Med 345:340–350

    Article  PubMed  CAS  Google Scholar 

  • Del Vecchio M, Bajetta E, Canova S et al (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13:4677–4685

    Article  PubMed  Google Scholar 

  • Fadok VA, Bratton DL, Konowal A et al (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890–898

    Article  PubMed  CAS  Google Scholar 

  • Fairweather D, Rose NR (2004) Women and autoimmune diseases. Emerg Infect Dis 10:2005–2011

    Article  PubMed  CAS  Google Scholar 

  • Fan LY, Tu XQ, Cheng QB et al (2004) Cytotoxic T lymphocyte associated antigen-4 gene polymorphisms confer susceptibility to primary biliary cirrhosis and autoimmune hepatitis in Chinese population. World J Gastroenterol 10:3056–3059

    PubMed  CAS  Google Scholar 

  • Feizi T (1968) Immunoglobulins in chronic liver disease. Gut 9:193–198

    Article  PubMed  CAS  Google Scholar 

  • Forger F, Marcoli N, Gadola S et al (2008) Pregnancy induces numerical and functional changes of CD4 + CD25 high regulatory T cells in patients with rheumatoid arthritis. Ann Rheum Dis 67:984–990

    Article  PubMed  CAS  Google Scholar 

  • Fouassier L, Rosenberg P, Mergey M et al (2009) Ezrin-radixin-moesin-binding phosphoprotein (EBP50), an estrogen-inducible scaffold protein, contributes to biliary epithelial cell proliferation. Am J Pathol 174:869–880

    Article  PubMed  CAS  Google Scholar 

  • Fredrickson JK, Brockman FJ, Workman DJ et al (1991) Isolation and characterization of a subsurface bacterium capable of growth on toluene, naphthalene, and other aromatic compounds. Appl Environ Microbiol 57:796–803

    PubMed  CAS  Google Scholar 

  • Fredrickson JK, Balkwill DL, Drake GR et al (1995) Aromatic-degrading Sphingomonas isolates from the deep subsurface. Appl Environ Microbiol 61:1917–1922

    PubMed  CAS  Google Scholar 

  • Fujii K, Kikuchi S, Satomi M et al (2002) Degradation of 17beta-estradiol by a gram-negative bacterium isolated from activated sludge in a sewage treatment plant in Tokyo, Japan. Appl Environ Microbiol 68:2057–2060

    Article  PubMed  CAS  Google Scholar 

  • Fujii K, Yamamoto R, Tanaka T et al (2003) Potential of a new biotreatment: sphingomonas cloacae S-3T degrades nonylphenol in industrial wastewater. J Ind Microbiol Biotechnol 30:531–535

    Article  PubMed  CAS  Google Scholar 

  • Fussey SP, Guest JR, James OF et al (1988) Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis. Proc Natl Acad Sci USA 85:8654–8658

    Article  PubMed  CAS  Google Scholar 

  • Fussey SP, Ali ST, Guest JR et al (1990) Reactivity of primary biliary cirrhosis sera with Escherichia coli dihydrolipoamide acetyltransferase (E2p): characterization of the main immunogenic region. Proc Natl Acad Sci USA 87:3987–3991

    Article  PubMed  CAS  Google Scholar 

  • Gabriel FL, Giger W, Guenther K et al (2005) Differential degradation of nonylphenol isomers by Sphingomonas xenophaga Bayram. Appl Environ Microbiol 71:1123–1129

    Article  PubMed  CAS  Google Scholar 

  • Galanello R, Origa R (2010) Beta-thalassemia. Orphanet J Rare Dis 5:11

    Article  PubMed  Google Scholar 

  • Gershwin ME, Mackay IR, Sturgess A et al (1987) Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 138:3525–3531

    PubMed  CAS  Google Scholar 

  • Gershwin ME, Selmi C, Worman HJ et al (2005) Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 42:1194–1202

    Article  PubMed  Google Scholar 

  • Getts DR, Turley DM, Smith CE et al (2011) Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. J Immunol 187:2405–2417

