Inflammation in thoracic aortic aneurysms.

Mutations in extracellular matrix and smooth muscle cell contractile proteins predispose to thoracic aortic aneurysms in Marfan syndrome (MFS) and related disorders. These genetic alterations lead to a compromised extracellular matrix-smooth muscle cell contractile unit. The abnormal aortic tissue responds with defective mechanosensing under hemodynamic stress. Aberrant mechanosensing is associated with transforming growth factor-beta (TGF-ß) hyperactivity, enhanced angiotensin-II (Ang-II) signaling, and perturbation of other cellular signaling pathways. The downstream consequences include enhanced proteolytic activity, expression of inflammatory cytokines and chemokines, infiltration of inflammatory cells in the aortic wall, vascular smooth muscle cell apoptosis, and medial degeneration. Mouse models highlight aortic inflammation as a contributing factor in the development of aortic aneurysms. Anti-inflammatory drugs and antioxidants can reduce aortic oxidative stress that prevents aggravation of aortic disease in MFS mice. Targeting TGF-ß and Ang-II downstream signaling pathways such as ERK1/2, mTOR, PI3/Akt, P38/MAPK, and Rho kinase signaling attenuates disease pathogenesis. Aortic extracellular matrix degradation and medial degeneration were reduced upon inhibition of inflammatory cytokines and matrix metalloproteinases, but the latter lack specificity. Treating inflammation associated with aortic aneurysms in MFS and related disorders could prove to be beneficial in limiting disease pathogenesis.

[THE ROLE OF TRANSFORMING GROWTH FACTOR-B IN IMMUNOPATHOGENESIS OF DISEASES OF CONNECTIVE TISSUE].

The recent studies of molecular physiology of fibrillin and pathophysiology of inherent disorders of structure and function of connective tissue such as dissection and aneurysm of aorta, myxomatously altered cusps and prolapses of mitral valve, syndrome of hyper-mobility of joints, demonstrated that important role in development of these malformations play alterations of transfer of signals by growth factors and matrix cellular interaction. These conditions under manifesting Marfan's syndrome can be a consequence of anomalies of fibrillin-1 which deficiency unbrakes process of activation of transforming growth factor-ß (TGFß). The involvement of TGFß in pathogenesis of Marfan's syndrome permits consider antagonists of angiotensin-transforming enzymes as potential pharmaceuticals in therapy of this disease. The article presents analysis of publications' data related to this problem.

Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome.

Marfan syndrome is a connective tissue disorder caused by mutations in the gene encoding fibrillin-1 (FBN1). A dominant-negative mechanism has been inferred based upon dominant inheritance, mulitimerization of monomers to form microfibrils, and the dramatic paucity of matrix-incorporated fibrillin-1 seen in heterozygous patient samples. Yeast artificial chromosome-based transgenesis was used to overexpress a disease-associated mutant form of human fibrillin-1 (C1663R) on a normal mouse background. Remarkably, these mice failed to show any abnormalities of cellular or clinical phenotype despite regulated overexpression of mutant protein in relevant tissues and developmental stages and direct evidence that mouse and human fibrillin-1 interact with high efficiency. Immunostaining with a human-specific mAb provides what we believe to be the first demonstration that mutant fibrillin-1 can participate in productive microfibrillar assembly. Informatively, use of homologous recombination to generate mice heterozygous for a comparable missense mutation (C1039G) revealed impaired microfibrillar deposition, skeletal deformity, and progressive deterioration of aortic wall architecture, comparable to characteristics of the human condition. These data are consistent with a model that invokes haploinsufficiency for WT fibrillin-1, rather than production of mutant protein, as the primary determinant of failed microfibrillar assembly. In keeping with this model, introduction of a WT FBN1 transgene on a heterozygous C1039G background rescues aortic phenotype.

Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome.

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.

Takayasu's arteritis concurrent with Marfan syndrome--a case report.

Marfan syndrome (MS) is a dominantly inherited connective tissue disorder characterized by arachnodactyly, tall stature, the presence of aortic aneurysm, and lens dislocation. Takayasu's arteritis (TA) is a chronic vasculitis that primarily affects the aorta and its branches. The authors report the first case of TA in a patient with MS. The simultaneous presence of TA and MS could be a coincidence, however; the pathogenesis of TA might be linked with autoimmunity induced by abnormal extracellular matrix protein derived from the genetic mutations in MS.

Defective expression of HLA class I and CD1a molecules in boy with Marfan-like phenotype and deep skin ulcers.

We report the case of a boy with low expression of HLA class I molecules on peripheral blood mononuclear cells, which is associated with immunodeficiency. The patient, who had a Marfan-like phenotype, had chronic deep skin ulcers and sinobronchiectasis. Immunohistologic examination of the ulcerated skin showed a dense perivascular infiltrate composed of normal mature lymphocytes and macrophages. All cells in the infiltrate showed an apparently normal expression of HLA class I molecules, but intraepidermal dendritic Langerhans' cells were negative for CD1a, an antigen that is a highly specific marker for these cells and is abundantly expressed in some self-healing forms of cutaneous lesions. It is therefore speculated that a defective expression of CD1a molecules can contribute to the chronic persistence of deep skin ulcers, which have already been reported in association with defective expression of HLA class I molecules.

[A clinico-immunological analysis of clinical variants of connective tissue dysplasia]. / Kliniko-immunologicheskii analiz klinicheskikh variantov displazii soedinitel'noi tkani.

The clinico-immunogenetic analysis of 47 patients with Marfan's syndrome and 83 patients with chest deformities combined with valvular prolapses and other connective tissues dysplasias elucidated a close relation of HLA-antigens allele variants with clinical dysplasia variants and specific immune alterations. The findings support the suggestion that clinical heterogeneity of connective tissue dysplasia forms results from their pathogenetic heterogeneity.

[Immunologic disorders in children with developmental thoracic defects]. / Immunologicheskie narusheniia u detei s defektami razvitiia grudnoi kletki.

As the result of immunological examination of 21 children with developmental defects of the chest and analysis of the course of the postoperative period in 136 children, among which 36 had hereditary syndromes of systemic connective-tissue dyshistogenesis, it was found that suppurative complications of thoracoplasty, which are encountered in 15% of children with isolated developmental chest defects and in 33.3% of those with the above mentioned syndromes, were caused to a great measure by disorders of the immune status. The most serious immunological deviations were encountered in the Marfan syndrome due to impaired phagocytic activity of neutrophils and monocytes, decreased number of T, T active, and B lymphocytes, and diminished function of T helpers. In unclassified complexes of developmental defects with Marfaneic ++ phenotypes, the immunological disorders were similar, but less deep. In the Ehlers-Danlos syndrome, a decrease of the number of immunocompetent cells, function of T helpers, and neutrophils was mainly revealed. In isolated forms of funnel chest the function of monocytes and the number of immunoglobulins are mainly decreased.

Marfan's syndrome with 47,XXX genotype and possible immunologic abnormality.

A 2-year-old girl with Marfan's syndrome also had recurrent episodes of upper respiratory infection, otitis media, tonsillitis, and asthma. Chromosomal study revealed the karyotype 47,XXX. Immunologic evaluation showed lack of delayed hypersensitivity skin test response despite previous exposure. The coincidence of Marfan's syndrome and either XXX or immunologic dysfunction has not been reported previously. This case clearly illustrates that more than one abnormality may occur in a single patient.