Autoimmune Disease and LPS

There are many research articles that state that LPS plays a key role in the development of autoimmune syndrome. The influence of LPS is so powerful that it can even overcome genetics. Even mice who are genetically resistant to autoimmunity may develop autoimmune diseases if they are given a high dose of LPS.

View this article in PubMed

1: Clin Exp Immunol. 1991 Apr;84(1):134-8.

Bacterial lipopolysaccharide induces long-lasting IgA deficiency concurrently with features of polyclonal B cell activation in normal and in lupus-prone mice.

Cavallo T, Granholm NA.

Department of Pathology and Laboratory Medicine, Brown University, Providence, RI 02912.

Polyclonal B cell activation (PBA) and autoimmune disease can be induced in immunologically normal mice, or enhanced in lupus-prone mice, by bacterial lipopolysaccharide (LPS). Because immune defects are common in autoimmune diseases and IgA deficiency is prevalent in patients with systemic lupus erythematosus, we investigated: (i) whether LPS might induce IgA deficiency in normal mice; (ii) whether IgA deficiency might be a feature in lupus-prone mice; (iii) whether, if present in lupus-prone mice, IgA deficiency could be further accentuated by LPS; and (iv) whether the effects of LPS on IgA concentrations of normal and lupus-prone mice might be reversible upon withdrawal of LPS. We injected normal (C57BL/6) and lupus-prone (NZB/W) mice with 50 micrograms of LPS from Salmonella minnesota Re595 twice a week for 5 weeks and then discontinued LPS for 6 weeks. We determined the concentrations of plasma immunoglobulins, DNA antibodies, and circulating immune complexes before, during, and after mice were exposed to LPS. Our results indicate that: (i) LPS induces IgA deficiency in normal mice concurrently with PBA; (ii) IgA deficiency is a feature of lupus-prone mice; (iii) LPS accentuates naturally occurring PBA and IgA deficiency in lupus-prone mice; and (iv) LPS induced, or LPS enhanced, IgA deficiency and PBA in normal and lupus-prone mice persist long after withdrawal of LPS. Thus, LPS triggers or enhances autoimmune disease by a mechanism that involves in part PBA with selective increase (IgG, IgM) and concurrent decrease (IgA) of specific isotypes.

PMID: 2015704 [PubMed - indexed for MEDLINE]

View this article in PubMed 1: J Immunol. 1995 Nov 1;155(9):4497-503.
Treatment with bacterial LPS renders genetically resistant C57BL/6 mice susceptible to Theiler's virus-induced demyelinating disease.

Pullen LC, Park SH, Miller SD, Dal Canto MC, Kim BS.

Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611, USA.

Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible strains, which clinically and histopathologically resembles human multiple sclerosis. Since bacterial LPS produced by Gram-negative bacteria is known to potentiate an immune response and trigger resident central nervous system cells to produce various inflammatory cytokines, we examined the ability of LPS to affect resistance to TMEV-induced demyelinating disease (TMEV-IDD). Intraperitoneal injection of LPS, concomitant with intracerebral of genetically resistant C57BL/6 mice with TMEV, resulted in clinical symptoms in approximately 50% of the group. The increase in susceptibility following LPS treatment correlated with the enhanced levels of TMEV-specific delayed-type hypersensitivity and T cell proliferative responses. Similar treatment with LPS, however, did not accelerate the clinical course of susceptible (SJL/J) or intermediately susceptible (C3H) mice. The LPS-treated C57BL/6 mice displayed an increased viral persistence in the central nervous system when compared with nontreated control mice. Intraperitoneal administration of IL-1 beta could mimic the LPS effect in C57BL/6 mice, suggesting that the increase in susceptibility to TMEV-IDD may function via IL-1 produced following LPS stimulation.

PMID: 7594613 [PubMed - indexed for MEDLINE]

View this article in PubMed 1: J Immunol. 2005 Jul 15;175(2):959-66.