    Article  PubMed  CAS  Google Scholar 

  • Ghoreschi K, Laurence A, O’Shea JJ (2009) Janus kinases in immune cell signaling. Immunol Rev 228:273–287

    Article  PubMed  CAS  Google Scholar 

  • Gilmore W, Weiner LP, Correale J (1997) Effect of estradiol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 158:446–451

    PubMed  CAS  Google Scholar 

  • Gough SC, Walker LS, Sansom DM (2005) CTLA4 gene polymorphism and autoimmunity. Immunol Rev 204:102–115

    Article  PubMed  CAS  Google Scholar 

  • Gray M, Miles K, Salter D et al (2007) Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci USA 104:14080–14085

    Article  PubMed  CAS  Google Scholar 

  • Gregersen PK, Olsson LM (2009) Recent advances in the genetics of autoimmune disease. Annu Rev Immunol 27:363–391

    Article  PubMed  CAS  Google Scholar 

  • Gupta SK, Lal D, Lal R (2009) Novosphingobium panipatense sp. nov. and Novosphingobium mathurense sp. nov., from oil-contaminated soil. Int J Syst Evol Microbiol 59(Pt 1):156–161

    Article  PubMed  CAS  Google Scholar 

  • Habe H, Omori T (2003) Genetics of polycyclic aromatic hydrocarbon metabolism in diverse aerobic bacteria. Biosci Biotechnol Biochem 67:225–243

    Article  PubMed  CAS  Google Scholar 

  • Habe H, Ashikawa Y, Saiki Y et al (2002) Sphingomonas sp. strain KA1, carrying a carbazole dioxygenase gene homologue, degrades chlorinated dibenzo-p-dioxins in soil. FEMS Microbiol Lett 211:43–49

    Article  PubMed  CAS  Google Scholar 

  • Harada K, Isse K, Tsuneyama K et al (2003) Accumulating CD57 + CD3 + natural killer T cells are related to intrahepatic bile duct lesions in primary biliary cirrhosis. Liver Int 23:94–100

    Article  PubMed  Google Scholar 

  • He XS, Ansari AA, Ridgway WM et al (2006) New insights to the immunopathology and autoimmune responses in primary biliary cirrhosis. Cell Immunol 239:1–13

    Article  PubMed  CAS  Google Scholar 

  • Heathcote EJ (2000) Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology 31:1005–1013

    Article  PubMed  CAS  Google Scholar 

  • Heathcote EJ (2003) Primary biliary cirrhosis: historical perspective. Clin Liver Dis 7:735–740

    Article  PubMed  Google Scholar 

  • Hill AV, Bowden DK, O’Shaughnessy DF et al (1988) Beta thalassemia in Melanesia: association with malaria and characterization of a common variant (IVS-1 nt 5 G—C). Blood 72:9–14

    PubMed  CAS  Google Scholar 

  • Hirschfield GM, Liu X, Xu C et al (2009) Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 360:2544–2555

    Article  PubMed  CAS  Google Scholar 

  • Hirschfield GM, Liu X, Han Y et al (2010) Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet 42:655–657

    Article  PubMed  CAS  Google Scholar 

  • Holmberg D, Cilio CM, Lundholm M et al (2005) CTLA-4 (CD152) and its involvement in autoimmune disease. Autoimmunity 38:225–233

    Article  PubMed  CAS  Google Scholar 

  • Honda M, Kawai H, Shirota Y et al (2005) Differential gene expression profiles in stage I primary biliary cirrhosis. Am J Gastroenterol 100:2019–2030

    Article  PubMed  CAS  Google Scholar 

  • Hopf U, Moller B, Stemerowicz R et al (1989) Relation between Escherichia coli R(rough)-forms in gut, lipid A in liver, and primary biliary cirrhosis. Lancet 2:1419–1422

    Article  PubMed  CAS  Google Scholar 

  • Invernizzi P, Miozzo M, Battezzati PM et al (2004) Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 363:533–535

    Article  PubMed  Google Scholar 

  • Invernizzi P, Selmi C, Gershwin ME (2010) Update on primary biliary cirrhosis. Dig Liver Dis 42:401–408

