Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet β cell microchimerism

doi:10.1073/pnas.0606169104

Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet β cell microchimerism

^†Human Immunogenetics and
^§§Clinical Statistics, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109;
^‡Department of Medicine, 1959 NE Pacific Street, University of Washington, Seattle, WA 98195;
^¶Diabetes and Metabolism, Department of Clinical Science at North Bristol, University of Bristol, Southmead Hospital, Bristol BS10 5NB, United Kingdom;
^‖Laboratoire Inserm, U639, Faculté de Medicine Timone, 27 Boulevard Jean Moulin, 13385 Marseille, France; and
^††Pediatric Rheumatology and
^‡‡Department of Pathology, Children's Regional Hospital and Medical Center, 4800 Sand Point Way, Seattle, WA 98105

Edited by Johannes van Rood, Europdonor Foundation, Leiden, The Netherlands, and approved December 5, 2006 (received for review July 20, 2006)

Abstract

Maternal cells have recently been found in the circulation and tissues of mothers' immune-competent children, including in adult life, and is referred to as maternal microchimerism (MMc). Whether MMc confers benefits during development or later in life or sometimes has adverse effects is unknown. Type 1 diabetes (T1D) is an autoimmune disease that primarily affects children and young adults. To identify and quantify MMc, we developed a panel of quantitative PCR assays targeting nontransmitted, nonshared maternal-specific HLA alleles. MMc was assayed in peripheral blood from 172 individuals, 94 with T1D, 54 unaffected siblings, and 24 unrelated healthy subjects. MMc levels, expressed as the genome equivalent per 100,000 proband cells, were significantly higher in T1D patients than unaffected siblings and healthy subjects. Medians and ranges, respectively, were 0.09 (0–530), 0 (0–153), and 0 (0–7.9). Differences between groups were evident irrespective of HLA genotypes. However, for patients with the T1D-associated DQB1*0302-DRB1*04 haplotype, MMc was found more often when the haplotype was paternally (70%) rather than maternally transmitted (14%). In other studies, we looked for female islet β cells in four male pancreases from autopsies, one from a T1D patient, employing FISH for X and Y chromosomes with concomitant CD45 and β cell insulin staining. Female islet β cells (presumed maternal) formed 0.39–0.96% of the total, whereas female hematopoietic cells were very rare. Thus, T1D patients have higher levels of MMc in their circulation than unaffected siblings and healthy individuals, and MMc contributes to islet β cells in a mother's progeny.

Footnotes

^§To whom correspondence should be addressed at:
Immunogenetics D2-100, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109-1024.
E-mail: nelsonlab{at}fhcrc.org
Author contributions: J.L.N., K.M.G., J.C.R., and E.A.M.G. designed research; K.M.G., N.C.L., A.M.S., T.D.E., Z.Y., M.E.M., N.D.B., and P.J.B. performed research; J.C.R., N.C.L., and A.M.S. contributed new reagents/analytic tools; J.L.N., L.S.L., and W.M.L. analyzed data; and J.L.N., K.M.G., N.C.L., A.M.S., L.S.L., W.M.L., and E.A.M.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0606169104/DC1.
Abbreviations:

MMc,

maternal microchimerism;

T1D,

type 1 diabetes;

Q-PCR,

quantitative real-time PCR.