Lipopolysaccharide injection induces relapses of experimental autoimmune encephalomyelitis in nontransgenic mice via bystander activation of autoreactive CD4+ cells.

Nogai A, Siffrin V, Bonhagen K, Pfueller CF, Hohnstein T, Volkmer-Engert R, Brück W, Stadelmann C, Kamradt T.

Deutsches Rheumaforschungszentrum Berlin, Berlin, Germany.

Infections sometimes associate with exacerbations of autoimmune diseases through pathways that are poorly understood. Ag-specific mechanisms such as cross-reactivity between a microbial Ag and a self-Ag have received no direct support. In this study, we show that injection of LPS induces experimental autoimmune encephalomyelitis in TCR-transgenic mice and relapse of encephalomyelitis in normal mice. This form of treatment induces proliferation and cytokine production in a fraction of effector/memory Th lymphocytes in vitro via physical contact of Th cells with CD4(-) LPS-responsive cells. TCR-mediated signals are not necessary; rather what is required is ligation of costimulatory receptors on Th cells by costimulatory molecules on the CD4(-) cells. This form of bystander activation provides an Ag-independent link between infection and autoimmunity that might fit the clinical and epidemiological data on the connection between infection and autoimmunity better than the Ag-specific models.

PMID: 16002695 [PubMed - indexed for MEDLINE]

A major article on immunity was written to explain why women are more likely to develop autoimmune syndrome. The article also explains the role of LPS in autoimmune syndrome.

Women and Autoimmune Diseases1

DeLisa Fairweather* and Noel R. Rose*
*Johns Hopkins University, Baltimore, Maryland, USA

Excerpt from this article:

[Note from Webowner: LPS induces the body to produce Proinflammatory Cytokines, interleukin (IL)-1?, and tumor necrosis factor (TNF).]

Proinflammatory Cytokines Determine the Development of Myocarditis

Key to understanding the control of susceptibility to autoimmune myocarditis was the finding that adding bacterial lipopolysaccharide (LPS), interleukin (IL)-1?, or tumor necrosis factor (TNF)-? during the innate response to CB3 infection results in the development of the chronic phase of disease in resistant strains of mice (28,29). Thus, by increasing proinflammatory cytokine production during the innate immune response to infection, genetic resistance to the development of autoimmune disease can be altered. We have found that susceptible BALB/c mice have significantly increased levels of the proinflammatory cytokines TNF-? (Figure 3A) and IL-1? (Figure 3B) in the heart during acute CB3 myocarditis. In fact, many autoimmune diseases, such as rheumatoid arthritis, are associated with increases in TNF-? and IL-1? levels, and treatments that block these cytokines have proven beneficial in animal models and clinical settings (30). We have a long-standing interest in the adjuvant effect of lipopolysaccharide (LPS) on the development of autoimmune disease (28,29,31), but only recently has LPS been shown to mediate its effects in part by increasing TNF-?, IL-1?, and IL-18 levels through TLR4 signaling (18). Recently, we demonstrated that CB3 infection increases IL-1? and IL-18 levels in the heart during acute myocarditis through IL-12R?1 and TLR4 signaling (26). Furthermore, the severity of acute myocarditis directly correlates with increased levels of IL-1? and IL-18 in the heart (26). Similarly, in the experimental autoimmune myocarditis model, IL-12R?1 signaling and increased IL-1? levels are associated with the development of myocarditis (24). This effect of LPS or TNF-? on the development of myocarditis is not limited to CB3 infection, but is also observed following MCMV infection (32). Thus, proinflammatory cytokine production is key in determining whether susceptible strains of mice develop autoimmune disease after infection.

This article also helps us understand why there are more boys with ASD despite the fact that autism is an autoimmune disease; the article states:

"However, autoimmune diseases that develop in men often are more severe (39)"

The explanation might then be that the same autoimmune disease that renders boys autistic will give the girls a milder set of symptoms such as depression or chronic fatigue instead of autism.