    Article  PubMed  CAS  Google Scholar 

  • Ishibashi H, Komori A, Shimoda S et al (2007) Guidelines for therapy of autoimmune liver disease. Semin Liver Dis 27:214–226

    Article  PubMed  CAS  Google Scholar 

  • Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995

    Article  PubMed  CAS  Google Scholar 

  • Jacobson NG, Szabo SJ, Weber-Nordt RM et al (1995) Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med 181:1755–1762

    Article  PubMed  CAS  Google Scholar 

  • Jakob T, Walker PS, Krieg AM et al (1998) Activation of cutaneous dendritic cells by CpG-containing oligodeoxynucleotides: a role for dendritic cells in the augmentation of Th1 responses by immunostimulatory DNA. J Immunol 161:3042–3049

    PubMed  CAS  Google Scholar 

  • Janssen WJ, Henson PM (2012) Cellular regulation of the inflammatory response. Toxicol Pathol 40:166–173

    Article  PubMed  CAS  Google Scholar 

  • Jenkins MK, Taylor PS, Norton SD et al (1991) CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol 147:2461–2466

    PubMed  CAS  Google Scholar 

  • Jin Q, Moritoki Y, Lleo A et al (2012) Comparative analysis of portal cell infiltrates in AMA positive versus AMA negative PBC. Hepatology 55:1495–1506

    Article  PubMed  CAS  Google Scholar 

  • Joshita S, Umemura T, Yoshizawa K et al (2010) Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients. J Hepatol 53:537–541

    Article  PubMed  CAS  Google Scholar 

  • Juran BD, Atkinson EJ, Schlicht EM et al (2008a) Primary biliary cirrhosis is associated with a genetic variant in the 3′ flanking region of the CTLA4 gene. Gastroenterology 135:1200–1206

    Article  PubMed  CAS  Google Scholar 

  • Juran BD, Atkinson EJ, Schlicht EM et al (2008b) Interacting alleles of the coinhibitory immunoreceptor genes cytotoxic T-lymphocyte antigen 4 and programmed cell-death 1 influence risk and features of primary biliary cirrhosis. Hepatology 47:563–570

    Article  PubMed  Google Scholar 

  • Kanda N, Tamaki K (1999) Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol 103(2 Pt 1):282–288

    Article  PubMed  CAS  Google Scholar 

  • Kanda N, Tsuchida T, Tamaki K (1999) Estrogen enhancement of anti-double-stranded DNA antibody and immunoglobulin G production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum 42:328–337

    Article  PubMed  CAS  Google Scholar 

  • Kang JH, Asai D, Katayama Y (2007) Bisphenol A in the aquatic environment and its endocrine-disruptive effects on aquatic organisms. Crit Rev Toxicol 37:607–625

    Article  PubMed  CAS  Google Scholar 

  • Kaplan MM (1996) Primary biliary cirrhosis. N Engl J Med 335:1570–1580

    Article  PubMed  CAS  Google Scholar 

  • Karaghiosoff M, Neubauer H, Lassnig C et al (2000) Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity 13:549–560

    Article  PubMed  CAS  Google Scholar 

  • Kawahara K, Moll H, Knirel YA et al (2000) Structural analysis of two glycosphingolipids from the lipopolysaccharide-lacking bacterium Sphingomonas capsulata. Eur J Biochem 267:1837–1846

    Article  PubMed  CAS  Google Scholar 

  • Kinjo Y, Wu D, Kim G et al (2005) Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434:520–525

    Article  PubMed  CAS  Google Scholar 

  • Kita H, Naidenko OV, Kronenberg M et al (2002) Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 123:1031–1043

    Article  PubMed  CAS  Google Scholar 

  • Krolewski JJ, Lee R, Eddy R et al (1990) Identification and chromosomal mapping of new human tyrosine kinase genes. Oncogene 5:277–282

    PubMed  CAS  Google Scholar 

  • Lakatos LP, Bajnok E, Hegedus D et al (2002) Vitamin D receptor, oestrogen receptor-alpha gene and interleukin-1 receptor antagonist gene polymorphisms in Hungarian patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol 14:733–740

