| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
,,,,
* Department of Neurology, Laboratory of Molecular Immunology, Center for Neurologic Diseases and Brigham and Women’s Hospital;
Children’s Hospital Informatics Program at the Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology; and
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women’s Hospital and
Harvard Medical School, Boston, MA 02115
The inflammatory myopathies are putative autoimmune disorders characterized by muscle weakness and the presence of intramuscular inflammatory infiltrates. Although inclusion body myositis and polymyositis have been characterized as cytotoxic CD8+ T cell-mediated diseases, we recently demonstrated high frequencies of CD138+ plasma cells in the inflamed muscle tissue of patients with these diseases. To gain a deeper understanding of the role these B cell family members play in the disease pathology, we examined the molecular characteristics of the H chain portion of the Ag receptor. Biopsies of muscle tissue were sectioned and tissue regions and individual cells were isolated through laser capture microdissection. Ig H chain gene transcripts isolated from the sections, regions, and cells were used to determine the variable region gene sequences. Analysis of these sequences revealed clear evidence of affinity maturation in that significant somatic mutation, isotype switching, receptor revision, codon insertion/deletion, and oligoclonal expansion had occurred within the B and plasma cell populations. Moreover, analysis of tissue regions isolated by laser capture microdissection revealed both clonal expansion and variation, suggesting that local B cell maturation occurs within muscle. In contrast, sequences from control muscle tissues and peripheral blood revealed none of these characteristics found in inflammatory myopathy muscle tissue. Collectively, these data demonstrate that Ag drives a B cell Ag-specific response in muscle in patients with dermatomyositis, inclusion body myositis, and polymyositis. These findings highlight the need for a revision of the current paradigm of exclusively T cell-mediated intramuscular Ag-specific autoimmunity in inclusion body myositis and polymyositis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These studies were supported by grants to S.A.G. from the National Institutes of Health (R01 NS043471), the Muscular Dystrophy Association, and the Sporadic Inclusion Body Myositis Research Foundation and to D.A.H. from the National Institutes of Health (RO1 NS24247). These studies were also supported, in part, by a Career Transition Fellowship awarded to K.C.O. from the National Multiple Sclerosis Society (TA 3000A2/1). E.M.B. is a National Institute of Allergy and Infectious Diseases, Kirschstein-National Research Service Award Fellowship Recipient (F32 AI065100-01 A1).
2 S.A.G. and K.C.O. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Kevin C. O’Connor, Harvard Medical School, Center for Neurologic Diseases, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: koconnor{at}rics.bwh.harvard.edu and Dr. Steven A. Greenberg, Department of Neurology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail address: sagreenberg{at}partners.org
This article has been cited by other articles:
|
|
 |
|
  A A Amato and R J Barohn Inclusion body myositis: old and new concepts J. Neurol. Neurosurg. Psychiatry, November 1, 2009; 80(11): 1186 - 1193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A A Amato and R J Barohn Evaluation and treatment of inflammatory myopathies J. Neurol. Neurosurg. Psychiatry, October 1, 2009; 80(10): 1060 - 1068. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Willis, S. S. Mallozzi, S. J. Rodig, K. M. Cronk, S. L. McArdel, T. Caron, G. S. Pinkus, L. Lovato, K. L. Shampain, D. E. Anderson, et al. The Microenvironment of Germ Cell Tumors Harbors a Prominent Antigen-Driven Humoral Response J. Immunol., March 1, 2009; 182(5): 3310 - 3317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Greenberg Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications Neurology, November 20, 2007; 69(21): 2008 - 2019. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
