Inflammation Aggravates Disease Severity in Marfan Syndrome Patients

Background Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far. Methodology/Principal Findings Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10−6, 95% CI: 70–159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients. Conclusion/Significance In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

[1]  J. Stockman,et al.  Noncanonical TGFβ Signaling Contributes to Aortic Aneurysm Progression in Marfan Syndrome Mice , 2012 .

[2]  P. Robinson,et al.  Induction of Macrophage Chemotaxis by Aortic Extracts from Patients with Marfan Syndrome Is Related to Elastin Binding Protein , 2011, PloS one.

[3]  D. Judge,et al.  Angiotensin II Type 2 Receptor Signaling Attenuates Aortic Aneurysm in Mice Through ERK Antagonism , 2011, Science.

[4]  Samarjit Patnaik,et al.  Noncanonical TGFβ Signaling Contributes to Aortic Aneurysm Progression in Marfan Syndrome Mice , 2011, Science.

[5]  L. Rénia,et al.  TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. , 2010, The Journal of clinical investigation.

[6]  A. Zwinderman,et al.  Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial , 2010, Trials.

[7]  R. Bank,et al.  Distinct defects in collagen microarchitecture underlie vessel-wall failure in advanced abdominal aneurysms and aneurysms in Marfan syndrome , 2009, Proceedings of the National Academy of Sciences.

[8]  E. Fleck,et al.  Chronic Treatment With Losartan Results in Sufficient Serum Levels of the Metabolite EXP3179 for PPAR&ggr; Activation , 2009, Hypertension.

[9]  Yang Liu,et al.  CD24 and Siglec-10 Selectively Repress Tissue Damage–Induced Immune Responses , 2009, Science.

[10]  Jan-Fang Cheng,et al.  Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy , 2009, Proceedings of the National Academy of Sciences.

[11]  A. Cava.  Natural Tregs and autoimmunity. , 2009 .

[12]  A. La Cava.  Natural Tregs and autoimmunity. , 2009, Frontiers in bioscience.

[13]  D. Milewicz,et al.  Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms. , 2008, The Journal of thoracic and cardiovascular surgery.

[14]  H. Dietz,et al.  Fibrillin‐rich microfibrils: Structural determinants of morphogenetic and homeostatic events , 2007, Journal of cellular physiology.

[15]  M Claustres,et al.  Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. , 2007, American journal of human genetics.

[16]  A. De Paepe,et al.  Utility of molecular analyses in the exploration of extreme intrafamilial variability in the Marfan syndrome , 2007, Clinical genetics.

[17]  D. Judge,et al.  Angiotensin II type 1 receptor blockade attenuates TGF-β–induced failure of muscle regeneration in multiple myopathic states , 2007, Nature Medicine.

[18]  D. Middleton,et al.  The role of human leukocyte antigen genes in the formation of abdominal aortic aneurysms. , 2007, Journal of vascular surgery.

[19]  P. Robinson,et al.  Induction of Macrophage Chemotaxis by Aortic Extracts of the mgR Marfan Mouse Model and a GxxPG-Containing Fibrillin-1 Fragment , 2006, Circulation.

[20]  Marc K. Halushka,et al.  Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome , 2006, Science.

[21]  A. Vaglio,et al.  Chronic periaortitis and HLA-DRB1*03: another clue to an autoimmune origin. , 2006, Arthritis and rheumatism.

[22]  D. Judge,et al.  TGF-β–dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome , 2004 .

[23]  D. Judge,et al.  TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. , 2004, The Journal of clinical investigation.

[24]  D. Arking,et al.  Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome , 2003, Nature Genetics.

[25]  D. Arking,et al.  Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. , 2003, Nature genetics.

[26]  H. Drexler,et al.  Angiotensin II Receptor–Independent Antiinflammatory and Antiaggregatory Properties of Losartan: Role of the Active Metabolite EXP3179 , 2002, Circulation research.

[27]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A de Roos,et al.  Changes in aortic distensibility and pulse wave velocity assessed with magnetic resonance imaging following beta-blocker therapy in the Marfan syndrome. , 1998, The American journal of cardiology.

[29]  W. Harmsen,et al.  Genetic risk factors in inflammatory abdominal aortic aneurysms: polymorphic residue 70 in the HLA-DR B1 gene as a key genetic element. , 1997, Journal of vascular surgery.

[30]  K. Ozsvath,et al.  A Genetic Basis for Autoimmune Manifestations in the Abdominal Aortic Aneurysm Resides in the MHC Class II Locus DR‐beta‐1 a , 1996, Annals of the New York Academy of Sciences.

[31]  R E Pyeritz,et al.  Revised diagnostic criteria for the Marfan syndrome. , 1996, American journal of medical genetics.

[32]  N. Tsukuda,et al.  The influence of divalent cations and doxycycline on iodoacetamide-inhibitable leukocyte adherence. , 1991, Research communications in chemical pathology and pharmacology.

[33]  Ada Hamosh,et al.  Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene , 1991, Nature.

[34]  N. Esterly,et al.  Neutrophil chemotaxis in patients with acne receiving oral tetracycline therapy. , 1984, Archives of dermatology.

[35]  A. Ferrante,et al.  Inhibition of mitogen-induced human lymphocyte proliferative responses by tetracycline analogues. , 1979, Clinical and experimental immunology.

[36]  K. Nath,et al.  Marfan's syndrome. , 1959, Journal of the Indian Medical Association.