    Article  PubMed  CAS  Google Scholar 

  • Lan RY, Salunga TL, Tsuneyama K et al (2009) Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun 32:43–51

    Article  PubMed  CAS  Google Scholar 

  • Lee BW, Yap HK, Chew FT et al (1996) Age- and sex-related changes in lymphocyte subpopulations of healthy Asian subjects: from birth to adulthood. Cytometry 26:8–15

    Article  PubMed  CAS  Google Scholar 

  • Leitner J, Grabmeier-Pfistershammer K, Steinberger P (2010) Receptors and ligands implicated in human T cell costimulatory processes. Immunol Lett 128:89–97

    Article  PubMed  CAS  Google Scholar 

  • Lenschow DJ, Walunas TL, Bluestone JA (1996) CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233–258

    Article  PubMed  CAS  Google Scholar 

  • Leung PS, Quan C, Park O (2003) Immunization with a xenobiotic 6-bromohexanoate bovine serum albumin conjugate induces antimitochondrial antibodies. J Immunol 170:5326–5332

    PubMed  CAS  Google Scholar 

  • Leung PS, Park O, Tsuneyama K (2007) Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization. J Immunol 179:2651–2657

    PubMed  CAS  Google Scholar 

  • Leung PS, Yang GX, Dhirapong A et al (2012) Animal models of primary biliary cirrhosis: materials and methods. Methods Mol Biol 900:291–316

    Article  PubMed  Google Scholar 

  • Libert C, Dejager L, Pinheiro I (2010) The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol 10:594–604

    Article  PubMed  CAS  Google Scholar 

  • Linsley PS, Brady W, Grosmaire L et al (1991) Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med 173:721–730

    Article  PubMed  CAS  Google Scholar 

  • Linsley PS, Greene JL, Tan P et al (1992) Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 176:1595–1604

    Article  PubMed  CAS  Google Scholar 

  • Liu JZ, Almarri MA, Gaffney DJ et al (2012) Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet 44:1137–1141

    Article  PubMed  CAS  Google Scholar 

  • Manetti R, Parronchi P, Giudizi MG et al (1993) Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med 177:1199–1204

    Article  PubMed  CAS  Google Scholar 

  • Masteller EL, Chuang E, Mullen AC et al (2000) Structural analysis of CTLA-4 function in vivo. J Immunol 164:5319–5327

    PubMed  CAS  Google Scholar 

  • Mattalia A, Quaranta S, Leung PS et al (1998) Characterization of antimitochondrial antibodies in health adults. Hepatology 27:656–661

    Article  PubMed  CAS  Google Scholar 

  • Mattner J, Debord KL, Ismail N et al (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525–529

    Article  PubMed  CAS  Google Scholar 

  • Mattner J, Savage PB, Leung P et al (2008) Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe 3:304–315

    Article  PubMed  CAS  Google Scholar 

  • Maurer M, Loserth S, Kolb-Maurer A et al (2002) A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics 54:1–8

    Article  PubMed  CAS  Google Scholar 

  • McGonagle D, McDermott MF (2006) A proposed classification of the immunological diseases. PLoS Med 3:e297

    Article  PubMed  CAS  Google Scholar 

  • Mells GF, Floyd JA, Morley KI et al (2011) Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet 43:329–332

    Article  PubMed  CAS  Google Scholar 

  • Metcalf JV, Mitchison HC, Palmer JM et al (1996) Natural history of early primary biliary cirrhosis. Lancet 348:1399–1402

    Article  PubMed  CAS  Google Scholar 

  • Miozzo M, Selmi C, Gentilin B et al (2007) Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis. Hepatology 46:456–462

    Article  PubMed  CAS  Google Scholar 

  • Mitchell MM, Lleo A, Zammataro L et al (2011) Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis. Epigenetics 6:95–102

    Article  PubMed  CAS  Google Scholar 

  • Mohammed JP, Fusakio ME, Rainbow DB et al (2011) Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity. J Immunol 187:337–349

