PATHOPHYSIOLOGY: THE MICROBIOME AND RAdbbs.wustl.edu/curstudents/Documents/Markey/Microbiome... · 2012. 9. 20. · PATHOPHYSIOLOGY: THE MICROBIOME AND RA Lucille Markey Pathway 2012

PATHOPHYSIOLOGY: THE MICROBIOME AND RALucille Markey Pathway2012 September 4Kristi Kuhn, MD, PhD

RA as a New World disease that has ‘spread’ to the rest of the world

Scher, J. U. & Abramson, S. B. (2011)Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2011.121

Permission to use image ‘Sir Alfred Baring Garrod.Photograph by Elliot and Fry’

obtained from the Wellcome Library, London ©

What is the human microbiome?

Ilseung Cho & Martin J. BlaserNature Reviews Genetics 13, 260‐270 (April 2012)

How do we acquire our microbiome?


How to study the microbiome


C Huttenhower et al. Nature 486, 207-214 (2012) doi:10.1038/nature11234

Diversity of the human microbiome is concordant among measures, unique to each individual, and strongly determined by microbial habitat.

C Huttenhower et al. Nature 486, 207-214 (2012) doi:10.1038/nature11234

Abundant taxa in the human microbiome that have been metagenomically and taxonomically well defined in the HMP population.

How do we live in synergy with our microbiome?

Gut Microbes Influence Immune Development

• Germ‐free mice:• Splenic and LN architecture altered

• Hypoplastic Peyer’s patches and reduced T cells in lamina propria

• Reduced T and B cells (and Ig)

Macpherson AJ, Harris NL. Nat Rev Immunol. 2004 Jun;4(6):478‐85

T cell responses differ based on bacterial species

Round JL, Mazmanian SK. Nat Rev Immunol. 2009 May;9(5):313‐23.

Segmented filamentous bacteria (SFB) drive Th17 responses

Ivanov II et al. Cell. 2009 Oct 30;139(3):485‐98.

(or do they?)

Correla on ≠ Causa on

Ivanov II et al. Cell. 2009 Oct 30;139(3):485‐98.

Recolonization of mice leads to Th17 reconstitution in the lamina propria

Ivanov II, et al. Cell. 2009 Oct 30;139(3):485‐98.

Th17 responses are thought to participate in RA pathogenesis• Largely based on animal models• Supported by effectiveness of IL‐6 antagonist to treat disease

Host–microbiota interactions in health and inflammatory arthritis

Scher, J. U. & Abramson, S. B. (2011)Nat. Rev. Rheumatol.

Multiple animal models of inflammatory arthritis have demonstrated that the gut microbiota is critical for the development of disease


Association of microbes and disease


Lundberg, K. et al. (2010)Nat. Rev. Rheumatol.

Schematic illustration of the etiological hypothesis for P. gingivalis and citrullinated α‐enolase involvement in RA

Autoantibody Systems in Rheumatoid Arthritis (RA)

●Rheumatoid Factor, anti-keratinocyte antibodies (AKA), anti-perinuclear factor (APF) – specificity & sensitivity issues

●Collagen●Glucose-6-Phosphate Isomerase (GPI)

●Cyclic Citrullinated Peptide (CCP) Reactivity to CCP has increased sensitivity and specificity of diagnostic ELISA

68% sensitivity 98% specificity

The most specific assay available for RAPredictive for disease

Citrulline‐Modified Proteins

• Post-translational modification of arginine residues by peptidylarginine deiminase (PAD) yields citrulline

• Occurs during development of specific cell types (keratinocytes)• Thought to be active during apoptosis of most cells• PAD not expressed in thymus

ArginineCitrullineCa2+

peptidylarginine deiminase

N

H O

NH

H2N+ NH2

N

H O

NH

O NH2

Citrullinated antigens are presented with higher affinity by MHC genes that associate with RA

Hill, JA et al. J Immunol 2003 171:538‐541

P. gingivalis can generate citrullinated antigens

Wegner N Arthritis & RheumatismVolume 62, Issue 9, pages 2662‐2672, 6 MAY 2010

Exposure to P. gingivalis correlates with RA and anti-CCP antibodies

Hitchon CA et al. J Rheumatol. 2010 Jun;37(6):1105‐12.

PERIODONTAL DISEASE AND THE ORAL MICROBIOTA IN NEW-ONSET RHEUMATOID ARTHRITISScher JU, Ubeda C, Equinda M, Khanin R, Buischi Y, Viale A, Lipuma L, Attur M, PillingerMH, Weissmann G, Littman DR, Pamer EG, Bretz WA, Abramson SB.

Arthritis Rheum. 2012 May 10. doi: 10.1002/art.34539. [Epub ahead of print]

Oral microflora in RA

Scher JU et al. Arthritis Rheum. 2012 May 10.

P. gingivalis does not associate with early onset RA

P. gingivalis does not correlate with RA

Conclusions• Anecdotal evidence associating microbes and RA• No solid studies