Microarrays Reveal Distinct Gene Signatures in the Thymus of Seropositive and Seronegative Myasthenia Gravis Patients and the Role of CC Chemokine Ligand 21 in Thymic Hyperplasia

Abstract

Myasthenia gravis (MG) is an autoimmune disease mainly caused by antiacetylcholine receptor autoantibodies (seropositive (SP) disease) or by Abs against unknown autoantigenic target(s) (seronegative (SN) disease). Thymectomy is usually beneficial although thymic hyperplasia with ectopic germinal centers is mainly observed in SP MG. To understand the role of thymus in the disease process, we compared the thymic transcriptome of non-MG adults to those of SP patients with a low or high degree of hyperplasia or SN patients. Surprisingly, an overexpression of MHC class II, Ig, and B cell marker genes is observed in SP but also SN MG patients. Moreover, we demonstrate an overexpression of CXCL13 in all MG thymuses leading probably to the generalized B cell infiltration. However, we find different chemotactic properties for MG subgroups and, especially, a specific overexpression of CCL21 in hyperplastic thymuses triggering most likely ectopic germinal center development. Besides, SN patients present a peculiar signature with an abnormal expression of genes involved in muscle development and synaptic transmission, but also genes implicated in host response, suggesting that viral infection might be related to SN MG. Altogether, these results underline differential pathogenic mechanisms in the thymus of SP and SN MG and propose new research areas.

Cell cycle and immune-related processes are significantly altered in chronic GVHD

“…CXCL13 is a highly effective attractant of human blood B lymphocytes, 29 and its overexpression has been reported in many autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, lupus nephritis, Sjogren's syndrome and myasthenia gravis. [29][30][31][32][33] Similarity of the symptoms between the aforementioned diseases and chronic GVHD suggests that CXCL13 may be responsible for inducing migration of B cells to the target tissues in chronic GVHD. While the roles of various chemokines in leukocyte trafficking and migration of donor T cells to the target tissues of GVHD have been studied, the roles of B cell chemokines have not been investigated in depth with regard to the pathogenesis of GVHD.…”

The thymic theme of acetylcholinesterase splice variants in myasthenia gravis

“…Thymuses containing more than 3 or fewer than 2 germinal centers per section were defined as severe or mild hyperplasia, respectively. 28 We chose to work with pools of thymic RNA (from homogeneous categories of patients) to minimize interindividual variations. Real time RT-PCR performed for several dysregulated genes in larger series of patients validated our results.…”

“…Real time RT-PCR performed for several dysregulated genes in larger series of patients validated our results. 28,29 Extraction of total RNA and hybridization on Agilent arrays (G4100A, Massy, France) was performed as previously described. 28 RNA quality was assessed on an Agilent Bioanalyser.…”

Ectopic GC in the thymus of myasthenia gravis patients show characteristics of normal GC

“…However, the MG IF Ig gene rearrangements exhibited a slight transversion bias that proved to be significantly different compared with the normal IF group. Interestingly, a microarray analysis study by Berrih-Aknin and coworkers [34,35] showed different expression patterns of DNA repair genes, which participate in SHM in MG patients compared with normal controls. AID, the key enzyme initiating SHM; MSH6 and MSH2, which are part of the mismatch repair mechanism and recognize the U:G mismatch introduced by AID, and other enzymes, were downregulated in MG patients.…”