    Article  PubMed  CAS  Google Scholar 

  • Molero L, Garcia-Duran M, Diaz-Recasens J et al (2002) Expression of estrogen receptor subtypes and neuronal nitric oxide synthase in neutrophils from women and men: regulation by estrogen. Cardiovasc Res 56:43–51

    Article  PubMed  CAS  Google Scholar 

  • Moreira RK, Revetta F, Koehler E (2010) Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease. World J Gastroenterol 16:453–457

    Article  PubMed  Google Scholar 

  • Munoz-Suano A, Kallikourdis M, Sarris M et al (2012) Regulatory T cells protect from autoimmune arthritis during pregnancy. J Autoimmun 38:J103–J108

    Article  PubMed  CAS  Google Scholar 

  • Munz C, Lunemann JD, Getts MT et al (2009) Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol 9:246–258

    Article  PubMed  CAS  Google Scholar 

  • Nalbandian G, Kovats S (2005) Understanding sex biases in immunity: effects of estrogen on the differentiation and function of antigen-presenting cells. Immunol Res 31:91–106

    Article  PubMed  CAS  Google Scholar 

  • Nelson JL, Ostensen M (1997) Pregnancy and rheumatoid arthritis. Rheum Dis Clin North Am 23:195–212

    Article  PubMed  CAS  Google Scholar 

  • Nilsson HO, Taneera J, Castedal M et al (2000) Identification of Helicobacter pylori and other Helicobacter species by PCR, hybridization, and partial DNA sequencing in human liver samples from patients with primary sclerosing cholangitis or primary biliary cirrhosis. J Clin Microbiol 38:1072–1076

    PubMed  CAS  Google Scholar 

  • Notomista E, Pennacchio F, Cafaro V et al (2011) The marine isolate Novosphingobium sp. PP1Y shows specific adaptation to use the aromatic fraction of fuels as the sole carbon and energy source. Microb Ecol 61:582–594

    Article  PubMed  CAS  Google Scholar 

  • Oertelt S, Kenny TP, Selmi C et al (2005) SNP analysis of genes implicated in T cell proliferation in primary biliary cirrhosis. Clin Dev Immunol 12:259–263

    Article  PubMed  CAS  Google Scholar 

  • Ortmann R, Smeltz R, Yap G et al (2001) A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis. J Immunol 166:5712–5719

    CAS  Google Scholar 

  • Oyamada A, Ikebe H, Itsumi M et al (2009) Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis. J Immunol 183:7539–7546

    Article  PubMed  CAS  Google Scholar 

  • Padgett KA, Selmi C, Kenny TP et al (2005) Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis. J Autoimmun 24:209–219

    Article  PubMed  CAS  Google Scholar 

  • Paharkova-Vatchkova V, Maldonado R et al (2004) Estrogen preferentially promotes the differentiation of CD11c + CD11b(intermediate) dendritic cells from bone marrow precursors. J Immunol 172:1426–1436

    PubMed  CAS  Google Scholar 

  • Porter AW, Hay AG (2007) Identification of opdA, a gene involved in biodegradation of the endocrine disrupter octylphenol. Appl Environ Microbiol 73:7373–7379

    Article  PubMed  CAS  Google Scholar 

  • Poupon R, Chretien Y, Poupon RE et al (1987) Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet 1:834–836

    Article  PubMed  CAS  Google Scholar 

  • Poupon R, Ping C, Chretien Y et al (2008) Genetic factors of susceptibility and of severity in primary biliary cirrhosis. J Hepatol 49:1038–1045

    Article  PubMed  CAS  Google Scholar 

  • Qureshi OS, Zheng Y, Nakamura K et al (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332:600–603

    Article  PubMed  CAS  Google Scholar 

  • Rieger R, Gershwin ME (2007) The X and why of xenobiotics in primary biliary cirrhosis. J Autoimmun 28:76–84

    Article  PubMed  CAS  Google Scholar 

  • Rioux JD, Abbas AK (2005) Paths to understanding the genetic basis of autoimmune disease. Nature 435:584–589

    Article  PubMed  CAS  Google Scholar 

  • Rose NR, Bona C (1993) Defining criteria for autoimmune diseases (Witebsky’s postulates revisited). Immunol Today 14:426–430

    Article  PubMed  CAS  Google Scholar 

  • Rosen A, Casciola-Rosen L (2009) Autoantigens in systemic autoimmunity: critical partner in pathogenesis. J Intern Med 265:625–631

    Article  PubMed  CAS  Google Scholar 

  • Rubtsov AV, Rubtsova K, Kappler JW et al (2010) Genetic and hormonal factors in female-biased autoimmunity. Autoimmun Rev 9:494–498

    Article  PubMed  CAS  Google Scholar 

  • Rudd CE (2008) The reverse stop-signal model for CTLA4 function. Nat Rev Immunol 8:153–160

    Article  PubMed  CAS  Google Scholar 

  • Ryan MP, Adley CC (2010) Sphingomonas paucimobilis: a persistent Gram-negative nosocomial infectious organism. J Hosp Infect 75:153–157

    Article  PubMed  CAS  Google Scholar 

  • Scalapino KJ, Daikh DI (2008) CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev 223:143–155

    Article  PubMed  CAS  Google Scholar 

  • Selmi C, Balkwill DL, Invernizzi P et al (2003) Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 38:1250–1257

    Article  PubMed  CAS  Google Scholar 

  • Seto Y, Nakajima H, Suto A et al (2003) Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice. J Immunol 170:1077–1083

    PubMed  CAS  Google Scholar 

  • Shackel NA, McGuinness PH, Abbott CA et al (2001) Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression. Gut 49:565–576

    Article  PubMed  CAS  Google Scholar 

  • Shahrizaila N, Yuki N (2011) Guillain-barre syndrome animal model: the first proof of molecular mimicry in human autoimmune disorder. J Biomed Biotechnol 2011:829129

    Article  PubMed  Google Scholar 

  • Shi T, Fredrickson JK, Balkwill DL (2001) Biodegradation of polycyclic aromatic hydrocarbons by Sphingomonas strains isolated from the terrestrial subsurface. J Ind Microbiol Biotechnol 26:283–289

    Article  PubMed  CAS  Google Scholar 

  • Shimoda S, Nakamura M, Ishibashi H et al (1995) HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med 181:1835–1845

    Article  PubMed  CAS  Google Scholar 

  • Shimoda K, Kato K, Aoki K et al (2000) Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. Immunity 13:561–571

    Article  PubMed  CAS  Google Scholar 

  • Shuttleworth KL, Sung J, Kim E et al (2000) Physiological and genetic comparison of two aromatic hydrocarbon-degrading Sphingomonas strains. Mol Cells 10:199–205

    PubMed  CAS  Google Scholar 

  • Sohn JH, Kwon KK, Kang JH et al (2004) Novosphingobium pentaromativorans sp. nov., a high-molecular-mass polycyclic aromatic hydrocarbon-degrading bacterium isolated from estuarine sediment. Int J Syst Evol Microbiol 54(Pt 5):1483–1487

    Article  PubMed  CAS  Google Scholar 

  • Spach KM, Noubade R, McElvany B et al (2009) A single nucleotide polymorphism in Tyk2 controls susceptibility to experimental allergic encephalomyelitis. J Immunol 182:7776–7783

    Article  PubMed  CAS  Google Scholar 

  • Sparwasser T, Koch ES, Vabulas RM et al (1998) Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 28:2045–2054

    Article  PubMed  CAS  Google Scholar 

  • Stimson WH (1988) Oestrogen and human T lymphocytes: presence of specific receptors in the T-suppressor/cytotoxic subset. Scand J Immunol 28:345–350

    Article  PubMed  CAS  Google Scholar 

  • Stolz A (2009) Molecular characteristics of xenobiotic-degrading sphingomonads. Appl Microbiol Biotechnol 81:793–811

    Article  PubMed  CAS  Google Scholar 

  • Stoop JW, Zegers BJ, Sander PC et al (1969) Serum immunoglobulin levels in healthy children and adults. Clin Exp Immunol 4:101–112

    PubMed  CAS  Google Scholar 

  • Suarez-Gestal M, Calaza M, Endreffy E et al (2009) Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study. Arthritis Res Ther 11:R69

    Article  PubMed  CAS  Google Scholar 

  • Suenaga R, Evans MJ, Mitamura K et al (1998) Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 25:1305–1312

    PubMed  CAS  Google Scholar 

  • Suzuki S, Hiraishi A (2007) Novosphingobium naphthalenivorans sp. nov., a naphthalene-degrading bacterium isolated from polychlorinated-dioxin-contaminated environments. J Gen Appl Microbiol 53:221–228

    Article  PubMed  CAS  Google Scholar 

  • Suzuki A, Kochi Y, Okada Y et al (2011) Insight from genome-wide association studies in rheumatoid arthritis and multiple sclerosis. FEBS Lett 585:3627–3632

    Article  PubMed  CAS  Google Scholar 

  • Takahashi T, Tagami T, Yamazaki S et al (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–310

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi M, Hamana K, Hiraishi A (2001) Proposal of the genus Sphingomonas sensu stricto and three new genera, Sphingobium, Novosphingobium and Sphingopyxis, on the basis of phylogenetic and chemotaxonomic analyses. Int J Syst Evol Microbiol 51(Pt 4):1405–1417

    PubMed  CAS  Google Scholar 

  • Tanghe T, Dhooge W, Verstraete W (1999) Isolation of a bacterial strain able to degrade branched nonylphenol. Appl Environ Microbiol 65:746–751

    PubMed  CAS  Google Scholar 

  • Ternes TA, Stumpf M, Mueller J et al (1999) Behavior and occurrence of estrogens in municipal sewage treatment plants–I. Investigations in Germany, Canada and Brazil. Sci Total Environ 225:81–90

    Article  PubMed  CAS  Google Scholar 

  • Thompson CB, Lindsten T, Ledbetter JA et al (1989) CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci USA 86:1333–1337

    Article  PubMed  CAS  Google Scholar 

  • Tiirola MA, Mannisto MK, Puhakka JA et al (2002) Isolation and characterization of Novosphingobium sp. strain MT1, a dominant polychlorophenol-degrading strain in a groundwater bioremediation system. Appl Environ Microbiol 68:173–180

    Article  PubMed  CAS  Google Scholar 

  • Tivol EA, Borriello F, Schweitzer AN et al (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547

    Article  PubMed  CAS  Google Scholar 

  • Tollerud DJ, Clark JW, Brown LM et al (1989) The influence of age, race, and gender on peripheral blood mononuclear-cell subsets in healthy nonsmokers. J Clin Immunol 9:214–222

    Article  PubMed  CAS  Google Scholar 

  • Tsuneyama K, Yasoshima M, Harada K et al (1998) Increased CD1d expression on small bile duct epithelium and epithelioid granuloma in livers in primary biliary cirrhosis. Hepatology 28:620–623

    Article  PubMed  CAS  Google Scholar 

  • Tsuneyama K, Moritoki Y, Kikuchi K et al (2012) Pathological features of new animal models for primary biliary cirrhosis. Int J Hepatol 2012:403954

    PubMed  Google Scholar 

  • Van de Water J, Ansari A, Prindiville T et al (1995) Heterogeneity of autoreactive T cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis. J Exp Med 181:723–733

    Article  PubMed  Google Scholar 

  • Van Norstrand MD, Malinchoc M, Lindor KD et al (1997) Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship of levels of autoantibodies to disease progression. Hepatology 25:6–11

    Article  PubMed  Google Scholar 

  • Verhasselt V, Buelens C, Willems F et al (1997) Bacterial lipopolysaccharide stimulates the production of cytokines and the expression of costimulatory molecules by human peripheral blood dendritic cells: evidence for a soluble CD14-dependent pathway. J Immunol 158:2919–2925

    PubMed  CAS  Google Scholar 

  • Voll RE, Herrmann M, Roth EA et al (1997) Immunosuppressive effects of apoptotic cells. Nature 390:350–351

    Article  PubMed  CAS  Google Scholar 

  • Walker LS, Abbas AK (2002) The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2:11–19

    Article  PubMed  CAS  Google Scholar 

  • Walker EJ, Hirschfield GM, Xu C et al (2009) CTLA4/ICOS gene variants and haplotypes are associated with rheumatoid arthritis and primary biliary cirrhosis in the Canadian population. Arthritis Rheum 60:931–937

    Article  PubMed  CAS  Google Scholar 

  • Wallace C, Smyth DJ, Maisuria-Armer M et al (2010) The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet 42:68–71

    Article  PubMed  CAS  Google Scholar 

  • Walunas TL, Lenschow DJ, Bakker CY et al (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413

    Article  PubMed  CAS  Google Scholar 

  • Waterhouse P, Penninger JM, Timms E et al (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988

    Article  PubMed  CAS  Google Scholar 

  • Weatherall DJ (2008) Genetic variation and susceptibility to infection: the red cell and malaria. Br J Haematol 141:276–286

    Article  PubMed  CAS  Google Scholar 

  • Wegmann TG, Lin H, Guilbert L et al (1993) Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14:353–356

    Article  PubMed  CAS  Google Scholar 

  • Wilder RL (1995) Neuroendocrine-immune system interactions and autoimmunity. Annu Rev Immunol 13:307–338

    Article  PubMed  CAS  Google Scholar 

  • Willcox M, Bjorkman A, Brohult J et al (1983) A case-control study in northern Liberia of Plasmodium falciparum malaria in haemoglobin S and beta-thalassaemia traits. Ann Trop Med Parasitol 77:239–246

    PubMed  CAS  Google Scholar 

  • Wing K, Onishi Y, Prieto-Martin P et al (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:271–275

    Article  PubMed  CAS  Google Scholar 

  • Xu L, Shen Z, Guo L et al (2003) Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci USA 100:8454–8459

    Article  PubMed  CAS  Google Scholar 

  • Yan QX, Hong Q, Han P et al (2007) Isolation and characterization of a carbofuran-degrading strain Novosphingobium sp. FND-3. FEMS Microbiol Lett 271:207–213

    Article  PubMed  CAS  Google Scholar 

  • Yeaman SJ, Fussey SP, Danner DJ et al (1988) Primary biliary cirrhosis: identification of two major M2 mitochondrial autoantigens. Lancet 1:1067–1070

    Article  PubMed  CAS  Google Scholar 

  • Yeaman SJ, Kirby JA, Jones DE (2000) Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis. Immunol Rev 174:238–249

    Article  PubMed  CAS  Google Scholar 

  • Yuan J, Lai Q, Zheng T et al (2009) Novosphingobium indicum sp. nov., a polycyclic aromatic hydrocarbon-degrading bacterium isolated from a deep-sea environment. Int J Syst Evol Microbiol 59(8):2084–2088

    Article  PubMed  CAS  Google Scholar 

  • Zaletel K, Krhin B, Gaberscek S et al (2010) Association of CT60 cytotoxic T lymphocyte antigen-4 gene polymorphism with thyroid autoantibody production in patients with Hashimoto’s and postpartum thyroiditis. Clin Exp Immunol 161:41–47

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

J. Mattner is supported by the Interdisciplinary Center for Clinical Research of the Universitätsklinikum Erlangen (IZKF_JB10_A48), the German Research Foundation DFG (MA 2621/2-1) and by a grant (award number R01DK084054) from the National Institute of Diabetes and Digestive and Kidney Diseases.

Author information

Authors and Affiliations

  1. Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie Und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Wasserturmstr. 3/5, 91054, Erlangen, Germany

    Claudia Danzer & Jochen Mattner

  2. Division of Cellular and Molecular Immunology, Cincinnati Children’s Hospital, Cincinnati, OH, 45229, USA

    Jochen Mattner

Authors
  1. Claudia Danzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jochen Mattner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jochen Mattner.

About this article

Cite this article

Danzer, C., Mattner, J. Impact of Microbes on Autoimmune Diseases. Arch. Immunol. Ther. Exp. 61, 175–186 (2013). https://doi.org/10.1007/s00005-013-0216-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-013-0216-3

Keywords

Search

Navigation